Pleural effusionFrom Wikipedia, the free encyclopedia

Pleural effusion

Classification and external resources

Massive left-sided pleural effusion (whiteness) in a patient presenting with

lung cancer.

Pleural effusion is excess fluid that accumulates in the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during inspiration.

Contents

 [hide]

1 Types of fluids2 Diagnosiso 2.1 Imagingo 2.2 Thoracentesiso 2.3 Transudate vs. exudate: Light's criteria

3 Causeso 3.1 Transudativeo 3.2 Exudativeo 3.3 Other/ungrouped

4 Treatment

5 See also6 External links7 References

1….Types of fluids

Four types of fluids can accumulate in the pleural space:

Serous fluid  (hydrothorax) Blood  (haemothorax) Chyle  (chylothorax) Pus  (pyothorax or empyema)[edit]Diagnosis

CT scan of chest showing left sided pleural effusion. Effusion fluid often settles at the lowest space due to gravity; here at the back as the patient is lying under scanner.

Pleural effusion is usually diagnosed on the basis of medical history and physical exam, and confirmed by chest x-ray. Once accumulated fluid is more than 500 ml, there are usually detectable clinical signs in the patient, such as decreased movement of the chest on the affected side, dullness to percussion over the fluid, diminished breath sounds on the affected side, decreased vocal resonance and fremitus (though this is an inconsistent and unreliable sign), and pleural friction rub. Above the effusion, where the lung is compressed, there may be bronchial breathing and egophony. In large effusion there may be tracheal deviation away from the effusion. A systematic review (2009) published as part of the Rational Clinical Examination Series in the Journal of the American Medical Association showed that dullness to conventional percussion was most accurate for diagnosing pleural effusion (summary positive likelihood ratio, 8.7; 95% confidence interval, 2.2-33.8), while the absence of reduced tactile vocal fremitus

made pleural effusion less likely (negative likelihood ratio, 0.21; 95% confidence interval, 0.12-0.37).[1]

[edit]Imaging

Normally the space between the two layers of the lung: visceral pleura and parietal pleura, cannot be seen. A pleural effusion infiltrates the space between these layers. Because the pleural effusion has a density similar to body fluid or water, it can be seen on radiographs. Since the effusion has greater density than the rest of the lung, it will gravitate towards the lower portions of the pleural cavity. The pleural effusion behaves according to basic fluid dynamics, conforming to the shape of the lung and chest cavity. If the pleural cavity contains both air and fluid, then the fluid will have a "fluid level" that is horizontal instead of conforming to the lung space.[2] Chest radiographs acquired in the lateral decubitus position (with the patient lying on his side) are more sensitive, and can pick up as little as 50 ml of fluid. At least 300 ml of fluid must be present before upright chest films can pick up signs of pleural effusion (e.g., blunted costophrenic angles).

Micrograph of a pleural fluidcytopathology specimen showing malignant mesothelioma, one cause of a pleural effusion.

[edit]Thoracentesis

Once a pleural effusion is diagnosed, the cause must be determined. Pleural fluid is drawn out of the pleural space in a process calledthoracentesis. A needle is inserted through the back of the chest wall in the sixth, seventh or eighth intercostal space on the midaxillary line, into the pleural space. The fluid may then be evaluated for the following:

1. Chemical composition including protein, lactate dehydrogenase (LDH), albumin, amylase, pH and glucose

2. Gram stain  and culture to identify possible bacterial infections

3. Cell  count and differential4. Cytopathology  to identify cancer cells, but may also identify some infective

organisms5. Other tests as suggested by the clinical situation - lipids, fungal culture, viral

culture, specific immunoglobulins[edit]Transudate vs. exudate: Light's criteria

Transudate vs. exudateview • talk • edit

Transudate Exudate

Main causes

Increased hydrostaticpressure,Decreased colloidosmotic pressure

Inflammation

Appearance Clear[3] Cloudy[3]

Specific gravity < 1.012 > 1.020

Protein content < 2 g/dL > 2.9 g/dL [4]

  fluid protein   serum protein < 0.5 > 0.5[5]

Difference ofalbumin contentwith blood albumin

> 1.2 g/dL < 1.2 g/dL[6]

        fluid  LDH         upper limit for serum < 0.6 or < ⅔ > 0.6[4] or > ⅔[5]

  fluid  glucose  serum glucose < 0.8 > 0.8

Cholesterol content < 45 mg/dL > 45 mg/dL[4]

See also: Rivalta test

Instruments for needle biopsy of the pleura

The definitions of the terms "transudate" and "exudate" are the source of much confusion.

Transudative pleural effusions are defined as effusions that are caused by systemic factors that alter the pleural equilibrium, or Starling forces. The components of the Starling forces: hydrostatic pressure, permeability, oncotic pressure (effective pressure due to the composition of the pleural fluid and blood), are altered in many diseases e.g., left ventricular failure, renal failure, hepatic failure, and cirrhosis. Exudative pleural effusions, by contrast, are caused by alterations inlocal factors that influence the formation and absorption of pleural fluid (e.g., bacterial pneumonia, cancer, pulmonary embolism, and viral infection).[7]

An accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on a comparison of the chemistries in the pleural fluid to those in the blood, using Light's criteria. According to Light's criteria (Light, et al. 1972), a pleural effusion is likely exudative if at least one of the following exists:[5]

1. The ratio of pleural fluid protein to serum protein is greater than 0.52. The ratio of pleural fluid LDH and serum LDH is greater than 0.63. Pleural fluid LDH is greater than 0.7 times the normal upper limit for serum

Although Light's criteria are relatively accurate, twenty-five percent of patients with transudative pleural effusions are mistakenly identified by Light's criteria as having exudative pleural effusions. Therefore, if a patient identified by Light's criteria as having an exudative pleural effusion appears clinically to have a condition that usually produces transudative effusions, additional testing is needed. In such cases albumin levels in blood and pleural fluid are measured. If the difference between the albumin levels in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), this suggests that the patient has a transudative pleural effusion[6]. However, pleural fluid testing is not perfect, and the final decision about whether a fluid is a transudate or an exudate is based not on chemical analysis of the fluid, but on accurate diagnosis of the disease that produces the fluid.

The traditional definitions of transudate as a pleural effusion due to systemic factors and an exudate as a pleural effusion due to local factors have been used since 1940 or earlier (Light et al, 1972). Previous to Light's landmark study, which was basd on work by Chandrasekhar, investigators unsuccessfully attempted to use other criteria, such as specific gravity, pH, and protein content of the fluid, to differentiate between transudates and exudates. Light's criteria are highly statistically sensitive for exudates (although not very statistically specific). More recent studies have examined other characteristics of pleural fluid that may help to determine whether the process producing the effusion is local (exudate) or systemic (transudate). The chart at right illustrates some of the results of these more recent studies. However, it should be borne in mind that Light's criteria are still the most widely used criteria.

The Rational Clinical Examination Series review found that bilateral effusions, symmetric and asymmetric, are the most common distribution in heart failure (60% of effusions in heart failure will be bilateral). When there is asymmetry in heart failure-associated pleural effusions (either unilateral or one side larger than the other), the right side is usually more involved than the left.[8]

[edit]Causes

[edit]Transudative

The most common causes of transudative pleural effusions in the United States are left ventricular failure, and cirrhosis (causing hepatic hydrothorax). Pulmonary embolisms were once thought to be transudative but have been recently shown to be exudative [9]

[edit]Exudative

Pleural effusion Chest x-ray of a pleural effusion. The arrow A shows fluid layering in the right pleural cavity. The B arrow shows the normal width of the lung in the cavity

Once identified as exudative, additional evaluation is needed to determine the cause of the excess fluid, and pleural fluid amylase, glucose, pH and cell counts are obtained.

Pleural fluid amylase is elevated in cases of esophageal rupture, pancreatic pleural effusion, or cancer.

Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis. Pleural fluid pH is low in empyema (<7.2) and may be low in cancer. If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative,

and cancer is still suspected, either a thoracoscopy, or needle biopsy[10] of the pleura may be performed.

The fluid is also sent for Gram staining and culture, and, if suspicious for tuberculosis, examination for TB markers (adenosine deaminase > 45 IU/L, interferon gamma > 140 pg/mL, or positive polymerase chain reaction (PCR) for tuberculous DNA).

The most common causes of exudative pleural effusions are bacterial pneumonia, cancer (with lung cancer, breast cancer, and lymphomacausing approximately 75% of all malignant pleural effusions), viral infection, and pulmonary embolism.

[edit]Other/ungrouped

Other causes of pleural effusion include tuberculosis (though pleural fluid smears are rarely positive for AFB, this is the most common cause of pleural effusion in some developing countries), autoimmune disease such as systemic lupus erythematosus, bleeding (often due to chest trauma), chylothorax (most commonly caused by trauma), and accidental infusion of fluids.

Less common causes include esophageal rupture or pancreatic disease, intraabdominal abscess, rheumatoid arthritis, asbestos pleural effusion, Meigs syndrome (ascites and pleural effusion due to a benign ovarian tumor), and ovarian hyperstimulation syndrome.

Pleural effusions may also occur through medical/surgical interventions, including the use of medications (pleural fluid is usually eosinophilic),coronary artery bypass surgery, abdominal surgery, endoscopic variceal sclerotherapy, radiation therapy, liver or lung transplantation, and intra- or extravascular insertion of central lines.

[edit]Treatment

The free end of the Chest Drainage Device is usually attached to an underwater seal, below the level of the chest. This allows the air or fluid to escape from the pleural space, and prevents anything returning to the chest.

Treatment depends on the underlying cause of the pleural effusion.

Therapeutic aspiration may be sufficient; larger effusions may require insertion of an intercostal drain (either pigtail or surgical). When managing these chest tubes it is important to make sure the chest tubes do not become occluded or clogged. A clogged chest tube in the setting of continued production of fluid will result in residual fluid left behind when the chest tube is removed. This fluid can lead to complications such as hypoxia due to lung collapse from the fluid, or fibrothorax, late, when the space scars down. Repeated effusions may require chemical (talc, bleomycin, tetracycline/doxycycline) or surgical pleurodesis, in which the two pleural surfaces are scarred to each other so that no fluid can accumulate between them. This is a surgical procedure that involves inserting a chest tube, then either mechanically abrading the pleura, or inserting the chemicals to induce a scar. This requires the chest tube to stay in until the fluid drainage stops. This can be days to weeks and can require prolonged hospitilizations. If the chest tube becomes clogged fluid will be left behind and the pleurodesis will fail.

Pleurodesis fails in as many as 30% of cases. An alternative is to place a Pleurex or Aspira Drainage Catheter. This is a 15Fr chest tube with a one way valve. Each day the patient or care givers connect it to a simple vacuum tube and remove from 600 cc to 1000 cc. This can be repeated daily. When not in use, the tube is capped. This allows patients to be outside the hospital. For patients with malignant pleural effusions, it allows them to continue chemotherapy, if indicated. Generally the tube is in about 30 days and then it is removed when the space undergoes a spontaneous pleurodesis.

Papilloma

From Wikipedia, the free encyclopedia

Papilloma

Classification and external resources

Intraductal papilloma of breast, H&E, 10x

ICD-O: 8050/0

MeSH D010212

Papilloma refers to a benign epithelial tumor [1]  growing exophytically (outwardly projecting) in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla (such as the nipple). When used without context, it frequently refers to infections caused by human papillomavirus (HPV), such as warts. There are, however, a number of other conditions that cause papilloma, such as choroid plexus papilloma (CPP) and pearly penile papules of the penis.

Human Papilloma Virus infection is a major cause of cervical cancer, although most HPV infections do not cause cancer.

Hemangioma

From Wikipedia, the free encyclopedia

Hemangioma of Infancy

Classification and external resources

A small hemangioma of infancy

ICD-10 D18.0 (ILDS D18.010)

ICD-9 228.0

ICD-O: M9120/0

DiseasesDB 30033

MedlinePlus 001459

eMedicine derm/201

MeSH D006391

A hemangioma of infancy (or haemangioma of infancy) is a benign self-involuting tumor of endothelial cells (the cells that line blood vessels). In most cases it appears during the first days or weeks of life and will have resolved at the latest by age 10. In infancy, it is the most common tumor.[1]

The word "hemangioma" comes from the Greek word haema- (Greek: αίμα) meaning "blood", angeio (Greek: αγγείο) meaning "vessel" and the suffix -oma (Greek: -ωμα) meaning "tumor".

Contents

 [hide]

1 Terminology2 Presentation

3 Causes4 Complications5 Treatment6 Prognosis7 Notes8 External links

[edit]Terminology

Hemangioma on forehead showing signs of early regression

Before considering the hemangioma, it is important to understand that there have been changes in the terminology used to define, describe and categorize vascular anomalies (abnormal lumps made up of blood vessels). The term hemangioma was originally used to describe any vascular tumor-like structure, whether it was present at or around birth or appeared later in life. Mulliken et al. categorized these conditions into two families: a family of self-involuting tumors (growing lesions that eventually disappear) and another family of malformations (enlarged or abnormal vessels present at birth and essentially permanent). The importance of this distinction is that it makes it possible for early-in-life differentiation between lesions that will resolve versus those that are permanent. Examples of permanent malformations include Port-wine stains(capillary vascular malformation) and masses of abnormal swollen veins (venous malformations).[2] Unfortunately many textbooks and dictionaries are not up to date on this point, creating great confusion.

[edit]Presentation

Hemangiomas are connected to the circulatory system and filled with blood. The appearance depends on location. If they are on the surface of the skin, they are reminiscent of a ripe strawberry (hence, they are sometimes referred to as "strawberry hemangiomas"); however, if they are just under the skin they present as a bluish swelling. Sometimes they grow in internal organs such as the liver or larynx. In most cases, hemangiomas will disappear over time. Some are formed during gestation; others (the most common) are not present at birth but appear during the first few weeks of life. They are often misdiagnosed, initially, as a scratch or bruise; but the correct diagnosis becomes obvious with further growth. Typically, at the earliest phase in a superficial lesion, one will see a bluish red area with obvious blood vessels and surrounding pallor. Sometimes they present as a flat red or pink area. Hemangiomas are the most common childhood tumor, occurring in approximately ten percent of Caucasians, and are less prevalent in other races. Females are three to five times as likely to have hemangiomas as males. Hemangiomas are also more common in twin pregnancies. Approximately 80% are located on the face and neck, with the next most prevalent location being the liver.

[edit]Causes

The cause of hemangioma is currently unknown; however, several studies have suggested the importance of estrogen signaling in hemangioma proliferation. In 2007, a paper from the Stanford Children's Surgical Laboratory revealed that localized soft tissue hypoxia coupled with increased circulating estrogen after birth may be the stimulus.[3] There is also a hypothesis presented by researchers at Harvard and the University of Arkansas that maternal placenta embolizes to the fetal dermis during gestation resulting in hemangiomagenesis,[4][5]. However, researchers at Duke University conducted genetic analyses of small nucleotide polymorphisms in hemangioma tissue compared to the mother's DNA that contradicted this hypothesis.[6] More research is required in order to fully understand the explosive nature of hemangioma growth, which will hopefully yield targeted therapeutics to treat its most complicated presentations.

[edit]Complications

The vast majority of hemangiomas are not associated with complications. Hemangiomas may break down on the surface (ulcerate). If the ulceration is deep, significant bleeding may occur in rare occasions. Ulceration on the diaper area can be painful and problematic.

If a hemangioma develops in the larynx, breathing can be compromised. A hemangioma can grow and block one of the eyes, causing an occlusion amblyopia. Very rarely, extremely large hemangiomas can cause high-output heart failure due to the amount of blood that must be pumped to excess blood vessels. Lesions adjacent to bone can also cause erosion of the bone.

The most frequent complaints about hemangiomas, however, stem from psychosocial complications: the condition can affect a person's appearance and can provoke attention and malicious reactions from others. Particular problems occur if the lip or nose is involved, as distortion can be difficult to treat surgically. The potential for psychological injury develops from school age onward. It is therefore important to consider treatment prior to school if adequate spontaneous improvement has not occurred

Children with large Segmental Hemangiomas of the head and neck can be associated with a disorder called PHACES Syndrome.[7][8]

[edit]Treatment

Most hemangiomas disappear without treatment, leaving minimal or no visible marks. Large hemangiomas can leave visible skin changes secondary to severe stretching of the skin or damage to surface texture. When hemangiomas interfere with vision, breathing, or threaten significant cosmetic injury, they are usually treated.

Up until recently, the mainstay of treatment was oral corticosteroid therapy. Beta-blocker treatment using agents such as propranolol is revolutionising therapy, producing impressive responses. A publication in the international literature in June 2008 first suggested that propranolol (a Beta Blocker) could be used to treat severe hemangiomas[9]. This treatment is proving superior to corticosteroids, in terms of both effectiveness and safety. The topically applied Beta Blocker gel Timolol, is also being trialled for small facial hemangiomas that do not justify systemic treatment. Early results are showing a modest benefit; however more study is needed[10].

Other treatments that have been used include interferon[11] or vincristine. They may be considered if first-line therapy fails. Surgical removal is sometimes indicated, particularly if there has been delay in commencing treatment and structural changes have become irreversible. Surgery may also be necessary to correct distortion of facial features, again in the case of inadequate or failed early medical intervention.

Blockage of the airway will often require a tracheostomy to be performed (insertion of an external airway through the front of the neck into the trachea below the level of the obstruction). Smaller raised lesions are sometimes treated with injection of corticosteroid directly into the lesion. Pulsed dye laser can be useful for very early flat superficial lesions if they appear in cosmetically significant areas or for those lesions that leave residual surface blood vessels in the case of incomplete resolution. Unfortunately raised lesions or lesions under the skin do not respond to laser.

Ulceration will usually heal with topical medication and special dressings under medical supervision. Sometimes pulsed dye laser can be used to accelerate healing.

[edit]Prognosis

Hemangiomas go through three stages of development and decay:

1. In the proliferation stage, a hemangioma grows very quickly. This stage can last up to twelve months.

2. In the rest stage, there is very little change in a hemangioma's appearance. This usually lasts until the infant is one to two years old.

3. In the involution phase, a hemangioma finally begins to diminish in size. 50% of lesions will have disappeared by 5 years of age, and the vast majority will have gone by 10 years of age.

cefadroxil

CIMS Class : 头孢菌素类 ( Cephalosporins )  See available brands of cefadroxil

P  - Caution when used during pregnancyL  - Caution when used during lactation

Lab ☼ - Lab interference

See related cefadroxil information

Indication Susceptible infections.

Dosage Adult: PO 1-2 g/day as a single dose or in 2 divided doses.Click to view Dosage by Indications

Administration May be taken with or without food. (May be taken w/ meals to reduce GI discomfort.)

Contraindications Hypersensitivity to cephalosporins.

Special Precautions Impaired renal function; pregnancy and lactation.

Adverse Drug Reactions

Nausea, vomiting, diarrhoea, abdominal discomfort; skin rash, angioedema; elevated liver enzyme values; superinfection with resistant organisms especially candida.Potentially Fatal: Anaphylactic reaction; pseudomembranous colitis.

Drug Interactions Prothrombin time prolonged; bleeding may occur when taken with anticoagulants. Decreased elimination with probenecid.Click to view more Drug Interactions

Lab Interference For caution against possible drug interference in lab test results ... click to view

Pregnancy Category (US FDA) Category B: Either animal-reproduction studies have not

demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Storage For special storage condition to ensure optimal shelf-life of medicine... click to view

Mechanism of Action

For details of the mechanism of action, pharmacology and pharmacokinetics and toxicology ... click to view

CIMS Class Cephalosporins

ATC Classification J01DB05 - cefadroxil;

Ascites

From Wikipedia, the free encyclopedia

Ascites

Classification and external resources

The major signs and symptoms of heart failure. (Ascites labeled near center.)

ICD-10 R 18.

ICD-9 789.5

DiseasesDB 943

eMedicine ped/2927 med/173

MeSH D001201

Ascites ( / ə ̍ s aɪ t iː z / , ə-SYE-teez, from Greek askites, "baglike")[1] is a gastroenterological term for an accumulation of fluid in the peritoneal cavity. The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically asabdominal dropsy. Although most commonly due to cirrhosis and severe liver disease, its presence can portend other significant medical problems. Diagnosis of the cause is usually with blood tests, an ultrasound scan of the abdomen, and direct removal of the fluid by needle orparacentesis (which may also be therapeutic). Treatment may be with medication (diuretics), paracentesis, or other treatments directed at the cause.

Contents

[hide]

1 Signs and symptoms

2 Classification

3 Diagnosis

4 Causes

5 Pathophysiology

6 Treatment

o 6.1 High SAAG

6.1.1 Salt restriction

6.1.2 Diuretics

6.1.3 Water restriction

6.1.4 Paracentesis

6.1.5 Liver transplantation

6.1.6 Shunting

o 6.2 Low SAAG

7 Complications

o 7.1 Spontaneous bacterial peritonitis

8 Society and culture

9 References

[edit]Signs and symptoms

Mild ascites is hard to notice, but severe ascites leads to abdominal distension. Patients with ascites generally will complain of progressive abdominal heaviness and pressure as well asshortness of breath due to mechanical impingement on the diaphragm.

Ascites is detected on physical examination of the abdomen by visible bulging of the flanks in the reclining patient ("flank bulging"), "shifting dullness" (difference in percussion note in the flanks that shifts when the patient is turned on the side) or in massive ascites with a "fluid thrill" or "fluid wave" (tapping or pushing on one side will generate a wave-like effect through the fluid that can be felt in the opposite side of the abdomen).

Other signs of ascites may be present due to its underlying etiology. For instance, in portal hypertension (perhaps due to cirrhosis or fibrosis of the liver) patients may also

complain of leg swelling, bruising, gynecomastia, hematemesis, or mental changes due to encephalopathy. Those with ascites due to cancer (peritoneal carcinomatosis) may complain of chronic fatigue or weight loss. Those with ascites due to heart failure may also complain of shortness of breath as well as wheezing and exercise intolerance.

[edit]Classification

Ascites exists in three grades:[2]

Grade 1: mild, only visible on ultrasound Grade 2: detectable with flank bulging and shifting dullness Grade 3: directly visible, confirmed with fluid thrill[edit]Diagnosis

Routine complete blood count (CBC), basic metabolic profile, liver enzymes, and coagulation should be performed. Most experts recommend a diagnostic paracentesis be performed if the ascites is new or if the patient with ascites is being admitted to the hospital. The fluid is then reviewed for its gross appearance, protein level, albumin, and cell counts (red and white). Additional tests will be performed if indicated such as Gram stain and cytopathology.[3]

The Serum-ascites albumin gradient (SAAG) is probably a better discriminant than older measures (transudate versus exudate) for the causes of ascites.[4] A high gradient (> 1.1 g/dL) indicates the ascites is due to portal hypertension. A low gradient (< 1.1 g/dL) indicates ascites of non-portal hypertensive etiology.

Ultrasound investigation is often performed prior to attempts to remove fluid from the abdomen. This may reveal the size and shape of the abdominal organs, and Doppler studies may show the direction of flow in the portal vein, as well as detecting Budd-

Chiari syndrome and portal vein thrombosis. Additionally, the sonographer can make an estimation of the amount of ascitic fluid, and difficult-to-drain ascites may be drained under ultrasound guidance. Abdominal CT scan is a more accurate alternate to reveal abdominal organ structure and morphology.

[edit]Causes

Causes of high SAAG ("transudate") are:[3]

Cirrhosis  - 81% (alcoholic in 65%, viral in 10%, cryptogenic in 6%) Heart failure  - 3% Hepatic Venous occlusion: Budd-Chiari syndrome or veno-occlusive disease Constrictive pericarditis Kwashiorkor

Causes of low SAAG ("exudate") are:

Cancer  (primary peritoneal carcinomatosis and metastasis) - 10% Infection: Tuberculosis - 2% or Spontaneous bacterial peritonitis Pancreatitis  - 1% Serositis Nephrotic syndrome  or Protein losing enteropathy Hereditary angioedema [5]

Other Rare causes:

Meigs syndrome Vasculitis Hypothyroidism Renal Dialysis Peritoneum Mesothelioma[edit]Pathophysiology

Ascitic fluid can accumulate as a transudate or an exudate. Amounts of up to 25 liters are possible.

Roughly, transudates are a result of increased pressure in the portal vein (>8 mmHg, usually around 20 mmHg[6]), e.g. due to cirrhosis, while exudates are actively secreted fluid due toinflammation or malignancy. As a result, exudates are high in protein, high

in lactate dehydrogenase, have a low pH (<7.30), a low glucose level, and more white blood cells. Transudates have low protein (<30g/L), low LDH, high pH, normal glucose, and fewer than 1 white cell per 1000 mm³. Clinically, the most useful measure is the difference between ascitic and serum albumin concentrations. A difference of less than 1 g/dl (10 g/L) implies an exudate.[3]

Portal hypertension plays an important role in the production of ascites by raising capillary hydrostatic pressure within the splanchnic bed.

Regardless of the cause, sequestration of fluid within the abdomen leads to additional fluid retention by the kidneys due to stimulatory effect on blood pressure hormones, notablyaldosterone. The sympathetic nervous system is also activated, and renin production is increased due to decreased perfusion of the kidney. Extreme disruption of the renal blood flow can lead to the feared hepatorenal syndrome. Other complications of ascites include spontaneous bacterial peritonitis (SBP), due to decreased antibacterial factors in the ascitic fluid such ascomplement.

[edit]Treatment

Ascites is generally treated while an underlying etiology is sought, in order to prevent complications, relieve symptoms, and prevent further progression. In patients with mild ascites, therapy is usually as an outpatient. The goal is weight loss of no more than 1.0 kg/day for patients with both ascites and peripheral edema and no more than 0.5 kg/day for patients with ascites alone.[7] In those with severe ascites causing a tense abdomen, hospitalization is generally necessary for paracentesis.[8][9]

[edit]High SAAG

[edit]Salt restriction

Salt restriction is the initial treatment, which allows diuresis (production of urine) since the patient now has more fluid than salt concentration. Salt restriction is effective in about 15% of patients.[10]

[edit]Diuretics

Since salt restriction is the basic concept in treatment, and aldosterone is one of the hormones that acts to increase salt retention, a medication that counteracts aldosterone should be sought. Spironolactone (or other distal-tubule diuretics such as triamterene or amiloride) is the drug of choice since they block the aldosterone receptor in the collecting tubule. This choice has been confirmed in a randomized controlled trial.[11] Diuretics for ascites should be dosed once per day.[12] Generally, the

starting dose is oral spironolactone 100 mg/day (max 400 mg/day). 40% of patients will respond to spironolactone.[10] For nonresponders, a loop diuretic may also be added and generally, furosemide is added at a dose of 40 mg/day (max 160 mg/day), or alternatively (bumetanide or torasemide). The ratio of 100:40 reduces risks of potassium imbalance.[12] Serum potassium level and renal function should be monitored closely while on these medications.[13]

Monitoring diuresis: Diuresis can be monitored by weighing the patient daily. The goal is weight loss of no more than 1.0 kg/day for patients with both ascites and peripheral edema and no more than 0.5 kg/day for patients with ascites alone.[7] If daily weights cannot be obtained, diuretics can also be guided by the urinary sodium concentration. Dosage is increased until a negative sodium balance occurs.[12] A random urine sodium-to-potassium ratio of > 1 is 90% sensitivity in predicting negative balance (> 78-mmol/day sodium excretion).[14]

Diuretic resistance: Diuretic resistance can be predicted by giving 80 mg intravenous furosemide after 3 days without diuretics and on an 80 mEq sodium/day diet. The urinary sodium excretion over 8 hours < 50 mEq/8 hours predicts resistance. [15]

If a patient exhibits a resistance to or poor response to diuretic therapy, ultrafiltration [disambiguation needed] or aquapheresis may be needed to achieve adequate control of fluid retention and congestion. The use of such mechanical methods of fluid removal can produce meaningful clinical benefits in patients with diuretic resistance and may restore responsiveness to conventional doses of diuretics.[16][17]

[edit]Water restriction

Water restriction is needed if hyponatremia < 130 mmol per liter develops.[13]

[edit]Paracentesis

Main article: Paracentesis

In those with severe (tense) ascites, therapeutic paracentesis may be needed in addition to medical treatments listed above.[8][9] As this may deplete serum albumin levels in the blood, albumin is generally administered intravenously in proportion to the amount of ascites removed.

[edit]Liver transplantation

Main article: liver transplantation

Ascites that is refractory to medical therapy is considered an indication for liver transplantation. In the United States, the MELD score (online calculator)[18] is used to prioritize patients for transplantation.

[edit]Shunting

In a minority of patients with advanced cirrhosis that have recurrent ascites, shunts may be used. Typical shunts used are portacaval shunt, peritoneovenous shunt, and the transjugular intrahepatic portosystemic shunt (TIPS). However, none of these shunts has been shown to extend life expectancy, and are considered to be bridges to liver transplantation. A meta-analysis of randomized controlled trials by the international Cochrane Collaboration concluded that "TIPS was more effective at removing ascites as compared with paracentesis...however, TIPS patients develop hepatic encephalopathy significantly more often.

Low SAAG

Exudative ascites generally does not respond to manipulation of the salt balance or diuretic therapy. Repeated paracentesis and treatment of the underlying cause is the mainstay of treatment.

Complications

Spontaneous bacterial peritonitis

Cirrhosis

From Wikipedia, the free encyclopedia

Cirrhosis

Classification and external resources

Micrograph showing cirrhosis. Trichrome stain.

ICD-10 K 70.3 , K 71.7 , K 74.

ICD-9 571

DiseasesDB 2729

eMedicine med/3183 radio/175

MeSH D008103

Cirrhosis (pronounced /sɪˈroʊsɪs/) is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scartissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated),[1][2][3] leading to loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C, and fatty liver disease but has many other possible causes. Some cases are idiopathic, i.e., of unknown cause.

Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy(confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible, and treatment usually focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant.

The word "cirrhosis" derives from Greek κίρῥος, meaning tawny (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.[4]

Contents

[hide]

1 Signs and symptoms

o 1.1 Complications

2 Causes

3 Pathophysiology

4 Diagnosis

o 4.1 Lab findings

o 4.2 Imaging

o 4.3 Endoscopy

o 4.4 Pathology

o 4.5 Grading

5 Management

o 5.1 Treating underlying causes

o 5.2 Preventing further liver damage

o 5.3 Preventing complications

5.3.1 Ascites

5.3.2 Esophageal variceal bleeding

5.3.3 Hepatic encephalopathy

5.3.4 Hepatorenal syndrome

5.3.5 Spontaneous bacterial peritonitis

o 5.4 Transplantation

o 5.5 Decompensated cirrhosis

6 Epidemiology

7 References

8 External links

[edit]Signs and symptoms

Some of the following signs and symptoms may occur in the presence of cirrhosis or as a result of the complications of cirrhosis. Many are nonspecific and may occur in other diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does not rule out the possibility of cirrhosis.

Spider angiomata  or spider nevi. Vascular lesions consisting of a central arteriole surrounded by many smaller vessels due to an increase in estradiol. These occur in about 1/3 of cases.[5]

Palmar erythema . Exaggerations of normal speckled mottling of the palm, due to altered sex hormone metabolism.

Nail changes. Muehrcke's lines  - paired horizontal bands separated by normal color due

to hypoalbuminemia (inadequate production of albumin). Terry's nails  - proximal two-thirds of the nail plate appears white with distal one-

third red, also due to hypoalbuminemia Clubbing  - angle between the nail plate and proximal nail fold > 180 degrees

Hypertrophic osteoarthropathy . Chronic proliferative periostitis of the long bones that can cause considerable pain.

Dupuytren's contracture . Thickening and shortening of palmar fascia that leads to flexion deformities of the fingers. Thought to be due to fibroblastic proliferation and disorderly collagen deposition. It is relatively common (33% of patients).

Gynecomastia . Benign proliferation of glandular tissue of male breasts presenting with a rubbery or firm mass extending concentrically from the nipples. This is due to increased estradiol and can occur in up to 66% of patients.

Hypogonadism . Manifested as impotence, infertility, loss of sexual drive, and testicular atrophy due to primary gonadal injury or suppression of hypothalamic or pituitary function.

Liver size. Can be enlarged, normal, or shrunken. Splenomegaly  (increase in size of the spleen). Due to congestion of the red pulp as

a result of portal hypertension. Ascites . Accumulation of fluid in the peritoneal cavity giving rise to flank dullness

(needs about 1500 mL to detect flank dullness). It may be associated with hydrocele and penile flomation (swelling of the penile shaft)[citation needed] in men.

Caput medusa . In portal hypertension, the umbilical vein may open. Blood from the portal venous system may be shunted through the periumbilical veins into the umbilical vein and ultimately to the abdominal wall veins, manifesting as caput medusa.

Cruveilhier-Baumgarten murmur. Venous hum heard in epigastric region (on examination by stethoscope) due to collateral connections between portal system and the remnant of the umbilical vein in portal hypertension.

Fetor hepaticus . Musty odor in breath due to increased dimethyl sulfide. Jaundice . Yellow discoloring of the skin, eye, and mucus membranes due to

increased bilirubin (at least 2–3 mg/dL or 30 mmol/L). Urine may also appear dark. Asterixis . Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in

patients with hepatic encephalopathy. Other. Weakness, fatigue, anorexia, weight loss.[edit]Complications

As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

Bruising  and bleeding due to decreased production of coagulation factors. Jaundice due to decreased processing of bilirubin. Itching  (pruritus) due to bile salts products deposited in the skin. Hepatic encephalopathy  - the liver does not clear ammonia and related nitrogenous

substances from the blood, which are carried to the brain, affecting cerebral functioning: neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits.

Sensitivity to medication due to decreased metabolism of the active compounds. Hepatocellular carcinoma  is primary liver cancer, a frequent complication of

cirrhosis. It has a high mortality rate. Portal hypertension  - blood normally carried from the intestines and spleen through

the hepatic portal vein flows more slowly and the pressure increases; this leads to the following complications: Ascites - fluid leaks through the vasculature into the abdominal cavity. Esophageal varices  - collateral portal blood flow through vessels in the stomach

and esophagus. These blood vessels may become enlarged and are more likely to burst.

Problems in other organs. Cirrhosis can cause immune system dysfunction, leading to infection. Signs and

symptoms of infection may be aspecific are more difficult to recognize (e.g., worsening encephalopathy but no fever).

Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis).

Hepatorenal syndrome  - insufficient blood supply to the kidneys, causing acute renal failure. This complication has a very high mortality (over 50%).

Hepatopulmonary syndrome  - blood bypassing the normal lung circulation (shunting), leading to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.[6]

Portopulmonary hypertension  - increased blood pressure over the lungs as a consequence of portal hypertension.[6]

Portal hypertensive gastropathy  which refers to changes in the mucosa of the stomach in patients with portal hypertension, and is associated with cirrhosis severity.[7]

[edit]Causes

Cirrhosis has many possible causes; sometimes more than one cause is present in the same patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes.

Alcoholic liver disease  (ALD). Alcoholic cirrhosis develops for between 10% and 20% of individuals who drink heavily for a decade or more.[8] There is great variability in the amount of alcohol needed to cause cirrhosis (as little as 3-4 drinks a day in some men and 2-3 in some women[citation needed]). Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT are both elevated but less than 300 IU/L with a AST:ALT ratio > 2.0, a value rarely seen in other liver diseases. Liver biopsy may show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular inflammation.

Chronic hepatitis C. Infection with the hepatitis C virus causes inflammation of the liver and a variable grade of damage to the organ that over several decades can lead to cirrhosis. Cirrhosis caused by hepatitis C is the most common reason for liver transplant. Can be diagnosed with serologic assays that detect hepatitis C antibody or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used screening test in the US.

Chronic hepatitis B. The hepatitis B virus causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic hepatitis B

can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG and HBV DNA are determined to assess whether patient will need antiviral therapy.

Non-alcoholic steatohepatitis  (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications. This disorder is similar to that of alcoholic liver disease but patient does not have an alcohol history. Biopsy is needed for diagnosis.

Primary biliary cirrhosis . May be asymptomatic or complain of fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin. Gold standard diagnosis is antimitochondrial antibodies with liver biopsy as confirmation if showing florid bile duct lesions. It is more common in women.

Primary sclerosing cholangitis . PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded appearance. Non-specific serum immunoglobulins may also be elevated.

Autoimmune hepatitis . This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins. Therapy with prednisone +/- azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-year survival of 90%+. There is no specific tool to diagnose autoimmune but it can be beneficial to initiate a trial of corticosteroids.

Hereditary hemochromatosis . Usually presents with family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all due to signs of iron overload. Labs will show fasting transferrin saturation of > 60% and ferritin > 300 ng/mL. Genetic testing may be used to identify HFE mutations. If these are present, biopsy may not need to be performed. Treatment is with phlebotomy to lower total body iron levels.

Wilson's disease . Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also have Kayser-Fleischer rings in the cornea and altered mental status.

Alpha 1-antitrypsin deficiency  (AAT). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking. Serum AAT

levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency.

Cardiac cirrhosis . Due to chronic right sided heart failure which leads to liver congestion.

Galactosemia Glycogen storage disease type IV Cystic fibrosis Hepatotoxic drugs or toxins Certain parasitic infections (such as schistosomiasis)[edit]Pathophysiology

The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting factors and complement), detoxification and storage (e.g., vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.

Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible.

The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2), leading tomatrix breakdown and replacement by connective tissue-secreted matrix.[9]

The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.

[edit]Diagnosis

The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. Histologically

cirrhosis can be classified as micronodular, macronodular, or mixed, but this classification has been abandoned since it is non-specific to the aetiology, it may change as the disease progresses, and serological markers are much more specific.[citation needed]. However, a biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.[10]

[edit]Lab findings

The following findings are typical in cirrhosis:

Aminotransferases  - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis.

Alkaline phosphatase  - usually slightly elevated. Gamma-glutamyl transferase  – correlates with AP levels. Typically much higher in

chronic liver disease from alcohol. Bilirubin  - may elevate as cirrhosis progresses. Albumin  - levels fall as the synthetic function of the liver declines with worsening

cirrhosis since albumin is exclusively synthesized in the liver Prothrombin time  - increases since the liver synthesizes clotting factors. Globulins  - increased due to shunting of bacterial antigens away from the liver to

lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from

high levels of ADH and aldosterone. Thrombocytopenia - due to both congestive splenomegaly as well as

decreased thrombopoietin from the liver. However, this rarely results in platelet count < 50,000/mL.

Leukopenia  and neutropenia - due to splenomegaly with splenic margination. Coagulation  defects - the liver produces most of the coagulation factors and thus

coagulopathy correlates with worsening liver disease.

There is now a validated and patented combination of 6 of these markers as non-invasive biomarker of fibrosis (and so of cirrhosis) : FibroTest [11].

Other laboratory studies performed in newly diagnosed cirrhosis may include:

Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, anti-LKM)

Ferritin  and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers of copper overload)

Immunoglobulin  levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes

Cholesterol  and glucose Alpha 1-antitrypsin [edit]Imaging

Liver cirrhosis as seen on an axial CT of the abdomen.

Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein).

A new type of device, the FibroScan (transient elastography), uses elastic waves to determine liver stiffness which theoretically can be converted into a liver score based on the METAVIR scale. The FibroScan produces an ultrasound image of the liver (from 20–80 mm) along with a pressure reading (in kPa.) The test is much faster than a biopsy (usually last 2.5–5 minutes) and is completely painless. It shows reasonable correlation with the severity of cirrhosis.[12]

Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

[edit]Endoscopy

Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced.

Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be causes of cirrhosis. Imaging of the bile ducts, such as ERCPor MRCP (MRI of biliary tract and pancreas) can show abnormalities in these patients, and may aid in the diagnosis.

[edit]Pathology

Cirrhosis leading to hepatocellular carcinoma (autopsy specimen).

Macroscopically, the liver is initially enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The mixed cirrhosis consists in a variety of nodules with different sizes.

However, cirrhosis is defined by its pathological features on microscopy: (1) the presence of regenerating nodules of hepatocytes and (2) the presence of fibrosis, or the deposition of connective tissue between these nodules. The pattern of fibrosis seen can depend upon the underlying insult that led to cirrhosis; fibrosis can also proliferate even if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis can lead to destruction of other normal tissues in the liver: including the sinusoids, the space of Disse, and other vascular structures, which leads to altered resistance to blood flow in the liver and portal hypertension.[13]

As cirrhosis can be caused by many different entities which injure the liver in different ways, different cause-specific patterns of cirrhosis, and other cause-specific abnormalities can be seen in cirrhosis. For example, in chronic hepatitis B, there is infiltration of the liver parenchyma with lymphocytes;[13] in cardiac cirrhosis there are erythrocytes and a greater amount of fibrosis in the tissue surrounding the hepatic veins;[14] in primary biliary cirrhosis, there is fibrosis around the bile duct, the presence ofgranulomas and pooling of bile;[15] and in alcoholic cirrhosis, there is infiltration of the liver with neutrophils.[13]

[edit]Grading

The severity of cirrhosis is commonly classified with the Child-Pugh score. This score uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to classify patients in class A, B or C; class A has a favourable prognosis, while class C is at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973 by Pugh et al..[16]

More modern scores, used in the allocation of liver transplants but also in other contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, thePediatric End-Stage Liver Disease (PELD) score.

The hepatic venous pressure gradient, i.e., the difference in venous pressure between afferent and efferent blood to the liver, also determines severity of cirrhosis, although hard to measure. A value of 16 mm or more means a greatly increased risk of dying.[17]

[edit]Management

Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop or delay further progression and reduce complications. A healthy diet is encouraged, as cirrhosis may be an energy-consuming process. Close follow-up is often necessary. Antibiotics will be prescribed for infections, and various medications can help with itching. Laxatives, such aslactulose, decrease risk of constipation; their role in preventing encephalopathy is limited.

[edit]Treating underlying causes

Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol. Treatment for hepatitis-related cirrhosis involves medications used to treat the different types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper builds up in organs, is treated withchelation therapy (e.g., penicillamine) to remove the copper.

[edit]Preventing further liver damage

Regardless of underlying cause of cirrhosis, alcohol and paracetamol, as well as other potentially damaging substances, are discouraged. Vaccination of susceptible patients should be considered for Hepatitis A and Hepatitis B.

[edit]Preventing complications

[edit]Ascites

Main article: Ascites

Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites.

[edit]Esophageal variceal bleeding

Main article: Esophageal varices

For portal hypertension, propranolol is a commonly used agent to lower blood pressure over the portal system. In severe complications from portal hypertension, transjugular intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of encephalopathy, and is generally regarded only as a bridge to liver transplantation or as a palliative measure.

[edit]Hepatic encephalopathy

Main article: Hepatic encephalopathy

High-protein food increases the nitrogen balance, and would theoretically increase encephalopathy; in the past, this was therefore eliminated as much as possible from the diet. Recent studies show that this assumption was incorrect, and high-protein foods are even encouraged to maintain adequate nutrition.[18]

[edit]Hepatorenal syndrome

Main article: Hepatorenal syndrome

The hepatorenal syndrome is defined as a urine sodium less than 10 mmol/L and a serum creatinine > 1.5 mg/dl (or 24 hour creatinine clearance less than 40 ml/min) after a trial of volume expansion without diuretics.[19]

[edit]Spontaneous bacterial peritonitis

Main article: Spontaneous bacterial peritonitis

Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

[edit]Transplantation

Main article: Liver transplantation

If complications cannot be controlled or when the liver ceases functioning, liver transplantation is necessary. Survival from liver transplantation has been improving over the 1990s, and the five-year survival rate is now around 80%, depending largely on the severity of disease and other medical problems in the recipient.[20] In the United States, the MELD score is used to prioritize patients for transplantation.[21] Transplantation necessitates the use of immune suppressants (cyclosporine or tacrolimus).

[edit]Decompensated cirrhosis

In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed above.

Patients with decompensated cirrhosis generally require admission to hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and medical treatment - often with diuretics, antibiotics, laxatives and/or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is generally avoided as it would add to the already high total body sodium content that typically occurs in cirrhosis.

[edit]Epidemiology

Disability-adjusted life year for cirrhosis of the liver per 100,000 inhabitants in 2004.[22]

     no data     less than 50     50-100     100-200     200-300     300-400     400-500     500-600     600-700     700-800     800-900     900-1000     more than 1000

Cirrhosis and chronic liver disease were the 10th leading cause of death for men and the 12th for women in the United States in 2001, killing about 27,000 people each year.[23] Also, the cost of cirrhosis in terms of human suffering, hospital costs, and lost productivity is high.

Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. The risk of death due to all causes is increased twelvefold; if one excludes the direct consequences of the liver disease, there is still a fivefold increased risk of death in all disease categories.[24]

Little is known on modulators of cirrhosis risk, apart from other diseases that cause liver injury (such as the combination of alcoholic liver disease and chronic viral hepatitis, which may act synergistically in leading to cirrhosis). Studies have recently suggested that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis. [25]

What is Polyarthralgia?Polyarthralgia is defined as aches in the joints, joint pains, arthralgia of multiple joints, and multiple joint pain. Polyarthritis is the word usually used to describe pain affecting five or more joints, while a patient with 2 to 4 joints involved would be said to have oligoarticular disease.Polyarthralgia is more common in women and even more so with increasing age.Polyarthralgia: Signs and SymptomsThe initial symptoms, which usually appear in the third to fifth decade of life, include painless swelling or thickening of the skin of the hands and fingers, pain and stiffness of the joints (polyarthralgia), often mistaken for rheumatoid arthritis, and paroxysmal blanching and cyanosis (becoming blue) of the fingers induced by exposure to cold (Raynaud syndrome).Simple arthralgia - Literally means joint pain, it is a symptom of injury, infection, illnesses (in particular arthritis) or an allergic reaction to medication. Main symptom is pain; no clinical features of inflammation in the joints or morning stiffness; history of intercurrent illness or viral infection.Rheumatoid arthritis - At least four of these signs or symptoms for six weeks: pain and swelling in at least three joint areas; symmetrical presentation; early morning joint stiffness for more than one hour; involvement of metacarpophalangeal joints, proximal interphalangeal joints, and wrists; subcutaneous nodules; positive rheumatoid factor; radiological evidence of erosions.Fibromyalgia - People with Fibromyalgia experience pain in their tendons and ligaments, along with tender points throughout their body along with fatigue. Even slight pressure on tender points can cause pain. More women than men have Fibromyalgia, which has been known as, 'chronic muscle pain,' psychogenic rheumatism,' 'tension myalgias,' and, 'fibrositis,' in the past.Seronegative (non-rheumatoid) arthritis - Linked with psoriasis, bowel disease (ulcerative colitis, Crohn's disease), bladder symptoms, and anterior uveitis. May occur

after infections (streptococcal throat infection, chlamydial urethritis, or bowel infection with yersinia, salmonella, shigella). Mainly asymmetrical, large joint oligoarticular involvement; possible spinal involvement (sacroiliitis)Osteoarthritis - Pain is usually in large, weight bearing joints, carpometacarpal joint of thumb, or distal interphalangeal joints of the fingers; presence of Heberden's nodes, crepitus; lifestyle factors such as overweight, sedentary occupation, repetitive use of joints, and history of trauma to affected joints may be relevant.

Hepatic encephalopathy

From Wikipedia, the free encyclopedia

Hepatic encephalopathy

Classification and external resources

Micrograph of Alzheimer type II astrocytes, as may be seen in hepatic encephalopathy.

ICD-10 K 72.

ICD-9 572.2

MedlinePlus 000302

eMedicine med/3185 article/182208

MeSH D006501

Hepatic encephalopathy (also known as portosystemic encephalopathy) is the occurrence of confusion, altered level of consciousnessand coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum. It may ultimately lead to death.[1]

It is caused by accumulation in the bloodstream of toxic substances that are normally removed by the liver. The diagnosis of hepatic encephalopathy requires the presence of impaired liver function, and the exclusion of an alternative explanation for the symptoms. Blood tests (ammonia levels) may assist in the diagnosis. Attacks are often precipitated by an intercurrent problem, such as infection orconstipation.[1][2]

Hepatic encephalopathy is reversible with treatment. This relies on suppressing the production of the toxic substances in the intestine. This is most commonly done with the laxative lactulose or with non-absorbable antibiotics. In addition, the treatment of any underlying condition may improve the symptoms. In particular settings, such as acute liver failure, the onset of encephalopathy may indicate the need for a liver transplant.[1][3]

Contents

[hide]

1 Signs and symptoms

2 Causes

3 Classification and grading

o 3.1 West Haven Criteria

o 3.2 Types

4 Pathogenesis

5 Diagnosis

o 5.1 Investigations

o 5.2 Minimal HE

6 Treatment

o 6.1 Diet

o 6.2 Lactulose/lactitol

o 6.3 Antibiotics

o 6.4 LOLA

7 Epidemiology and prognosis

8 History

9 References

Signs and symptoms

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion and irritability. More severe encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night), marked irritability, tremor, difficulties with coordination and trouble writing.[1]

More severe forms of hepatic encephalopathy lead to a worsening level of consciousness, from lethargy to somnolence and eventually coma. In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis, "liver flap" due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. Coma and seizures represent the most advanced stage; cerebral oedema (swelling of the brain tissue) leads to death.[1]

Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice (yellow discolouration of the skin and the whites of the eyes), ascites(fluid accumulation in the abdominal cavity), and peripheral oedema (swelling of the legs due to fluid build-up in the skin). The tendon reflexes may be exaggerated, and the plantar reflexmay be abnormal, namely extending rather than flexing (Babinski's sign) in severe encephalopathy. A particular smell (foetor hepaticus) may be detected.[2]

Causes

In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic encephalopathy is caused or aggravated by an additional cause, and identifying these causes can be important to treat the episode effectively.[1]

Type Causes[1][2][4]

Excessivenitrogen load

Consumption of large amounts of protein, gastrointestinal bleeding e.g. from oesophageal varices (blood is high in protein, which is reabsorbed from the bowel), renal failure (inability to

excrete nitrogen-containing waste products such as urea), constipation

Electrolyte ormetabolic disturbance

Hyponatraemia (low sodium level in the blood) and hypokalaemia (low potassium levels)—these are both common in those taking diuretics, often used for the treatment of ascites; furthermore alkalosis (decreased acid level), hypoxia (insufficient oxygen levels), dehydration

Drugs andmedications

Sedatives such as benzodiazepines (often used to suppress alcohol withdrawal or anxiety disorder), narcotics(used as painkillers or drugs of abuse) and sedative antipsychoticsintoxication

Infection Pneumonia, urinary tract infection, spontaneous bacterial peritonitis, other infections

OthersSurgery, progression of the liver disease, additional cause for liver damage (e.g. alcoholic hepatitis, hepatitis A)

Unknown In 20–30% of cases, no clear cause for an attack can be found

Hepatic encephalopathy may also occur after the creation of a transjugular intrahepatic portosystemic shunt (TIPSS). This is used in the treatment of refractory ascites, bleeding fromoesophageal varices and hepatorenal syndrome.[5][6] TIPSS-related encephalopathy occurs in about 30% of cases, with the risk being higher in those with previous episodes of encephalopathy, higher age, female sex and liver disease due to causes other than alcohol.[4]

Classification and grading

West Haven Criteria

The severity of hepatic encephalopathy is graded with the West Haven Criteria; this is based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy.[1][7][8].

Grade 1 - Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired performance of addition or subtraction

Grade 2 - Lethargy or apathy; Minimal disorientation for time or place; Subtle personality change; Inappropriate behaviour

Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; Confusion; Gross disorientation

Grade 4 - Coma (unresponsive to verbal or noxious stimuli)Types

Micrograph showing liver cirrhosis, a condition that often precedes hepatic encephalopathy. Trichrome stain.

A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology 1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause. [7]

Type A (=acute) describes hepatic encephalopathy associated with acute liver failure Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic

liver disease Type C (=cirrhosis) occurs in patients with cirrhosis - this type is subdivided

in episodic, persistent and minimal encephalopathy

The term minimal encephalopathy (MHE) is defined as encephalopathy that does not lead to clinically-overt cognitive dysfunction, but can be demonstrated with neuropsychological studies.[7][9] This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life and increase the risk of involvement in road traffic accidents.[10]

[edit]Pathogenesis

Image of ball and stick model of ammonia; one nitrogen atom with three hydrogen atoms. Accumulation of ammonia in the bloodstream is associated with hepatic encephalopathy.

There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported by the portal vein to the liver, where 80–90% ismetabolised and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocytes(liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt. Nitrogenous waste products accumulate in the systemic circulation (hence the older term "portosystemic encephalopathy"). The most important waste product is ammonia (NH3). This small molecule crosses the blood-brain barrier and is absorbed and metabolised by the astrocytes, a population of cells in the brain that constitutes 30% of the cerebral cortex. Astrocytes become swollen, there is increased activity of the inhibitory γ-aminobutyric acid (GABA) system, and the energy supply to other brain cells is decreased. Despite numerous studies demonstrating the central role of ammonia, ammonia levels don't always correlate with the severity of the encephalopathy; it is suspected that this means that more ammonia has already been absorbed into the brain in those with severe symptoms whose serum levels are relatively low.[1][2] Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol.[2]

Numerous other abnormalities have been described in hepatic encephalopathy, although their relative contribution to the disease state is uncertain. Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the

GABA neurotransmission system. An imbalance between aromatic amino acids (phenylalanine, tryptophan and tyrosine) and branched-chain amino acids (leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitters (such octopamine and 2-hydroxyphenethylamine). Dysregulation of the serotoninsystem, too, has been reported. Depletion of zinc and accumulation of manganese may play a role.[1][2] Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokines and bacterial lipopolysaccharide on astrocytes.[4]

[edit]Diagnosis

Micrograph of Alzheimer type II astrocytes, as may be seen in hepatic encephalopathy.

[edit]Investigations

Alt=Two-dimensional graph of slow brain activity on an electroencephalogram

The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as it leads to similar symptoms to other encephalopathies. To make the distinction, abnormal liver function tests and/orultrasound suggesting liver disease are required, and ideally liver biopsy.[1][2] The symptoms of hepatic encephalopathy may also arise from other conditions, such as cerebral haemorrhage and seizures (both of which are more common in chronic liver disease). A CT scan of the brain may be required to exclude haemorrhage, and if seizure activity is suspected an electroencephalograph (EEG) study may be performed.[1]Rarer mimics of encephalopathy are meningitis, encephalitis, Wernicke's encephalopathy and Wilson's disease; these may be suspected on clinical grounds and confirmed with investigations. [2][7]

The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum ammonia levels are elevated in 90% of patients, but not all hyperammoninaemia (high ammonia levels) is associated with encephalopathy.[1][2] A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible.[2] Other neuroimaging modalities, such as magnetic resonance imaging (MRI), are not currently regarded as useful, although they may show abnormalities.[7] Electroencephalography shows no clear abnormalities in stage 0, even if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal lobes that oscillate at 5 Hz, and in stage IV there is slow delta wave activity.[1]However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.[7]

Once the diagnosis of encephalopathy has been made, efforts are made to exclude underlying causes (such as listed above in "causes"). This requires blood tests (urea and electrolytes, full blood count, liver function tests), usually a chest X-ray, and urinalysis. If there is ascites, diagnostic paracentesis (removal of a fluid sample with a needle) may be required to identify spontaneous bacterial peritonitis (SBP).[1]

[edit]Minimal HE

The diagnosis of minimal hepatic encephalopathy requires neuropsychological testing by definition. Older tests include the "numbers connecting test" A and B (measuring the speed at which one could connect randomly dispersed numbers 1–20), the "block design test" and the "digit-symbol test".[7] In 2009 an expert panel concluded that neuropsychological test batteries aimed at measuring multiple domains of cognitive

function are generally more reliable than single tests, and tend to be more strongly correlated with functional status. Both the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)[11] and PSE-Syndrom-Test[12] may be used for this purpose.[9] The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test.[7][9][10][12]

[edit]Treatment

Those with severe encephalopathy (stages 3 and 4) are at risk of obstructing their airway due to decreased protective reflexes such as the gag reflex. This can lead to respiratory arrest. Nursing in an appropriate area, such as the intensive care unit, is advocated in such situations, with intubation of the airway if necessary.[2][3] If the level of consciousness is low there is a significant risk of aspiration pneumonia, and a nasogastric tube is often inserted to allow the safe administration of nutrients and medication.[1]

The treatment of hepatic encephalopathy depends on the suspected underlying cause (types A, B or C) and the presence or absence of underlying causes. If encephalopathy develops in acute liver failure (type A), even in a mild form (grade 1–2), it indicates that a liver transplant may be required, and transfer to a specialist centre is advised.[3] Hepatic encephalopathy type B may arise in those who have undergone a TIPSS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion of the shunt is required to address the symptoms.[4]

In hepatic encephalopathy type C, the identification and treatment of alternative or underlying causes is central to the initial management.[1][2][4][10] Given the frequency of infection as the underlying cause, antibiotics are often administered empirically (without knowledge of the exact source and nature of the infection).[1][4] Once an episode of encephalopathy has been effectively treated, a decision may need to be made on whether to prepare for a liver transplant.[10]

[edit]Diet

In the past, it was thought that consumption of protein even at normal levels increased the risk of hepatic encephalopathy. This has been shown to be incorrect. Furthermore, many people with chronic liver disease are malnourished and require adequate protein

to maintain a stable body weight. A diet with adequate protein and energy is therefore recommended.[1][4]

Dietary supplementation with branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis.[1][4] Some studies have shown benefit of administration of probiotics ("healthy bacteria").[4]

[edit]Lactulose/lactitol

Lactulose and lactitol are disaccharides that are not absorbed from the digestive tract. They are thought to improve the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4), and increase transit of bowel content through the gut. Doses of 15-30 ml are administered three times a day; the result is aimed to be 3–5 soft stools a day, or (in some settings) a stool pH of <6.0.[1]

[2][4][10] Lactulose may also be given by enema, especially if encephalopathy is severe.[10] More commonly, phosphateenemas are used. This may relieve constipation, one of the causes of encephalopathy, and increase bowel transit.[1]

A 2004 review by the Cochrane Collaboration concluded that there was insufficient evidence to determine whether lactulose and lactitol are of benefit of hepatic encephalopathy,[13] but it remains the first-line treatment for type C hepatic encephalopathy.[1] In acute liver failure, it is unclear whether lactulose is beneficial. Furthermore, it may lead to bloating and as such interfere with a liver transplant procedure if required.[3]

[edit]Antibiotics

The antibiotics neomycin and metronidazole were previously used as a treatment for hepatic encephalopathy. Again, the rationale of their use was the fact that ammonia and other waste products are generated and converted by intestinal bacteria, and killing of these bacteria would reduce the generation of these waste products. Neomycin was chosen because of its low intestinal absorption, as neomycin and similar aminoglycoside antibiotics may cause hearing loss and renal failure if used extensively. Later studies showed that neomycin was indeed absorbed enterally, with resultant complications. Metronidazole, similarly, was abandoned because prolonged use could cause a peripheral neuropathy (nerve damage), and many experience gastrointestinal side effects.[1]

A safer and probably more effective antibiotic is rifaximin, a nonabsorbable antibiotic from the rifamycin class. This is thought to work in a similar way, but without the

complications attached to neomycin and metronidazole. The use of rifaximin is supported by better evidence than lactulose.[13] Due to more widespread experience, it is only used as a second-line treatment if lactulose is not effective or poorly tolerated. When added to lactulose two combination may be more effective than each component separately.[1] Rifaximin is more expensive than lactulose, but the cost may be offset by reduced hospital admissions for encephalopathy.[10]

[edit]LOLA

A preparation of L -ornithine  and L -aspartate  (LOLA) is used to increase the generation of urea through the urea cycle, a metabolic pathway that removes ammonia by turning it into the neutral substance urea. It may be combined with lactulose and/or rifaximin if these alone are ineffective at controlling symptoms.[1]

[edit]Epidemiology and prognosis

In those with cirrhosis, the risk of developing hepatic encephalopathy is 20% per year, and at any time about 30–45% of people with cirrhosis exhibit evidence of overt encephalopathy. The prevalence of minimal hepatic encephalopathy detectable on formal neuropsychological testing is 60–80%; this increases the likelihood of developing overt encephalopathy in the future.[10] Once hepatic encephalopathy has developed, the prognosis is determined largely by other markers of liver failure, such as the levels of albumin (a protein produced by the liver), the prothrombin time (a test of coagulation, which relies on proteins produced in the liver), the presence of ascites and the level of bilirubin (a breakdown product of hemoglobin which is conjugated and excreted by the liver). Together with the severity of encephalopathy, these markers have been incorporated into the Child-Pugh score; this score determines the one- and two-year survival and may assist in a decision to offer liver transplantation.[7]

In acute liver failure, the development of severe encephalopathy strongly predicts short-term mortality, and is almost as important as the nature of the underlying cause of the liver failure in determining the prognosis. Historically widely used criteria for offering liver transplantation, such as King's College Criteria, are of limited use and recent guidelines discourage excessive reliance on these criteria. The occurrence of hepatic encephalopathy in patients with Wilson's disease (hereditary copper accumulation) and mushroom poisoning indicates an urgent need for a liver transplant. [3]

[edit]History

The occurrence of disturbed behaviour in people with jaundice may have been described in antiquity by Hippocrates of Cos (ca. 460–370 BCE). Celsus and Galen (first and third century respectively) both recognised the condition. Many modern descriptions of the link between liver disease and neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for instance, Giovanni Battista Morgagni (1682–1771) reported in 1761 that it was a progressive condition.[12][14]

In the 1950s, several reports enumerated the numerous abnormalities reported previously, and confirmed the previously enunciated theory that metabolic impairment and portosystemic shunting are the underlying mechanism behind hepatic encephalopathy, and that the nitrogen-rich compounds originate from the intestine. [12]

[15] Many of these studies were done by Professor Dame Sheila Sherlock (1918–2001), then at the Royal Postgraduate Medical School in London and subsequently at the Royal Free Hospital. The same group investigated protein restriction[14] and neomycin.[16]

The West Haven classification was formulated by Prof Harold Conn and colleagues at Yale University while investigating the therapeutic efficacy of lactulose.[7][8]

[edit]References

Ileus

From Wikipedia, the free encyclopedia

Ileus

Classification and external resources

ICD-10 K 31.5 , K 56.0 , K 56.3 ,K 56.7 , P 75. , P 76.1

ICD-9 537.2, 560.1, 560.31,777.1, 777.4

DiseasesDB 6706

MeSH D045823

Ileus or gastrointestinal atony[1] is a disruption of the normal propulsive gastrointestinal motor activity due to non-mechanical causes[2][3]. In contrast,

motility disorders that result from structural abnormalities are termed mechanical bowel obstruction. Some mechanical obstructions are misnomers, such as gallstone ileus and meconium ileus, and are not true examples of ileus by the classic definition [4].

Contents

[hide]

1 Types

o 1.1 Postoperative Ileus

o 1.2 Paralytic Ileus

o 1.3 Acute colonic pseudoobstruction

2 Pathogenesis

o 2.1 Inhibitory neural reflexes

o 2.2 Inflammation

o 2.3 Neurohumoral peptides

3 Symptoms

4 Risk Factors

5 Treatment in humans

6 External links

7 See also

8 References

[edit]Types

[edit]Postoperative Ileus

It is a temporary paralysis of a portion of the intestines typically after an abdominal surgery. Since the intestinal content of this portion is unable to move forward, food or drink should be avoided until peristaltic sound is heard from auscultation of the area where this portion lies.

[edit]Paralytic Ileus

Paralysis of the intestine. To be termed "paralytic ileus," the intestinal paralysis need not be complete, but it must be sufficient to prohibit the passage of food through the intestine and lead to intestinal blockage.

Paralytic ileus is a common side effect of some types of surgery. It can also result from certain drugs and from various injuries and illnesses. Paralytic ileus causes constipation

and bloating. On listening to the abdomen with a stethoscope, no bowel sounds are heard because the bowel is inactive.

[edit]Acute colonic pseudoobstruction

Also known as Ogilvie's syndrome.

[edit]Pathogenesis

Gangrenous ileum.

[edit]Inhibitory neural reflexes

[edit]Inflammation

Ileus may increase adhesion formation, because intestinal segments have more prolonged contact, allowing fibrous adhesions to form, and intestinal distention causes serosal injury and ischemia. Intestinal distention has been shown to cause adhesions in foals [5]. Some respondents also mentioned the importance of walking horses postoperatively to stimulate motility. Repeat celiotomy to decompress chronically

distended small intestine and remove fibrinous adhesions is also a useful method of treating ileus and reducting adhesions, and it has been associated with a good outcome [6][7]

[edit]Neurohumoral peptides

[edit]Symptoms

Symptoms of ileus include, but are not limited to:

moderate, diffuse abdominal discomfort constipation abdominal distension nausea /vomiting, especially after meals lack of bowel movement and/or flatulence excessive belching[edit]Risk Factors

gastrointestinal surgery  or other GI procedures electrolyte imbalance diabetic ketoacidosis  (DKA)[8], and other causes of metabolic acidosis hypothyroidism medications  (e.g. opiates) severe illness (Inflammation with peritonitis) spinal cord injury (SCI), those with injury above thoracic vertebrae 5 (T5) will have

hypomotility problems within the bowel[edit]Treatment in humans

Nil per os (NPO or "Nothing by Mouth") is mandatory in all cases. Nasogastric suction and parenteral feeds may be required until passage is restored.

There are several options in the case of paralytic ileus. Most treatment is supportive. If caused by medication, the offending agent is discontinued or reduced. Bowel movements may be stimulated by prescribing lactulose, erythromycin or, in severe cases (Ogilvie's syndrome), neostigmine.

If possible the underlying cause is corrected (e.g. replace electrolytes).

Ganglion cyst

From Wikipedia, the free encyclopedia

Ganglion cyst

Classification and external resources

Cyst on right wrist

ICD-10 M 67.4

ICD-9 727.4

DiseasesDB 31229

eMedicine orthoped/493

MeSH D045888

A ganglion cyst, also known as a bible cyst, is a swelling that often appears on or around joints and tendons in the hand or foot. The size of the cyst can vary over time. It is most frequently located around the dorsum of wrist and on the fingers. The term "Bible bump" comes from a common urban legend that treatment in the past consisted of hitting the cyst with a Bible or another large book.[1]

Contents

[hide]

1 Cause

2 Treatment

3 Epidemiology

4 Image gallery

5 See also

6 References

7 External links

Cause

Ganglion cysts are idiopathic, but presumably reflect a variation in normal joint or tendon sheath function. Cysts near joints are connected to the joint and the leading theory is that a type of check valve forms that allows fluid out of the joint, but not back in. The cyst contains clear fluid similar to, but thicker than, normal synovial fluid. They are most often found around the wrist joint, especially at the scapho-lunate joint, which accounts for 80% of all ganglion cysts.

Treatment

If a ganglion cyst is symptomatic, it can be managed by aspiration or excision. Aspiration and injection of hyaluronidase into the cyst is the simpler of the two procedures, but cysts recur in more than 50% of cases. With surgery, the recurrence rate is reduced to only 5 to 10% if the check valve at the joint capsule is

removed. Arthroscopy of the wrist is becoming available as an alternative to open excision of ganglion cysts. During arthroscopy, the origin of the cyst can be seen within the joint.

An out-dated method of treating a ganglion cyst was supposedly to strike the lump with a large heavy book, causing the cyst to rupture and drain into the surrounding tissues. An urban legend states that since even the poorest households often possessed a Bible, this was commonly used, which led to the nicknaming of ganglion cysts as "Jillian's lump", "Bible bumps" or "Gideon's disease."[1] This type of treatment is not recommended by some doctors as it can damage the area around the cyst and may have a higher recurrence rate than aspiration or excision.[citation needed]

Epidemiology

The epidemiology of ganglion cysts is not well studied, but some have stated that they occur most often in the 20–40 age group and are three times more common in women.[2]

[edit]Image gallery

Ganglion

From Wikipedia, the free encyclopedia

For other uses, see Ganglion (disambiguation).

"Ganglia" redirects here. For other uses, see Ganglia (disambiguation).

Micrograph of a ganglion. H&E stain.

In anatomy, a ganglion (pronounced /ˈɡæŋɡliən/, GANG-glee-ən, plural ganglia) is a biological tissue mass, most commonly a mass of nerve cell bodies.[1] Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells.

Contents

[hide]

1 Neurology

o 1.1 Basal ganglia

2 Additional image

3 See also

4 References

[edit]Neurology

In neurological contexts, ganglia are composed mainly of somata and dendritic structures which are bundled or connected together. Ganglia often interconnect with other ganglia to form a complex system of ganglia known as a plexus. Ganglia provide relay points and intermediary connections between different neurological structures in the body, such as the peripheral and central nervous systems.

There are two major groups of ganglia:

Dorsal root ganglia  (also known as the spinal ganglia) contain the cell bodies of sensory (afferent) nerves.

Autonomic ganglia  contain the cell bodies of autonomic nerves.

In the autonomic nervous system, fibers from the central nervous system to the ganglia are known as preganglionic fibers, while those from the ganglia to the effector organ are calledpostganglionic fibers.

[edit]Basal ganglia

The term "ganglion" usually refers to the peripheral nervous system.[2]

However, in the brain (part of the central nervous system), the "basal ganglia" is a group of nuclei interconnected with the cerebral cortex, thalamus and brainstem, associated with a variety of functions: motor control, cognition, emotions and learning.

Partly due to this ambiguity, the Terminologia Anatomica recommends using the term basal nuclei instead of basal ganglia.

[edit]Additional image

A dorsal root ganglion (DRG) from a chicken embryo (around stage of day 7) after incubation overnight in NGF growth medium stained with anti-neurofilament antibody. Note the axons growing out of the ganglion.

What is it? In the hand, a ganglion is a particular type of lump which shows up next to a joint or a

tendon. Inside, it is like a balloon filled with a thick liquid. It may be soft or hard, may or may not be painful, and may get bigger or smaller on its own. It may also be referred to as a mucous cyst, a mucinous cyst or a synovial cyst.

What caused it? Normally, joints and tendons are lubricated by a special liquid which is sealed in a small

compartment. Sometimes, because of arthritis, an injury, or just for no good reason, a leak occurs from the compartment. Now, the liquid is thick, like honey, and if the hole is small, it can be like having a pinhole in a tube of toothpaste - when you squeeze the tube, even though the hole is small and the toothpaste is thick, it will leak out - and once it is out, there is no way it can go back in on its own. It works almost like a one way valve, and fills up a little balloon next to the area of the leak. When we use our hands for normal activities, our joints squeeze and create a tremendous pressure in the lubricating compartment - this can pump up a balloon leak with so much pressure that it feels as hard as a bone.

The lubricating liquid has special proteins dissolved in it which make it thick and also make it hard for the body to absorb it when it has leaked out. The body tries to absorb the liquid, but may only be able to draw out the water, making it even more thick. Usually, by the time the lump is big enough to see, the liquid has gotten to be as thick as jelly.

Common sites for ganglions are:o The wrist - on the back ("dorsal wrist ganglion"), on the front ("volar wrist

ganglion"), or sometimes on the thumb side. These come from one of the wrist joints, sometimes aggravated by a wrist sprain.

o The palm at the base of the finger ("flexor tendon sheath cyst"). These come from the tube which holds the finger tendons in place, and are often due to tendon irritation - tendinitis.

o The back of the end joint of the finger ("mucous cyst"), next to the base of the fingernail. These can cause a groove in the fingernail, or rarely can become infected and lead to a joint infection. These are usually due to some arthritis or bone spurs in the joint.

What can you do to help? Wait and watch. "Over the counter" non-steroidal anti inflammatory medication (NSAID), such as aspirin,

ibuprofen, naprosyn, or ketoprofen. Check with your pharmacist regarding possible side effects and drug interactions.

Some people, following non-medical advice, will smash the lump with a heavy book, and rupture the cyst. Sometimes this works, but I don't recommend it. The lump can come back even if it has been successfully treated this way. The urban legend regarding this traditionally involves using a Bible as the book, leading ganglions to be called "Giddeon's disease" in some circles.

Some people attempt to drain the cyst by sticking it with a needle - particularly when the cyst is on the end joint of the finger. Don't try this at home! It can lead to a serious infection in the joint.

What can a therapist do to help? Provide a variety of hand splints to support the area. 

What can a doctor do to help? Confirm that this actually is the problem.  Prescribe a custom prescription splint.  Drain the cyst with a needle and possibly inject the area with cortisone. This works much

better for cysts coming from the tendon than those coming from joints. Perform surgery to remove the cyst and clean out the area where the cyst comes from.

How successful is treatment?It depends on several things.

Tendon sheath cysts are more likely to be cured with a cortisone shot than cysts coming from joints.

Cysts coming from joints are less likely to come back after surgery if the joint itself is "cleaned out", but cleaning the joint out increases the chance that the joint will be somewhat stiff after surgery.  For example, cysts on the back of the wrist come back about one out of three times give the joint is not cleaned out, but only about one out of twenty times if the joint is cleaned out.

Cysts on the front of the wrist (volar wrist ganglions) are more likely to come back after surgery than cysts on the back of the wrist (dorsal wrist ganglions).

What happens if you have no treatment?This depends on what kinds of problems you're having, but it is a good idea to have your cyst checked out by a doctor and possibly have x-rays to make sure that you are not ignoring a potential health problem.  For example,

Painful cysts may be painful because of underlying problems other than a simple cyst.  Although uncommon, pain associated with a ganglion may be due to underlying arthritis, bone tumor, ligament injury or fracture.

Cysts can extend into the underlying bones and cause other types of problems.  Cysts on the back of the end joint of the finger (mucus cysts) may gradually thin and

weaken the overlying skin, allowing liquid to drain out but also allowing bacteria to enter

the joint, sometimes causing a serious infection.

Once these types of issues have been evaluated by a physician, the choice is yours.  Most ganglions do not pose a serious health risk, and can be simply left alone. Many ganglions go away on their own. Between one-third and two-thirds of wrist ganglions eventually go alway with no treatment.

CholecystitisFrom Wikipedia, the free encyclopedia

Cholecystitis

Classification and external resources

Micrograph of a gallbladder with cholecystitisand cholesterolosis.

ICD-10 K 81.

ICD-9 575.0, 575.1

DiseasesDB 2520

eMedicine med/346

MeSH D002764

Cholecystitis is inflammation of the gall bladder.

Contents

[hide]

1 Causes and pathology

2 Symptoms

3 Diagnosis

o 3.1 Differential diagnosis

3.1.1 Acute cholecystitis

3.1.2 Chronic cholecystitis

3.1.3 Quick Differential

4 Investigations

o 4.1 Blood

o 4.2 Radiology

5 Therapy

6 Complications of cholecystitis

o 6.1 Complications of cholecystectomy

6.1.1 Gall bladder perforation

7 See also

8 References

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with

choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,

bile stasis, and secondary infection by gut organisms, predominantly E. coli and Bacteroides species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation

often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the

absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might

develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic

and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The

pain may be felt to 'refer' to the right flank or right scapular region at first.

This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies

and fried foods.

This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such

as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the

gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal

obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,

and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

fever (usually low grade in uncomplicated cases)

tender right upper quadrant +/- Murphy's sign

Ortner's sign - tenderness when hand taps the edge of right costal arch.

Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid

muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]Differential diagnosis[edit]Acute cholecystitis

This should be suspected whenever there is acute right upper quadrant or epigastric pain.

Other possible causes include:

Perforated peptic ulcer

Acute peptic ulcer exacerbation

Amoebic liver abscess

Acute amoebic liver colitis

Acute pancreatitis

Acute intestinal obstruction

Renal colic

Acute retrocolic appendicitis

[edit]Chronic cholecystitis

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other

common disorders:

Peptic ulcer

Hiatus hernia

Colitis

Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

[edit]Quick Differential

Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and

constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver

function tests are within normal limits since the obstruction does not necessarily cause blockage in the

common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to

visualise the gallbladder and associated ducts, and also to determine the size and precise position of the

obstruction.

Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to

infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in

the right upper quadrant. Infectious agents that cause cholecystitis include E

coli, klebsiella, pseudomonas, B. fragilis and enterococcus. Murphy's sign is positive, particularly because

of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,

flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised

hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to

visualise the gallbladder and ducts.

Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the

gallbladder or has formed in the common bile duct (primary cholelithiasis). As with other biliary tree

obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary

output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with

high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are

associated with biliary epithelium. The diagnosis is made using endoscopic retrograde

cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious

complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent

pancreatic damage and brittle diabetes.

Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which

refers to the presence of pathogens that typically inhabit more distal regions of the bowel [4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute

liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant

pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,

GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

It is worth noting that bile is an extremely favourable growth medium for bacteria, and infections in this space

develop rapidly and may become quite severe.

[edit]Investigations

[edit]Blood

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.

CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on

the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest

abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]Radiology

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and

specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria

are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than

3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive

than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic

abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified

gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for

diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall

bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.

However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is

usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy

X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive

measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid

resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as

piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a

cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)

and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and

clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.

Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually

done if complications have developed or the patient has had prior surgery to the area, making laparoscopic

surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the

operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open

procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required

for cholecystectomy), the managing physician may elect to have an interventional radiologist insert

a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the

patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if

their condition improves.

[edit]Complications of cholecystitis

Perforation or rupture

Ascending cholangitis

Rokitansky-Aschoff sinuses

[edit]Complications of cholecystectomy

bile leak ("biloma")

bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal

rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open

cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)

abscess

wound infection

bleeding (liver surface and cystic artery are most common sites)

hernia

organ injury (intestine and liver are at highest risk, especially if the gallbladder has become

adherent/scarred to other organs due to inflammation (e.g. transverse colon)

deep vein thrombosis /pulmonary embolism (unusual- risk can be decreased through use of sequential

compression devices on legs during surgery)

fatty acid and fat-soluble vitamin malabsorption

[edit]Gall bladder perforation

Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early

diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the

treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure

necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the

general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result

in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis

of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after

admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6

patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the

present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of

gallbladder perforation are of crucial importance.[5]

CholecystitisFrom Wikipedia, the free encyclopedia

Cholecystitis

Classification and external resources

Micrograph of a gallbladder with cholecystitisand cholesterolosis.

ICD-10 K 81.

ICD-9 575.0, 575.1

DiseasesDB 2520

eMedicine med/346

MeSH D002764

Cholecystitis is inflammation of the gall bladder.

Contents

[hide]

1 Causes and pathology

2 Symptoms

3 Diagnosis

o 3.1 Differential diagnosis

3.1.1 Acute cholecystitis

3.1.2 Chronic cholecystitis

3.1.3 Quick Differential

4 Investigations

o 4.1 Blood

o 4.2 Radiology

5 Therapy

6 Complications of cholecystitis

o 6.1 Complications of cholecystectomy

6.1.1 Gall bladder perforation

7 See also

8 References

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with

choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,

bile stasis, and secondary infection by gut organisms, predominantly E. coli and Bacteroides species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation

often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the

absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might

develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic

and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The

pain may be felt to 'refer' to the right flank or right scapular region at first.

This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies

and fried foods.

This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such

as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the

gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal

obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,

and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

fever (usually low grade in uncomplicated cases)

tender right upper quadrant +/- Murphy's sign

Ortner's sign - tenderness when hand taps the edge of right costal arch.

Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid

muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]Differential diagnosis[edit]Acute cholecystitis

This should be suspected whenever there is acute right upper quadrant or epigastric pain.

Other possible causes include:

Perforated peptic ulcer

Acute peptic ulcer exacerbation

Amoebic liver abscess

Acute amoebic liver colitis

Acute pancreatitis

Acute intestinal obstruction

Renal colic

Acute retrocolic appendicitis

[edit]Chronic cholecystitis

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other

common disorders:

Peptic ulcer

Hiatus hernia

Colitis

Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

[edit]Quick Differential

Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and

constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver

function tests are within normal limits since the obstruction does not necessarily cause blockage in the

common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to

visualise the gallbladder and associated ducts, and also to determine the size and precise position of the

obstruction.

Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to

infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in

the right upper quadrant. Infectious agents that cause cholecystitis include E

coli, klebsiella, pseudomonas, B. fragilis and enterococcus. Murphy's sign is positive, particularly because

of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,

flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised

hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to

visualise the gallbladder and ducts.

Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the

gallbladder or has formed in the common bile duct (primary cholelithiasis). As with other biliary tree

obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary

output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with

high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are

associated with biliary epithelium. The diagnosis is made using endoscopic retrograde

cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious

complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent

pancreatic damage and brittle diabetes.

Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which

refers to the presence of pathogens that typically inhabit more distal regions of the bowel [4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute

liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant

pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,

GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

It is worth noting that bile is an extremely favourable growth medium for bacteria, and infections in this space

develop rapidly and may become quite severe.

[edit]Investigations

[edit]Blood

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.

CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on

the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest

abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]Radiology

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and

specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria

are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than

3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive

than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic

abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified

gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for

diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall

bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.

However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is

usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy

X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive

measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid

resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as

piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a

cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)

and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and

clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.

Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually

done if complications have developed or the patient has had prior surgery to the area, making laparoscopic

surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the

operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open

procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required

for cholecystectomy), the managing physician may elect to have an interventional radiologist insert

a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the

patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if

their condition improves.

[edit]Complications of cholecystitis

Perforation or rupture

Ascending cholangitis

Rokitansky-Aschoff sinuses

[edit]Complications of cholecystectomy

bile leak ("biloma")

bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal

rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open

cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)

abscess

wound infection

bleeding (liver surface and cystic artery are most common sites)

hernia

organ injury (intestine and liver are at highest risk, especially if the gallbladder has become

adherent/scarred to other organs due to inflammation (e.g. transverse colon)

deep vein thrombosis /pulmonary embolism (unusual- risk can be decreased through use of sequential

compression devices on legs during surgery)

fatty acid and fat-soluble vitamin malabsorption

[edit]Gall bladder perforation

Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early

diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the

treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure

necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the

general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result

in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis

of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after

admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6

patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the

present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of

gallbladder perforation are of crucial importance.[5]

CholecystitisFrom Wikipedia, the free encyclopedia

Cholecystitis

Classification and external resources

Micrograph of a gallbladder with cholecystitisand cholesterolosis.

ICD-10 K 81.

ICD-9 575.0, 575.1

DiseasesDB 2520

eMedicine med/346

MeSH D002764

Cholecystitis is inflammation of the gall bladder.

Contents

[hide]

1 Causes and pathology

2 Symptoms

3 Diagnosis

o 3.1 Differential diagnosis

3.1.1 Acute cholecystitis

3.1.2 Chronic cholecystitis

3.1.3 Quick Differential

4 Investigations

o 4.1 Blood

o 4.2 Radiology

5 Therapy

6 Complications of cholecystitis

o 6.1 Complications of cholecystectomy

6.1.1 Gall bladder perforation

7 See also

8 References

[edit]Causes and pathology

Cholecystitis is often caused by cholelithiasis (the presence of choleliths, or gallstones, in the gallbladder), with

choleliths most commonly blocking the cystic duct directly. This leads toinspissation (thickening) of bile,

bile stasis, and secondary infection by gut organisms, predominantly E. coli and Bacteroides species.

The gallbladder's wall becomes inflamed. Extreme cases may result in necrosis and rupture. Inflammation

often spreads to its outer covering, thus irritating surrounding structures such as the diaphragm and bowel.

Less commonly, in debilitated and trauma patients, the gallbladder may become inflamed and infected in the

absence of cholelithiasis, and is known as acute acalculous cholecystitis.

Stones in the gallbladder may cause obstruction and the accompanying acute attack. The patient might

develop a chronic, low-level inflammation which leads to a chronic cholecystitis, where the gallbladder is fibrotic

and calcified.

[edit]Symptoms

Cholecystitis usually presents as a pain in the right upper quadrant. This is usually a constant, severe pain. The

pain may be felt to 'refer' to the right flank or right scapular region at first.

This may also present with the above mentioned pain after eating greasy or fatty foods such as pastries, pies

and fried foods.

This is usually accompanied by a low grade fever, vomiting and nausea.

More severe symptoms such as high fever, shock and jaundice indicate the development of complications such

as abscess formation, perforation or ascending cholangitis. Another complication, gallstone ileus, occurs if the

gallbladder perforates and forms a fistula with the nearby small bowel, leading to symptoms of intestinal

obstruction.

Chronic cholecystitis manifests with non-specific symptoms such as nausea, vague abdominal pain, belching,

and diarrhea.

[edit]Diagnosis

Cholecystitis is usually diagnosed by a history of the above symptoms, as well examination findings:

fever (usually low grade in uncomplicated cases)

tender right upper quadrant +/- Murphy's sign

Ortner's sign - tenderness when hand taps the edge of right costal arch.

Georgievskiy-Myussi's sign (phrenic nerve sign) - pain when press between edges of sternocleidomastoid

muscle. [1]

Subsequent laboratory and imaging tests are used to confirm the diagnosis and exclude other possible causes.

Ultrasound can assist in the differential.[2][3]

[edit]Differential diagnosis[edit]Acute cholecystitis

This should be suspected whenever there is acute right upper quadrant or epigastric pain.

Other possible causes include:

Perforated peptic ulcer

Acute peptic ulcer exacerbation

Amoebic liver abscess

Acute amoebic liver colitis

Acute pancreatitis

Acute intestinal obstruction

Renal colic

Acute retrocolic appendicitis

[edit]Chronic cholecystitis

The symptoms of chronic cholecystitis are non-specific, thus chronic cholecystitis may be mistaken for other

common disorders:

Peptic ulcer

Hiatus hernia

Colitis

Functional bowel syndrome

It is defined pathologically by the columnar epithelium has reached down the muscular layer.

[edit]Quick Differential

Biliary colic - Caused by obstruction of the cystic duct. It is associated with sharp and

constant epigastric pain in the absence of fever and usually there is a negative Murphy's sign. Liver

function tests are within normal limits since the obstruction does not necessarily cause blockage in the

common hepatic duct, thereby allowing normal bile excretion from the liver. An ultrasound scan is used to

visualise the gallbladder and associated ducts, and also to determine the size and precise position of the

obstruction.

Cholecystitis - Caused by blockage of the cystic duct with surrounding inflammation, usually due to

infection. Typically, the pain is initially 'colicky' (intermittent), and becomes constant and severe, mostly in

the right upper quadrant. Infectious agents that cause cholecystitis include E

coli, klebsiella, pseudomonas, B. fragilis and enterococcus. Murphy's sign is positive, particularly because

of increased irritation of the gallbladder lining, and similarly this pain radiates (spreads) to the shoulder,

flank or in a band like pattern around the lower abdomen. Laboratory tests frequently show raised

hepatocellular liver enzymes (AST, ALT) with a high white cell count (WBC). Ultrasound is used to

visualise the gallbladder and ducts.

Choledocholithiasis - This refers to blockage of the common bile duct where a gallstone has left the

gallbladder or has formed in the common bile duct (primary cholelithiasis). As with other biliary tree

obstructions it is usually associated with 'colicky' pain, and because there is direct obstruction of biliary

output, obstructive jaundice. Liver function tests will therefore show increased serum bilirubin, with

high conjugated bilirubin. Liver enzymes will also be raised, predominately GGT and ALP, which are

associated with biliary epithelium. The diagnosis is made using endoscopic retrograde

cholangiopancreatography (ERCP), or the nuclear alternative (MRCP). One of the more serious

complications of choledocholithiasis isacute pancreatitis, which may result in significant permanent

pancreatic damage and brittle diabetes.

Cholangitis - An infection of entire biliary tract, and may also be known as 'ascending cholangitis', which

refers to the presence of pathogens that typically inhabit more distal regions of the bowel [4]

Cholangitis is a medical emergency as it may be life threatening and patients can rapidly succumb to acute

liver failure or bacterial sepsis. The classical sign of cholangitis is Charcot's triad, which is right upper quadrant

pain, fever and jaundice. Liver function tests will likely show increases across all enzymes (AST, ALT, ALP,

GGT) with raised bilirubin. As with choledocholithiasis, diagnosis is confirmed using cholangiopancreatography.

It is worth noting that bile is an extremely favourable growth medium for bacteria, and infections in this space

develop rapidly and may become quite severe.

[edit]Investigations

[edit]Blood

Laboratory values may be notable for an elevated alkaline phosphatase, possibly an

elevated bilirubin (although this may indicate choledocholithiasis), and possibly an elevation of theWBC count.

CRP (C-reactive protein) is often elevated. The degree of elevation of these laboratory values may depend on

the degree of inflammation of the gallbladder. Patients with acute cholecystitis are much more likely to manifest

abnormal laboratory values, while in chronic cholecystitis the laboratory values are frequently normal.

[edit]Radiology

Sonography is a sensitive and specific modality for diagnosis of acute cholecystitis; adjusted sensitivity and

specificity for diagnosis of acute cholecystitis are 88% and 80%, respectively. The 2 major diagnostic criteria

are cholelithiasis and sonographic Murphy's sign. Minor criteria include gallbladder wall thickening greater than

3mm, pericholecystic fluid, and gallbladder dilatation.

The reported sensitivity and specificity of CT scan findings are in the range of 90-95%. CT is more sensitive

than ultrasonography in the depiction of pericholecystic inflammatory response and in localizing pericholecystic

abscesses, pericholecystic gas, and calculi outside the lumen of the gallbladder. CT cannot see noncalcified

gallbladder calculi, and cannot assess for a Murphy's sign.

Hepatobiliary scintigraphy with technetium-99m DISIDA (bilirubin) analog is also sensitive and accurate for

diagnosis of chronic and acute cholecystitis. It can also assess the ability of the gall bladder to expel bile (gall

bladder ejection fraction), and low gall bladder ejection fraction has been linked to chronic cholecystitis.

However, since most patients with right upper quadrant pain do not have cholecystitis, primary evaluation is

usually accomplished with a modality that can diagnose other causes, as well.

[edit]Therapy

X-Ray during laparoscopic cholecystectomy

For most patients, in most centres, the definitive treatment is surgical removal of the gallbladder. Supportive

measures are instituted in the meantime and to prepare the patient for surgery. These measures include fluid

resuscitation and antibiotics. Antibiotic regimens usually consist of a broad spectrum antibiotic such as

piperacillin-tazobactam (Zosyn), ampicillin-sulbactam (Unasyn), ticarcillin-clavulanate (Timentin), or a

cephalosporin (e.g.ceftriaxone) and an antibacterial with good coverage (fluoroquinolone such asciprofloxacin)

and anaerobic bacteria coverage, such as metronidazole. For penicillin allergic patients, aztreonam and

clindamycin may be used.cis

Gallbladder removal, cholecystectomy, can be accomplished via open surgery or a laparoscopic procedure.

Laparoscopic procedures can have less morbidity and a shorter recovery stay. Open procedures are usually

done if complications have developed or the patient has had prior surgery to the area, making laparoscopic

surgery technically difficult. A laparoscopic procedure may also be 'converted' to an open procedure during the

operation if the surgeon feels that further attempts at laparoscopic removal might harm the patient. Open

procedure may also be done if the surgeon does not know how to perform a laparoscopic cholecystectomy.

In cases of severe inflammation, shock, or if the patient has higher risk for general anesthesia (required

for cholecystectomy), the managing physician may elect to have an interventional radiologist insert

a percutaneous drainage catheter into the gallbladder ('percutaneous cholecystostomy tube') and treat the

patient with antibiotics until the acute inflammation resolves. The patient may later warrant cholecystectomy if

their condition improves.

[edit]Complications of cholecystitis

Perforation or rupture

Ascending cholangitis

Rokitansky-Aschoff sinuses

[edit]Complications of cholecystectomy

bile leak ("biloma")

bile duct injury (about 5-7 out of 1000 operations. Open and laparoscopic surgeries have essentially equal

rate of injuries, but the recent trend is towards fewer injuries with laparoscopy. It may be that the open

cases often result because the gallbladder is too difficult or risky to remove with laparoscopy)

abscess

wound infection

bleeding (liver surface and cystic artery are most common sites)

hernia

organ injury (intestine and liver are at highest risk, especially if the gallbladder has become

adherent/scarred to other organs due to inflammation (e.g. transverse colon)

deep vein thrombosis /pulmonary embolism (unusual- risk can be decreased through use of sequential

compression devices on legs during surgery)

fatty acid and fat-soluble vitamin malabsorption

[edit]Gall bladder perforation

Gall bladder perforation (GBP) is a rare but life-threatening complication of acute cholecystitis. The early

diagnosis and treatment of GBP are crucial to decrease patient morbidity and mortality.

Approaches to this complication will vary based on the condition of an individual patient, the evaluation of the

treating surgeon or physician, and the facilities' capability. Perforation can happen at the neck from pressure

necrosis due to the impacted calculus, or at the fundus. It can result in a local abscess, or perforation into the

general peritoneal cavity. If the bile is infected, diffuse peritonitis may occur readily and rapidly and may result

in death.

A retrospective study looked at 332 patients who received medical and/or surgical treatment with the diagnosis

of acute cholecystitis. Patients were treated with analgesics and antibiotics within the first 36 hours after

admission (with a mean of 9 hours), and proceeded to surgery for a cholecystectomy. Two patients died and 6

patients had further complications. The morbidity and mortality rates were 37.5% and 12.5%, respectively in the

present study. The authors of this study suggests that early diagnosis and emergency surgical treatment of

gallbladder perforation are of crucial importance.[5]

AngiogramAn angiogram is an X-ray test that uses a special dye and camera (fluoroscopy) to take pictures of the blood flow in an artery (such as the aorta) or a vein (such as the vena cava). An angiogram can be used to look at the arteries or veins in the head, arms, legs, chest, back, or belly.

Common angiograms can look at the arteries near the heart (coronary angiogram),lungs (pulmonary angiogram), brain (cerebral angiogram), head and neck (carotid angiogram), legs or arms (peripheral), and the aorta (aortogram).

During an angiogram, a thin tube called a catheter is placed into a blood vessel in the groin (femoral artery or vein) or just above the elbow (brachial artery or vein). See a picture of catheter placement in the femoral vein  . The catheter is guided to the area to be studied. Then an iodine dye (contrast material) is injected into the vessel to make the area show clearly on the X-ray pictures. This method is known as conventional or catheter angiogram. The angiogram pictures can be made into regular X-ray films or stored as digital pictures in a computer.

An angiogram can find a bulge in a blood vessel (aneurysm). It can also show narrowing or a blockage in a blood vessel that affects blood flow. An angiogram can show if coronary artery disease is present and how bad it is.

A magnetic resonance angiogram (MRA) or computed tomography angiogram (CTA) may be an option instead of an angiogram. Each of these tests is less invasive than a standard angiogram. Some MRA tests and all CTA tests require an injection of dye. A CTA also involves radiation exposure.

Nephrotic syndromeFrom Wikipedia, the free encyclopedia

Nephrotic syndrome

Classification and external resources

Histopathological image of diabetic glomerulosclerosis with nephrotic

syndrome. H&E stain.

ICD-10 N 04.

ICD-9 581.9

DiseasesDB 8905

eMedicine med/1612 ped/1564

MeSH D009404

This article may require cleanup to meet Wikipedia's quality standards. Please improve this article if you can. (April 2008)

Not to be confused with nephritic syndrome

Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak

large amounts of protein [1] (proteinuria at least 3.5 grams per day per 1.73m2 body surface area)[2] from

the blood into the urine.

Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to

permit proteinuria (and subsequentlyhypoalbuminemia, because some of the protein albumin has gone

from the blood to the urine) but not large enough to allow cells through (hence no hematuria). By contrast,

in nephritic syndrome, RBCs pass through the pores, causing hematuria.

Contents

[hide]

1 Presentation

2 Investigations

3 Classification and causes

o 3.1 Etiologic classification

o 3.2 Histologic classification

o 3.3 Primary causes

o 3.4 Secondary causes

4 Differential diagnosis of gross edema

5 Diagnosis

6 Treatment

o 6.1 General measures (supportive)

o 6.2 Specific treatment of underlying cause

o 6.3 Dietary recommendations

7 Complications

8 Prognosis

9 See also

10 References

11 External links

[edit]Presentation

It is characterized

by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia and edema. Lipiduria (lipids in urine) can

also occur, but is not essential for diagnosis of nephrotic syndrome.

Hyperlipidemia is caused by 2 factors:

Hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of

lipoproteins.

Lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in

lipoprotein breakdown.[3]

A few other characteristics seen in nephrotic syndrome are:

The most common sign is excess fluid in the body due to the serum hypoalbuminemia. Lower serum

oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention

aggravate the edema. This may take several forms:

Puffiness around the eyes, characteristically in the morning.

Edema  over the legs which is pitting (i.e., leaves a little pit when the fluid is pressed out, which

resolves over a few seconds).

Fluid in the pleural cavity causing pleural effusion. More commonly associated with excess fluid

is pulmonary edema.

Fluid in the peritoneal cavity causing ascites.

A generalized edema throughout the body known as anasarca

Hypertension  (rarely)

Some patients may notice foamy urine, due to a lowering of the surface tension by the

severe proteinuria. Actual urinary complaints such as hematuria or oliguria are uncommon, and are

seen commonly in nephritic syndrome.

May have features of the underlying cause, such as the rash associated with Systemic Lupus

Erythematosus, or the neuropathy associated with diabetes.

Examination should also exclude other causes of gross edema—especially

the cardiovascular and hepatic system.

[edit]Investigations

The following are baseline, essential investigations

Urine sample shows proteinuria (>3.5g per 1.73 m2 per 24 hour). It is also examined for urinary casts;

which is more a feature of active nephritis.

Comprehensive metabolic panel (CMP) shows Hypoalbuminemia: albumin level ≤2.5g/dL (normal=3.5-

5g/dL).

High levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly

elevated VLDL

Electrolytes , urea and creatinine (EUCs): to evaluate renal function

Further investigations are indicated if the cause is not clear

Biopsy of kidney

Auto-immune  markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis)

[edit]Classification and causes

Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney,

called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body,

called secondary nephrotic syndrome.

[edit]Etiologic classification

A broad classification of nephrotic syndrome based on etiology:

Nephroticsyndrome

Primary Secondary

[edit]Histologic classification

Nephrotic syndrome is often classified histologically:

Nephrotic syndrome

MCD FSGS MN MPGN

[edit]Primary causes

Primary causes of nephrotic syndrome are usually described by the histology, i.e., minimal change

disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN).

They are considered to be "diagnoses of exclusion", i.e., they are diagnosed only after secondary causes

have been excluded.

[edit]Secondary causes

Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes,

though may exhibit some differences suggesting a secondary cause, such asinclusion bodies.

They are usually described by the underlying cause.

Secondary causes by histologic pattern

Hepatitis B

Sjögren's syndrome

Systemic lupus erythematosus (SLE)

Diabetes mellitus

Sarcoidosis

Syphilis

Drugs (such as corticosteroids, gold, intravenous heroin)

Malignancy  (cancer)

Focal segmental glomerulosclerosis (FSGS)[4]

Hypertensive Nephrosclerosis

Human immunodeficiency virus  (HIV)

Diabetes mellitus

Obesity

Kidney loss

Minimal change disease (MCD)[4]

Drugs, especially NSAID's in the elderly

Malignancy, especially Hodgkin's lymphoma

[edit]Differential diagnosis of gross edema

When someone presents with generalized edema, the following causes should be excluded:

1. Heart failure : The patient is older, with a history of heart disease. Jugular venous pressure is

elevated on examination, might hear heart murmurs. An echocardiogram is the gold standard

investigation.

2. Liver failure : History suggestive of hepatitis/ cirrhosis: alcoholic, IV drug user, some hereditary

causes.

Stigmata of liver disease are seen: jaundice (yellow skin and eyes), dilated veins over umbilicus

(caput medusae), scratch marks (due to widespread itching, known as "pruritus"), enlarged

spleen, spider angiomata, encephalopathy, bruising, nodular liver

3. Acute  fluid overload in someone with kidney failure: These people are known to have kidney

failure, and have either drunk too much or missed their dialysis.

4. Metastatic cancer : When cancer seeds the lungs or abdomen it causes effusions and fluid

accumulation due to obstruction of lymphatics and veins as well as serous exudation.

[edit]Diagnosis

The gold standard in diagnosis of nephrotic syndrome is 24-hour urine protein measurement. Aiding in

diagnosis are blood tests and sometimes imaging of the kidneys (for structure and presence of 2

kidneys), and/or a biopsy of the kidneys.

[edit]Treatment

This section does not cite any references or sources.Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2008)

Treatment includes:

[edit]General measures (supportive)

Monitoring and maintaining euvolemia (the correct amount of fluid in the body):

monitoring urine output, BP regularly

fluid restrict to 1L

diuretics (IV furosemide)

Monitoring kidney function:

do EUCs daily and calculating GFR

Treat hyperlipidemia to prevent further atherosclerosis.

Prevent and treat any complications [see below]

Albumin infusions are generally not used because their effect lasts only transiently.

Prophylactic anticoagulation may be appropriate in some circumstances.[5]

[edit]Specific treatment of underlying cause

Immunosuppression for the glomerulonephritides (corticosteroids [6] , cyclosporin).

Standard ISKDC regime for first episode: prednisolone -60 mg/m2/day in 3 divided doses for 4 weeks

followed by 40 mg/m2/day in a single dose on every alternate day for 4 weeks.

Relapses by prednisolone 2 mg/kg/day till urine becomes negative for protein. Then, 1.5 mg/kg/day for

4 weeks.

Frequent relapses treated by: cyclophosphamide or nitrogen mustard or ciclosporin or levamisole.

Achieving stricter blood glucose control if diabetic.

Blood pressure  control. ACE inhibitors are the drug of choice. Independent of their blood pressure

lowering effect, they have been shown to decrease protein loss.

[edit]Dietary recommendationsThis section does not cite any references or sources.Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2008)

Reduce sodium intake to 1000-2000 milligrams daily. Foods high in sodium include salt used in cooking

and at the table, seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned

vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods,

fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to

calories per serving. Sodium should be less than or equal to calories per serving.

Eat a moderate amount of high protein animal food: 3-5 oz per meal (preferably lean cuts of meat, fish,

and poultry)

Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry

skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and

nuts. Eat low-fat desserts.

Increase intake of fruits and vegetables. There is no potassium or phosphorus restriction necessary.

Monitor fluid intake, which includes all fluids and foods that are liquid at room temperature. Fluid

management in nephrotic syndrome is tenuous, especially during an acute flare.

[edit]Complications

Venous thrombosis : due to leak of anti-thrombin 3, which helps prevent thrombosis. This often occurs

in the renal veins. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin

3 which is lost in the proteinuria so it will be ineffective.)

Infection : due to leakage of immunoglobulins, encapsulated bacteria such as Haemophilus

influenzae and Streptococcus pneumoniae can cause infection.

Acute renal failure  is due to hypovolemia. Despite the excess of fluid in the tissues, there is less fluid in

the vasculature. Decreased blood flow to the kidneys causes them to shutdown. Thus it is a tricky

task to get rid of excess fluid in the body while maintaining circulatory euvolemia.

Pulmonary edema : again due to fluid leak, sometimes it leaks into lungs

causing hypoxia and dyspnoea.

Growth retardation : does not occur in MCNS.It occurs in cases of relapses or resistance to therapy.

Causes of growth retardation are protein deficiency from the loss of protein in

urine, anorexia (reduced protein intake), and steroid therapy (catabolism).

Vitamin D deficiency  can occur. Thyroxine is reduced due to decreased thyroid binding globulin.

Microcytic hypochromic anaemia is typical. It is iron-therapy resistant.

Hypocalcemia can occur as a result of Nephrotic Syndrome. It may be significant enough to

cause Tetany.

[edit]Prognosis

The prognosis depends on the cause of nephrotic syndrome. It is usually good in children,

because minimal change disease responds very well to steroids and does not cause chronic renal failure.

However other causes such as focal segmental glomerulosclerosis frequently lead to end stage renal

disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood

pressure control and kidney function (GFR).

Uterine fibroidsFrom Wikipedia, the free encyclopedia

Uterine fibroids

Classification and external resources

Uterine Fibroids

ICD-10 D 25.

ICD-9 218.9

OMIM 150699

DiseasesDB 4806

eMedicine radio/777

MeSH D007889

A uterine fibroid (also uterine leiomyoma,[1] myoma, fibromyoma, leiofibromyoma, fibroleiomyoma,

and fibroma) (plural of ... myoma is ...myomas or ...myomata) is a benign (non-cancerous) tumor that

originates from the smooth muscle layer (myometrium) and the accompanying connective tissue of the uterus.

Fibroids are the most common benign tumors in females and typically found during the middle and later

reproductive years. While most fibroids are asymptomatic, they can grow and cause heavy and painful

menstruation, painful sexual intercourse, and urinary frequency and urgency. Some fibroids may interfere with

pregnancy although this appears to be very rare.[2]

In the US, symptoms caused by uterine fibroids are a very frequent indication for hysterectomy.[3] Fibroids are

often multiple and if the uterus contains too many leiomyomatas to count, it is referred to as diffuse uterine

leiomyomatosis. The malignant version of a fibroid is uncommon and termed a leiomyosarcoma.

Contents

[hide]

1 Prevalence

2 Pathology and histology

o 2.1 Location

3 Aetiology and pathogenesis

4 Symptoms

5 Diagnosis

6 Coexisting disorders

7 Treatment

o 7.1 Expectant management

o 7.2 Surgery

o 7.3 Uterine artery embolization

o 7.4 Uterine artery ligation

o 7.5 Radio frequency ablation

o 7.6 Endometrial ablation

o 7.7 Medication

o 7.8 Magnetic Resonance-Guided Focused Ultrasound

o 7.9 Other

8 Malignancy

9 Metastasis

10 Organizations, research and political aspects

o 10.1 Fibroid Research and Education Act of 2005

11 Fibroids in animals

12 See also

13 References

[edit]Prevalence

A relatively large submucosal leiomyoma; it fills out the major part of the endometrial cavity

About 20–40% of women will be diagnosed with leiomyoma but only a fraction of those will cause problems or

require treatment.[3]

The condition is about twice as common in black women as white women.[4][5].

Leiomyoma are more common in overweight women (perhaps because of increased estrogen from

adipose aromatase activity).[6] Fibroids are dependent on estrogen and progesterone to grow and therefore

relevant only during the reproductive years, they are expected to shrink after menopause.

[edit]Pathology and histology

Leiomyomas grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white

or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of

considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the

abdominal wall.

Micrograph of a lipoleiomyoma, a type of leiomyoma. H&E stain.

Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus)

and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce

mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active.

[edit]Location

An enucleated uterine leiomyoma – external surface on left, cut surface on right.

large subserosal fibroid

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems. [3] A small

lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus

may go unnoticed. Different locations are classified as follows:

Intramural Fibroids are located within the wall of the uterus and are the most common type; unless large,

they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus.

With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.

Subserosal fibroids are located underneath the mucosal (peritoneal) surface of the uterus and can

become very large. They can also grow out in a papillary manner to become pedunculated fibroids.

These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma.

Submucosal fibroids are located in the muscle beneath the endometrium of the uterus and distort the

uterine cavity; even small lesion in this location may lead to bleeding and infertility. A pedunculated lesion

within the cavity is termed an intracavitary fibroid and can be passed through the cervix.

Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely fibroids are found in the

supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also

contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in an intramural location, that is the layer of the muscle of

the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the

internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification,

and cystic changes.

[edit]Aetiology and pathogenesis

Fibroids are monoclonal tumors, approximately 40 to 50% show karyotypically detectable chromosomal

abnormalities.

Their growth is strongly dependent on estrogen and progesterone. Although both estrogen and progesterone

are usually regarded as growth promoting they will also cause growth restriction in some circumstances.

Paradoxically fibroids will rarely grow during pregnancy despite very high steroid hormone levels and

pregnancy appears to exert a certain protective effect. [2]

It is believed that estrogen and progesterone have both mitogenic effect on leiomyoma cells and also act by

influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as

other hormones. Furthermore the actions of estrogen and progesterone are modulated by the cross-talk

between estrogen, progesterone and prolactin signalling which controls the expression of the respective

nuclear receptors. It is believed that estrogen is growth promoting by up-regulating IGF-1, EGFR, TGF-beta1,

TGF-beta3 and PDGF, promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing

expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signalling. Progesterone is

thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and the

survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to

counteract growth by downregulating IGF-1.[7][8][9] Expression of transforming growth interacting factor (TGIF) is

increased in leiomyoma compared with myometrium.[10] TGIF is a potential repressor of TGF-β pathways in

myometrial cells.[10]

Whereas in premenopausal fibroids the ER-beta, ER-alpha and progesterone receptors are found

overexpressed, in the rare postmenopausal fibroids only ER-beta was found significantly overexpressed.[11] Most studies found that polymorphisms in ER and PR gene encodings are not correlated with incidence of

fibroids in Caucasian populations [12][13] however a special ER-alpha genotype was found correlated with

incidence and size of fibroids. The higher prevalence of this genotype in black women may also explain the

high incidence of fibroids in this group.[14]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that

fibroids can convert circulating androstenedione into estradiol. [15] Similar mechanism of action has been

elucidated in endometriosis and other endometrial diseases. [16] Aromatase inhibotors are currently considered

for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely

affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is

particularly pronounced in Afro-American women [17]

Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable

genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold

risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy

compared to dizygotic twins.[18]

Like keloids fibroids have disregulated production of extracellular matrix. Recent studies suggest that this

production may represent an abnormal response to ischemic and mechanical tissue stress. [19] Several factors

indicate significant involvement of extracellular signaling pathways such as ERK1 and ERK2, which in fibroids

are prominently influenced by hormones.[20] Paradoxically and unlike most other conditions involving significant

fibrosis the Cyr61 gene has been found downregulated in fibroids.[21]

Cyr61 is also known for its role as tumor suppressing factor and in angiogenesis. Hence fibroids are one of the

very few tumors with reduced vascular density. [21]

[edit]Symptoms

Generally, symptoms relate to the location of the lesion and its size (mass effect). Important symptoms include

abnormal gynecologic hemorrhage, heavy or painful periods, abdominal discomfort or bloating, painful

defecation, back ache, urinary frequency or retention, and in some cases, infertility.[22] There may also be pain

during intercourse, depending on the location of the fibroid. During pregnancy they may be the cause

of miscarriage, bleeding, premature labor, or interference with the position of the fetus.

Fibroids, particularly when small, may be entirely asymptomatic. The U.S. Department of Health & Human

Services states that "Fibroids are almost always benign (not cancerous). Rarely (less than one in 1,000) a

cancerous fibroid will occur. This is called leiomyosarcoma. Doctors think that these cancers do not arise from

an already-existing fibroid. Having fibroids does not increase the risk of developing a cancerous fibroid. Having

fibroids also does not increase a woman's chances of getting other forms of cancer in the uterus." [23]

While fibroids are common, they are not a typical cause for infertility accounting for about 3% of reasons why a

woman may not have a child.[24] Typically in such cases a fibroid is located in a submucosal position and it is

thought that this location may interfere with the function of the lining and the ability of the embryo to implant.[24] Also larger fibroids may distort or block the fallopian tubes.

[edit]Diagnosis

While a bimanual examination typically can identify the presence of larger fibroids, gynecologic

ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography

will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the

ultrasound beam. The location can be determined and dimensions of the lesion measured. Also magnetic

resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the

uterus.

Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine

leiomyosarcoma, however, the latter is quite rare. However fast growth or unexpected growth such as

enlargement of a lesion after the menopause raise the level of suspicion that the lesion might be a sarcoma.

Also, with advanced malignant lesions there may be evidence of local invasion. A more recent study has

suggested that diagnostic capabilities using MRI have improved the ability to detect sarcomatous lesions.[25] Biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis

after ultrasounds and MRI imaging, surgery is generally indicated.

Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine

cavity are hysterosalpingography or sonohysterography.

[edit]Coexisting disorders

Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects

gastrointestinal problems are possible such as constipation and bloatedness. Compression of the ureter may

lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause

infertility. Adenomyosis may be mistaken for or coexist with fibroids.

In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop.[26]

[edit]Treatment

submucosal fibroid in hysteroscopy

Treatment of an intramural fibroid bylaparoscopic surgery

After treatment of an intramural fibroid bylaparoscopic surgery

[edit]Expectant management

The presence of fibroids does not mean that they need to be treated; lesions can be managed expectantly

depending on the symptomatology and presence of related conditions. Thus most cases of fibroids are

managed by "watchful waiting" which includes periodic sonographic assessment. After menopause fibroids

shrink and it is unusual for fibroids to cause problems.

The presence of symptomatic uterine fibroids can be solved by:

[edit]Surgery

Surgery: Surgical removal of a uterine fibroid usually takes place via hysterectomy, in which the entire uterus is

removed, or myomectomy, in which only the fibroid is removed. It is possible to remove multiple fibroids during

a myomectomy. Although a myomectomy cannot prevent the recurrence of fibroids at a later date, such surgery

is increasingly recommended, especially in the case of women who have not completed bearing children or

who express an explicit desire to retain the uterus. There are three different types of myomectomy:

In a hysteroscopic myomectomy, the fibroid is removed by the use of a resectoscope,

an endoscopic instrument that can use high-frequency electrical energy to cut tissue. Hysteroscopic

myomectomies can be done as an outpatient procedure, with either local or general anesthesia used.

Hysteroscopic myomectomy is most often recommended for submucosal fibroids. A French study collected

results from 235 patients suffering from submucous myomas who were treated with hysteroscopic

myomectomies; in none of these cases was the fibroid greater than 5 cm.[27]

A laparoscopic myomectomy requires a small incision near the navel. The physician then inserts a

laparoscope into the uterus and uses surgical instruments to remove the fibroids. Studies have suggested

that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic

myomectomy.[28] As with hysteroscopic myomectomy, laparoscopic myomectomy is not generally used on

very large fibroids. A study of laparoscopic myomectomies conducted between January 1990 and October

1998 examined 106 cases of laparoscopic myomectomy, in which the fibroids were intramural or

subserous and ranged in size from 3 to 10 cm.[29]

A laparotomic myomectomy (also known as an open or abdominal myomectomy) is the most invasive

surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes

the fibroid from the uterus. A particularly extensive laparotomic procedure may necessitate that any future

births be conducted by Caesarean section.[24] Recovery time from a laparatomic procedure is generally

expected to be four to six weeks.

[edit]Uterine artery embolization

Uterine artery embolization (UAE): Using interventional radiology techniques, the interventional radiologist

occludes both uterine arteries, thus reducing blood supply to the fibroid[30] . A small catheter (1 mm in diameter)

is inserted into the femoral artery at the level of the groin under local anesthesia. Under imaging guidance, the

interventional radiologist will enter selectively into both uterine arteries and inject small (500 µm) particles that

will block the blood supply to the fibroids. A patient will usually recover from the procedure within a few days.

The UAE procedure should result in limited blood supply to the fibroids which should prevent them from further

growth, heavy bleeding and possibly shrink them.

A retrospective cohort study showed that UAE has much fewer serious adverse effects than hysterectomy

(odds ratio 0.25) and similar rates of satisfaction. In this study, 86% of women treated with UAE would

recommend the treatment to a friend compared to 70% of those treated by hysterectomy. [31]

[edit]Uterine artery ligation

Uterine artery ligation: a minimaly invasive surgery to limit blood supply of the uterus that can be performed

transvaginally or laparoscopically. The principal mechanism of action is same like in UAE. This is a relatively

new method which demonstrated similar efficiacy like UAE but is easier to perform and for this reason fewer

side effects are expected.[32][33][34]

[edit]Radio frequency ablation

Radiofrequency ablation: One of the newest minimally invasive treatments for fibroids is radiofrequency

ablation [35]. In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the

abdomen and heating it with radio-frequency (RF) electrical energy. The treatment is a potential option for

women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

[edit]Endometrial ablation

Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively

small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.

[edit]Medication

Gonadotropin-releasing hormone analogs cause regression of fibroids by decreasing estrogen levels. Because

of the limitations and side effects of this medication it is rarely recommended other than for preoperative use to

shrink the size of the fibroids and uterus before surgery. Its is typically used for a maximum of 6 months or

shorter because after longer use they could cause osteoporosis and other typically postmenopausal

complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will

regrow after cessation of treatment, however significant benefits may persists for much longer time in some

cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease

the adverse effects of estrogen deficiency. Several add-back regimes are

possible, tibolone, raloxifene, progestogens alone, estrogen alone, and combined estrogens and progestogens.[36]

Levonorgestrel intrauterine devices are highly effective in limiting menstrual blood flow. Side effects are

typically very moderate because the levonorgestrel (a progestin) is released in low concentration locally. While

most Levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported very good

results specifically for women with fibroids.[37]One reported problem is that women with large fibroids had more

frequently spontaneous expulsion of the IUD, however many of those asked for reinsertion of the device

indicating a high rate of satisfaction despite the expulsion.[36][38]

Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due

partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in

fibroids.[36] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that

aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Progesterone antagonists have been shown in small studies to decrease the size of uterine

fibroids. Mifepristone was effective in a placebo-controlled pilot study.[39] Selective progesterone receptor

modulators, such as Progenta, have been under investigation.

The selective progesterone receptor modulator Asoprisnil is currently tested with very promising results as a

possible use as a treatment for fibroids - the hope is that it will provide the advantages of progesterone

antangonitst without their adverse effects.[36]

The long term safety of progesterone antagonists as well as selective progesterone receptor modulators has

yet to be established.[40][41]

A number of secondary medications are in use to alleviate symptoms caused by fibroids. This allows an

otherwise expectant approach to bring the patient hopefully to menopause when symptoms naturally regress.

Thus oral contraceptive pills, either combination pills with low-dose estrogens or progestin-only, are prescribed

in an effort to reduce uterine bleeding and cramps. Such medications seem to have little or no effect on the size

of the lesions.[24] Anemia may have to be treated with iron supplementation. NSAIDs can be used to reduce

painful menses.

[edit]Magnetic Resonance-Guided Focused Ultrasound

Magnetic Resonance guided Focused Ultrasound (MRgFUS), is a non-invasive intervention (requiring no

incision) that uses high intensity focused ultrasound (HIFU) waves to ablate (destroy) tissue in combination with

Magnetic Resonance Imaging (MRI), which guides and monitors the treatment. This technique was approved

by the FDA in 2004. Ultrasound is a form of energy that passes through skin, muscle, fat and other soft tissue.

High intensity focused ultrasound energy, focused on a small target volume (tumor), provides a therapeutic

effect by raising the tissue temperature of the target (tumor) high enough to destroy it. This is similar to the

manner in which sunlight focused by a magnifying glass can create sufficient heat to start a fire. The use of

heat to destroy tissue is called thermal ablation. Treatments consist of multiple exoposures of focused energy

or sonications. MRgFUS uses a Magnetic Resonance Imaging (MRI) scanner to identify tissues in the body and

plan the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using

MR thermal imaging. • MR imaging provides a three-dimensional view of the target tissue, allowing for precise

focusing of ultrasound energy within a desired volume. • Additionally, the MR imaging provides quantitative,

real-time, thermal images of the treated area. This allows the physician to ensure that the temperature

generated during each cycle of ultrasound energy is sufficient to cause thermal ablation within the desired

tissue and if not, to adapt the parameters. The advantage and value of MR guidance ensures safe and

accurate treatment. [42]

[edit]Other

The use of vitex herbal medicine lacks supporting evidence.

[edit]Malignancy

About 1 out of 1000 lesions[24] are or become malignant, typically as a leiomyosarcoma on histology. A sign that

a lesion may be malignant is growth after menopause.[24] There is no consensus among pathologists regarding

the transformation of Leiomyoma into a sarcoma. Most pathologists believe that a Leiomyosarcoma is a de

novo disease[citation needed].

[edit]Metastasis

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can

be dangerous depending on their location.[43]

In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a vessel but there is no

risk of recurrence.

In Intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as their source. Cardiac

involvement can be fatal.

In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such as the lungs and

lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.

In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the peritoneal and

omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves

benignly.

[edit]Organizations, research and political aspects

The Center for Uterine Fibroids which is associated with Brigham and Women’s Hospital in Boston MA ([1]) is

currently recruiting volunteers for an investigation of all aspects of the aetiology, pathology of fibroids and

development of treatment options. This institution also has a lot of clinical trials focused on African American

women. The focus of one study is the search for a specific gene associated with the development of fibroids.

Since one risk factor for uterine fibroids is having a family history of fibroids, the results of this study will provide

some answers on the heredity of the illness. Some women may interact with the healthcare system by getting

an ultrasound to diagnosis symptoms if they’ve had a mother, sister or grandmother who has previously

suffered with these benign tumors.

[edit]Fibroid Research and Education Act of 2005

The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor and Pensions but never

passed for a Senate or House vote. The proposed Uterine Fibroid Research and Education Act of 2005

mentioned that $5 billion dollars is spent annually on hysterectomy surgeries each year, which affect 22% of

African Americans and 7% of Caucasian women. The bill also called for more funding for research and

educational purposes. It also states that of the $27 million dollars issued to NIH, only $5 million was allocated

for Uterine Fibroids in 2004.

[edit]Fibroids in animals

Uterine fibroids are rare in animals. They have been observed in certain dogs and Baltic Gray Seals.[44]

FibroadenomaFrom Wikipedia, the free encyclopedia

Fibroadenoma

Classification and external resources

Histopathologic image of breast fibroadenoma. Core needle biopsy.

Hematoxylin & eosin stain.

ICD-10 D 24.

ICD-9 217

ICD-O: M 9010/0 -M9012, M9020, M9030

DiseasesDB 1595

MedlinePlus 007216

eMedicine radio/109

MeSH D018226

Fibroadenomas of the breast are small, solid, rubbery, noncancerous, harmless lumps composed of fibrous

and glandular tissue. Becausebreast cancer can also appear as a lump, doctors usually recommend a tissue

sample (biopsy) to rule out cancer. Unlike typical lumps from breast cancer, fibroadenomas are easy to move,

with clearly defined edges.[1][2]

Contents

[hide]

1 Signs and symptoms

2 Diagnosis

3 Etiology and epidemiology

4 Pathology

o 4.1 Cytology

o 4.2 Macroscopic

o 4.3 Microscopic

5 Treatment

o 5.1 Cryoablation Treatment

6 Fibroadenoma images

7 Video on Fibroadenoma

8 References

[edit]Signs and symptoms

The typical case is the presence of a painless, firm, solitary, mobile, slowly growing lump in the breast of a

woman of childbearing years.[2][3][4]

In the male breast, fibroepithelial tumors are very rare, and are mostly Phyllodes tumors. Exceptionally rare

case reports exist of fibroadenomas in the male breast, however these cases may be associated

with antiandrogen treatment.[5]

[edit]Diagnosis

A fibroadenoma is usually diagnosed through clinical examination, ultrasound or mammography, and often

a needle biopsy sample of the lump [3].

[edit]Etiology and epidemiology

Fibroadenomas arise in the terminal duct lobular unit of the breast. They are the most common breast tumor in

adolescent women. They also occur in a small number of post-menopausal women. Their incidence declines

with increasing age, and they generally appear before the age of thirty years, probably partly as a result of

normal estrogenic hormonal fluctuation. Although fibroadenoma is considered a neoplasm, some authors

believe fibroadenoma arises from hyperplasia of normal breast lobule components.[2][6].[4]

[edit]Pathology

[edit]Cytology

The diagnostic findings on needle biopsy consist of abundant stromal cells, which appear as bare bipolar

nuclei, throughout the aspirate; sheets of fairly uniform sized epithelial cells which are typically arranged in

either an antler-like pattern, or a honeycomb pattern. These epithelial sheets tend to show

typical metachromatic blue staining on DiffQuick staining. Foam cells and apocrine cells may also be seen,

although these are less diagnostic features.[3][6] The gallery images below demonstrate these features.

[edit]Macroscopic

Approximately ninety percent of fibroadenomas are less than three centimetres in diameter. The vast majority

of the remaining ten percent that are four centimetres or larger occur mostly in women under twenty years of

age. The tumor is round or ovoid, elastic, nodular, and has a smooth surface. The cut surface usually

appears homogenous and firm, and is grey-white or tan in colour.[6]

[edit]Microscopic

The proliferation forms duct-like spaces. These are surrounded by fibroblastic stroma. The proliferating

epithelium is of normal appearance. Fibroadenomas may be sub-classified into two types, intracanalicular and

pericanalicular, depending on the relative amounts of epithelial and stromal tissue present. There is also a

mixed type, in which both forms coexist simultaneously. Intracanalicular fibroadenomas show predominant

stromal proliferation that compresses the ducts, which are irregular and reduced to slits. Pericanalicular

fibroadenomas show fibrous stromal proliferation around the ductal spaces that allows the duct spaces remain

round or oval.[7] The gallery image below demonstrates both morphological subtypes.

[edit]Treatment

Most fibroadenomas are left in situ and monitored by a doctor, or the patient in question. Some are treated by

surgical excision. They are removed with a small margin of normal breast tissue if the preoperative clinical

investigations are suggestive of the diagnosis. A small amount of normal tissue must be removed in case the

lesion turns out to be a phyllodes tumouron microscopic examination.[6][8]

Because needle biopsy is often a reliable diagnostic investigation, some doctors may decide not to operate to

remove the lesion, and instead opt for clinical follow-up to serially observe the lesion over time using clinical

examination and mammography to determine the rate of growth, if any, of the lesion. A growth rate of less than

sixteen percent per month in women under fifty years of age, and a growth rate of less than thirteen percent per

month in women over fifty years of age have been published as safe growth rates for continued non-operative

treatment and clinical observation.[9]

Fibroadenomas have not been shown to recur following complete excision or transform into phyllodes

tumours following partial or incomplete excision.[6]

There are also natural treatments being touted to diminish fibroadenomas, such as Fibrosolve, but no definite

studies have been made as to prove their effectiveness.

[edit]Cryoablation Treatment

The FDA has approved cryoablation (the use of extreme cold to destroy tissue) of a fibroadenoma as a safe,

effective and minimally-invasive alternative to open surgical removal.[10] In the procedure, ultrasound imaging is

used to guide a probe into the mass of breast tissue. Extremely cold temperatures are then used to destroy the

abnormal cells[11] and over time the cells are reabsorbed into the body. The procedure can be performed in an

office setting with local anesthesia only and leaves substantially less scarring than open surgical procedures. [11]

The American Society of Breast Surgeons recommends the following criteria to establish a patient as a

candidate for cryoablation of a fibroadenoma:[10]

1. The lesion must be sonographically visible.

2. The diagnosis of fibroadenoma must be confirmed histologically.

3. Lesions should be less than 4 cm in diameter.

[edit]Fibroadenoma images

Fibroadenoma Histology

(H&E). The image

demonstrates intracanalicular

morphology (top right) and

pericanalicular morphology

(bottom left)

Fibroadenoma, Fine Needle

Aspiration Biopsy (Giemsa or

DiffQuickTMstain). The image

shows abundant bare bipolar

stromal nuclei surrounding sheets

ofmetachromatic epithelial cells.

Fibroadenoma, Fine Needle

Aspiration Biopsy

(Papanicolou stain). The image

shows a sheet of epithelial

cells in the typical antler

pattern.

Histopathologic image of

breast fibroadenoma. Core

needle biopsy. Hematoxylin

& eosin stain.

Cerebral venous sinus thrombosisFrom Wikipedia, the free encyclopedia

Cerebral venous sinus thrombosis

Classification and external resources

Dural veins

ICD-10 I 63.6 , I 67.6

ICD-9 325, 437.6

DiseasesDB 2242

eMedicine neuro/642 radio/105

Cerebral venous sinus thrombosis (CVST) is a rare form of stroke that results from thrombosis (a blood clot)

of the dural venous sinuses, which drain blood from the brain. Symptoms may include headache, abnormal

vision, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body,

and seizures. The diagnosis is usually by computed tomography (CT/CAT scan) or magnetic resonance

imaging (MRI) employing radiocontrast to demonstrate obstruction of the venous sinuses by thrombus.[1]

Treatment is with anticoagulants (medication that suppresses blood clotting), and

rarely thrombolysis (enzymatic destruction of the blood clot). Given that there is usually an underlying cause for

the disease, tests may be performed to look for these. The disease may be complicated by raised intracranial

pressure, which may warrant surgical intervention such as the placement of a shunt.[1] There are several other

terms for the condition, such as cerebral venous and sinus thrombosis, (superior) sagittal sinus

thrombosis, dural sinus thrombosis and intracranial venous thrombosis as well as the older

term cerebral thrombophlebitis.

Contents

[hide]

1 Signs and symptoms

2 Causes

o 2.1 Risk factors

3 Diagnosis

o 3.1 Investigations

o 3.2 Further tests

4 Pathogenesis

5 Treatment

6 Prognosis

7 Epidemiology

8 History

9 References

10 External links

[edit]Signs and symptoms

Nine in ten people with sinus thrombosis have a headache; this tends to worsen over the period of several

days, but may also develop suddenly (thunderclap headache).[1] The headache may be the only symptom of

cerebral venous sinus thrombosis.[2] Many patients have symptoms of stroke: inability to move one or more

limbs, weakness on one side of the face ordifficulty speaking. This does not necessarily affect one side of the

body as in the more common "arterial" stroke.[1]

40% of all patients have seizures, although it is more common still in women who develop sinus thrombosis

peripartum (in the period before and after giving birth).[3] These are mostly seizures affecting only one part of

the body and unilateral (occurring on one side), but occasionally the seizures are generalised and rarely they

lead to status epilepticus (persistent or recurrent seizure activity for a long period of time).[1]

In the elderly, many of the aforementioned symptoms may not occur. Common symptoms in the elderly with

this condition are otherwise unexplained changes in mental status and a depressed level of consciousness.[4]

The intracranial pressure (pressure around the brain) may rise, causing papilledema (swelling of the optic disc)

which may be experienced as visual obscurations. In severely raised intracranial pressure, the level of

consciousness is decreased, the blood pressure rises, the heart rate falls and the patient assumes an

abnormal posture.[1]

[edit]Causes

[edit]Risk factors

Cerebral venous sinus thrombosis is more common in particular situations. 85% of patients have at least one of

these risk factors:[1]

Thrombophilia , a tendency to develop blood clots due to abnormalities in coagulation, e.g. factor V Leiden,

deficiency of protein C, protein S or antithrombin, or related problems

Nephrotic syndrome , a kidney problem causing protein loss in the urine

Chronic inflammatory diseases, such as inflammatory bowel disease, lupus and Behçet's disease

Pregnancy  and puerperium (the period after giving birth)

Particular blood disorders, especially polycythemia vera and paroxysmal nocturnal hemoglobinuria

Use of estrogen-containing forms of hormonal contraception

Meningitis  and infections of the ear, nose and throat area such as mastoiditis and sinusitis

Direct injury to the venous sinuses

Medical procedures in the head and neck area

[edit]Diagnosis

[edit]Investigations

The diagnosis may be suspected on the basis of the symptoms, for example the combination of headache,

signs of raised intercranial pressure and focal neurological abnormalities, or when alternative causes of

headache and neurological abnormalities, such as a subarachnoid hemorrhage, have been excluded.[1]

CT, MRI and angiography

CT venogram showing a filling defect in the sagittal sinus (black arrow)

There are various neuroimaging investigations that may detect cerebral sinus thrombosis. Cerebral edema and

venous infarction may be apparent on any modality, but for the detection of the thrombus itself, the most

commonly used tests are computed tomography (CT) andmagnetic resonance imaging (MRI), both using

various types of radiocontrast to perform a venogram and visualise the veins around the brain.[1]

Computed tomography, with radiocontrast in the venous phase (CT venography or CTV), has a detection rate

that in some regards exceeds that of MRI. The test involves injection into a vein (usually in the arm) of a

radioopaque substance, and time is allowed for the bloodstream to carry it to the cerebral veins - at which point

the scan is performed. It has a sensitivity of 75-100% (it detects 75-100% of all clots present), and

a specificity of 81-100% (it would be incorrectly positive in 0-19%). In the first two weeks, the "empty delta sign"

may be observed (in later stages, this sign may disappear).[5]

Magnetic resonance venography employs the same principles, but uses MRI as a scanning modality. MRI has

the advantage of being better at detecting damage to the brain itself as a result of the increased pressure on

the obstructed veins, but it is not readily available in many hospitals and the interpretation may be difficult. [5]

Cerebral angiography may demonstrate smaller clots than CT or MRI, and obstructed veins may give the

"corkscrew appearance".[1] This, however, requires puncture of the femoral artery with a sheath and advancing

a thin tube through the blood vessels to the brain where radiocontrast is injected before X-ray images are

obtained. It is therefore only performed if all other tests give unclear results or when other treatments may be

administered during the same procedure.

D-dimer

A 2004 study suggested that the D-dimer blood test, already in use for the diagnosis of other forms of

thrombosis, was abnormal (above 500 μg/l) in 34 out of 35 patients with cerebral sinus thrombosis, giving it

a sensitivity of 97.1%, a negative predictive value of 99.6%, a specificity of 91.2%, and a positive predictive

value of 55.7%. Furthermore, the level of the D-dimer correlated with the extent of the thrombosis. [6] A

subsequent study, however, showed that 10% of patients with confirmed thrombosis had a normal D-dimer,

and in those who had presented with only a headache 26% had a normal D-dimer. The study concludes that D-

dimer is not useful in the situations where it would make the most difference, namely in lower probability cases.[7]

[edit]Further tests

In most patients, the direct cause for the cerebral sinus thrombosis is not readily apparent. Identifying a source

of infection is crucial; it is common practice to screen for various forms ofthrombophilia (a propensity to form

blood clots).[1]

[edit]Pathogenesis

The veins of the brain, both the superficial veins and the deep venous system, empty into the dural venous

sinuses, which carry blood back to the jugular vein and thence to the heart. In cerebral venous sinus

thrombosis, blood clots usually form both in the veins of the brain and the venous sinuses. The thrombosis of

the veins themselves causes venous infarction–damage to brain tissue due to a congested and therefore

insufficient blood supply. This results in cerebral edema (both vasogenic and cytotoxic edema), and leads to

small petechialhaemorrhages that may merge into large haematomas. Thrombosis of the sinuses is the main

mechanism behind the increase in intracranial pressure due to decreased resorption of cerebrospinal fluid

(CSF). The condition does not lead to hydrocephalus, however, because there is no difference in pressure

between various parts of the brain.[1]

Any blood clot forms due to an imbalance between coagulation (the formation of the insoluble blood

protein fibrin) and fibrinolysis. The three major mechanisms for such an imbalance are enumerated in Virchow's

triad: alterations in normal blood flow, injury to the blood vessel wall, and alterations in the constitution of blood

(hypercoagulability). Most cases of cerebral venous sinus thrombosis are due to hypercoagulability. [1]

It is possible for the clot to break off and migrate (embolise) to the lungs, causing a pulmonary embolism.[1][3] An

analysis of earlier case reports concludes that this occurs in about 10% of cases, but has a very poor

prognosis.[8]

[edit]Treatment

Various studies have investigated the use of anticoagulation to suppress blood clot formation in cerebral

venous sinus thrombosis. Before these trials had been conducted, there had been a concern that small areas

of hemorrhage in the brain would bleed further as a result of treatment; the studies showed that this concern

was unfounded.[9] Clinical practice guidelines now recommend heparin or low molecular weight heparin in the

initial treatment, followed by warfarin, provided there are no other bleeding risks that would make these

treatments unsuitable.[3][10][11] Some experts discourage the use of anticoagulation if there is extensive

hemorrhage; in that case, they recommend repeating the imaging after 7–10 days. If the hemorrhage has

decreased in size, anticoagants are commenced, while no anticoagulants are given if there is no reduction. [12]

The duration of warfarin treatment depends on the circumstances and underlying causes of the condition. If the

thrombosis developed under temporary circumstances (e.g. pregnancy), three months are regarded as

sufficient. If the condition was unprovoked but there are no clear causes or a "mild" form of thrombophilia, 6 to

12 months is advised. If there is a severe underlying thrombosis disorder, warfarin treatment may need to

continue indefinitely.[3]

Thrombolysis (removal of the blood clot with "clot buster" medication) has been described, either systemically

by injection into a vein or directly into the clot during angiography. The 2006European Federation of

Neurological Societies guideline recommends that thrombolysis is only used in patients who deteriorate despite

adequate treatment, and other causes of deterioration have been eliminated. It is unclear which drug and which

mode of administration is the most effective. Bleeding into the brain and in other sites of the body is a major

concern in the use of thrombolysis.[3] American guidelines make no recommendation with regards to

thrombolysis, stating that more research is needed.[11]

Raised intracranial pressure, if severe or threatening vision, may require therapeutic lumbar puncture (removal

of excessive cerebrospinal fluid), medication (acetazolamide), orneurosurgical treatment (optic nerve sheath

fenestration or shunting).[1] In certain situations, anticonvulsants may be used to prevent seizures; these are

focal neurological problems (e.g. inability to move a limb) and/or focal changes of the brain tissue on CT or MRI

scan.[3]

[edit]Prognosis

In 2004 the first adequately large scale study on the natural history and long-term prognosis of this condition

was reported; this showed that at 16 months follow-up 57.1% of patients had full recovery, 29.5%/2.9%/2.2%

had respectively minor/moderate/severe symptoms or impairments, and 8.3% had died. Severe impairment or

death were more likely in those aged over 37 years, male, affected by coma, mental status disorder,

intracerebral hemorrhage, thrombosis of the deep cerebral venous system, central nervous system infection

and cancer.[13] A subsequent systematic review of nineteen studies in 2006 showed that mortality is about 5.6%

during hospitalisation and 9.4% in total, while of the survivors 88% make a total or near-total recovery. After

several months, two thirds of the cases has resolution ("recanalisation") of the clot. The rate of recurrence was

low (2.8%).[14]

In children with CVST, the mortality averages 50%. Poor outcome is more likely if a child with CVST develops

seizures or has evidence of venous infarction on imaging.[15]

[edit]Epidemiology

Cerebral venous sinus thrombosis is rare, with an estimated 3-4 cases per million annual incidence in adults.

While it may occur in all age groups, it is most common in the third decade. 75% are female. [3] Given that older

studies show no difference in incidence between men and women, it has been suggested that the use of oral

contraceptives in women is behind the disparity between the sexes.[1] A 1995 report from Saudi Arabia found a

doubled incidence at 7 cases per 100,000; this was attributed to the fact that Behçet's disease, which increases

risk of CVST, is more common in the Middle East.[16]

A 1973 report found that CVST could be found on autopsy (examination of the body after death) in nine percent

of all people. Many of these were elderly and had neurological symptoms in the period leading up to their

death, and many suffered from concomitant heart failure.[17]

In children, a Canadian study reported in 2001 that CVST occurs in 6.7 per million annually. 43% occur in the

newborn (less than one month old), and a further 10% in the first year of life. Of the newborn, 84% were

already ill, mostly from complications after childbirth and dehydration.[15]

[edit]History

The first description of thrombosis of the cerebral veins and sinuses is attributed to the French physician Ribes,

who in 1825 observed thrombosis of the saggital sinus and cerebral veins in a man who had suffered from

seizures and delirium.[18] Until the second half of the 20th century it remained a diagnosis generally made after

death.[19] In the 1940s, reports by DrCharles Symonds and others allowed for the clinical diagnosis of cerebral

venous thrombosis, using characteristic signs and symptoms and results of lumbar puncture.[20][21]

Improvements on the diagnosis of cerebral venous sinus thrombosis in life were made with the introduction

of venography in 1951,[22] which also aided in the distinction from idiopathic intracranial hypertension,[23] which

has similar presenting signs and symptoms in many cases.[19]

The British gynecologist Stansfield is credited with the introduction, in 1942, of the just recently introduced

anticoagulant heparin in the treatment of CVST in 1942.[19][21] Clinical trials in the 1990s finally resolved the

concern about using anticoagulants in most cases of CVST.[3]

CyanosisFrom Wikipedia, the free encyclopedia

Cyanosis

A baby with a heart condition. Note purple nailbeds.

ICD-10 R 23.0

ICD-9 782.5

Cyanosis is a blue coloration of the skin and mucous membranes due to the presence of greater than, or

equal to, 2.5 g/dL of deoxygenatedhemoglobin in blood vessels near the skin surface. [1]

Although human blood is always a shade of red (except in rare cases of hemoglobin-related disease), the

optical properties of skin distort the dark red color of deoxygenated blood to make it appear bluish. [2]

The elementary principle behind cyanosis is that deoxygenated hemoglobin is more prone to the optical bluish

discoloration, and also produces vasoconstriction that makes it more evident. The scattering of color that

produces the blue hue of veins and cyanosis is similar to the process that makes the sky appear blue: some

colors are refracted and absorbed more than others. During cyanosis, tissues are uncharacteristically low on

oxygen, and therefore tissues that would normally be filled with bright oxygenated blood are instead filled with

darker, deoxygenated blood. Darker blood is much more prone to the blue-shifting optical effects, [3] and thus

oxygen deficiency - hypoxia - leads to blue discoloration of the lips and other mucous membranes.

The name is derived from the color cyan, which comes from kyanous, the Greek word for blue.

Cyanosis is an abnormal blue discoloration of the skin and mucous membranes and requires an absolute

concentration of deoxygenated haemoglobin of > 5 g/dL. It is actually easier to appreciate in those with high

hemoglobin than those with anemia. It can be difficult to detect in patients with deeply pigmented skin. When

signs of cyanosis first appear, intervention must be made within 3–5 minutes.

Contents

[hide]

1 Definition

2 Differential diagnosis

o 2.1 Central cyanosis

2.1.1 Causes

o 2.2 Peripheral cyanosis

2.2.1 Causes

3 See also

4 References

5 External links

[edit]Definition

Cyanosis is divided in to two main types: central (around the core and lips) and peripheral (only the extremities

are affected).

[edit]Differential diagnosis

Cyanosis can occur in the fingers, including underneath the fingernails, as well as other extremities (called

peripheral cyanosis), or in the lips and tongue (central cyanosis).

[edit]Central cyanosis

Central cyanosis is often due to a circulatory or ventilatory problem that leads to poor blood oxygenation in the

lungs or greater oxygen extraction due to slowing down of blood circulation in the skin's blood vessels.

Acute cyanosis can be a result of asphyxiation or choking, and is one of the surest signs that respiration is

being blocked.

[edit]Causes

1. Central Nervous System:

Intracranial hemorrhage

Cerebral anoxia

Drug overdose  (e.g. Heroin)

2. Respiratory System:

Bronchiolitis

Bronchospasm  (e.g. Asthma)

Lung disease

Pulmonary embolism

Hypoventilation

COPD  (emphysema and chronic bronchitis)

3.Cardiac Disorders:

Congenital heart disease  (e.g. Tetralogy of Fallot, Right to left shunts in heart or great vessels)

Heart failure

Heart valve  disease

Myocardial infarction

4.Blood:

Methemoglobinemia

Polycythaemia

5.Others:

High altitude

Hypothermia

Congenital cyanosis (HbM Boston) arises from a mutation in the α-codon which results in a change

of primary sequence, H --> Y. Tyrosine stabilises the Fe(III) form (oxyhaemoglobin) creating a permanent

T-state of Hb.

[edit]Peripheral cyanosis

Peripheral cyanosis is the blue tint in fingers or extremities, due to inadequate circulation. The blood reaching

the extremities is not oxygen rich and when viewed through the skin a combination of factors can lead to the

appearance of a blue color. All factors contributing to central cyanosis can also cause peripheral symptoms to

appear, however peripheral cyanosis can be observed without there being heart or lung failures. Small blood

vessels may be restricted and can be treated by increasing the normal oxygenation level of the blood.

[edit]Causes

All common causes of central cyanosis

Arterial  obstruction

Cold exposure (due to vasoconstriction)

Raynaud's phenomenon  (vasoconstriction)

Reduced cardiac output (e.g. heart failure, hypovolaemia)

Vasoconstriction

Venous  obstruction (e.g. deep vein thrombosis)

Circulatory systemFrom Wikipedia, the free encyclopedia

This article is about the organ system. For the band, see Circulatory System. For transport in plants,

see Vascular tissue.

Circulatory system

The human circulatory system. Red indicates oxygenated blood, blue

indicates deoxygenated.

Latin systema cardiovasculare

The circulatory system is an organ system that passes nutrients (such as amino acids and electrolytes),

gases, hormones, blood cells, etc. to and from cells in the body to help fight diseases and help stabilize body

temperature and pH to maintain homeostasis.

This system may be seen strictly as a blood distribution network, but some consider the circulatory system as

composed of thecardiovascular system, which distributes blood,[1] and the lymphatic system,[2] which

distributes lymph. While humans, as well as other vertebrates, have a closed cardiovascular system (meaning

that the blood never leaves the network of arteries, veins and capillaries), some invertebrate groups have an

open cardiovascular system. The most primitive animal phyla lack circulatory systems. The lymphatic system,

on the other hand, is an open system.

Two types of fluids move through the circulatory system: blood and lymph. The blood, heart, and blood vessels

form the cardiovascular system. The lymph, lymph nodes, and lymph vessels form the lymphatic system. The

cardiovascular system and the lymphatic system collectively make up the circulatory system.

Contents

[hide]

1 Human cardiovascular system

o 1.1 Pulmonary circulation

o 1.2 Systemic circulation

o 1.3 Coronary circulation

o 1.4 Heart

o 1.5 Closed cardiovascular system

o 1.6 Measurement techniques

o 1.7 Health and disease

o 1.8 Oxygen transportation

2 Nonhuman

o 2.1 Other vertebrates

o 2.2 Open circulatory system

o 2.3 Absence of circulatory system

3 History of discovery

4 Other images

5 See also

6 References

7 External links

Human cardiovascular system

The main components of the human cardiovascular system are the heart and the blood vessels.[3] It includes:

the pulmonary circulation, a "loop" through the lungs where blood is oxygenated; and the systemic circulation, a

"loop" through the rest of the body to provide oxygenated blood. An average adult contains five to six quarts

(roughly 4.7 to 5.7 liters) of blood, which consists of plasma, red blood cells, white blood cells, and platelets.

Also, the digestive system works with the circulatory system to provide the nutrients the system needs to keep

the heart pumping.

Pulmonary circulationMain article: Pulmonary circulation

The Pulmonary circulation is the portion of the cardiovascular system which transports oxygen-

depleted blood away from the heart, to the lungs, and returns oxygenated blood back to the heart.

Oxygen deprived blood from the vena cava enters the right atrium of the heart and flows through the tricuspid

valve into the right ventricle, from which it is pumped through the pulmonary semilunar valve into the pulmonary

arteries which go to the lungs. Pulmonary veins return the now oxygen-rich blood to the heart, where it enters

the left atrium before flowing through themitral valve into the left ventricle. Then, oxygen-rich blood from the left

ventricle is pumped out via the aorta, and on to the rest of the body.

Systemic circulationMain article: Systemic circulation

Systemic circulation is the portion of the cardiovascular system which transports oxygenated blood away from

the heart, to the rest of the body, and returns oxygen-depleted blood back to the heart. Systemic circulation is,

distance-wise, much longer than pulmonary circulation, transporting blood to every part of the body.

Coronary circulationMain article: Coronary circulation

The coronary circulatory system provides a blood supply to the heart. As it provides oxygenated blood to the

heart, it is by definition a part of the systemic circulatory system.

Heart

View from the front, which means the right side of the heart is on the left of the diagram (and vice-versa)

Main article: heart

The heart pumps oxygenated blood to the body and deoxygenated blood to the lungs. In the human heart there

is one atrium and one ventricle for each circulation, and with both a systemic and a pulmonary circulation there

are four chambers in total: left atrium, left ventricle, right atrium and right ventricle. The right atrium is the upper

chamber of the right side of the heart. The blood that is returned to the right atrium is deoxygenated (poor in

oxygen) and passed into the right ventricle to be pumped through the pulmonary artery to the lungs for re-

oxygenation and removal of carbon dioxide. The left atrium receives newly oxygenated blood from the lungs as

well as the pulmonary vein which is passed into the strong left ventricle to be pumped through the aorta to the

different organs of the body.

Closed cardiovascular system

The cardiovascular systems of humans are closed, meaning that the blood never leaves the network of blood

vessels. In contrast, oxygen and nutrients diffuse across the blood vessel layers and enters interstitial fluid,

which carries oxygen and nutrients to the target cells, and carbon dioxide and wastes in the opposite direction.

The other component of the circulatory system, thelymphatic system, is not closed. The heart is located in the

center of the body between the two lungs. The reason that the heart beat is felt on the left side is because the

left ventricle is pumping harder.

Measurement techniques

Electrocardiogram —for cardiac electrophysiology

Sphygmomanometer  and stethoscope—for blood pressure

Pulse meter —for cardiac function (heart rate, rhythm, dropped beats)

Pulse —commonly used to determine the heart rate in absence of certain cardiac pathologies

Heart rate variability  -- used to measure variations of time intervals between heart beats

Nail  bed blanching test—test for perfusion

Vessel cannula or catheter pressure measurement—pulmonary wedge pressure or in older animal

experiments.

Health and diseaseMain article: Cardiovascular disease

Main article: Congenital heart defect

Oxygen transportationMain article: Blood#Oxygen transport

About 98.5% of the oxygen in a sample of arterial blood in a healthy human breathing air at sea-level pressure

is chemically combined with haemoglobin molecules. About 1.5% is physically dissolved in the other blood

liquids and not connected to Hgb. The haemoglobin molecule is the primary transporter of oxygen

in mammals and many other species.

Nonhuman

Other vertebrates

The circulatory systems of all vertebrates, as well as of annelids (for example, earthworms)

and cephalopods (squid and octopus) are closed, just as in humans. Still, the systems

of fish,amphibians, reptiles, and birds show various stages of the evolution of the circulatory system.

In fish, the system has only one circuit, with the blood being pumped through the capillaries of the gills and on

to the capillaries of the body tissues. This is known as single cyclecirculation. The heart of fish is therefore only

a single pump (consisting of two chambers).

In amphibians and most reptiles, a double circulatory system is used, but the heart is not always completely

separated into two pumps. Amphibians have a three-chambered heart.

In reptiles, the ventricular septum of the heart is incomplete and the pulmonary artery is equipped with

a sphincter muscle. This allows a second possible route of blood flow. Instead of blood flowing through the

pulmonary artery to the lungs, the sphincter may be contracted to divert this blood flow through the incomplete

ventricular septum into the left ventricle and out through the aorta. This means the blood flows from the

capillaries to the heart and back to the capillaries instead of to the lungs. This process is useful

to ectothermic (cold-blooded) animals in the regulation of their body temperature.

Birds and mammals show complete separation of the heart into two pumps, for a total of four heart chambers; it

is thought that the four-chambered heart of birds evolved independently from that of mammals.

Open circulatory system

The Open Circulatory System is a system in which fluid (called hemolymph) in a cavity called

the hemocoel bathes the organs directly with oxygen and nutrients and there is no distinction

between blood and interstitial fluid; this combined fluid is called hemolymph or haemolymph. Muscular

movements by the animal during locomotion can facilitate hemolymph movement, but diverting flow from one

area to another is limited. When the heart relaxes, blood is drawn back toward the heart through open-ended

pores (ostia).

Hemolymph fills all of the interior hemocoel of the body and surrounds all cells. Hemolymph is composed

of water, inorganic salts (mostly Na + , Cl - , K + , Mg 2+ , and Ca 2+ ), and organic

compounds (mostly carbohydrates, proteins, and lipids). The primary oxygen transporter molecule

is hemocyanin.

There are free-floating cells, the hemocytes, within the hemolymph. They play a role in the arthropod immune

system.

Absence of circulatory system

Circulatory systems are absent in some animals, including flatworms (phylum Platyhelminthes). Their body

cavity has no lining or enclosed fluid. Instead a muscular pharynx leads to an extensively branched digestive

system that facilitates direct diffusion of nutrients to all cells. The flatworm's dorso-ventrally flattened body

shape also restricts the distance of any cell from the digestive system or the exterior of the

organism. Oxygen can diffuse from the surrounding water into the cells, and carbon dioxide can diffuse out.

Consequently every cell is able to obtain nutrients, water and oxygen without the need of a transport system.

Some animals, such as jellies, have more extensive branching from their gastrovascular cavity (which functions

as both a place of digestion and a form of circulation), this branching allows for bodily fluids to reach the outer

layers, since the digestion begins in the inner layers.

History of discovery

The earliest known writings on the circulatory system are found in the Ebers Papyrus (16th century BCE),

an ancient Egyptian medical papyrus containing over 700 prescriptions and remedies, both physical and

spiritual. In the papyrus, it acknowledges the connection of the heart to the arteries. The Egyptians thought air

came in through the mouth and into the lungs and heart. From the heart, the air traveled to every member

through the arteries. Although this concept of the circulatory system is greatly flawed, it represents one of the

earliest accounts of scientific thought.

In the 6th century BCE, the knowledge of circulation of vital fluids through the body was known to

the Ayurvedic physician Sushruta in ancient India.[4] He also seems to have possessed knowledge of

the arteries, described as 'channels' by Dwivedi & Dwivedi (2007).[4] The valves of the heart were discovered by

a physician of the Hippocratean school around the 4th century BCE. However their function was not properly

understood then. Because blood pools in the veins after death, arteries look empty. Ancient anatomists

assumed they were filled with air and that they were for transport of air.

The Greek physician, Herophilus, distinguished veins from arteries but thought that the pulse was a property of

arteries themselves. Greek anatomist Erasistratus observed that arteries that were cut during life bleed. He

ascribed the fact to the phenomenon that air escaping from an artery is replaced with blood that entered by

very small vessels between veins and arteries. Thus he apparently postulated capillaries but with reversed flow

of blood.[5]

In 2nd century AD Rome, the Greek physician Galen knew that blood vessels carried blood and identified

venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions. Growth

and energy were derived from venous blood created in the liver from chyle, while arterial blood gave vitality by

containing pneuma (air) and originated in the heart. Blood flowed from both creating organs to all parts of the

body where it was consumed and there was no return of blood to the heart or liver. The heart did not pump

blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the

arteries themselves.

Galen believed that the arterial blood was created by venous blood passing from the left ventricle to the right by

passing through 'pores' in the interventricular septum, air passed from the lungs via the pulmonary artery to the

left side of the heart. As the arterial blood was created 'sooty' vapors were created and passed to the lungs

also via the pulmonary artery to be exhaled.

In 1025, The Canon of Medicine by the Persian physician, Avicenna, "erroneously accepted the Greek notion

regarding the existence of a hole in the ventricular septum by which the blood traveled between the ventricles."

Despite this, Avicenna "correctly wrote on the cardiac cycles and valvular function", and "had a vision of blood

circulation" in his Treatise on Pulse.[6] While also refining Galen's erroneous theory of the pulse, Avicenna

provided the first correct explanation of pulsation: "Every beat of the pulse comprises two movements and two

pauses. Thus, expansion : pause : contraction : pause. [...] The pulse is a movement in the heart and

arteries ... which takes the form of alternate expansion and contraction."[7]

In 1242, the Arabian physician, Ibn al-Nafis, became the first person to accurately describe the process

of pulmonary circulation, for which he is sometimes considered the father ofcirculatory physiology.[8][not in citation

given] Ibn al-Nafis stated in his Commentary on Anatomy in Avicenna's Canon:

"...the blood from the right chamber of the heart must arrive at the left chamber but there is no direct pathway

between them. The thick septum of the heart is not perforated and does not have visible pores as some people

thought or invisible pores as Galen thought. The blood from the right chamber must flow through the vena

arteriosa (pulmonary artery) to the lungs, spread through its substances, be mingled there with air, pass

through the arteria venosa (pulmonary vein) to reach the left chamber of the heart and there form the vital

spirit..."

In addition, Ibn al-Nafis had an insight into what would become a larger theory of the capillary circulation. He

stated that "there must be small communications or pores (manafidh in Arabic) between the pulmonary artery

and vein," a prediction that preceded the discovery of the capillary system by more than 400 years. [9] Ibn al-

Nafis' theory, however, was confined to blood transit in the lungs and did not extend to the entire body.

Finally William Harvey, a pupil of Hieronymus Fabricius (who had earlier described the valves of the veins

without recognizing their function), performed a sequence of experiments, and published Exercitatio Anatomica

de Motu Cordis et Sanguinis in Animalibus in 1628, which "demonstrated that there had to be a direct

connection between the venous and arterial systems throughout the body, and not just the lungs. Most

importantly, he argued that the beat of the heart produced a continuous circulation of blood through minute

connections at the extremities of the body. This is a conceptual leap that was quite different from Ibn al-Nafis'

refinement of the anatomy and bloodflow in the heart and lungs."[10] This work, with its essentially correct

exposition, slowly convinced the medical world. However, Harvey was not able to identify the capillary system

connecting arteries and veins; these were later discovered by Marcello Malpighi in 1661.

Other images

More accurate drawing

Bubonic plagueFrom Wikipedia, the free encyclopedia

This article is about the disease in general. For information about the medieval European plague, see Black

Death.

Bubonic plague

Classification and external resources

ICD-10 A200 [1]

ICD-9 02 0.0 [1]

DiseasesDB 14226

Bubonic plague is the best known manifestation of the plague, caused by the Gram-

negative bacterium Yersinia pestis (formerly known asPasteurella pestis). It belongs to the

family Enterobacteriaceae. The term bubonic plague is derived from the Greek word bubo, meaning "swollen

gland". Swollen lymph nodes (buboes) especially occur in the armpit and groin in persons suffering from

bubonic plague. Bubonic plague was often used synonymously for plague, but it does in fact refer specifically to

an infection that enters through the skin and travels through the lymphatics, as is often seen in flea-borne

infections. The bubonic plague kills about two out of three of infected patients in 2–6 days without treatment. It

may have been the cause of the Black Death that swept through Europe in the 14th century and killed more

than 25 million people, one third of the European population.[2]

Contents

[hide]

1 Signs and symptoms

2 Pathophysiology

3 Treatment

4 History

5 Biological warfare

6 See also

7 Footnotes

8 References

9 Further reading

[edit]Signs and symptoms

The most famous symptom of bubonic plague is painful, swollen lymph glands, called buboes. These are

commonly found in the armpits, groin or neck. Due to its bite-based form of infection, the bubonic plague is

often the first step of a progressive series of illness. Two other forms of the plague, pneumonic and septicemic,

often resulted after a patient with the bubonic plague developed pneumonia or blood poisoning.

However, pneumonic plague, unlike the bubonic or septicemic, induced coughing, was also very infectious and

allowed person-to-person spread.

Other symptoms include heavy breathing, continuous blood vomiting, urination of blood, aching limbs,

coughing, and extreme pain. The pain is usually caused by the decaying, or decomposing, of the skin while the

person is still alive. Additional symptoms include fever, headaches, chills, extreme tiredness, gastrointestinal

problems, lenticulae (black dots scattered throughout the body), delirium, coma and death.

[edit]Pathophysiology

The bubonic plague is an infection of the lymphatic system, usually resulting from the bite of an infected

flea, Xenopsylla cheopis (the rat flea). The fleas are often found on rodents, such as rats and mice, and seek

out other prey when their rodent hosts die. The bacteria form aggregates in the gut of infected fleas and this

results in the flea regurgitating ingested blood, which is now infected, into the bite site of a rodent or human

host. Once established, bacteria rapidly spread to the lymph nodes and multiply. Y. pestis bacilli can resist

phagocytosis and even reproduce inside phagocytes and kill them. As the disease progresses, the lymph

nodes can haemorrhage and become swollen and necrotic. Bubonic plague can progress to lethal septicemic

plague in some cases. The plague is also known to spread to the lungs and become the disease known as

the pneumonic plague. This form of the disease is highly infectious as the bacteria can be transmitted in

droplets emitted when coughing or sneezing, as well as physical contact with victims of the plague or flea-

bearing rodents that carry the plague.

[edit]Treatment

In modern times, several classes of antibiotics are effective in treating bubonic plague. These include

the aminoglycosides streptomycin and gentamicin, the tetracyclines anddoxycycline and

the fluoroquinolone ciprofloxacin. Mortality associated with treated cases of bubonic plague are about 1-15%,

compared to a mortality rate of 40-60% in untreated cases.[3]

[edit]History

Main articles: Plague of Justinian, Black Death, and Third Pandemic

The deadly disease has claimed nearly 200 million lives (although there is some debate as to whether all of the

plagues attributed to it are in fact the same disease). The first recorded epidemic ravaged the Byzantine

Empire during the sixth century, and was named the Plague of Justinian after emperor Justinian I, who was

infected but survived through extensive treatment.[4][5]

The most infamous and devastating instance of the plague was the Black Death, which killed a quarter to half

of the population of Europe. In affected cities, proper burial rituals were abandoned and bodies were buried in

mass graves, or abandoned in the street. The Black Death is thought to have originated in the Gobi Desert.

Carried by the fleas on rats, it spread along trade routes and reached the Crimea in 1346. (It also spread

eastward to the Yangtse river valley, and the resulting epidemic, ignored by the government, brought down

the Yuan dynasty[citation needed].) In 1347 it spread to Constantinople and then Alexandria, killing thousands every

day, and soon arrived in Western Europe. It is thought that the name Black Death comes from the fact that the

tissue turns a distinctive black color during necrosis, or from the general gloominess surrounding the plague.

However, this name was not applied until many years later.

Terrible conditions in medieval Europe were only part of the reason it reached such pandemic proportions. The

people of Europe believed cats were evil and so domestic house cats were killed. Without these cats, the rat

population was dramatically increased, there were more infectious fleas, and disease transmission was more

likely.[6] Also, poor harvests over the previous decades may have led to an undernourished European

population that was more susceptible to disease.[citation needed]

The next few centuries were marked by several local outbreaks of lesser severity. The Great Plague of Seville,

1649, the Great Plague of London, 1665–1666, and the Great Plague of Vienna, 1679, were the last major

outbreaks of the bubonic plague in Europe.

The children's game of "Ring Around the Rosy" (or Ring a Ring o' Roses) may be derived from the appearance

of the bubonic plague. Proponents claim that "Ring around the rosy" refers to the rosy-red, rash-like ring that

appeared as a symptom of the plague. "Pocket full of posy" referred to carrying flower petals as at the time it

was believed the disease was spread through the ether of unhygene and scent stopped the spread. "Ashes,

ashes" referred to the burning of infected corpses (in the UK the words of the rhyme are "atishoo, atishoo"

mimicing sneezing), and "we all fall down" referred to the virulent deaths attributed to the plague. [7] Some

folklorists state the claim is baseless.[8][9]

Directions for searchers, Pune plague of 1897

The plague resurfaced in the mid-19th century; like the Black Death, the Third Pandemic began in Central Asia.

The disease killed millions in China and India - then a British colony - and then spread worldwide. The outbreak

continued into the early 20th century. In 1897, Pune in India, was severely affected by the outbreak. The

government responded to the plague with a committee system that used the military to perpetrate repression

and tyranny as it tackled the pandemic. Nationalistspublicly berated the government. On 22 June 1897, two

young brahmins, the Chapekar brothers, shot and killed two British officers, the Committee chairman and his

military escort. This act has been considered a landmark event in India's struggle for freedom as well as the

worst violence against political authority seen in the world during the third plague pandemic. [10] The award

winning Marathi film 22 June 1897 covers events prior to the assassination, the act and its aftermath.[11][12] In

1994 and 2010 there have been cases reported in Peru.[13]

InfluenzaFrom Wikipedia, the free encyclopedia

"Flu" redirects here. For other uses, see Flu (disambiguation).

This article is about the disease influenza. For the family of viruses that cause the disease,

see Orthomyxoviridae.

Influenza

Classification and external resources

TEM of negatively stained influenza virions, magnified approximately

100,000 times

ICD-10 J 10. , J 11.

ICD-9 487

DiseasesDB 6791

MedlinePlus 000080

eMedicine med/1170 ped/3006

MeSH D007251

Influenza (Flu)

Types

Avian (A/H5N1 subtype) · Canine

Equine · Swine (A/H1N1 subtype)

Vaccines

2009 pandemic (Pandemrix)

ACAM-FLU-A · Fluzone · Influvac

Live attenuated (FluMist) · Optaflu

Treatment

Amantadine · Arbidol · Laninamivir

Oseltamivir · Peramivir · Rimantadine

Vitamin D · Zanamivir

Pandemics

2009 · 1968–1969 Hong Kong · 1918

Outbreaks

2008 West Bengal

2007 Bernard Matthews H5N1

2007 Australian equine

2006 H5N1 India · 1976 swine flu

See also

Flu season · Influenza evolution

Influenza research

Influenza-like illness

v • d • e

Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of

the family Orthomyxoviridae (the influenza viruses), that affects birds and mammals. The most common

symptoms of the disease are chills, fever, sore throat, muscle pains, severeheadache, coughing,

weakness/fatigue and general discomfort.[1] Sore throat, fever and coughs are the most frequent symptoms. In

more serious cases, influenza causes pneumonia, which can be fatal, particularly for the young and the elderly.

Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more

severe disease than the common cold and is caused by a different type of virus. [2] Influenza may

produce nausea and vomiting, particularly in children,[1] but these symptoms are more common in the

unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu".[3]

Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus.

Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact

with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which

means of transmission is most important is not absolutely clear.[4] Influenza viruses can be inactivated

by sunlight, disinfectants and detergents.[5][6] As the virus can be inactivated by soap, frequent hand washing

reduces the risk of infection.

Influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 250,000

and 500,000 people every year,[7] up to millions in some pandemic years. On average 41,400 people died each

year in the United States between 1979 and 2001 from influenza.[8]Three influenza pandemics occurred in the

20th century and killed tens of millions of people, with each of these pandemics being caused by the

appearance of a new strain of the virus in humans. Often, these new strains appear when an existing flu virus

spreads to humans from other animal species, or when an existing human strain picks up new genes from a

virus that usually infects birds or pigs. An avian strain named H5N1 raised the concern of a new influenza

pandemic, after it emerged in Asia in the 1990s, but it has not evolved to a form that spreads easily between

people.[9] In April 2009 a novel flu strain evolved that combined genes from human, pig, and bird flu, initially

dubbed "swine flu" and also known as influenza A/H1N1, emerged in Mexico, the United States, and several

other nations. The World Health Organization officially declared the outbreak to be a pandemic on June 11,

2009 (see 2009 flu pandemic). The WHO's declaration of a pandemic level 6 was an indication of spread, not

severity, the strain actually having a lower mortality rate than common flu outbreaks. [10]

Vaccinations against influenza are usually given to people in developed countries [11]  and to farmed poultry.[12] The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and

inactivated material from three viral strains. Typically, this vaccine includes material from two influenza A

virus subtypes and one influenza B virus strain.[13] The TIV carries no risk of transmitting the disease, and it has

very low reactivity. A vaccine formulated for one year may be ineffective in the following year, since the

influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs can be used to

treat influenza, with neuraminidase inhibitors being particularly effective.

Contents

[hide]

1 Classification

o 1.1 Types of influenza virus

1.1.1 Influenzavirus A

1.1.2 Influenzavirus B

1.1.3 Influenzavirus C

o 1.2 Structure, properties, and subtype nomenclature

o 1.3 Replication

2 Signs and symptoms

3 Mechanism

o 3.1 Transmission

o 3.2 Pathophysiology

4 Prevention

o 4.1 Vaccination

o 4.2 Infection control

5 Treatment

o 5.1 Neuraminidase inhibitors

o 5.2 M2 inhibitors (adamantanes)

6 Prognosis

7 Epidemiology

o 7.1 Seasonal variations

o 7.2 Epidemic and pandemic spread

8 History

o 8.1 Etymology

o 8.2 Pandemics

9 Society and culture

10 Research

11 Infection in other animals

o 11.1 Bird flu

o 11.2 Swine flu

12 See also

13 References

14 Further reading

15 External links

[edit]Classification

[edit]Types of influenza virus

Structure of the influenza virion. Thehemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the

particle. The viral RNAs that make up thegenome are shown as red coils inside the particle and bound to Ribonuclear

Proteins (RNPs).

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the

family Orthomyxoviridae:[14]

Influenzavirus A

Influenzavirus B

Influenzavirus C

These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging

to the paramyxovirus family that are a common cause of respiratory infections in children such as croup,[15] but

can also cause a disease similar to influenza in adults.[16]

[edit]Influenzavirus A

This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of

influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks

in domestic poultry or give rise to human influenza pandemics.[17]The type A viruses are the most virulent

human pathogens among the three influenza types and cause the most severe disease. The influenza A virus

can be subdivided into different serotypes based on the antibody response to these viruses.[18] The serotypes

that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

H1N1 , which caused Spanish flu in 1918, and the 2009 flu pandemic

H2N2 , which caused Asian Flu in 1957

H3N2 , which caused Hong Kong Flu in 1968

H5N1 , a current pandemic threat

H7N7 , which has unusual zoonotic potential[19]

H1N2 , endemic in humans and pigs

H9N2

H7N2

H7N3

H10N7

[edit]Influenzavirus B

Influenza virus nomenclature (for a Fujian flu virus)

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans [18] and is less

common than influenza A. The only other animals known to be susceptible to influenza B infection are

the seal [20]  and the ferret.[21] This type of influenza mutates at a rate 2–3 times slower than type A[22] and

consequently is less genetically diverse, with only one influenza B serotype.[18] As a result of this lack

of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However,

influenza B mutates enough that lasting immunity is not possible.[23] This reduced rate of antigenic change,

combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of

influenza B do not occur.[24]

[edit]Influenzavirus C

This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both

severe illness and local epidemics.[25][26] However, influenza C is less common than the other types and usually

only causes mild disease in children.[27][28]

[edit]Structure, properties, and subtype nomenclature

Influenzaviruses A, B and C are very similar in overall structure.[29] The virus particle is 80–120 nanometres in

diameter and usually roughly spherical, although filamentous forms can occur.[30][31] These filamentous forms

are more common in influenza C, which can form cordlike structures up to 500 micrometres long on the

surfaces of infected cells.[32] However, despite these varied shapes, the viral particles of all influenza viruses

are similar in composition.[32] These are made of a viral envelope containing two main types of glycoproteins,

wrapped around a central core. The central core contains the viral RNA genome and other viral proteins that

package and protect this RNA. RNA tends to be single stranded but in special cases it is double. [31] Unusually

for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of

segmented negative-sense RNA, each piece of RNA containing either one or two genes.[32] For example, the

influenza A genome contains 11 genes on eight pieces of RNA, encoding for

11 proteins: hemagglutinin (HA),neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1,

PB1-F2 and PB2.[33]

Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral

particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the

target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind

the mature viral particles.[34] Thus, these proteins are targets for antiviral drugs.[35] Furthermore, they

are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on

antibody responses to HA and NA. These different types of HA and NA form the basis of

the H and N distinctions in, for example, H5N1.[36] There are 16 H and 9 N subtypes known, but only H 1, 2 and

3, and N 1 and 2 are commonly found in humans.[37]

[edit]Replication

Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.

Viruses can only replicate in living cells.[38] Influenza infection and replication is a multi-step process: firstly the

virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral

proteins and RNA, assemble these components into new viral particles and finally exit the host cell. [32]

Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells; typically

in the nose, throat and lungs of mammals and intestines of birds (Stage 1 in infection figure).[39] After the

hemagglutinin is cleaved by aprotease, the cell imports the virus by endocytosis.[40]

Once inside the cell, the acidic conditions in the endosome cause two events to happen: first part of the

hemagglutinin protein fuses the viral envelope with the vacuole's membrane, then the M2 ion

channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the

core to dissemble and release the viral RNA and core proteins.[32] The viral RNA (vRNA) molecules, accessory

proteins and RNA-dependent RNA polymerase are then released into the cytoplasm (Stage 2).[41] The M2 ion

channel is blocked by amantadine drugs, preventing infection.[42]

These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-

dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b). [43] The

vRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly

synthesised viral proteins are either secreted through theGolgi apparatus onto the cell surface (in the case of

neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new

viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading

cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell

mRNAs.[44]

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other

viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in

the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion

(step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring

hemagglutinin and neuraminidase with this membrane coat (step 7).[45] As before, the viruses adhere to the cell

through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues

from the host cell.[39] Drugs that inhibit neuraminidase, such as oseltamivir, therefore prevent the release of new

infectious viruses and halt viral replication.[35] After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the

viral genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the

influenza vRNA. Hence, the majority of newly manufactured influenza viruses are mutants; this causes

"antigenic drift", which is a slow change in the antigens on the viral surface over time.[46] The separation of the

genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type

of influenza virus infects a single cell. The resulting rapid change in viral genetics produces antigenic shifts,

which are sudden changes from one antigen to another. These sudden large changes allow the virus to infect

new host species and quickly overcome protective immunity.[36] This is important in the emergence of

pandemics, as discussed below in the section onEpidemiology.

[edit]Signs and symptoms

Symptoms of influenza,[48] with fever and cough the most common

symptoms.[47]

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are

chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from

38-39 °C (approximately 100-103 °F).[49] Many people are so ill that they are confined to bed for several days,

with aches and pains throughout their bodies, which are worse in their backs and legs. [1]Symptoms of influenza

may include:

Fever  and extreme coldness (chills shivering, shaking (rigor))

Cough

Nasal congestion

Body aches , especially joints and throat

Fatigue

Headache

Irritated, watering eyes

Reddened eyes, skin (especially face), mouth, throat and nose

In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[50][51] (may be severe in

children with influenza B)[52]

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections,[2] but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not normally a

symptom of influenza in adults,[47] although it has been seen in some human cases of the H5N1 "bird flu"[53] and

can be a symptom in children.[50] The symptoms most reliably seen in influenza are shown in the table to the

right.[47]

Most sensitive symptoms for diagnosing influenza[47]

Symptom: sensitivity specificity

Fever 68–86% 25–73%

Cough 84–98% 7–29%

Nasal congestion

68–91% 19–41%

All three findings, especially fever, were less sensitive

in patients over 60 years of age.

Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be

important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore

throat and/or nasal congestion can improve diagnostic accuracy.[54]Two decision analysis studies[55][56] suggest

that during local outbreaks of influenza, the prevalence will be over 70%,[56] and thus patients with any of these

combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence

of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the

prevalence is over 15%.[56]

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control

and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.[57] According to the CDC,

rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% when compared with viral culture.

These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a

local outbreak, or peri-influenza season (prevalence=10%[56]).

[edit]Mechanism

[edit]Transmission

Sneezing can transmit influenza.

Influenza virus shedding (the time during which a person might be infectious to another person) begins the day

before symptoms appear and virus is then released for between 5 to 7 days, although some people may shed

virus for longer periods. People who contract influenza are most infective between the second and third days

after infection.[58] The amount of virus shed appears to correlate with fever, with higher amounts of virus shed

when temperatures are highest.[59] Children are much more infectious than adults and shed virus from just

before they develop symptoms until two weeks after infection.[58][60] The transmission of influenza can

be modeled mathematically, which helps predict how the virus will spread in a population.[61]

Influenza can be spread in three main ways:[62][63] by direct transmission (when an infected person sneezes

mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales

the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-

nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such

as a hand-shake. The relative importance of these three modes of transmission is unclear, and they may all

contribute to the spread of the virus.[4][64] In the airborne route, the droplets that are small enough for people to

inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an infection.[62] Although a single sneeze releases up to 40,000 droplets,[65] most of these droplets are quite large and will

quickly settle out of the air.[62] How long influenza survives in airborne droplets seems to be influenced by the

levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter aiding its survival.[62]

As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such

as banknotes,[66] doorknobs, light switches and other household items.[1] The length of time the virus will persist

on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or

metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin.[67] However, if the virus is

present in mucus, this can protect it for longer periods (up to 17 days on banknotes).[62][66]Avian influenza

viruses can survive indefinitely when frozen.[68] They are inactivated by heating to 56 °C (133 °F) for a minimum

of 60 minutes, as well as by acids (at pH <2).[68]

[edit]Pathophysiology

The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1. This influences their lethality and ability

to spread.

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One

of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone (ACTH) resulting in lowered

cortisol levels.[69] Knowing which genes are carried by a particular strain can help predict how well it will infect

humans and how severe this infection will be (that is, predict the strain's pathophysiology).[26][70]

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the

viral hemagglutinin protein by any one of several human proteases.[40] In mild and avirulent viruses, the

structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so

these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin

can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body. [70]

The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where

in the human respiratory tract a strain of influenza will bind.[71] Strains that are easily transmitted between

people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in

the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found

deep in the lungs.[72] This difference in the site of infection may be part of the reason why the H5N1 strain

causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing. [73][74]

Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of

proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from

influenza-infected cells.[2][75] In contrast to the rhinovirus that causes the common cold, influenza does cause

tissue damage, so symptoms are not entirely due to the inflammatory response.[76] This massive immune

response might produce a life-threatening cytokine storm. This effect has been proposed to be the cause of the

unusual lethality of both the H5N1 avian influenza,[77] and the 1918 pandemic strain.[78][79] However, another

possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication

produced by these strains, and the immune response does not itself contribute to the disease. [80]

[edit]Prevention

[edit]VaccinationFurther information: Influenza vaccine

Giving an influenza vaccination.

Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as

children and the elderly, or in people who have asthma, diabetes, heart disease, or are immuno-compromised.

Influenza vaccines can be produced in several ways; the most common method is to grow the virus in

fertilized hen eggs. After purification, the virus is inactivated (for example, by treatment with detergent) to

produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses virulence and

the avirulent virus given as a live vaccine.[36] The effectiveness of these influenza vaccines are variable. Due to

the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a

few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be

circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best

immunity against these strains.[81] Vaccines have also been developed to protect poultry from avian influenza.

These vaccines can be effective against multiple strains and are used either as part of a preventative strategy,

or combined with culling in attempts to eradicate outbreaks.[82]

It is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few

specific flu strains but cannot possibly include all the strains actively infecting people in the world for that

season. It takes about six months for the manufacturers to formulate and produce the millions of doses

required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent

during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003–

2004 flu season).[83] It is also possible to get infected just before vaccination and get sick with the very strain

that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective. [84]

The 2006–2007 season was the first in which the CDC had recommended that children younger than 59

months receive the annual influenza vaccine.[85] Vaccines can cause the immune system to react as if the body

were actually being infected, and general infection symptoms (many cold and flu symptoms are just general

infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza.

The most dangerous side effect is a severe allergic reaction to either the virus material itself or residues from

the hen eggs used to grow the influenza; however, these reactions are extremely rare. [86]

In addition to vaccination against seasonal influenza, researchers are working to develop a vaccine against a

possible influenza pandemic. The rapid development, production, and distribution of pandemic influenza

vaccines could potentially save millions of lives during an influenza pandemic. Due to the short time frame

between identification of a pandemic strain and need for vaccination, researchers are looking at non-egg-based

options for vaccine production. Live attenuated (egg-based or cell-based) technology and recombinant

technologies (proteins and virus-like particles) could provide better "real-time" access and be produced more

affordably, thereby increasing access for people living in low- and moderate-income countries, where an

influenza pandemic may likely originate. As of July 2009, more than 70 known clinical trials have been

completed or are ongoing for pandemic influenza vaccines.[87]In September 2009, the US Food and Drug

Administration approved four vaccines against the 2009 H1N1 influenza virus (the current pandemic strain),

and expect the initial vaccine lots to be available within the following month.[88]

[edit]Infection controlFurther information: Influenza prevention

Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene

habits such as: not touching your eyes, nose or mouth;[89] frequent hand washing (with soap and water, or with

alcohol-based hand rubs);[90] covering coughs and sneezes; avoiding close contact with sick people; and

staying home yourself if you are sick. Avoiding spitting is also recommended.[91]

Although face masks might help prevent transmission when caring for the sick,[92][93] there is mixed evidence on

beneficial effects in the community.[91][94] Smoking raises the risk of contracting influenza, as well as producing

more severe disease symptoms.[95][96] Thus, according to the laws of mathematical modelling of infectious

diseases, smokers raise theexponential growth rates of influenza epidemics and may indirectly be responsible

for a large percentage of influenza cases.

Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may

help prevent some infections.[97] Alcohol is an effective sanitizer against influenza viruses, while quaternary

ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer.[98] In hospitals,

quaternary ammonium compounds andbleach are used to sanitize rooms or equipment that have been

occupied by patients with influenza symptoms.[98] At home, this can be done effectively with a diluted chlorine

bleach.[99]

During past pandemics, closing schools, churches and theatres slowed the spread of the virus but did not have

a large effect on the overall death rate.[100][101] It is uncertain if reducing public gatherings, by for example closing

schools and workplaces, will reduce transmission since people with influenza may just be moved from one area

to another; such measures would also be difficult to enforce and might be unpopular. [91] When small numbers of

people are infected, isolating the sick might reduce the risk of transmission.[91]

[edit]Treatment

Further information: Influenza treatment

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid

using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve

the fever and muscle aches associated with the flu.[102] Children and teenagers with flu symptoms (particularly

fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so

can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.[103] Since influenza is caused by a

virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial

pneumonia. Antiviral medication can be effective, but some strains of influenza can show resistance to the

standard antiviral drugs.[104]

The two classes of antiviral drugs used against influenza are neuraminidase inhibitors and M2 protein inhibitors

(adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are

less toxic and more effective.[80] The CDC recommended against using M2 inhibitors during the 2005–06

influenza season due to high levels of drug resistance.[105] As pregnant women seem to be more severely

affected than the general population by the 2009 H1N1 influenza virus, prompt treatment with anti-influenza

drugs has been recommended.[106]

[edit]Neuraminidase inhibitors

Antiviral drugs such as oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza)

are neuraminidase inhibitors that are designed to halt the spread of the virus in the body.[107]These drugs are

often effective against both influenza A and B.[108] The Cochrane Collaboration reviewed these drugs and

concluded that they reduce symptoms and complications.[109]Different strains of influenza viruses have differing

degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future

pandemic strain might have.[110]

[edit]M2 inhibitors (adamantanes)

The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus

from infecting cells.[42] These drugs are sometimes effective against influenza A if given early in the infection but

are always ineffective against influenza B because B viruses do not possess M2 molecules. [108] Measured

resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005.[111] This

high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold

remedies in countries such as China and Russia,[112] and their use to prevent outbreaks of influenza in farmed

poultry.[113][114]

[edit]Prognosis

Influenza's effects are much more severe and last longer than those of the common cold. Most people will

recover completely in about one to two weeks, but others will develop life-threatening complications (such

as pneumonia). Influenza, thus, can be deadly, especially for the weak, young and old, or chronically ill.[36] People with a weak immune system, such as people with advanced HIV infection or transplant patients

(whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from

particularly severe disease.[115] Other high-risk groups include pregnant women and young children.[116]

The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may

experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart

disease or congestive heart failure.[117] Smoking is another risk factor associated with more serious disease and

increased mortality from influenza.[118]

According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only

ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the

worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the

numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who

died of a flu-like illness."[119] Even healthy people can be affected, and serious problems from influenza can

happen at any age. People over 50 years old, very young children and people of any age with chronic medical

conditions are more likely to get complications from influenza, such as pneumonia,bronchitis, sinus, and ear

infections.[84]

In some cases, an autoimmune response to an influenza infection may contribute to the development

of Guillain-Barré syndrome.[120] However, as many other infections can increase the risk of this disease,

influenza may only be an important cause during epidemics.[120][121] This syndrome can also be a rare side effect

of influenza vaccines, with an incidence of about one case per million vaccinations. [122]

[edit]Epidemiology

[edit]Seasonal variationsFurther information: Flu season

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have

winter at different times of the year, there are actually two different flu seasons each year. This is why

the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two

different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere. [81]

A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the

year. One possible explanation is that, because people are indoors more often during the winter, they are in

close contact more often, and this promotes transmission from person to person. Increased travel due to the

Northern Hemisphere winter holiday season may also play a role.[123] Another factor is that cold temperatures

lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The

virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in

cold environments (less than 5 °C) with low relative humidity.[124] Indeed, the lower air humidity in winter seems

to be the main cause of seasonal influenza transmission in temperate regions.[125][126]

However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks

of infection are seen mainly during the rainy season.[127] Seasonal changes in contact rates from school terms,

which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the

flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the

endogenous disease cycles.[128] H5N1 exhibits seasonality in both humans and birds.[129]

An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on

immunity to the virus.[130] This idea was first proposed by Robert Edgar Hope-Simpson in 1965.[131] He proposed

that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D,

which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why

influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the

sun, and their vitamin D levels fall.

[edit]Epidemic and pandemic spreadFurther information: Flu pandemic

Antigenic drift creates influenza viruses with slightly modified antigens, whileantigenic shift generates viruses with entirely

novel antigens.

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out

while others create epidemics, while yet another strain can cause a pandemic. Typically, in a year's normal

two flu seasons (one per hemisphere), there are between three and five million cases of severe illness and up

to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic. [132]Although the

incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000

hospitalizations are directly associated with influenza every year in the United States.[133][134] Roughly three

times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill

tens of millions of people (see history section). Indeed, one study estimated that if a strain with

similar virulence to the 1918 influenza emerged today, it could kill between 50 and 80 million people.[135]

Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

New influenza viruses are constantly evolving by mutation or by reassortment.[18] Mutations can cause small

changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic

drift, which slowly creates an increasing variety of strains until one evolves that can infect people who are

immune to the pre-existing strains. This new variant then replaces the older strains as it rapidly sweeps through

the human population—often causing an epidemic.[136] However, since the strains produced by drift will still be

reasonably similar to the older strains, some people will still be immune to them. In contrast, when influenza

viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains

and human strains; this is called antigenic shift. If a human influenza virus is produced that has entirely new

antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a

pandemic.[137] In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach

has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains

with a human population with a constantly changing set of immunities to different viral strains. [138]

[edit]History

[edit]Etymology

The word Influenza comes from the Italian language meaning "influence" and refers to the cause of the

disease; initially, this ascribed illness to unfavorable astrological influences.[139] Changes in medical thought led

to its modification to influenza del freddo, meaning "influence of the cold". The word influenza was first used in

English in 1743 when it was adopted, with an anglicized pronunciation, during an outbreak of the disease in

Europe.[140] Archaic terms for influenza include epidemic catarrh, grippe (from the French), sweating sickness,

and Spanish fever(particularly for the 1918 flu pandemic strain).[141]

[edit]PandemicsFurther information: Influenza pandemic, Spanish flu, Hong Kong flu

The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per

100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic

year 1918 (solid line).[142]

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.[143]

[144] Although the virus seems to have caused epidemics throughout human history, historical data on influenza

are difficult to interpret, because the symptoms can be similar to those of other respiratory diseases. [145][146] The

disease may have spread from Europe to the Americas as early as the European colonization of the Americas;

since almost the entire indigenous population of the Antilles was killed by an epidemic resembling influenza

that broke out in 1493, after the arrival of Christopher Columbus.[147][148]

The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Russia and

spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost

wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of

1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed. [146]

The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A

influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but

estimates range from 20 to 100 million people.[149][150] This pandemic has been described as "the greatest

medical holocaust in history" and may have killed as many people as the Black Death.[146] This huge death toll

was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms,

suspected to be caused by cytokine storms.[150] Indeed, symptoms in 1918 were so unusual that initially

influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of

the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine.

Bleeding from the ears and petechial hemorrhages in the skin also occurred."[149] The majority of deaths were

from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly,

causing massivehemorrhages and edema in the lung.[142]

The 1918 flu pandemic (Spanish flu pandemic) was truly global, spreading even to the Arctic and

remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed

to the more usual flu epidemic mortality rate of 0.1%.[142][149] Another unusual feature of this pandemic was that it

mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than

half in young adults 20 to 40 years old.[151] This is unusual since influenza is normally most deadly to the very

young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not

known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have

been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.[149]

The influenza viruses that causedHong Kong flu. (magnified approximately 100,000 times)

Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the

1968 Hong Kong Flu (type A, H3N2strain), but even these smaller outbreaks killed millions of people. In later

pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality

compared to the Spanish Flu of 1918.[142]

Known flu pandemics [36] [146] [152]

Name of pandemic Date DeathsCase fatality

rateSubtype involved

Pandemic Severity Index

Asiatic (Russian) Flu [153]

1889–1890 1 million 0.15% possibly H3N8 NA

1918 flu pandemic(Spanish flu)[154] 1918–1920

20 to 100 million

2% H1N1 5

Asian Flu 1957–1958 1 to 1.5 million 0.13% H2N2 2

Hong Kong Flu 1968–19690.75 to 1 million

<0.1% H3N2 2

2009 flu pandemic [155] 2009–

Present10,000 to Dec 6 0.01-0.03% H1N1 NA

The first influenza virus to be isolated was from poultry, when in 1901 the agent causing a disease called "fowl

plague" was passed throughChamberland filters, which have pores that are too small for bacteria to pass

through.[156] The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered

inpigs by Richard Shope in 1931.[157] This discovery was shortly followed by the isolation of the virus from

humans by a group headed by Patrick Laidlaw at the Medical Research Councilof the United Kingdom in 1933.[158] However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-

cellular nature of viruses was appreciated.

The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring

influenza pandemics. Broken lines indicate uncertain strain identifications.[159]

The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for

influenza byThomas Francis, Jr.. This built on work by Australian Frank Macfarlane Burnet, who showed that

the virus lost virulence when it was cultured in fertilized hen's eggs.[160] Application of this observation by

Francis allowed his group of researchers at theUniversity of Michigan to develop the first influenza vaccine,

with support from the U.S. Army.[161] The Army was deeply involved in this research due to its experience of

influenza in World War I, when thousands of troops were killed by the virus in a matter of months.[149] In

comparison to vaccines, the development of anti-influenza drugs has been slower, with amantadine being

licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being

developed.[37]

[edit]Society and culture

Further information: Social impact of H5N1

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect

costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion

per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct

and indirect costs.[162] However, the economic impacts of past pandemics have not been intensively studied,

and some authors have suggested that theSpanish influenza actually had a positive long-term effect on per-

capita income growth, despite a large reduction in the working population and severe short-

term depressive effects.[163]Other studies have attempted to predict the costs of a pandemic as serious as the

1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30%

sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional

costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be

approximately $700 billion.[164]

Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and

planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and

vaccines as well as developing disaster drills and strategies for improved border controls.[165] On 1 November

2005, United States President George W. Bushunveiled the National Strategy to Safeguard Against the Danger

of Pandemic Influenza[166] backed by a request to Congress for $7.1 billion to begin implementing the plan.[167]Internationally, on 18 January 2006, donor nations pledged US$2 billion to combat bird flu at the two-day

International Pledging Conference on Avian and Human Influenza held in China. [168]

In an assessment of the 2009 H1N1 pandemic on selected countries in the Southern Hemisphere, data

suggest that all countries experienced some time-limited and/or geographically isolated socio/economic effects

and a temporary decrease in tourism most likely due to fear of 2009 H1N1 disease. It is still too early to

determine whether the H1N1 pandemic has caused any long-term economic impacts. [169]

[edit]Research

Further information: Influenza research

Dr. Terrence Tumpey examining a reconstructed 1918 Spanish flu virus in abiosafety level 3 environment.

Research on influenza includes studies on molecular virology, how the virus produces disease (pathogenesis),

host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in

developing influenza countermeasures; for example, a better understanding of the body's immune system

response helps vaccine development, and a detailed picture of how influenza invades cells aids the

development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing

Project, which is creating a library of influenza sequences; this library should help clarify which factors make

one strain more lethal than another, which genes most affectimmunogenicity, and how the virus evolves over

time.[170]

Research into new vaccines is particularly important, as current vaccines are very slow and expensive to

produce and must be reformulated every year. The sequencing of the influenza genome and recombinant

DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new

antigens into a previously developed vaccine strain.[171] New technologies are also being developed to grow

viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity.[172] Research

on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2

protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their team[173][174]

[175] and has now successfully concluded Phase I clinical trials.

A number of biologics, therapeutic vaccines and immunobiologics are also being investigated for treatment of

infection caused by viruses. Therapeutic biologics are designed to activate the immune response to virus or

antigens. Typically, biologics do not target metabolic pathwayslike anti-viral drugs, but stimulate immune cells

such as lymphocytes, macrophages, and/or antigen presenting cells, in an effort to drive an immune response

towards a cytotoxic effect against the virus. Infuenza models, such as murine influenza, are convenient models

to test the effects of prophylactic and therapeutic biologics. For example, Lymphocyte T-Cell Immune

Modulator inhibits viral growth in the murine model of influenza.[176]

[edit]Infection in other animals

H5N1

Influenza A virus

subtype H5N1

Genetic structure

Infection

Human mortality

Global spread

in 2004

in 2005

in 2006

in 2007

Social impact

Pandemic

v • d • e

Further information: Influenzavirus A, H5N1 and Transmission and infection of H5N1

Influenza infects many animal species, and transfer of viral strains between species can occur. Birds are

thought to be the main animal reservoirs of influenza viruses.[177] Sixteen forms of hemagglutinin and nine forms

of neuraminidase have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are

endemic in humans, dogs, horses, and pigs; populations of camels, ferrets, cats, seals, mink, and whales also

show evidence of prior infection or exposure to influenza.[23] Variants of flu virus are sometimes named

according to the species the strain is endemic in or adapted to. The main variants named using this convention

are: Bird Flu, Human Flu, Swine Flu, Horse Flu and Dog Flu. (Cat flu generally refers to Feline viral

rhinotracheitis or Feline calicivirus and not infection from an influenza virus.) In pigs, horses and dogs,

influenza symptoms are similar to humans, with cough, fever and loss of appetite.[23] The frequency of animal

diseases are not as well-studied as human infection, but an outbreak of influenza in harbour seals caused

approximately 500 seal deaths off the New England coast in 1979–1980.[178] On the other hand, outbreaks in

pigs are common and do not cause severe mortality.[23]

[edit]Bird flu

Flu symptoms in birds are variable and can be unspecific.[179] The symptoms following infection with low-

pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or weight

loss combined with minor respiratory disease.[180] Since these mild symptoms can make diagnosis in the field

difficult, tracking the spread of avian influenza requires laboratory testing of samples from infected birds. Some

strains such as AsianH9N2 are highly virulent to poultry and may cause more extreme symptoms and

significant mortality.[181] In its most highly pathogenic form, influenza inchickens and turkeys produces a sudden

appearance of severe symptoms and almost 100% mortality within two days.[182] As the virus spreads rapidly in

the crowded conditions seen in the intensive farming of chickens and turkeys, these outbreaks can cause large

economic losses to poultry farmers.

An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian

influenza virus of type A of subtype H5N1") causesH5N1 flu, commonly known as "avian influenza" or simply

"bird flu", and is endemic in many bird populations, especially in Southeast Asia. This Asian lineage strain of

HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in non-humans) and panzootic (a disease

affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring

the culling of hundreds of millions of other birds in an attempt to control its spread. Most references in the

media to "bird flu" and most references to H5N1 are about this specific strain. [183][184]

At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human

transmission of HPAI A(H5N1). In almost all cases, those infected have had extensive physical contact with

infected birds.[185] In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human

transmission. The exact changes that are required for this to happen are not well understood. [186] However, due

to the high lethality and virulence of H5N1, its endemic presence, and its large and increasing biological host

reservoir, the H5N1 virus was the world's pandemic threat in the 2006–07 flu season, and billions of dollars are

being raised and spent researching H5N1 and preparing for a potential influenza pandemic. [165]

[edit]Swine flu

Chinese inspectors on an airplane, checking passengers for fevers, a common symptom of swine flu

In pigs swine influenza produces fever, lethargy, sneezing, coughing, difficulty breathing and decreased

appetite.[187] In some cases the infection can cause abortion. Although mortality is usually low, the virus can

produce weight loss and poor growth, causing economic loss to farmers.[187] Infected pigs can lose up to 12

pounds of body weight over a 3 to 4 week period.[187] Direct transmission of an influenza virus from pigs to

humans is occasionally possible (this is called zoonotic swine flu). In all, 50 human cases are known to have

occurred since the virus was identified in the mid-20th century, which have resulted in six deaths. [188]

In 2009, a swine-origin H1N1 virus strain commonly referred to as "swine flu" caused the 2009 flu pandemic,

but there is no evidence that it is endemic to pigs (i.e. actually a swine flu) or of transmission from pigs to

people, instead the virus is spreading from person to person.[189][190]This strain is a reassortment of several

strains of H1N1 that are usually found separately, in humans, birds, and pigs.[191]

RubellaFrom Wikipedia, the free encyclopedia

This page is for the disease. For the virus, see rubella virus.

Rubella

Classification and external resources

ICD-10 B 06.

ICD-9 056

DiseasesDB 11719

MedlinePlus 001574

eMedicine emerg/388 peds/2025 derm/259

MeSH D012409

Rubella, commonly known as German measles, is a disease caused by the rubella virus. The name "rubella"

is derived from the Latin, meaning little red. Rubella is also known as German measles because the disease

was first described by German physicians in the mid-eighteenth century. This disease is often mild and attacks

often pass unnoticed. The disease can last one to three days. Children recover more quickly than adults.

Infection of the mother by Rubella virus during pregnancy can be serious; if the mother is infected within the

first 20 weeks of pregnancy, the child may be born with congenital rubella syndrome (CRS), which entails a

range of serious incurable illnesses. Spontaneous abortion occurs in up to 20% of cases. [1]

Rubella is a common childhood infection usually with minimal systemic upset although

transient arthropathy may occur in adults. Serious complications are very rare. Apart from the effects of

transplacental infection on the developing fetus, rubella is a relatively trivial infection.

Acquired (i.e. not congenital) rubella is transmitted via airborne droplet emission from the upper respiratory

tract of active cases. The virus may also be present in the urine, feces and on the skin. There is no carrier

state: the reservoir exists entirely in active human cases. The disease has an incubation period of 2 to 3 weeks.[2]

In most people the virus is rapidly eliminated. However, it may persist for some months post partum in infants

surviving the CRS. These children are a significant source of infection to other infants and, more importantly, to

pregnant female contacts.

The name rubella is sometimes confused with rubeola, an alternative name for measles in English-speaking

countries; the diseases are unrelated.[3][4] In some other European languages, rubella and rubeola are

synonyms, and rubeola is not an alternative name for measles.[5]

Contents

[hide]

1 Signs and symptoms

o 1.1 Congenital rubella syndrome

2 Cause

3 Diagnosis

4 Prevention

5 Treatment

6 Prognosis

7 Epidemiology

8 History

9 See also

10 References

11 External links

[edit]Signs and symptoms

After an incubation period of 14–21 days, German measles causes symptoms that are similar to the flu. The

primary symptom of rubella virus infection is the appearance of a rash (exanthem) on the face which spreads to

the trunk and limbs and usually fades after three days (that is why it is often referred to as three-day measles).

The facial rash usually clears as it spreads to other parts of the body. Other symptoms include low grade fever,

swollen glands (sub occipital & posterior cervical lymphadenopathy), joint pains, headache and conjunctivitis.[6] The swollen glands or lymph nodes can persist for up to a week and the fever rarely rises above 38 oC

(100.4 oF). The rash of German measles is typically pink or light red. The rash causes itching and often lasts for

about three days. The rash disappears after a few days with no staining or peeling of the skin. When the rash

clears up, the patient may notice that his skin sheds in very small flakes wherever the rash covered it.

Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft

palate.

Rubella can affect anyone of any age and is generally a mild disease, rare in infants or those over the age of

40. The older the person is the more severe the symptoms are likely to be. Up to two-thirds of older girls or

women experience joint pain or arthritic type symptoms with rubella. The virus is contracted through the

respiratory tract and has an incubation period of 2 to 3 weeks. During this incubation period, the patient is

contagious typically for about one week before he develops a rash and for about one week thereafter.

[edit]Congenital rubella syndrome

Main article: Congenital rubella syndrome

Rubella can cause congenital rubella syndrome in the newly born. The syndrome (CRS) follows intrauterine

infection by Rubella virus and comprises cardiac, cerebral, ophthalmic and auditory defects. [7] It may also cause

prematurity, low birth weight, and neonatal thrombocytopenia, anaemia and hepatitis. The risk of major defects

or organogenesis is highest for infection in the first trimester. CRS is the main reason a vaccine for rubella was

developed. Many mothers who contract rubella within the first critical trimester either have a miscarriage or a

still born baby. If the baby survives the infection, it can be born with severe heart disorders (PDA being the

most common), blindness, deafness, or other life threatening organ disorders. The skin manifestations are

called "blueberry muffin lesions." [8]

[edit]Cause

Main article: Rubella virus

The disease is caused by Rubella virus, a togavirus that is enveloped and has a single-stranded RNA genome.[9] The virus is transmitted by the respiratory route and replicates in thenasopharynx and lymph nodes. The

virus is found in the blood 5 to 7 days after infection and spreads throughout the body. The virus

has teratogenic properties and is capable of crossing the placenta and infecting the fetus where it stops cells

from developing or destroys them.[6]

Increased susceptibility to infection might be inherited as there is some indication that HLA-A1 or factors

surrounding A1 on extended haplotypes are involved in virus infection or non-resolution of the disease.[10] [11]

[edit]Diagnosis

Rubella virus specific IgM antibodies are present in people recently infected by Rubella virus but these

antibodies can persist for over a year and a positive test result needs to be interpreted with caution. [12] The

presence of these antibodies along with, or a short time after, the characteristic rash confirms the diagnosis. [13]

[edit]Prevention

Main article: MMR vaccine

Rubella infections are prevented by active immunisation programs using live, disabled virus vaccines. Two live

attenuated virus vaccines, RA 27/3 and Cendehill strains, were effective in the prevention of adult disease.

However their use in prepubertile females did not produce a significant fall in the overall incidence rate of CRS

in the UK. Reductions were only achieved by immunisation of all children.

The vaccine is now given as part of the MMR vaccine. The WHO recommends the first dose is given at 12 to

18 months of age with a second dose at 36 months. Pregnant women are usually tested for immunity to rubella

early on. Women found to be susceptible are not vaccinated until after the baby is born because the vaccine

contains live virus.[14]

The immunisation program has been quite successful. Cuba declared the disease eliminated in the 1990s, and

in 2004 the Centers for Disease Control and Prevention announced that both the congenital and acquired

forms of rubella had been eliminated from the United States.[15][16]

[edit]Treatment

There is no specific treatment for Rubella; however, management is a matter of responding to symptoms to

diminish discomfort. Treatment of newly born babies is focused on management of the complications.

Congenital heart defects[citation needed] and cataracts can be corrected by direct surgery.[17] Management for ocular

CRS is similar to that for age-related macular degeneration, including counseling, regular monitoring, and the

provision of low vision devices, if required.[18]

[edit]Prognosis

Rubella infection of children and adults is usually mild, self-limiting and often asymptomatic. The prognosis in

children born with CRS is poor.[19]

[edit]Epidemiology

Rubella is a disease that occurs worldwide. The virus tends to peak during the spring in countries with

temperate climates. Before the vaccine to rubella was introduced in 1969, widespread outbreaks usually

occurred every 6–9 years in the United States and 3–5 years in Europe, mostly affecting children in the 5-9

year old age group.[20] Since the introduction of vaccine, occurrences have become rare in those countries with

high uptake rates.

Vaccination has interrupted the transmission of rubella in the Americas: no endemic case has been observed

since February 2009.[21] Since the virus can always be reintroduced from other continents, the population still

need to remain vaccinated to keep the western hemisphere free of rubella. During the epidemic in the US

between 1962-1965, Rubella virus infections during pregnancy were estimated to have caused 30,000 still

births and 20,000 children to be born impaired or disabled as a result of CRS. [22][23] Universal immunisation

producing a high level of herd immunity is important in the control of epidemics of rubella.[24]

In the UK, there remains a large population of men susceptible to rubella who have not been vaccinated.

Outbreaks of rubella occurred amongst many young men in the UK in 1993 and in 1996 the infection was

transmitted to pregnant women, many of whom were immigrants and were susceptible. Outbreaks still arise,

usually in developing countries where the vaccine is not as accessible.[25]

[edit]History

Rubella was first described in the mid-eighteenth century. Friedrich Hoffmann made the first clinical description

of rubella in 1740,[26] which was confirmed by de Bergen in 1752 and Orlow in 1758.[27]

In 1814, George de Maton first suggested that it be considered a disease distinct from both measles and

scarlet fever. All these physicians were German, and the disease was known as Rötheln (from the German

name Röteln), hence the common name of "German measles".[28] Henry Veale, an English Royal Artillery

surgeon, described an outbreak in India. He coined the name "rubella" (from the Latin, meaning "little red") in

1866.[26][29][30][31]

It was formally recognised as an individual entity in 1881, at the International Congress of Medicine in London.[32] In 1914, Alfred Fabian Hess theorised that rubella was caused by a virus, based on work with monkeys.[33] In

1938, Hiro and Tosaka confirmed this by passing the disease to children using filtered nasal washings from

acute cases.[30]

In 1940, there was a widespread epidemic of rubella in Australia. Subsequently, ophthalmologist Norman

McAllister Gregg found 78 cases of congenital cataracts in infants and 68 of them were born to mothers who

had caught rubella in early pregnancy.[29][30] Gregg published an account, Congenital Cataract Following

German Measles in the Mother, in 1941. He described a variety of problems now known as congenital rubella

syndrome (CRS) and noticed that the earlier the mother was infected, the worse the damage was. The virus

was isolated in tissue culture in 1962 by two separate groups led by physicians Parkman and Weller. [29][31]

There was a pandemic of rubella between 1962 and 1965, starting in Europe and spreading to the United

States.[31] In the years 1964-65, the United States had an estimated 12.5 million rubella cases. This led to

11,000 miscarriages or therapeutic abortions and 20,000 cases of congenital rubella syndrome. Of these, 2,100

died as neonates, 12,000 were deaf, 3,580 were blind and 1,800 were mentally retarded. In New York alone,

CRS affected 1% of all births [34]

In 1969 a live attenuated virus vaccine was licensed.[30] In the early 1970s, a triple vaccine containing

attenuated measles, mumps and rubella (MMR) viruses was introduced.[31]

MumpsFrom Wikipedia, the free encyclopedia

For other uses of the word Mumps or MUMPS, see Mumps (disambiguation).

Mumps

Classification and external resources

Child with mumps.

ICD-10 B 26.

ICD-9 072

DiseasesDB 8449

MedlinePlus 001557

eMedicine emerg/324 emerg/391 ped/1503

MeSH D009107

Mumps and epidemic parotitis is a viral disease of the human species, caused by the mumps virus. Before

the development of vaccinationand the introduction of a vaccine, it was a common childhood

disease worldwide, and is still a significant threat to health in the third world.[1]

Painful swelling of the salivary glands (classically the parotid gland) is the most typical presentation.[2] Painful

testicular swelling (orchitis) and rash may also occur. The symptoms are generally not severe in children. In

teenage males and men, complications such as infertility orsubfertility are more common, although still rare in

absolute terms.[3][4][5] The disease is generally self-limited, running its course before receding, with no specific

treatment apart from controlling the symptoms with painkillers.

Contents

[hide]

1 Signs and symptoms

o 1.1 Prodrome

2 Cause

3 Diagnosis

4 Prevention

5 Treatment

6 Prognosis

7 Epidemiology

8 References

9 External links

[edit]Signs and symptoms

Comparison of a person before and after contracting mumps

The more common symptoms of mumps are:

Parotid  inflammation (or parotitis) in 60–70% of infections and 95% of patients with symptoms.[2] Parotitis causes swelling and local pain, particularly when chewing. It can occur on one side (unilateral)

but is more common on both sides (bilateral) in about 90% of cases.[6]

Fever

Headache

Orchitis , referring to painful inflammation of the testicle.[7] Males past puberty who develop mumps have a

30 percent risk of orchitis.[8]

Other symptoms of mumps can include dry mouth, sore face and/or ears and occasionally in more serious

cases, loss of voice. In addition, up to 20% of persons infected with the mumps virus do not show symptoms,

so it is possible to be infected and spread the virus without knowing it.[9]

[edit]Prodrome

Fever and headache are prodromal symptoms of mumps, together with malaise and anorexia.

[edit]Cause

Mumps is a contagious disease that is spread from person-to-person through contact with respiratory

secretions such as saliva from an infected person. When an infected person coughs or sneezes, the droplets

aerosolize and can enter the eyes, nose, or mouth of another person. Mumps can also be spread by sharing

food, sharing drinks, and kissing. The virus can also survive on surfaces and then be spread after contact in a

similar manner. A person infected with mumps is contagious from approximately 6 days before the onset of

symptoms until about 9 days after symptoms start.[10][11] The incubation period (time until symptoms begin) can

be from 14–25 days but is more typically 16–18 days.[12]

[edit]Diagnosis

A physical examination confirms the presence of the swollen glands. Usually the disease is diagnosed on

clinical grounds and no confirmatory laboratory testing is needed. If there is uncertainty about the diagnosis, a

test of saliva, or blood may be carried out; a newer diagnostic confirmation, using real-time nested polymerase

chain reaction (PCR) technology, has also been developed.[13] An estimated 20%-30% of cases are

asymptomatic.[14] As with any inflammation of the salivary glands, serum amylase is often elevated.[15][16]

[edit]Prevention

The most common preventative measure against mumps is immunization with a mumps vaccine, invented

by Maurice Hilleman at Merck [17] . The vaccine may be given separately or as part of the MMR

immunization vaccine which also protects against measles and rubella. In the US, MMR is now being

supplanted by MMRV, which adds protection against chickenpox. The WHO (World Health Organization)

recommends the use of mumps vaccines in all countries with well-functioning childhood vaccination

programmes. In the United Kingdom it is routinely given to children at age 15 months. The American Academy

of Pediatrics recommends the routine administration of MMR vaccine at ages 12–15 months and at 4–6 years.[18] In some locations, the vaccine is given again between 4 to 6 years of age, or between 11 and 12 years of

age if not previously given. The efficacy of the vaccine depends on the strain of the vaccine, but is usually

around 80%.[19],[20] The Jeryl Lynn strain is most commonly used in developed countries but has been shown to

have reduced efficacy in epidemic situations. The Leningrad-Zagreb strain commonly used in developing

countries appears to have superior efficacy in epidemic situations.[21]

Due to the outbreaks within college and university settings, many governments have established vaccination

programs to prevent large-scale outbreaks. In Canada, provincial governments and the Public Health Agency

of Canada have all participated in awareness campaigns to encourage students ranging from grade 1 to

college and university to get vaccinated.[22]

Some anti-vaccine activists protest against the administration of a vaccine against mumps, claiming that the

attenuated vaccine strain is harmful, and/or that the wild disease is beneficial. There is no evidence whatsoever

that the wild disease is beneficial, or that the MMR vaccine is harmful. Claims have been made that the MMR

vaccine is linked to autism andinflammatory bowel disease, including one study by Andrew Wakefield[citation

needed] (paper retracted in 2010) that indicated a link between gastrointestinal disease, autism, and the MMR

vaccine. However, all further studies[citation needed] since that time have indicated no link between vaccination with

the MMR and autism or bowel disease. Furthermore, there is scant evidence to suggest that autism is linked to

bowel disease, though several poorly designed studies have indicated a weak link between the two disorders.

Since the dangers of the disease are well known, while the dangers of the vaccine are quite minimal, most

doctors recommend vaccination.

The WHO, the American Academy of Pediatrics, the Advisory Committee on Immunization Practices of

the Centers for Disease Control and Prevention, the American Academy of Family Physicians, the British

Medical Association and the Royal Pharmaceutical Society of Great Britain currently recommend routine

vaccination of children against mumps. The British Medical Association and Royal Pharmaceutical Society of

Great Britain had previously recommended against general mumps vaccination, changing that recommendation

in 1987. In 1988 it became United Kingdom government policy to introduce mass child mumps vaccination

programmes with the MMR vaccine, and MMR vaccine is now routinely administered in the UK. [citation needed]

Before the introduction of the mumps vaccine, the mumps virus was the leading cause of viral

meningoencephalitis in the United States. However, encephalitis occurs rarely (less than 2 per 100,000). [23] In

one of the largest studies in the literature, the most common symptoms of mumps meningoencephalitis were

found to be fever (97%), vomiting (94%) and headache (88.8%).[24] The mumps vaccine was introduced into the

United States in December 1967: since its introduction there has been a steady decrease in the incidence of

mumps and mumps virus infection. There were 151,209 cases of mumps reported in 1968. Since 2001, the

case average was only 265 per year, excluding an outbreak of >6000 cases in 2006 attributed largely to

university contagion in young adults.[25][26]

[edit]Treatment

There is no specific treatment for mumps. Symptoms may be relieved by the application of intermittent ice or

heat to the affected neck/testicular area and by acetaminophen/paracetamol (Tylenol) for pain relief. Aspirin is

not used due to a hypothetical link with Reye's syndrome. Warm salt water gargles, soft foods, and extra fluids

may also help relieve symptoms.

Patients are advised to avoid fruit juice or any acidic foods, since these stimulate the salivary glands, which can

be painful.

[edit]Prognosis

Death is very unusual. The disease is self-limiting, and general outcome is good, even if other organs are

involved.

Known complications of mumps include:

Infection of other organ systems

Mumps viral infections in adolescent and adult males carry an up to 30% risk that the testes may become

infected (orchitis or epididymitis), which can be quite painful; about half of these infections result

in testicular atrophy, and in rare cases sterility can follow.[27]

Spontaneous abortion in about 27% of cases during the first trimester of pregnancy. [27]

Mild forms of meningitis in up to 10% of cases[27] (40% of cases occur without parotid swelling)

Oophoritis  (inflammation of ovaries) in about 5% of adolescent and adult females,[27] but fertility is rarely

affected.

Pancreatitis  in about 4% of cases, manifesting as abdominal pain and vomiting

Encephalitis  (very rare, and fatal in about 1% of the cases when it occurs)[27]

Profound (91 dB or more) but rare sensorineural hearing loss, uni- or bilateral. Acute unilateral deafness

occurs in about 0.005% of cases.[27]

After the illness, life-long immunity to mumps generally occurs; reinfection is possible but tends to be mild and

atypical.[27]

Measles

From Wikipedia, the free encyclopedia

Measles

Classification and external resources

ICD-10 B 05.

ICD-9 055

DiseasesDB 7890

MedlinePlus 001569

eMedicine derm/259 emerg/389 ped/1388

MeSH D008457

Measles virus

Measles virus

Virus classification

Group: Group V ((-)ssRNA)

Order: Mononegavirales

Family: Paramyxoviridae

Genus: Morbillivirus

Type species

Measles virus

Measles is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the

genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense

RNA viruses. Symptoms include fever, cough, runny nose, red eyes and a

generalized, maculopapular, erythematous rash.

Measles (sometimes known as English Measles) is spread through respiration (contact with fluids from

an infected person's nose and mouth, either directly or through aerosol transmission), and is highly contagious

—90% of people without immunity sharing a house with an infected person will catch it. The infection has an

average incubation period of 14 days (range 6–19 days) and infectivity lasts from 2–4 days prior, until 2–5 days

following the onset of the rash (i.e. 4–9 days infectivity in total).[1]

An alternative name for measles in English-speaking countries is rubeola, which is sometimes confused

with rubella (German measles); the diseases are unrelated.[2][3]

Contents

[hide]

1 Signs and symptoms

o 1.1 Complications

2 Cause

3 Diagnosis

4 Prevention

5 Treatment

6 Prognosis

7 Epidemiology

8 History and culture

o 8.1 History

o 8.2 Recent outbreaks

o 8.3 The Americas

9 Additional images

10 See also

11 References

12 External links

[edit]Signs and symptoms

This patient presented on the third pre-eruptive day with “Koplik spots” indicative of the beginning onset of measles.

The classical symptoms of measles include four day fevers, the three Cs—cough, coryza (runny nose)

and conjunctivitis (red eyes). The fever may reach up to 40 °C (104 °F). Koplik's spots seen inside the mouth

are pathognomonic (diagnostic) for measles but are not often seen, even in real cases of measles, because

they are transient and may disappear within a day of arising.

The characteristic measles rash is classically described as a generalized, maculopapular, erythematousrash

that begins several days after the fever starts. It starts on the head before spreading to cover most of the body,

often causing itching. The rash is said to "stain", changing colour from red to dark brown, before disappearing.[citation needed]

[edit]Complications

Complications with measles are relatively common, ranging from relatively mild and less serious diarrhea,

to pneumonia and encephalitis (subacute sclerosing panencephalitis), corneal ulceration leading to corneal

scarring.[4] Complications are usually more severe amongst adults who catch the virus.

The fatality rate from measles for otherwise healthy people in developed countries is 3 deaths per thousand

cases, or 0.3%.[5] In underdeveloped nations with high rates of malnutritionand poor healthcare, fatality rates

have been as high as 28%.[5] In immunocompromised patients (e.g. people with AIDS) the fatality rate is

approximately 30%.[6]

[edit]Cause

Patients with the measles should be placed on respiratory precautions.[7]

Humans are the only known natural host of measles, although the virus can infect some non-human primate

species.

[edit]Diagnosis

Clinical diagnosis of measles requires a history of fever of at least three days together with at least one of the

three C's (cough, coryza, conjunctivitis). Observation of Koplik's spots is also diagnostic of measles.

Alternatively, laboratory diagnosis of measles can be done with confirmation of positive measles IgM antibodies

or isolation of measles virus RNA from respiratory specimens. In children, where phlebotomy is inappropriate,

saliva can be collected for salivary measles specific IgA test. Positive contact with other patients known to have

measles adds strong epidemiologicalevidence to the diagnosis. The contact with any infected person in any

way, including semen through sex, saliva, or mucus can cause infection.

[edit]Prevention

Rates of measles vaccination worldwide

Measles cases reported in the United States before and after introduction of the vaccine.

Measles cases reported in England andWales before and after the introduction of the vaccine. Coverage was not

widespread enough for herd immunity to interrupt episodic outbreaks until after the MMR vaccine was introduced in 1988.

In developed countries, most children are immunized against measles by the age of 18 months, generally as

part of a three-part MMR vaccine(measles, mumps, and rubella). The vaccination is generally not given earlier

than this because children younger than 18 months usually retain anti-measles immunoglobulins (antibodies)

transmitted from the mother during pregnancy. A second dose is usually given to children between the ages of

four and five, in order to increase rates of immunity. Vaccination rates have been high enough to make

measles relatively uncommon. Even a single case in a college dormitory or similar setting is often met with a

local vaccination program, in case any of the people exposed are not already immune.

In developing countries where measles is highly endemic, the WHO recommend that two doses of vaccine be

given at six months and at nine months of age. The vaccine should be given whether the child is HIV-infected

or not.[8] The vaccine is less effective in HIV-infected infants, but the risk of adverse reactions is low.

Unvaccinated populations are at risk for the disease. After vaccination rates dropped in northern Nigeria in the

early 2000s due to religious and political objections, the number of cases rose significantly, and hundreds of

children died.[9]

In 1998 the MMR vaccine controversy in the United Kingdom regarding a potential link between the combined

MMR vaccine (vaccinating children from mumps, measles and rubella) and autism prompted a reemergence of

the "measles party", where parents deliberately expose their child to measles in the hope of building up the

child's immunity without an injection. This practice poses many health risks to the child, and has been

discouraged by the public health authorities.[10] Scientific evidence provides no support for the hypothesis that

MMR plays a role in causing autism.[11] In 2009, The Sunday Times reported that Wakefield had manipulated

patient data and misreported results in his 1998 paper, creating the appearance of a link with autism. [12] The

Lancet fully retracted the 1998 paper on 2 February 2010.[13] In January 2010, another study of Polish children

found that vaccination with the measles,mumps,and rubella vaccine was not a risk factor for development of

autistic disorder, in fact the vaccinated patients had a slightly reduced risk of autistic disorder, although the

mechanism of action behind that is unknown,and this result may have been coincidental. [14][not specific enough to verify]

The autism related MMR study in Britain caused use of the vaccine to plunge, and measles cases came back:

2007 saw 971 cases in England and Wales, the biggest rise in occurrence in measles cases since records

began in 1995.[15] A 2005 measles outbreak in Indianawas attributed to children whose parents refused

vaccination.[16]

The joint press release by members of the Measles Initiative brings to light another benefit of the fight against

measles: "Measles vaccination campaigns are contributing to the reduction of child deaths from other causes.

They have become a channel for the delivery of other life-saving interventions, such as bed nets to protect

against malaria, de-worming medicine and vitamin A supplements. Combining measles immunization with other

health interventions is a contribution to the achievement of Millennium Development Goal Number 4: a two-

thirds reduction in child deaths between 1990 and 2015."[17]

[edit]Treatment

There is no specific treatment for measles. Most patients with uncomplicated measles will recover with rest and

supportive treatment. It is, however, important to seek medical advice if the patient becomes more unwell as

they may be developing complications.

Some patients will develop pneumonia as a sequel to the measles. Other complications include ear

infections, bronchitis, and encephalitis. Acute measles encephalitis has a mortality rate of 15%. While there is

no specific treatment for measles encephalitis, antibiotics are required for bacterial pneumonia, sinusitis,

and bronchitis that can follow measles.

All other treatment is symptomatic, with ibuprofen, or acetaminophen (also called paracetamol) to reduce fever

and pain and, if required, a fast-acting bronchodilator for cough. Note that young children should never be

given aspirin without medical advice due to the risk of inducing a disease known as Reye's syndrome.[citation needed]

The use of Vitamin A in treatment has been investigated. A systematic review of trials into its use found no

significant reduction in overall mortality, but that it did reduce mortality in children aged under 2 years. [18][19][20]

[edit]Prognosis

While the vast majority of patients survive measles, complications occur fairly frequently and may

include bronchitis, pneumonia, otitis media, hemorrhagic complications, acute disseminated encephalomyelitis,

acute measles encephalitis, subacute sclerosing panencephalitis (sspe), blindness, deafness, and death.

Statistically out of 1000 measles cases, 2-3 patients die, and 5-105 suffer complications. In patients who do not

develop complications, the prognosis is generally excellent. However, although most patients survive, it is still

important to get vaccinated, as up to 15 percent of measles patients experience complications, some fairly

mild, others (such as subacute sclerosing panencephalitis) typically fatal. Also, even if the patient is not

concerned about death or sequela from the measles, the person may spread the disease to an

immunocompromised patient, for whom the risk of death is much higher, due to complications such as giant

cell pneumonia. Acute measles encephalitis is another serious risk of measles virus infection. It typically occurs

2 days to one week after the breakout of the measles exanthem, and begins with very high fever, severe

headache, convulsions, and altered mentation. Patient may become comatose, and death or brain injury may

occur.[21]

[edit]Epidemiology

Disability-adjusted life year for measles per 100,000 inhabitants in 2002.

      no data       ≤ 10      10-25      25-50      50-75      75-100      100-250      250-500      500-750      750-1000      1000-1500      1500-2000      ≥ 2000

According to the World Health Organization (WHO), measles is a leading cause of vaccine-preventable

childhood mortality. Worldwide, the fatality rate has been significantly reduced by a vaccination campaign led

by partners in the Measles Initiative: the American Red Cross, the United States Centers for Disease Control

and Prevention (CDC), the United Nations Foundation, UNICEF and the World Health Organization (WHO).

Globally, measles fell 60% from an estimated 873,000 deaths in 1999 to 345,000 in 2005. [17] Estimates for 2008

indicate deaths fell further to 164,000 globally, with 77% of the remaining measles deaths in 2008 occurring

within the South-East Asian region.[22]

Five out of six WHO regions have set goals to eliminate measles, and at the 63rd World Health Assembly in

May 2010, delegates agreed a global target of a 95% reduction in measles mortality by 2015 from the level

seen in 2000, as well as to move towards eventual eradication. However, no specific global target date for

eradication has yet been agreed as of May 2010.[23][24]

[edit]History and culture

[edit]History

The Antonine Plague, 165-180 AD, also known as the Plague of Galen, who described it, was

probably smallpox or measles. Disease killed as much as one-third of the population in some areas, and

decimated the Roman army.[25] The first scientific description of measles and its distinction from smallpox

and chickenpox is credited to the Persian physician, Muhammad ibn Zakariya ar-Razi (860-932), known to the

West as "Rhazes", who published a book entitled The Book of Smallpox and Measles (in Arabic: Kitab fi al-

jadari wa-al-hasbah).[26]

Measles is an endemic disease, meaning that it has been continually present in a community, and many people

develop resistance. In populations that have not been exposed to measles, exposure to a new disease can be

devastating. In 1529, a measles outbreak in Cubakilled two-thirds of the natives who had previously survived

smallpox. Two years later measles was responsible for the deaths of half the population of Honduras, and had

ravaged Mexico, Central America, and the Inca civilization.[27]

In roughly the last 150 years, measles has been estimated to have killed about 200 million people worldwide.[28] During the 1850s, measles killed a fifth of Hawaii's people.[29] In 1875, measles killed over 40,000 Fijians,

approximately one-third of the population.[30] In the 19th century, the disease decimated

the Andamanese population.[31] In 1954, the virus causing the disease was isolated from an 11-year old boy

from the United States, David Edmonston, and adapted and propagated on chick embryo tissue culture.[32] To

date, 21 strains of the measles virus have been identified.[33] While at Merck, Maurice Hilleman developed the

first successful vaccine[34]. Licensed vaccines to prevent the disease became available in 1963.

[edit]Recent outbreaksMain article: Measles outbreaks in the 2000s

Since the beginning of September, 2009, Johannesburg, a city in Gauteng, South Africa reported about 48

cases of measles. Soon after the outbreak, the Government ordered that all children be vaccinated.

Vaccination programs were then initiated in all schools and parents of young children were advised to have

them vaccinated.[35] Many people were not willing to have the vaccination done, as it is believed to be unsafe

and ineffective. The Health Department assured the public that their program was indeed safe. Speculation

arose as to whether or not new needles were being used.[36] By mid-October there were at least 940 recorded

cases, and 4 deaths.[37]

On February 19, 2009, 505 measles cases were reported in twelve provinces in the North of Vietnam,

with Hanoi accounting for 160 cases.[38] A high rate of complications includingmeningitis & encephalitis has

worried health workers[39] and the U.S. CDC recommended that all travelers be immune to measles.[40]

On The 1st of April 2009, an outbreak has happened in two schools in North Wales. Ysgol John

Bright and Ysgol Ffordd Dyffryn in Wales have had the outbreak and are making sure every pupil has had

the Measles vaccine.

In 2007, a large measles outbreak in Japan caused a number of universities and other institutions to close in an

attempt to contain the disease.[41][42]

Approximately 1000 cases of the disease were reported in Israel between August 2007 and May 2008 (in sharp

contrast to just some dozen cases the year before).[citation needed] Many children in ultra-Orthodox Jewish

communities were affected due to low vaccination coverage.[43][44] As of 2008 the disease is endemic in

the United Kingdom with 1,217 cases diagnosed in 2008 [45] and epidemics have been reported

in Austria, Italy and Switzerland. Low vaccination rates are responsible.[46]

In March 2010, Philippines declared an epidemic about the continuously rising cases of measles. [citation needed]

[edit]The Americas

Indigenous measles were declared to have been eliminated in North, Central, and South America; the last

endemic case in the region was reported on November 12, 2002, with only Northern Argentina and

rural Canada, particularly in the provinces of Ontario, Quebec, and Alberta having minor endemic status.[47] Outbreaks are still occurring, however, following importations of measles viruses from other world regions. In

June 2006, an outbreak in Boston resulted after a resident became infected in India,[48] and in October 2007,

a Michigan girl who had been vaccinated contracted the disease in Sweden.[49]

Between January 1 and April 25, 2008, a total of 64 confirmed measles cases were preliminarily reported in the

United States to the Centers for Disease Control and Prevention,[50][51]the most reported by this date for any

year since 2001. Of the 64 cases, 54 were associated with importation of measles from other countries into the

United States, and 63 of the 64 patients were unvaccinated or had unknown or undocumented vaccination

status.[52]

By July 9, 2008, a total of 127 cases were reported in 15 states (including 22 in Arizona),[53] making it the

largest U.S. outbreak since 1997 (when 138 cases were reported). [54] Most of the cases were acquired outside

of the United States and afflicted individuals who had not been vaccinated.

By July 30, 2008, the number of cases had grown to 131. Of these, about half involved children whose parents

rejected vaccination. The 131 cases occurred in 7 different outbreaks. There were no deaths, and 15

hospitalizations. 11 of the cases had received at least one dose of the measles vaccine. 122 of the cases

involved children who were unvaccinated or whose vaccination status was unknown. Some of these were

under the age of one year old and below the age when vaccination is recommended, but in 63 cases the

vaccinations had been refused for religious or philosophical reasons.

[edit]Additional images

Intra oral rash of measlesMeasles in African Child

This European child shows a classic

day-4 rash with measles.

Histopathology of measles

pneumonia. Giant cell

ChickenpoxFrom Wikipedia, the free encyclopedia

"Varicella" redirects here. For the interactive fiction computer game, see Varicella (computer game).

For other uses, see Chickenpox (disambiguation).

This article needs attention from an expert on the subject. See the talk page for details. WikiProject Medicine or the Medicine Portal may be able to help recruit an expert. (March 2008)

This article may require cleanup to meet Wikipedia's quality standards. Please improve this article if you can. (September 2009)

Chickenpox

Classification and external resources

Child with varicella disease

ICD-10 B 01.

ICD-9 052

DiseasesDB 29118

MedlinePlus 001592

eMedicine ped/2385 derm/74,emerg/367

MeSH C02.256.466.175

Chickenpox or chicken pox is a highly contagious illness caused by primary infection with varicella zoster

virus (VZV).[1] It usually starts with vesicular skin rash mainly on the body and head rather than at the periphery

and become itchy, raw pockmarks, which mostly heal without scarring.

Chicken pox is spread easily through coughs or sneezes of ill individuals or through direct contact with

secretions from the rash. Following primary infection there is usually lifelong protective immunity from further

episodes of chickenpox.

Chickenpox is rarely fatal, although it is generally more severe in adult males than in adult females or children.

Pregnant women and those with a suppressed immune system are at highest risk of serious complications.

Chicken pox is now believed to be the cause of one third of stroke cases in children. [2] The most common late

complication of chicken pox is shingles, caused by reactivation of the varicella zoster virus decades after the

initial episode of chickenpox.

Chickenpox has been observed in other primates, including chimpanzees [3]  and gorillas.[4]

Contents

[hide]

1 Signs and symptoms

2 Diagnosis

3 Epidemiology

4 Pathophysiology

o 4.1 Infection in pregnancy and neonates

o 4.2 Shingles

5 Prevention

o 5.1 Hygiene measures

o 5.2 Vaccine

6 Treatment

o 6.1 Children

o 6.2 Adults

7 Prognosis

8 History

9 See also

10 References

11 External links

[edit]Signs and symptoms

Chickenpox is a highly infectious disease that spreads from person to person by direct contact or by air from an

infected person's coughing or sneezing. Touching the fluid blister can also spread the disease. A person with

chickenpox is infectious from one to five days before the rash appears.[5] The contagious period continues until

all blisters have formed scabs, which may take 5 to 6 days at which point they are no longer contagious. [6] It

takes from 10 to 21 days after contact with an infected person for someone to develop chickenpox. Chickenpox

(varicella) is often heralded by a prodrome of anorexia, myalgia, nausea, fever, headache, sore throat, pain in

both ears, complaints of pressure in head or swollen face, andmalaise in adolescents and adults, while in

children the first symptom is usually the development of a papular rash, followed by development

of malaise, fever (a body temperature of 38 °C (100 °F), but may be as high as 42 °C (108 °F) in rare cases),

and anorexia. Rarely cough, rhinitis, abdominal pain, and gastrointestinal distress has been reported in patients

with varicella. Typically, the disease is more severe in adults.[7]

A single blister, typical during the early stages of the rash The back of a 30-year-old male, taken on day 5 of the rash

[edit]Diagnosis

The diagnosis of varicella is primarily clinical, with typical early "prodromal" symptoms, and then the

characteristic rash. Confirmation of the diagnosis can be sought through either examination of the fluid within

the vesicles of the rash, or by testing blood for evidence of an acute immunologic response.

Vesicular fluid can be examined with a Tsanck smear, or better with examination for direct fluorescent antibody.

The fluid can also be "cultured", whereby attempts are made to grow the virus from a fluid sample. Blood tests

can be used to identify a response to acute infection (IgM) or previous infection and subsequent immunity

(IgG).[8]

Prenatal diagnosis of fetal varicella infection can be performed using ultrasound, though a delay of 5 weeks

following primary maternal infection is advised. A PCR (DNA) test of the mother's amniotic fluid can also be

performed, though the risk of spontaneous abortion due to the amniocentesis procedure is higher than the risk

of the baby developing foetal varicella syndrome.[9]

[edit]Epidemiology

Primary varicella is an endemic disease. Cases of varicella are seen throughout the year but more commonly in

winter and early spring. Varicella is one of the classic diseases of childhood, with the highest prevalence in the

4–10 year old age group. Like rubella, it is uncommon in preschool children. Varicella is highly communicable,

with an infection rate of 90% in close contacts. Most people become infected before adulthood but 10% of

young adults remain susceptible.

Historically, varicella has been a disease predominantly affecting preschool and school-aged children. In adults

the pock marks are darker and the scars more prominent than in children.[10]

[edit]Pathophysiology

Exposure to VZV in a healthy child initiates the production of host immunoglobulin G (IgG), immunoglobulin

M (IgM), and immunoglobulin A (IgA) antibodies; IgG antibodies persist for life and confer immunity. Cell-

mediated immune responses are also important in limiting the scope and the duration of primary varicella

infection. After primary infection, VZV is hypothesized to spread from mucosal and epidermal lesions to

local sensory nerves. VZV then remains latent in the dorsal ganglion cells of the sensory nerves. Reactivation

of VZV results in the clinically distinct syndrome of herpes zoster (i.e., shingles), and sometimes Ramsay Hunt

syndrome type II.[citation needed]

[edit]Infection in pregnancy and neonates

For pregnant women, antibodies produced as a result of immunization or previous infection are transferred via

the placenta to the fetus.[11] Women who are immune to chickenpox cannot become infected and do not need to

be concerned about it for themselves or their infant during pregnancy. [12]

Varicella infection in pregnant women can lead to viral transmission via the placenta and infection of the fetus.

If infection occurs during the first 28 weeks of gestation, this can lead to fetal varicella syndrome (also known

as congenital varicella syndrome).[13] Effects on the fetus can range in severity from underdeveloped toes and

fingers to severe anal and bladder malformation. Possible problems include:

Damage to brain: encephalitis,[14] microcephaly, hydrocephaly, aplasia of brain

Damage to the eye: optic stalk, optic cap, and lens vesicles, microphthalmia, cataracts, chorioretinitis, optic

atrophy

Other neurological disorder: damage to cervical and lumbosacral spinal cord, motor/sensory deficits,

absent deep tendon reflexes, anisocoria/Horner's syndrome

Damage to body: hypoplasia of upper/lower extremities, anal and bladder sphincter dysfunction

Skin disorders: (cicatricial) skin lesions, hypopigmentation

Infection late in gestation or immediately following birth is referred to as "neonatal varicella".[15] Maternal

infection is associated with premature delivery. The risk of the baby developing the disease is greatest

following exposure to infection in the period 7 days prior to delivery and up to 7 days following the birth. The

baby may also be exposed to the virus via infectious siblings or other contacts, but this is of less concern if the

mother is immune. Newborns who develop symptoms are at a high risk of pneumonia and other serious

complications of the disease.[9]

[edit]ShinglesMain article: Shingles

After a chickenpox infection, the virus remains dormant in the body's nerve tissues. The immune system keeps

the virus at bay, but later in life, usually as an adult, it can be reactivated and cause a different form of the virus

called shingles.[16]

[edit]Prevention

[edit]Hygiene measures

The spread of chicken pox can be prevented by isolating affected individuals. Contagion is by exposure to

respiratory droplets, or direct contact with lesions, within a period lasting from three days prior to the onset of

the rash, to four days after the onset of the rash.[17] Therefore, avoidance of close proximity or physical contact

with affected individuals during that period will prevent contagion. The chicken pox virus (VZV) is susceptible to

disinfectants, notably chlorine bleach (i.e., sodium hypochlorite). Also, like all enveloped viruses, VZV is

sensitive to desiccation, heat and detergents. Therefore these viruses are relatively easy to kill.

[edit]VaccineMain article: Varicella vaccine

A varicella vaccine was first developed by Michiaki Takahashi in 1974 derived from the Oka strain. It has been

available in the U.S. since 1995 to inoculate against the disease. Some countries require the varicella

vaccination or an exemption before entering elementary school. Protection is not lifelong and further

vaccination is necessary five years after the initial immunization.[18] The chickenpox vaccine is not part of the

routine childhood vaccination schedule in the UK. In the UK, the vaccine is currently only offered to people who

are particularly vulnerable to chickenpox.[19]

[edit]Treatment

This section requires expansion.

Although there have been no formal clinical studies evaluating the effectiveness of topical application

of calamine lotion, a topical barrier preparation containing zinc oxide and one of the most commonly used

interventions, it has an excellent safety profile.[20] It is important to maintain good hygiene and daily cleaning

of skin with warm water to avoid secondary bacterial infection.[21] Scratching may also increase the risk of

secondary infection.[22] Addition of a small quantity of vinegar to the water is sometimes advocated. Painkillers

could be taken to prevent feeling itchy [23]

To relieve the symptoms of chicken pox, people commonly use anti-itching creams and lotions. These lotions

are not to be used on the face or close to the eyes. An oatmeal bath also might help ease discomfort.[24]

Varicella treatment mainly consists of easing the symptoms as there is no actual cure of the condition. Some

treatments are however available for relieving the symptoms while theimmune system clears the virus from

the body. As a protective measure, patients are usually required to stay at home while they are infectious to

avoid spreading the disease to others. Also, sufferers are frequently asked to cut their nails short or to

wear gloves to prevent scratching and to minimize the risk of secondary infections.

The condition resolves by itself within a couple of weeks but meanwhile patients must pay attention to their

personal hygiene.[25] The rash caused by varicella zoster virus may however last for up to one month, although

the infectious stage does not take longer than a week or two.[26] Also, staying in a cold surrounding can help in

easing the itching as heat and sweatmakes it worse. Calamine lotion may be tried as it may relieve the

symptoms because of its soothing, cooling effect on the skin.

Natural chicken pox remedies include pea water, baking soda, vitamin E oil, honey, herbal

tea or carrot and coriander. It is believed that the irritation of the skin can be relieved to some extent with water

in which fresh peas have been cooked.[27] A lotion made of baking soda with water can be sponged onto the

skin of the patients to ease the itching. Also, rubbing vitamin E oil or honey on the skin is thought to have a

healing effect on the marks that could remain after the infection has been cured. Some people claim that the

mild sedative effect ofgreen tea is effective in relieving the symptoms. It is not however known to what extent

these home remedies can actually help the patients cope better with their symptoms.

A varicella vaccine is available for people who have been exposed to the virus, but have not experienced

symptoms. The vaccine is more effective if administered within three days and up to five days after exposure. It

has been shown that the chicken pox vaccine may prevent or reduce the symptoms in 90% of cases, if given

within three days after exposure. People who have been exposed to the virus but who are contraindicated to

receive the vaccine, there is a medication available, called varicella zoster immunoglobulin or VZIG which may

prevent or reduce the symptoms after exposure. VZIG is primarily administered to individuals who are at risk of

developing complications due to its high costs and temporary protection. This type of treatment is only

recommended in newborns whose mothers have had chicken pox few days prior or after delivery, children

with leukemia or lymphoma, people with a poor immune system or pregnant women. VZIG is recommended to

be administered no later than 96 hours after exposure to the virus.

[edit]Children

If oral acyclovir is started within 24 hours of rash onset it decreases symptoms by one day but has no effect on

complication rates. Use of acyclovir therefore is not currently recommended for immunocompetent individuals

(i.e., otherwise healthy persons without known immunodeficiency or those on immunosuppressive medication).[28]

Treatment of chicken pox in children is aimed at symptoms whilst the immune system deals with the virus.[29] With children younger than 12 years cutting nails and keeping them clean is an important part of treatment

as they are more likely to deep scratch their blisters. Children younger than 12 years old and older than one

month are not meant to receive antiviral medication if they are not suffering from another medical condition

which would put them at risk of developing complications.

Increased amounts of water are recommended to avoid dehydration, especially if the child develops fever.

Fever, headaches or pain can be relieved with painkillers such as ibuprofen orparacetamol. Children who are

older than one year may be administered antihistamine tablets or liquid medicines which are helpful in cases

when the child is not able to sleep because of the itching.

Acyclovir or immunoglobulin is generally prescribed in children who are at risk of complications from chicken

pox. They receive the same treatment as the one mentioned above plus antiviral medication additionally. The

category of children that are considered at risk to develop complications includes infants less than one month

old, those with a suppressed immune system, those who are taking steroids or immune suppressing

medication or children with severe heart, lung and skin conditions. Moreover, adults and teenagers are

considered at risk of complications and they are normally administered antiviral medication.

Aspirin is highly contraindicated in children younger than 16 years as it has been related with a potentially fatal

condition known as Reye's syndrome.

[edit]Adults

Infection in otherwise healthy adults tends to be more severe and active; treatment with

antiviral drugs (e.g. acyclovir) is generally advised, as long as it is started within 24–48 hours from rash onset.[30]

Remedies to ease the symptoms of chicken pox in adults are basically the same as those used on children.

Moreover, adults are often prescribed antiviral medication as it is effective in reducing the severity of the

condition and the likelihood of developing complications. Antiviral medicines are not however aimed to kill the

virus, but to stop it from multiplying.

Adults are also advised to increase the water intake to reduce dehydration and to relieve headaches.

Painkillers such as paracetamol and ibuprofen are also recommended as they are effective in relieving itching

and other symptoms such as fever or pains. Antihistamines may be used in cases when the symptoms cause

the inability to sleep, as they are efficient for easing the itching and they are acting as a sedative.

As with children, antiviral medication is considered more useful for those adults who are more prone to develop

complications. These include pregnant women or people who have a poor immune system.[31]

Sorivudine, a nucleoside analogue has been found in few case reports effective in the treatment of primary

varicella in healthy adults. Larger scale clinical trials are needed to demonstrate the efficacy of this medication.[32]

[edit]Prognosis

The duration of the visible blistering caused by varicella zoster virus varies in children usually from 4 to 7 days,

and the appearance of new blisters begins to subside after the 5th day. Chickenpox infection is milder in young

children, and symptomatic treatment, with sodium bicarbonate baths or antihistamine medication may ease

itching.[33] Paracetamol(acetaminophen) is widely used to reduce fever. Aspirin, or products containing aspirin,

must not be given to children with chickenpox as this risks causing Reye's Syndrome.[34]

In adults, the disease is more severe,[35] though the incidence is much less common. Infection in adults is

associated with greater morbidity and mortality due to pneumonia,[36] hepatitis , and encephalitis.[citation needed] In

particular, up to 10% of pregnant women with chickenpox develop pneumonia, the severity of which increases

with onset later in gestation. In England and Wales, 75% of deaths due to chickenpox are in adults.[9] Inflammation of the brain, or encephalitis, can occur in immunocompromised individuals, although the risk is

higher with herpes zoster.[37] Necrotizing fasciitis is also a rare complication.[38]

Secondary bacterial infection of skin lesions, manifesting as impetigo, cellulitis, and erysipelas, is the most

common complication in healthy children. Disseminated primary varicella infection usually seen in the

immunocompromised may have high morbidity. Ninety percent of cases of varicella pneumonia occur in the

adult population. Rarer complications of disseminated chickenpox also include myocarditis, hepatitis,

and glomerulonephritis.[39]

Hemorrhagic complications are more common in the immunocompromised or immunosuppressed populations,

although healthy children and adults have been affected. Five major clinical syndromes have been

described: febrile purpura, malignant chickenpox with purpura, postinfectious purpura, purpura fulminans,

and anaphylactoid purpura. These syndromes have variable courses, with febrile purpura being the most

benign of the syndromes and having an uncomplicated outcome. In contrast, malignant chickenpox with

purpura is a grave clinical condition that has a mortality rate of greater than 70%. The etiology of these

hemorrhagic chickenpox syndromes is not known.[39]

CholeraFrom Wikipedia, the free encyclopedia

To comply with Wikipedia's guidelines, the introduction of this article may need to be rewritten. Please discuss this issue on the talk page and read the layout guide to make sure the section will be inclusive of all essential details. (April 2010)

Cholera

Classification and external resources

Scanning Electron Microscope image of Vibrio cholerae

ICD-10 A A00.htm+ A00 00 . ,

ICD-9 001

DiseasesDB 29089

MedlinePlus 000303

eMedicine med/351

MeSH D002771

Cholera[1] is a severe bacterial infection caused by the bacteria Vibrio cholerae, which primarily affects

the small intestine. The main symptoms include profuse watery diarrhea and vomiting. Transmission is

primarily by the acquisition of the pathogen through contaminated drinking water or infected food. The severity

of the diarrhea and associated vomiting can lead to rapid dehydration and electrolyte loss, which can lead to

death. Cholera is a major cause of death in the world.

The study of cholera has been used as an example of early epidemiology. Study of the V. cholerae bacterium

has also shed light on many of the mechanisms used by bacteria to infect and survive in their hosts.

Contents

[hide]

1 Signs and symptoms

2 Cause

3 Pathophysiology

o 3.1 Susceptibility

o 3.2 Transmission

3.2.1 Potential human contribution to transmissibility

4 Diagnosis

o 4.1 Enrichment media

o 4.2 Plating media

5 Prevention

6 Treatment

7 Epidemiology

o 7.1 Pandemic genetic diversity

8 History

o 8.1 Origin and spread

o 8.2 False historical report

o 8.3 Cholera morbus

o 8.4 Other historical information

o 8.5 Research

o 8.6 Famous victims

9 Notes

10 See also

11 References

12 Further reading

13 External links

[edit]Signs and symptoms

The primary symptoms of cholera are profuse diarrhea, severe dehydration and abdominal pain. Cholera may

also cause vomiting. These symptoms start suddenly, usually one to five days after infection, and are the result

of a toxin produced by the vibrio cholerae bacterium that compels profuse amounts of fluid from the blood

supply into the small and large intestines.D.Kindersley (editor) (1989). AMA Encyclopedia of Medicine. Random

House. ISBN 0-394-56528-2.</ref> An untreated cholera patient may produce several gallons of diarrhoeal

fluid a day.

[edit]Cause

TEM image of Vibrio cholerae

Most of the V. cholerae bacteria in the contaminated water consumed by the host do not survive the highly

acidic conditions of the human stomach.[2] The few bacteria that do survive conserve their energy and stored

nutrients during the passage through the stomach by shutting down much protein production. When the

surviving bacteria exit the stomach and reach the small intestine, they need to propel themselves through the

thick mucus that lines the small intestine to get to the intestinal wall where they can thrive. V. cholerae bacteria

start up production of the hollow cylindrical protein flagellin to make flagella, the curly whip-like tails that they

rotate to propel themselves through the mucus of the small intestine.

Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move any longer.

The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the

mix of proteins which they manufacture in response to the changed chemical surroundings. On reaching the

intestinal wall, V. cholerae start producing the toxic proteins that give the infected person a watery diarrhea.

This carries the multiplying new generations of V. cholerae bacteria out into the drinking water of the next host

if proper sanitation measures are not in place.

The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A

subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits

form a five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium cells. The

A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, while the A2 chain fits into the

central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated

endocytosis. Once inside the cell, the disulfide bond is reduced and the A1 subunit is freed to bind with a

human partner protein called ADP-ribosylation factor 6 (Arf6).[3] Binding exposes its active site, allowing it to

permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP

production, which in turn leads to secretion of H2O, Na+, K+, Cl−, and HCO3− into the lumen of the small intestine

and rapid dehydration. The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene

transfer. Virulent strains of V. cholerae carry a variant of lysogenic bacteriophage called CTXf or CTXφ.

Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated

inside the cell (PDB code: 1xtc).

Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off the production

of some proteins and turn on the production of other proteins as they respond to the series of chemical

environments they encounter, passing through the stomach, through the mucous layer of the small intestine,

and on to the intestinal wall.[4] Of particular interest have been the genetic mechanisms by which cholera

bacteria turn on the protein production of the toxins that interact with host cell mechanisms to

pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from

entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which

through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive

amounts of diarrhea. The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and

sugar is not taken to replace the blood's water and salts lost in the diarrhea.

By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria such as E.

coli that would not naturally produce the protein toxins, researchers have investigated the mechanisms by

which V. cholerae responds to the changing chemical environments of the stomach, mucous layers, and

intestinal wall. Researchers have discovered that there is a complex cascade of regulatory proteins that control

expression of V. cholerae virulence determinants. In responding to the chemical environment at the intestinal

wall, the V. choleraebacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins,

activate the expression of the ToxT regulatory protein. ToxT then directly activates expression

of virulence genes that produce the toxins that cause diarrhea in the infected person and that permit the

bacteria to colonize the intestine.[4] Current research aims at discovering "the signal that makes the cholera

bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine." [4]

[edit]Pathophysiology

[edit]Susceptibility

Recent epidemiologic research suggests that an individual's susceptibility to cholera (and other diarrheal

infections) is affected by their blood type: those with type O blood are the most susceptible,[5][6] while those

with type AB are the most resistant. Between these two extremes are the A and B blood types, with type A

being more resistant than type B.[citation needed]

About one million V. cholerae bacteria must typically be ingested to cause cholera in normally healthy adults,

although increased susceptibility may be observed in those with a weakened immune system, individuals with

decreased gastric acidity (as from the use of antacids), or those who are malnourished.

It has also been hypothesized that the cystic fibrosis genetic mutation has been maintained in humans due to a

selective advantage: heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are

more resistant to V. cholerae infections.[7] In this model, the genetic deficiency in the cystic fibrosis

transmembrane conductance regulator channel proteins interferes with bacteria binding to

the gastrointestinal epithelium, thus reducing the effects of an infection.

[edit]Transmission

Drawing of Death bringing the cholera, inLe Petit Journal

People infected with cholera suffer acute diarrhea. This highly liquid diarrhea, colloquially referred to as "rice-

water stool," is loaded with bacteria that can infect water used by other people. [8] Cholera is transmitted through

ingestion of water contaminated with the cholera bacterium, usually from feces or other effluent. The source of

the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get

into waterways or into groundwater or drinking water supplies. Any infected water and any foods washed in the

water, as well as shellfish living in the affected waterway, can cause an infection. Cholera is rarely spread

directly from person to person. V. cholerae harbors naturally in the zooplankton of fresh, brackish, and salt

water, attached primarily to their chitinous exoskeleton.[9] Both toxic and non-toxic strains exist. Non-toxic

strains can acquire toxicity through a lysogenic bacteriophage.[10] Coastal cholera outbreaks typically

follow zooplankton blooms, thus making cholera a zoonotic disease.

[edit]Potential human contribution to transmissibility

Cholera bacteria grown in vitro encounter difficulty subsequently growing in humans without additional stomach

acid buffering. In a 2002 study at Tufts University School of Medicine, it was found that stomach acidity is a

principal agent that advances epidemic spread.[11] In their findings, the researchers found that human

colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may

contribute to epidemic spread of the disease. When these hyperinfectious bacteria underwent transcription

profiles, they were found to possess a unique physiological and behavioral state, characterized by high

expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes

required for bacterial chemotaxis. Thus, the spread of cholera can be expedited by host physiology.

[edit]Diagnosis

In epidemic situations, a clinical diagnosis is made by taking a history of symptoms from the patient and by a

brief examination only. Treatment is usually started without or before confirmation by laboratory analysis of

specimens.

Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered,

are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most

common causative agent is Vibrio cholerae O1. If V. cholerae serogroup O1 is not isolated, the laboratory

should test for V. cholerae O139. However, if neither of these organisms is isolated, it is necessary to send

stool specimens to a reference laboratory. Infection with V. cholerae O139 should be reported and handled in

the same manner as that caused by V. cholerae O1. The associated diarrheal illness should be referred to as

cholera and must be reported.[12]

A number of special media have been employed for the cultivation for cholera vibrios. They are classified as

follows:

[edit]Enrichment media

1. Alkaline peptone water at pH 8.6

2. Monsur's taurocholate tellurite peptone water at pH 9.2

[edit]Plating media

1. Alkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar.

2. Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios produce small

translucent colonies with a greyish black centre.

3. TCBS medium: This the mostly widely used medium. This medium contains thiosulphate, citrate, bile

salts and sucrose. Cholera vibrios produce flat 2–3 mm in diameter, yellow nucleated colonies.

Direct microscopy of stool is not recommended as it is unreliable. Microscopy is preferred only after

enrichment, as this process reveals the characteristic motility of Vibrios and its inhibition by

appropriate antiserum. Diagnosis can be confirmed as well as serotyping done by agglutination with specific

sera.

[edit]Prevention

Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper

sanitation practices are followed. In the first world, due to nearly universal advancedwater treatment and

sanitation practices, cholera is no longer a major health threat. The last major outbreak of cholera in the United

States occurred in 1910-1911.[13][14] Travelers should be aware of how the disease is transmitted and what can

be done to prevent it. Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to

stop an epidemic. There are several points along the cholera transmission path at which its spread may be

(and should be) halted:

Cholera hospital in Dhaka, showing typical cholera beds.

Sterilization: Proper disposal and treatment of infected fecal waste water produced by cholera victims and

all contaminated materials (e.g. clothing, bedding, etc.) is essential. All materials that come in contact with

cholera patients should be sterilized by washing in hot water using chlorine bleach if possible. Hands that

touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with

chlorinated water or other effective anti-microbial agents.

Sewage: anti-bacterial treatment of general sewage by chlorine, ozone, ultra-violet light or other effective

treatment before it enters the waterways or underground water supplies helps prevent undiagnosed

patients from inadvertently spreading the disease.

Sources: Warnings about possible cholera contamination should be posted around contaminated water

sources with directions on how todecontaminate the water (boiling, chlorination etc.) for possible use.

Water purification: All water used for drinking, washing, or cooking should be sterilized by either

boiling, chlorination, ozone water treatment, ultra-violet light sterilization, or anti-microbal filtration in any

area where cholera may be present. Chlorination and boiling are often the least expensive and most

effective means of halting transmission. Cloth filters, though very basic, have significantly reduced the

occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water.

Better anti-microbial filters like those present in advanced individual water treatment hiking kits are most

effective. Public health education and adherence to appropriate sanitation practices are of primary

importance to help prevent and control transmission of cholera and other diseases.

A vaccine for cholera is available in some countries, but prophylactic usage is not currently recommended for

routine use by the Centers for Disease Control and Prevention (CDC).[15] During recent years, substantial

progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which

have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are

commercially available in several countries: a killed whole-cell V. cholerae O1 in combination with purified

recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the

genetically manipulated V. cholerae O1 strain CVD 103-HgR. The appearance of V. cholerae O139 has

influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently

available vaccines is effective against this strain.[12] The newer vaccine (brand name: Dukoral), an orally

administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer

adverse effects than the previously available vaccine.[15] This safe and effective vaccine is available for use by

individuals and health personnel. Work is under way to investigate the role of mass vaccination. [16]

Sensitive surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a

seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance

systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in

preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for

potential cholera outbreaks. Understanding the seasonality and location of outbreaks provide guidance for

improving cholera control activities for the most vulnerable. This will also aid in the developing indicators for

appropriate use of oral cholera vaccine.[17]

[edit]Treatment

Cholera patient being treated by medical staff in 1992.

In most cases cholera can be successfully treated with oral rehydration therapy (ORT). ORT is highly effective,

safe, and simple to administer: prompt replacement of water and electrolytes is the principal treatment for

cholera, as dehydration and electrolyte depletion occur rapidly. In situations where commercially produced

ORT sachets are too expensive or difficult to obtain, alternative homemade solutions using various formulas of

water, sugar, table salt, baking soda, and fruit offer less expensive methods of electrolyte repletion. In severe

cholera cases with significant dehydration, the administration of intravenous rehydration solutions may be

necessary.

Antibiotics shorten the course of the disease and reduce the severity of the symptoms; however, oral

rehydration therapy remains the principal treatment. Tetracycline is typically used as the primary antibiotic,

although some strains of V. cholerae have shown resistance. Other antibiotics that have been proven effective

against V. cholerae include cotrimoxazole, erythromycin, doxycycline, chloramphenicol, andfurazolidone.[18] Fluoroquinolones such as norfloxacin also may be used, but resistance has been reported.[19]

Rapid diagnostic assay methods are available for the identification of multi-drug resistant V. cholerae.[20] New

generation antimicrobials have been discovered which are effective against V. cholerae in in vitro studies.[21]

The success of treatment is significantly affected by the speed and method of treatment. If cholera patients are

treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality

rate rises to 50–60%.[22][23]

[edit]Epidemiology

By 12 February 2009, the number of cases of infection by cholera in sub-Saharan Africa had reached 128,548 and the

number of fatalities, 4,053.

In 2000, some 140,000 cholera cases were officially notified to WHO. Africa accounted for 87% of these

cases.[24]

July - December 2007 - A lack of clean drinking water in Iraq has led to an outbreak of cholera.[25] As of 2

December 2007, the UN has reported 22 deaths and 4,569 laboratory-confirmed cases. [26]

August 2007 - The cholera epidemic started in Orissa, India. The outbreak has affected Rayagada,

Koraput and Kalahandi districts where more than 2,000 people have been admitted to hospitals. [27]

August - October 2008 - As of 29 October 2008, a total of 644 laboratory-confirmed cholera cases,

including eight deaths, had been verified in Iraq.[28]

March - April 2008 - 2,490 people from 20 provinces throughout Vietnam have been hospitalized with acute

diarrhea. Of those hospitalized, 377 patients tested positive for cholera. [29]

November 2008 - Doctors Without Borders reported an outbreak in a refugee camp in the Democratic

Republic of the Congo's eastern provincial capital of Goma. Some 45 cases were reportedly treated

between November 7 through 9th.

August 2008 - April 2009: In the 2008 Zimbabwean cholera outbreak, which is still continuing, an

estimated 96,591 people in thecountry have been infected with cholera and, by 16 April 2009, 4,201

deaths had been reported.[30] According to the World Health Organization, during the week of 22–28 March

2009, the "Crude Case Fatality Ratio (CFR)" had dropped from 4.2% to 3.7%.[30] The daily updates for the

period 29 March 2009 to 7 April 2009, list 1748 cases and 64 fatalities, giving a weekly CFR of 3.66% (see

table above);[31]however, those for the period 8 April to 16 April list 1375 new cases and 62 deaths (and a

resulting CFR of 4.5%).[31] The CFR had remained above 4.7% for most of January and early February

2009.[32]

January 2009 - The Mpumalanga province of South Africa has confirmed over 381 new cases of Cholera,

bringing the total number of cases treated since November 2008 to 2276. 19 people have died in the

province since the outbreak.[33]

[edit]Pandemic genetic diversity

Amplified fragment length polymorphism (AFLP) fingerprinting of the pandemic isolates of Vibrio cholerae has

revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. For the

most part Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from

the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the

strains from the African Continent.[34]

[edit]History

Hand bill from the New York City Board of Health, 1832. The outdated public health advice demonstrates the lack of

understanding of the disease and its actual causative factors.

[edit]Origin and spread

Cholera likely has its origins in and is endemic to the Indian subcontinent. The disease spread by trade routes

(land and sea) to Russia, then to Western Europe, and from Europe to North America. Cholera is now no

longer considered a pressing health threat in Europe and North America due to filtering and chlorination of

water supplies, but still heavily affects populations in developing countries.

1816-1826 - First cholera pandemic: Previously restricted, the pandemic began in Bengal, and then

spread across India by 1820. 10,000British troops and countless Indians died during this pandemic.[35] The

cholera outbreak extended as far as China, Indonesia (where more than 100,000 people succumbed on

the island of Java alone) and the Caspian Sea before receding. Deaths in India between 1817 and 1860

are estimated to have exceeded 15 million persons. Another 23 million died between 1865 and 1917. [36]

1829-1851 - Second cholera pandemic reached Russia (see Cholera Riots), Hungary (about 100,000

deaths) and Germany in 1831,London (more than 55,000 people died in the United Kingdom)[37] and Paris in 1832. In London, the disease claimed 6,536 victims and came to be known as "King

Cholera"; in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all

ofFrance.[38] The epidemic reached Quebec, Ontario and New York in the same year and the Pacific coast

of North America by 1834.[39] The 1831 cholera epidemic killed 150,000 people in Egypt.[40] In 1846, cholera

struck Mecca, killing over 15,000 people.[41] A two-year outbreak began in England and Wales in 1848 and

claimed 52,000 lives.[42] Cholera was found in Dundee in 1832. One influential UK pamphlet explaining how

to nurse cholera patients and prevent the disease was Hints on the Cholera morbus (1832) by the home

economics writer Esther Copley.

1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming

14,137 lives, over twice as many as the 1832 outbreak. Cholera hit Ireland in 1849 and killed many of

the Irish Famine survivors already weakened by starvation and fever.[43] In 1849 cholera claimed 5,308

lives in the port city of Liverpool, England, and 1,834 inHull, England.[38] An outbreak in North America took

the life of former U.S. President James K. Polk. Cholera, believed spread from ship(s) from England,

spread throughout theMississippi river system killing over 4,500 in St. Louis [38]  and over 3,000 in New

Orleans [38]  as well as thousands in New York.[38] Mexico was similarly attacked.[41] In 1849 cholera was

spread along the California, Mormon and Oregon Trails as 6,000 to 12,000[44] are believed to have died on

their way to the California Gold Rush, Utah and Oregon in the cholera years of 1849-1855.[38] It is believed

that over 150,000 Americans died during the two pandemics between 1832 and 1849. [45][46]

1852-1860 - Third cholera pandemic mainly affected Russia, with over a million deaths. In 1852, cholera

spread east to Indonesia and later invaded China and Japan in 1854. ThePhilippines were infected in 1858

and Korea in 1859. In 1859, an outbreak in Bengal once again led to the transmission of the disease

to Iran, Iraq, Arabia and Russia.[41] There were at least seven major outbreaks of cholera in Japan between

1858 and 1902. The Ansei outbreak of 1858-60, for example, is believed to have killed between 100,000

and 200,000 people in Tokyo alone.[47]

1854 - Outbreak of cholera in Chicago took the lives of 5.5% of the population (about 3,500 people).[38][48] In

1853-4, London's epidemic claimed 10,738 lives. The Soho outbreak in London ended after removal of the

handle of the Broad Street pump by a committee instigated to action by John Snow.[49] This proved that

contaminated water (although it didn't identify the contaminant) was the main agent spreading cholera. It

would take almost 50 years for this message to be believed and acted upon. Building and maintaining a

safe water system was and is not cheap—but is absolutely essential.

1863-1875 - Fourth cholera pandemic spread mostly in Europe and Africa. At least 30,000 of the

90,000 Mecca pilgrims fell victim to the disease. Cholera claimed 90,000 lives in Russia in 1866.[50] The

epidemic of cholera that spread with the Austro-Prussian War (1866) is estimated to have claimed 165,000

lives in the Austrian Empire.[51] Hungary andBelgium both lost 30,000 people and in the Netherlands 20,000

perished. In 1867, Italy lost 113,000 lives.[52]

1892 cholera outbreak in Hamburg, hospital ward

1892 cholera outbreak in Hamburg, disinfection team

1866 - 1873 - Outbreaks in North America. It killed some 50,000 Americans.[45] In London, a localized

epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water

treatment systems—the East End was not quite complete. William Farr, using the work of John Snow et al.

as to contaminated drinking water being the likely source of the disease, was able to relatively quickly

identify the East London Water Company as the source of the contaminated water. Quick action prevented

further deaths.[38] Also a minor outbreak at Ystalyfera in South Wales. Caused by the local water works

using contaminated canal water, it was mainly its workers and their families who suffered, 119 died. In the

same year more than 21,000 people died in Amsterdam, The Netherlands. In the 1870s, cholera spread in

the US as epidemic from New Orleans along the Mississippi River and related ports of tributaries, with

thousands dying.

1881-1896 - Fifth cholera pandemic ; According to Dr A. J. Wall, the 1883-1887 epidemic cost 250,000

lives in Europe and at least 50,000 in Americas. Cholera claimed 267,890 lives in Russia (1892);[53] 120,000 in Spain;[54] 90,000 in Japan and over 60,000 in Persia.[53]In Egypt cholera claimed more that

58,000 lives. The 1892 outbreak in Hamburg killed 8,600 people. Although generally held responsible for

the virulence of the epidemic, the city government went largely unchanged. This was the last serious

European cholera outbreak.

1899-1923 - Sixth cholera pandemic had little effect in Europe because of advances in public health, but

major Russian cities (more than 500,000 people dying of cholera during the first quarter of the 20th

century)[55] and the Ottoman Empire were particularly hard hit by cholera deaths. The 1902-1904 cholera

epidemic claimed 200,000 lives in the Philippines.[56] 27 epidemics were recorded during pilgrimages

toMecca from the 19th century to 1930, and more than 20,000 pilgrims died of cholera during the 1907–

08 hajj.[55] The sixth pandemic killed more than 800,000 in India. The last outbreak in the United States was

in 1910-1911 when the steamship Moltke brought infected people to New York City. Vigilant health

authorities isolated the infected on Swinburne Island. Eleven people died, including a health care worker

onSwinburne Island.[13][14][57]

1961-1970s - Seventh cholera pandemic began in Indonesia, called El Tor after the strain, and

reached Bangladesh in 1963, India in 1964, and the USSR in 1966. From North Africa it spread into Italy

by 1973. In the late 1970s, there were small outbreaks in Japan and in the South Pacific. There were also

many reports of a cholera outbreak near Baku in 1972, but information about it was suppressed in

theUSSR.

January 1991 to September 1994 - Outbreak in South America, apparently initiated when a ship

discharged ballast water. Beginning in Peruthere were 1.04 million identified cases and almost 10,000

deaths. The causative agent was an O1, El Tor strain, with small differences from the seventh pandemic

strain. In 1992 a new strain appeared in Asia, a non-O1, nonagglutinable vibrio (NAG) named O139

Bengal. It was first identified in Tamil Nadu, India and for a while displaced El Tor in southern Asia before

decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate

between El Tor and the classic strain and occurs in a new serogroup. There is evidence of the emergence

of wide-spectrum resistance to drugs such as trimethoprim, sulfamethoxazole and streptomycin.

[edit]False historical reportMain article: Chicago 1885 cholera epidemic myth

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885, but this story

has no factual basis.[58] In 1885, there was a torrential rainstorm that flushed the Chicago River and its

attendant pollutants into Lake Michigan far enough that the city's water supply was contaminated. However,

because cholera was not present in the city, there were no cholera-related deaths, though the incident caused

the city to become more serious about its sewage treatment.

[edit]Cholera morbus

The term cholera morbus was used in the 19th and early 20th centuries to describe both non-epidemic cholera

and other gastrointestinal diseases (sometimes epidemic) that resembled cholera. The term is not in current

use, but is found in many older references.[59] The other diseases are now known collectively as gastroenteritis.

[edit]Other historical information

In the past, people traveling in ships would hang a yellow quarantine flag if one or more of the crew members

suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an

extended period, typically 30 to 40 days.[60]. In modern international maritime signal flags the quarantine flag is

yellow and black.

[edit]Research

The Russian-born bacteriologist Waldemar Haffkine developed the first cholera vaccine around 1900. The

bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist Filippo Pacini, but its exact

nature and his results were not widely known around the world.

One of the major contributions to fighting cholera was made by the physician and pioneer medical

scientist John Snow (1813–1858), who found a link between cholera and contaminated drinking water in 1854.[38] Dr Snow proposed a microbial origin for epidemic cholera in 1849. In his major "state of the art" review of

1855, he proposed a substantially complete and correct model for the aetiology of the disease. In two

pioneering epidemiological field-studies, he was able to demonstrate that human sewage contamination was

the most probable disease vector in two major epidemics in London in 1854.[61] His model was not immediately

accepted, but it was seen to be the more plausible as medical microbiology developed over the next thirty

years or so.

Cities in developed nations made massive investment in clean water supply and well-separated sewage

treatment infractures was made between the mid-1850s and the 1900s. This eliminated the threat of cholera

epidemics from the major developed cities in the world. Robert Koch, 30 years later, identified V. cholerae with

a microscope as the bacillus causing the disease in 1885.

Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in British

India was partitioned into West Bengal and East Pakistan in 1947. Prior to partition, both regions had cholera

pathogens with similar characteristics. After 1947, India made more progress on public health than East

Pakistan (now Bangladesh). As a consequence,[clarification needed] the strains of the pathogen that succeeded in India

had a greater incentive in the longevity of the host. They have become less virulent than the strains prevailing

in Bangladesh. These uninhibitedly draw upon the resources of the host population, thus rapidly killing many

victims.

More recently, in 2002, Alam et al. studied stool samples from patients at the International Centre for

Diarrhoeal Disease (ICDDR) in Dhaka, Bangladesh. From the various experiments they conducted, the

researchers found a correlation between the passage of V. cholerae through the human digestive system and

an increased infectivity state. Furthermore, the researchers found that the bacterium creates a hyper-infected

state where genes that control biosynthesis of amino acids, iron uptake systems, and formation of periplasmic

nitrate reductase complexes were induced just before defecation. These induced characteristics allow the

cholera vibrios to survive in the "rice water" stools, an environment of limited oxygen and iron, of patients with a

cholera infection.[11]

Yellow feverFrom Wikipedia, the free encyclopedia

"American Plague" redirects here. For the rock band, see The American Plague. For other uses of "yellow

fever", see Yellow fever (disambiguation).

Yellow Fever

Classification and external resources

A TEM micrograph of the yellow fever virus (234,000X magnification).

ICD-10 A 95.

ICD-9 060

DiseasesDB 14203

MedlinePlus 001365

eMedicine med/2432 emerg/645

MeSH D015004

Yellow fever is an acute viral hemorrhagic disease.[1] The virus is a 40 to 50 nm enveloped RNA virus with

positive sense of the Flaviviridaefamily.

The yellow fever virus is transmitted by the bite of female mosquitos (the yellow fever mosquito, Aedes aegypti,

and other species) and is found in tropical and subtropical areas in South America and Africa, but not in Asia.[2] The only known hosts of the virus are primates and several species of mosquito. The origin of the disease is

most likely to be Africa, from where it was introduced to South America through theslave trade in the 16th

century. Since the 17th century, several major epidemics of the disease have been recorded in the Americas,

Africa and Europe. In the 19th century, yellow fever was deemed one of the most dangerous infectious

diseases.[3]

Clinically, yellow fever presents in most cases with fever, nausea, and pain and it generally subsides after

several days. In some patients, a toxic phase follows, in which liver damage with jaundice (giving the name of

the disease) can occur and lead to death. Because of the increased bleeding tendency (bleeding diathesis),

yellow fever belongs to the group of hemorrhagic fevers. The WHO estimates that yellow fever causes 200,000

illnesses and 30,000 deaths every year in unvaccinated populations;[4] around 90% of the infections occur in

Africa.[5]

A safe and effective vaccine against yellow fever has existed since the middle of the 20th century and some

countries require vaccinations for travelers.[6] Since no therapy is known, vaccination programs are, along with

measures to reduce the population of the transmitting mosquito, of great importance in affected areas. Since

the 1980s, the number of cases of yellow fever has been increasing, making it a reemerging disease.[7]

Contents

[hide]

1 Signs and symptoms

2 Cause

3 Transmission

4 Pathogenesis

5 Diagnosis

6 Prevention

o 6.1 Vaccination

o 6.2 Compulsory vaccination

o 6.3 Vector control

7 Treatment

8 Epidemiology

9 History

10 Research

11 References

12 External links

[edit]Signs and symptoms

Yellow fever begins after an incubation period of three to six days. Most cases only cause a mild infection with

fever, headache, chills, back pain, loss of appetite, nausea and vomiting.[8]In these cases the infection lasts

only three to four days. 15% of cases enter a second, toxic phase of the disease with recurring fever, this time

accompanied by jaundice due to liver damage, as well as abdominal pain. Bleeding in the mouth, the eyes and

in the gastrointestinal tract can cause vomitus containing blood (giving the name black vomit).[9] The toxic

phase is fatal in approximately 20% of cases.[10]

Surviving the infection causes life-long immunity [11]  and normally there is no remaining organ damage.[12]

[edit]Cause

Yellow fever virus

Virus classification

Group: Group IV ((+)ssRNA)

Family: Flaviviridae

Genus: Flavivirus

Species: Yellow fever virus

Yellow fever is caused by the yellow fever virus, a 40 to 50 nm wide enveloped RNA virus belonging to the

family Flaviviridae. The positive sensesingle-stranded RNA is approximately 11,000 nucleotides long and has a

single open reading frame encoding a polyprotein. Host proteases cut this polyprotein into three structural (C,

prM, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration

corresponds to the arrangement of the protein coding genes in the genome.[13] The viruses infect amongst

others monocytes, macrophages anddendritic cells. They attach to the cell surface via specific receptors and

are taken up by an endosomal vesicle. Inside the endosome, the decreasedpH induces the fusion of the

endosomal membrane with the virus envelope. Thus, the capsid reaches the cytosol, decays and releases the

genome. Receptor binding as well as membrane fusion are catalyzed by the protein E, which changes its

conformation at low pH, which causes a rearrangement of the 90 homodimers to 60 homotrimers.[13]

After entering the host cells, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the

so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-

protein is not yet cleaved to its mature form and is therefore denoted as prM (precursor M) and forms a

complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin,

which cleaves prM to M. This releases E from the complex which can now take its place in the mature,

infectious virion.[13]

[edit]Transmission

Aedes aegypti feeding

Adults of the yellow fever mosquitoAedes aegypti. The male on the left, females on the right. Only the female mosquito bites

and can transmit the disease

The yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but

other mosquitos such as the " tiger mosquito" (Aedes albopictus) can also serve as a vector for the virus. Like

other Arboviruses which are transmitted via mosquitos, the yellow fever virus is taken up by a female mosquito

which sucks the blood of an infected person. Viruses reach the stomach of the mosquito, and if the virus

concentration is high enough, the virions can infect epithelial cells and replicate there. From there they reach

the haemocoel (the blood system of mosquitos) and from there the salivary glands. When the mosquito sucks

blood the next time, it injects its saliva into the wound, and thus the virus reaches the blood of the bitten

person. There are also indications for vertical infection of the yellow fever virus withinA. aegypti, i.e., the

transmission from a female mosquito to her eggs and then larvae. This infection of vectors without a previous

blood meal seems to play a role in single, sudden breakouts of the disease.[14]

There are three epidemiologically different infectious cycles,[7] in which the virus is transmitted from mosquitos

to humans or other primates. In the urban cycle, only the yellow fever mosquito Aedes aegypti is involved,

which is well adapted to urban centres and can also transmit other diseases

including Dengue and Chikungunya. The urban cycle is responsible for the major outbreaks of yellow fever that

occur in Africa. Except in an outbreak in 1999 in Bolivia, this urban cycle no longer exists in South America and

is only present in Africa.

Besides the urban cycle there is, both in Africa and South America, a sylvatic cycle (Forest cycle

or Jungle cycle), where Aedes africanus (in Africa) or mosquitos of the genus Haemagoggus and Sabethes (in

South America) serve as a vector. In the jungle, mainly non-human primates get infected; the disease is mostly

asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can

infect themselves, which explains the low incidence of yellow fever cases on this continent. People who

become infected in the jungle can carry the virus to urban centres, where Aedes aegypti acts as a vector. It is

because of this sylvatic cycle that yellow fever cannot be eradicated.[7]

In Africa there is a third infectious cycle, also known as savannah cycle or intermediate cycle, which occurs

between the jungle and urban cycle. Different mosquitos of the genus Aedes are involved. In recent years this

is the most common form of yellow fever seen in Africa.[4]

[edit]Pathogenesis

After transmission of the virus from a mosquito the viruses replicate in the lymph nodes and infect dendritic

cells in particular. From there they reach the liver and infect hepatocytes(probably indirectly via Kupffer cells),

which leads to eosinophilic degradation of these cells and to the release of cytokines. Necrotic masses

(Councilman bodies) appear in thecytoplasm of hepatocytes.[6][15]

When the disease takes a deadly course, a cardiovascular shock and multi organ failure with strongly

increased cytokine levels (cytokine storm) follow.[10]

[edit]Diagnosis

Yellow fever is a clinical diagnosis, which often relies on the whereabouts of the diseased person during

the incubation time. Mild courses of the disease can only be confirmed virologically. Since also mild courses of

yellow fever can significantly contribute to regional outbreaks, every suspected yellow fever has to be treated

seriously (six to ten days after leaving the affected area symptoms of fever, pain, nausea and vomiting).

If yellow fever is suspected, the virus can be confirmed until six to ten days after the illness. A direct

confirmation can be obtained by Reverse transcription polymerase chain reactionwhere the genome of the

virus is amplified.[5] Another direct approach is the isolation of the virus and its growth in cell culture using blood

plasma; this can take one to four weeks.

Serologically an enzyme linked immunosorbent assay during the acute phase of the disease using

specific IgM against yellow fever or an increase in specific IgG-titer (compared to an earlier sample) can

confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is

considered sufficient indication for yellow fever. Since these tests can cross-react with other Flaviviruses,

like Dengue virus, these indirect methods can never prove yellow fever infection. Liver biopsy can

verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of

yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death.

In a differential diagnosis, infections with yellow fever have to be distinguished from other feverish illnesses

like malaria. Other viral hemorrhagic fever, such as Ebola virus, Lassa virus,Marburg virus or Junin virus have

to be excluded as cause.

[edit]Prevention

Personal prevention of yellow fever includes vaccination as well as avoidance of mosquito bites in areas where

yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes

and measures of controlling mosquitos.

[edit]Vaccination

Injection of protective vaccination into thedeltoid muscle

The cover of a certificate that confirms that the holder has been vaccinated against yellow fever

Main article: Yellow fever vaccine

For journeys into affected areas, vaccination is highly recommended since mostly non-native people are

affected by severe cases of yellow fever. The protective effect is established 10 days after vaccination in 95%

of the vaccinated people[16] and lasts for at least 10 years (even 30 years later, 81% of patients retained the

immunity). The attenuated live vaccine (stem 17D) was developed in 1937 by Max Theiler [16]  from a diseased

patient in Ghana and is produced in chicken eggs. WHO recommends routine vaccinations for people living in

endemic areas between the 9th and 12th month after birth.[5]

In about 20% of all cases,[17] mild, flu-like symptoms may develop. In rare cases (less than one in 200,000 to

300,000[16]), the vaccination can cause YEL-AVD (yellow fever vaccine-associated viscerotropic disease),

which is fatal in 60% of all cases. It is probably due to a genetic defect in the immune system. But in some

vaccination campaigns, a 20 fold higher incidence rate has been reported. Age is an important risk factor; in

children the complication rate is less than one case per 10 million vaccinations. Another possible side effect is

an infection of the nervous system that occurs in one in 200,000 to 300,000 of all cases, causing YEL-AND

(yellow fever vaccine-associated neurotropic disease), which can cause meningoencephalitis and is less than

5%[16] of all cases fatal.[5][10]

In 2009, the largest mass vaccination against yellow fever commenced in West Africa,

specifically Benin, Liberia and Sierra Leone.[18][19]When it is completed in 2015, more than 12 million people will

have been vaccinated against the disease.[18] According to the World Health Organization, the mass

vaccination cannot eliminate yellow fever because of the massive number of infected mosquitoes in urban

areas of the target countries, but it will significantly reduce the number of people infected. [18] However, the

WHO plans to continue the vaccination campaign in another five African countries—Central African

Republic, Ghana, Guinea, Ivory Coast and Nigeria—and claimed that approximately 160 million people in the

continent could be at risk unless the organization acquires additional funding. [20]

[edit]Compulsory vaccination

Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitoes with the capability to

transmit yellow fever and susceptible monkeys are present), even though the disease does not yet occur there.

To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors, if they

have passed through yellow fever areas. Vaccination has to be proven in a vaccination certificate which is valid

10 days after the vaccination and lasts for 10 years. A list of the countries which require yellow fever

vaccination is published by the WHO.[21] If the vaccination cannot be conducted for some reasons, dispensation

is possible. In this case an exemption certificate issued by a WHO approved vaccination center is required.

Even though 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in

many of these countries fewer than 50% of their population is vaccinated.[5]

[edit]Vector control

Information campaign for prevention of Dengue and yellow fever in Paraguay

Besides vaccination, control of the yellow fever mosquito Aedes aegypti is of major importance, especially

because the same mosquito can also transmit Dengue and Chikungunya disease. Aedes aegypti breeds

preferentially in water, for example in installations by inhabitants of areas with precarious drinking water supply,

or in domestic waste; especially tires, cans and plastic bottles. Especially in proximity to urban centres of

developing countries these conditions are very common and make a perfect habitat forAedes aegypti. Two

strategies are employed to fight the mosquito:

One approach is to kill the developing larva. Measures are taken to reduce water build-up (the habitat of the

larva), and larvicides are used as well as larva-eating fish and copepods, which reduce the number of larva and

thus indirectly the number of disease-transmitting mosquitos. For many years, copepods of the

genus Mesocyclops have been used in Vietnam for fighting Dengue fever (yellow fever does not occur in Asia),

with the effect that in the affected areas no cases of Dengue fever have occurred since 2001. Similar

mechanisms are probably also effective against yellow fever. Pyriproxyfen is recommended as a chemical

larvicide, mainly because it is safe for humans and effective even in small doses.[5]

Besides larva, the adult yellow fever mosquitos are also targeted. The curtains and lids of water tanks are

sprayed with insecticides. Spraying insecticides inside houses is another measure, although it is not

recommended by the WHO. Similar to the malaria carrier, the Anopheles mosquito, insecticide

treated mosquito nets are used successfully against Aedes aegypti.[5]

[edit]Treatment

For yellow fever there is, like for all diseases caused by Flaviviruses, no causative cure. Hospitalization is

advisable and intensive care may be necessary because of rapid deterioration in some cases. Different

methods for acute treatment of the disease have been shown to not be very successful; passive immunisation

after emergence of symptoms is probably without effect. Ribavirin and other antiviral drugs as well as treatment

with interferons do not have a positive effect in patients.[10] A symptomatic treatment includes rehydration and

pain relief with drugs like paracetamol. Acetylsalicylic acid (for example Aspirin) should not be given because of

its haemodiluting effect, which can be devastating in the case of inner bleeding that can occur with yellow fever.

[edit]Epidemiology

Endemic range of yellow fever in South America (2009).

Endemic range of yellow fever in Africa (2009).

Yellow fever is endemic in tropical and subtropical areas of South America and Africa. Even though the main

vector Aedes aegypti also occurs in Asia, in the Pacific and the Middle East, yellow fever does not occur in

these areas; the reason for this is unknown. Worldwide there are about 600 million people living in endemic

areas and the official estimations of the WHO amount to 200,000 cases of disease and 30,000 deaths a year;

the number of officially reported cases is far lower. An estimated 90% of the infections occur on the African

continent.[5] In 2008, the largest number of cases was recorded in Togo.

Phylogenetic analysis identified seven genotypes of yellow fever viruses, and it is assumed that they are

differently adapted to humans and to the vector Aedes aegypti. Five genotypes occur solely in Africa, and is

assumed that the West Africa–genotype I is especially virulent or infectious, because this type is often

associated with major outbreaks of yellow fever. In South America two genotypes have been identified. [7]

[edit]History

Main articles: History of yellow fever and Yellow Fever Epidemic of 1793

Carlos Finlay

Walter Reed

The evolutionary origins of yellow fever most likely lie in Africa.[22] It is thought that the virus originated in East

or Central Africa and spread from there to West Africa. The virus as well as the vector A. aegypti were probably

brought to South America by ship after 1492. The first probable outbreak of the disease was in 1648

in Yucatan, where the illness was termed xekik (black vomit). At least 25 major outbreaks followed, such as

in Philadelphia 1793, where several thousand people died and the American administration as well as George

Washington had to flee the city.[23] Yellow fever epidemics in North America caused some 100,000-150,000

deaths.[24] Major outbreaks also occurred in Europe, e.g. in 1821 in Barcelona with several thousand victims. In

1878, about 20,000 people died in an epidemic in the Mississippi River Valley and the last major outbreak in

the US occurred in 1905 in New Orleans.[7] In colonial times, West Africa became known as "the white man's

grave" because of malaria and yellow fever.[25]

Carlos Finlay, a Cuban doctor and scientist, first proposed in 1881 that yellow fever may be transmitted

by mosquitoes rather than direct human contact.[26] Since the losses in the invasion of Cuba in the 1890s due to

yellow fever were thirteenfold higher than the losses due to military operations, further experiments conducted

by a team under Walter Reed successfully proved the ″Mosquito Hypothesis″. Yellow fever was thus the first

virus shown to be transmitted by mosquitos. The physician William Gorgas then applied these insights and

eradicated yellow fever from Havana and fought yellow fever during the construction of the Panama Canal –

after a French effort to build the canal had failed due, among other reasons, to the high incidence of yellow

fever and malaria.[7]

Although Dr. Reed received much of the credit in history books for "beating" yellow fever, Reed himself credited

Dr. Finlay with the discovery of the yellow fever vector, and thus how it might be controlled. Dr. Reed often

cited Finlay's papers in his own articles and gave him credit for the discovery, even in his personal

correspondence.[27] The acceptance of Finlay's work was one of the most important and far-reaching effects of

the Walter Reed Commission of 1900.[28] Applying methods first suggested by Finlay, yellow fever was

eradicated in Cuba and later in Panama, allowing completion of the of the Panama Canal.

In 1927, the yellow fever virus was isolated in West Africa, which led to the development of two vaccines in the

1930s. The vaccine D17 was developed by the South African microbiologist Max Theiler at the Rockefeller

Institute. Following the work of Ernest Goodpasture, he used chicken eggs to culture the virus and won a Nobel

Prize for this achievement in 1951. A French team developed the vaccine FNV (French neurotropic vaccine),

which was extracted from mouse brain tissue – but since it was associated with a higher incidence

of encephalitis, FNV was not recommended after 1961. 17D on the other hand is still in use and over 400

million doses have been distributed. Since little has been invested in the development of new vaccines, the 60

year old technology cannot adopt fast enough to a yellow fever epidemic. Newer vaccines based on vero

cells are in development and should replace 17D at some point.[5]

Using vector control and strict vaccination programs, the urban cycle of yellow fever has been eradicated from

South America and since 1943 – apart from an urban outbreak in Santa Cruz de la Sierra (Bolivia) – there has

been no yellow fever transmission by A. aegypti reported. Since the 1980s, the number of yellow fever cases

has been increasing again and A. aegypti has returned to the urban centres of South America; partly because

the vector control program was abandoned. Even though no new urban cycle has yet established itself, it is

feared that this might happen at any point. An outbreak in Paraguay in 2008 was first thought to be urban in

nature, but this turned out to not be the case.[5]

In Africa on the other hand, virus eradication programs have mostly used vaccination, but have been

unsuccessful since the sylvatic cycle could not be eradicated. After the measures to fight yellow fever were

abandoned since few countries have established regular vaccination programs, the virus could spread again. [5]

BrucellosisFrom Wikipedia, the free encyclopedia

Brucellosis

Classification and external resources

ICD-10 A 23.

ICD-9 023

DiseasesDB 1716

MedlinePlus 000597

eMedicine med/248

MeSH D002006

Brucellosis, also called Bang's disease, Gibraltar fever, Malta fever, Maltese fever, Mediterranean

fever, rock fever, or undulant fever,[1][2] is a highly contagious zoonosis caused by ingestion

of unsterilized milk or meat from infected animals, or close contact with their secretions. Transmission from

human to human, for example through sexual contact or from mother to child, is exceedingly rare, but possible.[3] Brucella spp. are small, Gram-negative, non-motile, non-spore-forming rods, which function as facultative

intracellular parasites that cause chronic disease, which usually persists for life. Symptoms include profuse

sweating and joint and muscle pain. Brucellosis has been recognized in animals including humans since the

19th century.

Contents

[hide]

1 History and nomenclature

2 Brucellosis in animals

o 2.1 Brucellosis in cattle

o 2.2 Brucellosis in Ireland

o 2.3 Brucellosis in the Greater Yellowstone area

o 2.4 Brucellosis in dogs

3 Brucellosis in humans

o 3.1 Symptoms

o 3.2 Treatment and prevention

o 3.3 Biological warfare

4 Popular culture references

5 See also

6 References

7 External links

[edit]History and nomenclature

The disease now called brucellosis, under the name "Malta fever", first came to the attention of British medical

officers in Malta during the Crimean War in the 1850s. The causal relationship between organism and disease

was first established by Dr. David Bruce in 1887.[4][5]

In 1897, Danish veterinarian Bernhard Bang isolated Brucella abortus as the agent, and the additional name

"Bang's disease" was assigned. In modern usage, "Bang's disease" is often shortened to just "Bangs"

when ranchers discuss the disease or vaccine.

Maltese doctor and archaeologist Sir Themistocles Zammit earned a knighthood for identifying unpasteurized

milk as the major source of the pathogen in 1905, and it has since become known as Malta Fever. In cattle this

disease is also known as contagious abortion and infectious abortion.

The popular name "undulant fever" originates from the characteristic undulance (or "wave-like" nature) of the

fever which rises and falls over weeks in untreated patients. In the 20th century, this name, along with

"brucellosis" (after Brucella, named for Dr Bruce), gradually replaced the 19th century names "Mediterranean

fever" and "Malta fever".

In 1989, neurologists in Saudi Arabia discovered neurobrucellosis, a neurological involvement in brucellosis.[6]

[7]

The following obsolete names have previously been applied to brucellosis:

Brucelliasis

Bruce's septicemia

Chumble fever

continued fever

Crimean fever

Cyprus fever

febris melitensis

febris undulans

Fist of mercy

goat fever

melitensis septicemia

melitococcosis

milk sickness

mountain fever

Neapolitan fever

Satan's fever

slow fever

[edit]Brucellosis in animals

Disease incidence map of Brucella melitensis infections in animals in Europe during the first half of 2006.       never

reported      not reported in this period      confirmed clinical disease      confirmed infection      no information

Species infecting domestic livestock are B. melitensis (goats and sheep, see Brucella melitensis), B. suis (pigs,

see Swine brucellosis), B. abortus (cattle and bison), B. ovis (sheep), and B. canis (dogs). B. abortus also

infects bison and elk in North America and B. suis is endemic in caribou. Brucella species have also been

isolated from several marine mammal species (pinnipeds and cetaceans).

[edit]Brucellosis in cattle

The bacterium Brucella abortus is the principal cause of brucellosis in cattle. The bacteria are shed from an

infected animal at or around the time of calving or abortion. Once exposed, the likelihood of an animal

becoming infected is variable, depending on age, pregnancy status, and other intrinsic factors of the animal, as

well as the amount of bacteria to which the animal was exposed.[8] The most common clinical signs of cattle

infected with Brucella abortus are high incidences of abortions, arthritic joints and retained after-birth. There are

two main causes for spontaneous abortion in animals. The first is due to erythritol, which can promote

infections in the fetus and placenta. Second is due to the lack of anti-Brucella activity in the amniotic fluid.

Males can also harbor the bacteria in their reproductive tracts, namely seminal vesicles, ampullae, testicles,

and epididymides.

Dairy herds in the USA are tested at least once a year with the Brucella Milk Ring Test (BRT). [9] Cows that are

confirmed to be infected are often killed. In the United States, veterinarians are required to vaccinate all young

stock, thereby further reducing the chance of zoonotic transmission. This vaccination is usually referred to as a

"calfhood" vaccination. Most cattle receive a tattoo in their ear serving as proof of their vaccination status. This

tattoo also includes the last digit of the year they were born.[10]

Canada declared their cattle herd brucellosis-free on September 19, 1985. Brucellosis ring testing of milk and

cream, as well as testing of slaughter cattle, ended April 1, 1999. Monitoring continues through auction market

testing, standard disease reporting mechanisms, and testing of cattle being qualified for export to countries

other than the USA.[11]

The first state–federal cooperative efforts towards eradication of brucellosis caused by Brucella abortus in the

U.S. began in 1934.

[edit]Brucellosis in Ireland

Ireland was declared free of brucellosis on 1 July 2009. The disease had troubled the country's farmers and

veterinarians for several decades.[12][13] The Irish government submitted an application to the European

Commission, which verified that Ireland had been liberated.[13] Brendan Smith, Ireland's Minister for Agriculture,

Fisheries and Food, said the elimination of brucellosis was "a landmark in the history of disease eradication in

Ireland".[12][13] Ireland's Department of Agriculture, Fisheries and Food intends to reduce its brucellosis

eradication programme now that eradication has been confirmed.[12][13]

[edit]Brucellosis in the Greater Yellowstone area

Wild bison and elk in the Greater Yellowstone Area (GYA) are the last remaining reservoir of Brucella

abortus in the U.S. The recent transmission of brucellosis from cattle to elk in Idaho and Wyoming illustrates

how brucellosis in domestic cattle around the GYA may negatively affect wildlife. Eliminating brucellosis from

this area is a challenge, because these animals are on public land and there are many viewpoints involved in

the management of these animals.

[edit]Brucellosis in dogs

The causative agent of brucellosis in dogs is Brucella canis. It is transmitted to other dogs through breeding

and contact with aborted fetuses. Brucellosis can occur in humans that come in contact with infected aborted

tissue or semen. The bacteria in dogs normally infect the genitals and lymphatic system, but can also spread to

the eye, kidney, and intervertebral disc(causing discospondylitis). Symptoms of brucellosis in dogs include

abortion in female dogs and scrotal inflammation and orchitis (inflammation of the testicles) in males. Fever is

uncommon. Infection of the eye can cause uveitis, and infection of the intervertebral disc can cause pain or

weakness. Blood testing of the dogs prior to breeding can prevent the spread of this disease. It is treated with

antibiotics, as with humans, but it is difficult to cure.[14]

[edit]Brucellosis in humans

[edit]Symptoms

Granuloma and necrosis in the liver of a guinea pig infected with Brucella suis

Brucellosis in humans is usually associated with the consumption of unpasteurized milk and soft cheeses made

from the milk of infected animals, primarily goats, infected with Brucella melitensis and with occupational

exposure of laboratory workers, veterinarians and slaughterhouse workers. Some vaccines used in livestock,

most notably B. abortus strain 19, also cause disease in humans if accidentally injected. Brucellosis induces

inconstant fevers, sweating, weakness, anaemia, headaches, depression and muscular and bodily pain.

The symptoms are like those associated with many other febrile diseases, but with emphasis on muscular pain

and sweating. The duration of the disease can vary from a few weeks to many months or even years. In the

first stage of the disease, septicaemia occurs and leads to the classic triad of undulant fevers, sweating (often

with characteristic smell, likened to wet hay) and migratory arthralgia and myalgia. In blood tests, is

characteristic the leukopenia and anaemia, some elevation of AST and ALT and positivity of classic Bengal

Rose and Huddleson reactions. This complex is, at least in Portugal, known as the Malta fever. During

episodes of Malta fever, melitococcemia (presence of brucellae in blood) can usually be demonstrated by

means of blood culture in tryptose medium or Albini medium. If untreated, the disease can give origin to

focalizations or become chronic. The focalizations of brucellosis occur usually in bones and joints and

spondylodiscitis of lumbar spine accompanied by sacroiliitis is very characteristic of this disease. Orchitis is

also frequent in men.

Diagnosis of brucellosis relies on:

1. Demonstration of the agent: blood cultures in tryptose broth, bone marrow cultures. The growth of

brucellae is extremely slow (they can take until 2 months to grow) and the culture poses a risk to

laboratory personnel due to high infectivity of brucellae.

2. Demonstration of antibodies against the agent either with the classic Huddleson, Wright and/or Bengal

Rose reactions, either with ELISA or the 2-mercaptoethanol assay for IgM antibodies associated with

chronic disease

3. Histologic evidence of granulomatous hepatitis (hepatic biopsy)

4. Radiologic alterations in infected vertebrae: the Pedro Pons sign (preferential erosion of antero-

superior corner of lumbar vertebrae) and marked osteophytosis are suspicious of brucellic spondylitis.

The disease's sequelae are highly variable and may include granulomatous

hepatitis, arthritis, spondylitis, anaemia, leukopenia, thrombocytopenia, meningitis, uveitis, optic

neuritis,endocarditis and various neurological orders collectively known as neurobrucellosis.

[edit]Treatment and prevention

Antibiotics like tetracyclines, rifampicin and the aminoglycosides streptomycin and gentamicin are effective

against Brucella bacteria. However, the use of more than one antibiotic is needed for several weeks, because

the bacteria incubate within cells.

The gold standard treatment for adults is daily intramuscular injections of streptomycin 1 g for 14 days and

oral doxycycline 100 mg twice daily for 45 days (concurrently). Gentamicin5 mg/kg by intramuscular

injection once daily for 7 days is an acceptable substitute when streptomycin is not available or difficult to

obtain.[15] Another widely used regimen is doxycycline plus rifampin twice daily for at least 6 weeks. This

regimen has the advantage of oral administration. A triple therapy of doxycycline, together with rifampin and

cotrimoxazole has been used successfully to treat neurobrucellosis.[16] Doxycycline is able to cross the blood–

brain barrier, but requires the addition of two other drugs to prevent relapse. Ciprofloxacin and co-trimoxazole

therapy is associated with an unacceptably high rate of relapse. In brucellic endocarditis surgery is required for

an optimal outcome. Even with optimal antibrucellic therapy relapses still occur in 5–10 percent of patients with

Malta fever. The main way of preventing brucellosis is by using fastidious hygiene in producing raw milk

products, or bypasteurizing all milk that is to be ingested by human beings, either in its unaltered form or as a

derivate, such as cheese. Experiments have shown that cotrimoxazol and rifampin are both safe drugs to use

in treatment of pregnant women who have Brucellosis.

[edit]Biological warfare

In 1954, B. suis became the first agent weaponized by the United States at its Pine Bluff Arsenal in

Arkansas. Brucella species survive well in aerosols and resist drying. Brucella and all other remaining biological

weapons in the U.S. arsenal were destroyed in 1971–72 when the U.S. offensive biological weapons (BW)

program was discontinued.[17]

The United States BW program focused on three agents of the Brucella group:

Porcine Brucellosis (Agent US)

Bovine Brucellosis (Agent AB)

Caprine Brucellosis (Agent AM).

Agent US was in advanced development by the end of World War II. When the U.S. Air Force (USAF) wanted a

biological warfare capability, the Chemical Corps offered Agent US in theM114 bomblet, based after the 4-

pound bursting bomblet developed for anthrax in World War II. Though the capability was developed,

operational testing indicated that the weapon was less than desirable, and the USAF termed it an interim

capability until replaced by a more effective biological weapon. The main drawbacks of the M114 with Agent

US was that it was incapacitating (the USAF wanted "killer" agents), the storage stability was too low to allow

for storing at forward air bases, and the logistical requirements to neutralize a target were far higher than

originally anticipated, requiring unreasonable logistical air support.

Agents US and AB had a median infective dose of 500 org/person, and AM was 300 org/person. The rate-of-

action was believed to be 2 weeks, with a duration of action of several months. The lethality estimate was

based on epidemiological information at 1–2%. AM was always believed to be a more virulent disease, and a

3% fatality rate was expected.

Schick testFrom Wikipedia, the free encyclopedia

A boy receives an injection of diluted toxin for the Schick test in 1915.

The Schick test, invented between 1910 and 1911[1] is a test used to determine whether or not a person is

susceptible to diphtheria.[2] It was named after its inventor, Béla Schick (1877–1967), a Hungarian-born

American pediatrician.

The test is a simple procedure. A small amount (0.1 ml) of diluted (1/50 MLD) diphtheria toxin is injected

intradermally into the arm of the person. If a person does not have enough antibodies to fight it off, the skin

around the injection will become red and swollen, indicating a positive result. This swelling disappears after a

few days. If the person has an immunity, then little or no swelling and redness will occur, indicating a negative

result.

Results can be interpreted as:

1. Positive: when the test results in a wheal of 5–10 mm diameter

2. Pseudo-positive: when there is only a red colored inflammation and it disappears rapidly

3. Negative reaction:

4. pseudo negative reaction:

The test was created when immunizing agents were scarce and not very safe, however as newer and

safer toxoids were made available there was no more requirement for susceptibility tests.

AlmatyFrom Wikipedia, the free encyclopedia

Please expand this article with text translated from the corresponding article in the Russian Wikipedia. (May 2010)

After translating, {{Translated|ru|Алма-Ата}} must be added to the talk page to ensure copyright compliance.Translation instructions · Translate via Google

AlmatyАлматы

Алма-Ата

Flag

Seal

Almaty

Location in Kazakhstan

Coordinates: 43°16 ′ 39 ″ N 76°53 ′ 45 ″ E Coordinates :

43°16 ′ 39 ″ N 76°53 ′ 45 ″ E

Country Kazakhstan

Province

First settled 10–9th century BC

Founded 1854

Incorporated (city) 1867

Government

- Akim (mayor) Akhmetzhan Yesimov

Area

- Total 324.8 km2 (125.4 sq mi)

Elevation 500–1,700 m (1,640–5,577 ft)

Population (2009)

- Total 1,420,747[citation needed]

- Density 4,152/km2 (10,753.6/sq mi)

Time zone UTC+6 (UTC+6)

Postal code 050000–050063

Area code(s) +7 727[1]

ISO 3166-2 ALA

License plate A

Website http://www.almaty.kz

Almaty (Kazakh: Алматы / Almatı / الماتى), also known by its former name Alma-Ata (Russian: Алма-Ата,

until 1992) and Verny(Russian: Верный, until 1921), is the largest city in Kazakhstan, with a population of

1,348,500 (as of 1 September 2008),[2] which represents 9% of the population of the country.

It was the capital of Kazakhstan (and its predecessor, the Kazakh SSR) from 1929 to 1997. Despite losing its

status as the capital to Astana, Almaty remains the major commercial center of Kazakhstan.

Contents

[hide]

1 Toponomy

2 History

o 2.1 Prehistoric Almaty

o 2.2 Middle Ages

o 2.3 15th–18th centuries

o 2.4 Foundation of Verniy

o 2.5 20th century Almaty

2.5.1 Almaty from the Revolution of 1917 to World War II

2.5.2 Almaty in World War II

2.5.3 Almaty from 1945 to 2000

o 2.6 21st century Almaty

3 Climate

4 Demographics

5 Economy

6 Sights

o 6.1 Kök Töbe

o 6.2 Fountains

7 Universities of Almaty

8 Sports

9 Olympic aspirations

10 See also

11 References

12 External links

o 12.1 Olympic-related

o 12.2 Travel-related

[edit]Toponomy

The name "Almaty" derives from the Kazakh word for 'apple' (алма), and thus is often translated as "full of

apples;" alma is also 'apple' in other Turkic languages, as well as in Hungarian. The older Soviet-

era Russian version of its name, Alma-Ata, originates from the saint's tomb, buried in an apple orchard,

whence the name, "Saint of the Apple (orchard)" or "Father of Apples".[citation needed] "Ata" standing for father in

Kazakh and many other Turkic languages, also stands for a saint or a priest, as the term "padre" in

the Romance languages. The old name for the new capital of Kazakhstan, Astana was Akmolinsk/Akmola--,

"White Shrine/Mausoleum", a reference to another saint's burial ground.

In fact, in the region surrounding Almaty, there is a great genetic diversity among the wild apples; the region is

thought to be the ancestral home of the apple, and the wild Malus sieversii, is considered a likely candidate for

the ancestor of the modern domestic apple. The area is often visited by researchers and scientists from around

the world in order to learn more about the complex systems of genetics, and also to discover the true

beginnings of the domestic apple.

[edit]History

[edit]Prehistoric Almaty

During 1000–900 BCE in the Bronze Age the first farmers and cattle-breeders established settlements on the

territory of Almaty.

During the Saka’s period (from 700 BCE to the beginning of the Common Era), these lands were chosen for

residence by Saka tribes and later Uisun tribes inhabiting the territory north of the Tian Shan mountain range.

The evidences of these times are numerous burial tumuli and ancient settlements, especially giant burial

mounds of Saka tsars. The most famous archaeological finds are the Golden man from the Issyk Kurgan,

Zhalauly treasure, Kargaly diadem, Zhetysu arts bronze (boilers, lamps and altars). During the period of Saka

and uisun governance, Almaty became the early education center.[3]

Silver dirham coin minted in Almaty in 684 CE

[edit]Middle Ages

The next stage of Almaty evolution is attributed to the Middle Ages (8–10th centuries) and is characterized by

city culture development, transfer to a settled way of living, farming and handicraft development, and the

emergence of a number of towns and cities in the territory of Zhetysu.

In 10–14th centuries, settlements in the territory of the so called "Big Almaty" became part of the trade routes of

the Silk Road. At that time, Almaty became one of the trade, craft and agricultural centers on the Silk Road and

possessed an official mint. The city was first mentioned as Almatu in books from the 13th century.

[edit]15th–18th centuries

In the 15th–18th centuries, the city was on the way to degradation as trade activities were decreasing on this

part of the Silk Road. Notwithstanding, this period was saturated with very important political events that had

significant impact on the history of Almaty and Kazakhstan as a whole. It was a period of crucial ethnic and

political transformations. The Kazakh state and nation were founded here, close to Almaty.

These lands also witnessed the tragic developments related to the Dzungar intervention and rigorous efforts of

the Kazakh to protect their land and preserve independence. In 1730 the Kazakh defeated the Dzungar in the

Anyrakay mountains, 70 km to north-west from Almaty. It was a critical moment of the Patriotic War between

Kazakhs and Dzungars.

[edit]Foundation of Verniy

Zenkov Cathedral, a 19th-century Russian Orthodox cathedral located in Panfilov Park, is the second tallest wooden

building in the world.[4]

On 4 February 1854 the modern history of the city began with the strengthening of the Russian

piedmont Fort Verniy nearby the Zailiysky Alatau mountain range between Bolshaya and Malaya Almatinka

rivers. The construction of the Verniy Fort was almost finished by autumn 1854. It was a fenced pentagon and

one of its sides was built along the Malaya Almatinka. Later, wood fence was replaced with the wall of brick

with embrasures. Main facilities were erected around the big square for training and parading. [5]

In 1855 the first displaced Kazakh appeared in Verniy. Since 1856, Verniy started accepting Russian peasants.

They founded the Bolshaya Almatinskaya Stanitsa (Cossack village) nearby the fortification. The inflow of

migrants was increasing and led to construction of the Malaya Almatinskaya Stanitsa and Tatarskaya

(Tashkentskaya) sloboda. It was the place of settlement for Tatar mechants and craftsmen.

In 1867 the Verniy Fort was transformed into the town and called Almatinsk. However, the population did not

like the new name of the town and soon the town was re-named as Verniy.

According to the First City Plan, the city perimeters were 2 km on the south along Almatinka river, and 3 km on

the west. The new city area was divided into residential parts, and the latter — into districts. Three categories

of the city buildings were distinguished. Buildings of the first and second categories were two-storied or, at

least, one-storied constructions with the high semi-basement. Buildings of categories I and II were erected

around and in the center of the city, others — on the outskirts.

On 28 May 1887, at 4 a.m., an earthquake almost totally destroyed Verniy in 11–12 minutes. Brick buildings

were mostly damaged. As a result, people were inclined to build up one-storied construction made of wood

or adobe.

[edit]20th century Almaty

Holiday Inn

[edit]Almaty from the Revolution of 1917 to World War II

Samal

In 1921, the joint solemn sitting was summoned for the participation of the representative of government

regional and sub-regional institutions, professional trades, the Muslim people to make a decision to assign a

new name to Verniy — Alma-Ata.

In 1926, the Council of Labour and Defence approved the construction of the Turkestan-Siberia Railwayrailway

that was a crucial element of the republic reconstruction, specifically on the east and southeast of the republic.

The Turkestan-Siberia Railway construction was also a decisive economic aspect that foreordained the destiny

of Alma-Ata as a capital of Kazakh ASSR. In 1930 the construction of the highway and railway to the Alma-Ata

station was completed.

On 2 March 1927, It was the initiative of the Central Executive Committee of the Kazakh Republic to transfer

the capital from Kyzyl-Orda to Alma-Ata. The VI Kazakhstani Congress approved this initiative.[6]

On 29 April 1927, it was officially decided on the sitting of the Russian SFSR Committee to transfer the capital

of the Kazakh Autonomous Soviet Socialist Republic from Kyzyl-Orda to Alma-Ata.

Besides, the Alma-Ata airport was opened in 1930 and people from the capital of Kazakhstan could fly now

from Alma-Ata to Moscow. Alma-Ata became the air gate to Kazakhstan. Transformation of the small town into

the capital of the Republic was supplied by the large-scaled construction of new administrative and government

facilities and housing.

The Central Mosque of Almaty.

Given the transfer of the capital of Kazakhstan to Alma-Ata, in 1936 the Architecture and Planning Bureau

elaborated the General Plan aimed at re-creating Alma-Ata as the new cultural and comfortable capital of

Kazakhstan. The Plan was based on the existing rectangular system of districts that would further be

strengthened and reconstructed.

[edit]Almaty in World War II

During World War II the city territory was changed to a large extent. To organize the home front and

concentrate industrial and material resources, the residential stock was compressed to arrange

accommodation for 26,000 persons evacuated. Alma-Ata hosted over 30 industrial facilities from the front

areas, 8 evacuated hospitals, 15 institutes, universities and technical schools, around 20 cultural institutions,

etc. Motion picture production companies  from Leningrad, Kiev and Moscow were also evacuated to Alma-Ata.

Owing to self-denying labour, over 52,000 Alma-Ata residents were awarded. 48 residents were granted the

title of Hero of The Soviet Union. Threerifle divisions were raised in Alma-Ata , including the well-known 8th

Guards Rifle Division 'Panfilov', along with 2 rifle battalions and 3 aviation regiments that were raised on the

bases of the air club of Alma-Ata.

[edit]Almaty from 1945 to 2000

Furmanov street

From 1966 to 1971, 1,400,000 square meters of public and cooperative housing were put into operation.

Annually, around 300,000 square meters of dwellings were under construction. It was the period of

constructing earthquake-proof multi-storied buildings. Construction unification and type-design practice

diversified architectural forms. At that time lots of schools, hospitals, cultural and entertainment facilities were

constructed, including Lenin’s Palace, Kazakhstan Hotel, and the “Medeo” sports complex.

The Medeu Dam, designed to protect the city of Almaty and the Medeo skating rink from

catastrophic mudflows, was built in 1966 and reinforced a number of times in the 1960s and 1970s.

The supersonic transport Tupolev Tu-144 went into service on 26 December 1975, flying mail and freight

between Moscow and Alma-Ata in preparation for passenger services, which commenced in November 1977.

The Aeroflot flight on 1 June 1978 was the Tu-144's 55th and last scheduled passenger service.

Since 1981, the underground Almaty Metro construction project has been developed.

On 16 December 1986 Jeltoksan riot took place in response to General Secretary Mikhail Gorbachev's

dismissal of Dinmukhamed Kunayev.

Hotel Kazakhstan

In 1993 the government made a decision to rename Alma-Ata. The new name of the city is Almaty.

In 1997 the President of the Republic of Kazakhstan Nursultan Nazarbayev approved the Decree to transfer

the capital from Almaty to Astana.[7]

Dostyk Hotel

On 1 July 1998 a Law was passed concerning the special status of Almaty as a scientific, cultural, historical,

financial and industrial center.

[edit]21st century Almaty

The new 2030 General Plan of Almaty was developed in 1998 and aims at forming ecologically safe, secure

and socially comfortable living conditions. The main objective is to promote Almaty’s image as a garden-city.

One of the components of the General Plan is to continue multi-storied and individual construction, reorganize

industrial territories, improve transport infrastructure and launch Almaty Metro.[citation needed]

[edit]Climate

Almaty features a humid continental climate with very warm summers and cold winters. Its wettest months are

April and May, during which about a third of the city’s annual precipitation is received. August and September

are the driest months where on average under 30 mm (1.18 in) of precipitation is seen.

[hide]Climate data for Almaty

Month Jan Feb Mar Apr May Jun Jul Aug Sep

Record high °C (°F)18.2

(64.8)

19.0

(66.2)

28.0

(82.4)

33.2

(91.8)

35.1

(95.2)

39.3

(102.7)

49.7

(121.5)

42.5

(108.5)

38.1

(100.6)

Average high °C (°F)-0.2

(31.6)

1.4

(34.5)

7.0

(44.6)

17.2

(63)

21.6

(70.9)

26.7

(80.1)

29.8

(85.6)

28.7

(83.7)

23.8

(74.8)

Daily mean °C (°F)-4.9

(23.2)

-3.4

(25.9)

2.2

(36)

11.7

(53.1)

16.1

(61)

21.0

(69.8)

23.8

(74.8)

22.5

(72.5)

17.5

(63.5)

Average low °C (°F)-9.6

(14.7)

-8.2

(17.2)

-2.6

(27.3)

6.1

(43)

10.5

(50.9)

15.2

(59.4)

17.8

(64)

16.3

(61.3)

11.2

(52.2)

Record low °C (°F)-30.1

(-22.2)

-37.7

(-35.9)

-24.8

(-12.6)

-10.9

(12.4)

-7.0

(19.4)

2.0

(35.6)

7.3

(45.1)

4.7

(40.5)

-3.0

(26.6)

Precipitation mm (inches)33

(1.3)

41

(1.61)

62

(2.44)

111

(4.37)

106

(4.17)

61

(2.4)

38

(1.5)

27

(1.06)

29

(1.14)

Source: [1]

[edit]Demographics

Ethnic groups (2003)[citation needed]:

Kazakh  51.5 %

Russian  30.0 %

Uyghur  5.8 %

Tatar  2.0 %

Korean  2.0 %

Ukrainian  1.0 %

German  1.0 %

Indians  1.0 %

Chinese  1.0 %

Others : 5%

According to the USSR Census of 1989, population of Almaty was 1,071,900; Kazakhstan Census of 1999

reported 1,129,400.[8]

[edit]Economy

Almaty business centre

Almaty is also developing as the regional financial and business centre — RFCA.[citation needed].

Air Astana is headquartered in the Air Astana Centre 1 in Almaty.[9] Prior to their dissolution, Air

Kazakhstan [10]  and Kazakhstan Airlines [11] were also headquartered in Almaty.

[edit]Sights

[edit]Kök Töbe

Downtown Almaty as seen from Kok Tobe

An aerial tramway line connects downtown Almaty with a popular recreation area the top of Kök

Töbe (Kazakh: Көктөбе, which means 'Green Hill'), a mountain just to the southeast. The city television

tower, Alma-Ata Tower, is located on the hill, as well as a variety of amusement-park type attractions and

touristy restaurants.

[edit]Fountains

A section of the Zodiac Fountain (1979)

According to the city's Department of Natural Resources and Resource Use Management, [12] as of 2007 the city

has 125 fountain groups or isolated fountains. Among them is the "Oriental Calendar" Fountain, whose 12

sculpture figures represent the 12 animals of the Kazakh 12-year animal cycle (similar to its Chinese

counterpart).

[edit]Universities of Almaty

International IT University  (IITU)

Kazakh-British Technical University (KBTU)

Kazakh National Medical University

Almaty Institute of Power Engineering and Telecommunications

Kazakh National Technical University  (KazNTU)

Al-Farabi Kazakh National University  (KazUU)

Suleyman Demirel University  (SDU)

KIMEP  (Kazakhstan Institute of Management, Economics, and Strategic Research)

Kazakh-American University (KAU)

Kazakh Academy of Sciences

Kazakh Academy of Labour and Social Relations

Almaty State University (named after Abay)

Turan University

Kazakhstan University of Global Relationships and Languages (КазУМОиМЯ)

Central Asian University (ЦАУ)

Kazakh-German University (КНУ)

Apple Town

for further details: List of universities in Kazakhstan

Medeo, with bandy goals

[edit]Sports

The historic bandy team Dinamo won the Soviet Championships in 1977 and 1990 and the European Cup in

1978. Their home ground was Medeo, where bandy will be the only sport at the 2011 Winter Asian Games.

[edit]Olympic aspirations

Almaty was an official candidate to host the XXII Olympic Winter Games in 2014,[13] but was eliminated from

consideration after it failed to be included in the "short list" of candidate cities. Almaty won its bid to host

the 2011 Winter Asian Games. The city is exploring possible future bids, such as the 2018 Winter Olympics.

However, the city failed to submit a bid as an applicant city for the 2018 games.

BronchitisFrom Wikipedia, the free encyclopedia

Not to be confused with bronchiolitis.

Bronchitis

Classification and external resources

This diagram shows acute bronchitis.

ICD-10 J 20. -J 21. , J 42.

ICD-9 466, 491

DiseasesDB 29135

MedlinePlus 001087

eMedicine article/297108

MeSH D001991

This article needs additional citations for verification.Please help improve this article by adding reliable references. Unsourced material may be challenged and removed.(July 2009)

Bronchitis is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from

the trachea into the lungs. Bronchitis can be classified into two categories, acute and chronic, each of which

has unique etiologies, pathologies, and therapies.

Acute bronchitis is characterized by the development of a cough, with or without the production

of sputum, mucus that is expectorated(coughed up) from the respiratory tract. Acute bronchitis often occurs

during the course of an acute viral illness such as the common cold orinfluenza. Viruses cause about 90% of

cases of acute bronchitis while bacteria account for less than 10%.[1]

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is characterized by the presence of a

productive cough that lasts for 3 months or more per year for at least 2 years. Chronic bronchitis most often

develops due to recurrent injury to the airways caused by inhaled irritants. Cigarette smoking is the most

common cause, followed by air pollution and occupational exposure to irritants, and cold air.

Contents

[hide]

1 Classification

o 1.1 Acute bronchitis

o 1.2 Chronic bronchitis

o 1.3 Protracted bacterial bronchitis

2 References

3 External links

[edit]Classification

[edit]Acute bronchitisMain article: Acute bronchitis

Acute bronchitis is most often caused by viruses that infect the epithelium of the bronchi, resulting in

inflammation and increased secretion of mucus. Cough, a common symptom of acute bronchitis, develops in

an attempt to expel the excess mucus from the lungs. Other common symptoms include sore throat, runny

nose, nasal congestion (coryza), low-gradefever, pleurisy, malaise, and the production of sputum.[1]

Acute bronchitis often develops during the course of an upper respiratory infection (URI) such as the common

cold or influenza.[1] About 90% of cases of acute bronchitis are caused by viruses,

including rhinoviruses, adenoviruses, and influenza. Bacteria, including Mycoplasma pneumoniae, Chlamydia

pneumoniae, and Bordetella pertussis, account for about 10% of cases.[1]

Treatment for acute bronchitis is primarily symptomatic. Non-steroidal anti-inflammatory drugs (NSAIDs) may

be used to treat fever and sore throat. Decongestants can be useful in patients with nasal congestion,

and expectorants may be used to loosen mucus and increase expulsion of sputum. Cough suppressants may

be used if the cough interferes with sleep or is bothersome, although coughing may be useful in expelling

sputum from the airways. Even with no treatment, most cases of acute bronchitis resolve quickly. [1]

Only about 5-10% of bronchitis cases are caused by a bacterial infection. Most cases of bronchitis are caused

by a viral infection and are "self-limited" and resolve themselves in a few weeks. [2] As most cases of acute

bronchitis are caused by viruses, antibiotics should not be used since they are only effective against bacteria.

Using antibiotics in patients who do not have bacterial infections promotes the development of antibiotic-

resistant bacteria, which may lead to greater morbidity and mortality. Antibiotics should only be prescribed if

microscopic examination of Gram stained sputum shows large numbers of bacteria present.

[edit]Chronic bronchitisMain article: Chronic bronchitis

Chronic bronchitis, a type of chronic obstructive pulmonary disease, is defined by a productive cough that lasts

for 3 months or more per year for at least 2 years.[3] Other symptoms may include wheezing and shortness of

breath, especially upon exertion. The cough is often worse soon after awakening, and the sputum produced

may have a yellow or green color and may be streaked with blood.[1]

Chronic bronchitis is caused by recurring injury or irritation to the respiratory epithelium of the bronchi, resulting

in chronic inflammation, edema (swelling), and increased production of mucus by goblet cells.[1] Airflow into and

out of the lungs is partly blocked because of the swelling and extra mucus in the bronchi or due to

reversible bronchospasm.[4]

Most cases of chronic bronchitis are caused by smoking cigarettes or other forms of tobacco. Chronic

inhalation of irritating fumes or dust from occupational exposure or air pollution may also be causative. About

5% of the population has chronic bronchitis, and it is two times more common in males than females.[1]

Chronic bronchitis is treated symptomatically. Inflammation and edema of the respiratory epithelium may be

reduced with inhaled corticosteroids. Wheezing and shortness of breath can be treated by

reducing bronchospasm (reversible narrowing of smaller bronchi due to constriction of the smooth muscle)

with bronchodilators such as inhaled β-Adrenergic agonists (e.g.,albuterol) and

inhaled anticholinergics (e.g., ipratropium bromide). Hypoxemia, too little oxygen in the blood, can be treated

with supplemental oxygen.[1] However, oxygen supplementation can result in decreased respiratory drive

leading to increased blood levels of carbon dioxide and subsequent respiratory acidosis.

The most effective method of preventing chronic bronchitis and other forms of COPD is to avoid smoking

cigarettes and other forms of tobacco.[1]

On pulmonary tests, a bronchitic (bronchitis) may present a decreased FEV1 and FEV1/FVC. However, unlike

the other common obstructive disorders, asthma and emphysema, bronchitis rarely causes a high residual

volume. This is because the air flow obstruction found in bronchitis is due to increased resistance, which does

not generally cause the airways to collapse prematurely and trap air in the lungs. [citation needed]

[edit]Protracted bacterial bronchitis

Protracted bacterial bronchitis is defined as a cough of more than 8 weeks, with a positive bronchoalveolar

lavage (BAL), that resolves with antibiotics.[5] It is usually caused bystreptococcus pneumoniae, haemophilus

influenzae, or moraxella catarrhalis.[5]

MeningitisFrom Wikipedia, the free encyclopedia

Meningitis

Classification and external resources

Meninges of the central nervous system: dura mater, arachnoid, and pia

mater.

ICD-10 G 00. –G 03.

ICD-9 320–322

DiseasesDB 22543

MedlinePlus 000680

eMedicine med/2613 emerg/309 emerg/390

MeSH D008581

Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively

as the meninges.[1] The inflammation may be caused by infection with viruses, bacteria, or

other microorganisms, and less commonly by certain drugs.[2] Meningitis can be life-threatening because of the

inflammation's proximity to the brain and spinal cord; therefore the condition is classified as a medical

emergency.[1][3]

The most common symptoms of meningitis are headache and neck stiffness associated

with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud

noises (phonophobia). Sometimes, especially in small children, onlynonspecific symptoms may be present,

such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of meningitis; for

instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash.[1][4]

A lumbar puncture may be used to diagnose or exclude meningitis. This involves inserting a needle into

the spinal canal to extract a sample of cerebrospinal fluid (CSF), the fluid that envelops the brain and spinal

cord. The CSF is then examined in a medical laboratory.[3] The usual treatment for meningitis is the prompt

application of antibiotics and sometimes antiviral drugs. In some situations, corticosteroid drugs can also be

used to prevent complications from overactive inflammation.[3][4] Meningitis can lead to serious long-term

consequences such asdeafness, epilepsy, hydrocephalus and cognitive deficits, especially if not treated

quickly.[1][4] Some forms of meningitis (such as those associated with meningococci, Haemophilus

influenzae   type B , pneumococci or mumps virus infections) may be prevented byimmunization.[1]

Contents

[hide]

1 Signs and symptoms

o 1.1 Clinical features

o 1.2 Early complications

2 Causes

o 2.1 Bacterial

o 2.2 Aseptic

o 2.3 Viral

o 2.4 Parasitic

o 2.5 Non-infectious

3 Mechanism

4 Diagnosis

o 4.1 Blood tests and imaging

o 4.2 Lumbar puncture

o 4.3 Postmortem

5 Prevention

6 Treatment

o 6.1 Initial treatment

o 6.2 Bacterial meningitis

6.2.1 Antibiotics

6.2.2 Steroids

o 6.3 Viral meningitis

o 6.4 Fungal meningitis

7 Prognosis

8 Epidemiology

9 History

10 See also

11 References

12 External links

[edit]Signs and symptoms

[edit]Clinical features

In adults, a severe headache is the most common symptom of meningitis – occurring in almost 90% of cases of

bacterial meningitis, followed by nuchal rigidity (inability to flex the neck forward passively due to increased

neck muscle tone and stiffness).[5] The classic triad of diagnostic signs consists of nuchal rigidity, sudden high

fever, and altered mental status; however, all three features are present in only 44–46% of all cases of bacterial

meningitis.[5][6] If none of the three signs is present, meningitis is extremely unlikely.[6] Other signs commonly

associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to

loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and

looking unwell.[1] In infants up to 6 months of age, bulging of the fontanelle (the soft spot on top of a baby's

head) may be present. Other features that might distinguish meningitis from less severe illnesses in young

children are leg pain, cold extremities, and abnormal skin color.[7]

Nuchal rigidity occurs in 70% of adult cases of bacterial meningitis.[6] Other signs of meningism include the

presence of positive Kernig's sign or Brudzinski's sign. Kernig's sign is assessed with the patient lying supine,

with the hip and knee flexed to 90 degrees. In a patient with a positive Kernig's sign, pain limits passive

extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes involuntary flexion of

the knee and hip. Although Kernig's and Brudzinski's signs are both commonly used to screen for meningitis,

the sensitivity of these tests is limited.[6][8] They do, however, have very good specificity for meningitis: the signs

rarely occur in other diseases.[6] Another test, known as the "jolt accentuation maneuver" helps determine

whether meningitis is present in patients reporting fever and headache. The patient is told to rapidly rotate his

or her head horizontally; if this does not make the headache worse, meningitis is unlikely. [6]

Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be

differentiated from meningitis with other causes by a rapidly spreadingpetechial rash which may precede other

symptoms.[7] The rash consists of numerous small, irregular purple or red spots ("petechiae") on the

trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or soles of

the feet. The rash is typically non-blanching: the redness does not disappear when pressed with a finger or a

glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific

for the disease; it does, however, occasionally occur in meningitis due to other bacteria. [1] Other clues as to the

nature of the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes,

both of which are associated with various forms of viral meningitis.[9]

[edit]Early complications

A severe case of meningococcal meningitis in which the petechial rash progressed to gangrene and requiredamputation of

all limbs. The patient,Charlotte Cleverley-Bisman, survived the disease and became a poster child for a meningitis

vaccination campaign in New Zealand.

People with meningitis may develop additional problems in the early stages of their illness. These may require

specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis,

a systemic inflammatory response syndrome of falling blood pressure,fast heart rate, high or abnormally low

temperature and rapid breathing. Very low blood pressure may occur early, especially but not exclusively in

meningococcal illness; this may lead to insufficient blood supply to other organs. [1] Disseminated intravascular

coagulation, the excessive activation of blood clotting, may cause both the obstruction of blood flow to organs

and a paradoxical increase of bleeding risk. In meningococcal disease, gangrene of limbs can occur.[1] Severe

meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading

to Waterhouse-Friderichsen syndrome, which is often lethal.[10]

The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue getting

trapped. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex,

and abnormal positioning.[4] Inflammation of the brain tissue may also obstruct the normal flow of CSF around

the brain (hydrocephalus).[4] Seizures may occur for various reasons; in children, seizures are common in the

early stages of meningitis (30% of cases) and do not necessarily indicate an underlying cause. [3] Seizures may

result from increased pressure and from areas of inflammation in the brain tissue.[4] Focal seizures (seizures

that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to

control with medication are indicators of a poorer long-term outcome.[1]

The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising

from the brain stem that supply the head and neck area and control eye movement, facial muscles and hearing,

among other functions.[1][6] Visual symptoms and hearing loss may persist after an episode of meningitis (see

below).[1] Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the

formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation,

or abnormal movement or function of the part of the body supplied by the affected area in the brain. [1][4]

[edit]Causes

Meningitis is usually caused by infection from viruses or micro-organisms. Most cases are due to infection with

viruses,[6] with bacteria, fungi, and parasites being the next most common causes.[2] It may also result from

various non-infectious causes.[2]

[edit]Bacterial

The types of bacteria that cause bacterial meningitis vary by age group. In premature babies and newborns up

to three months old, common causes are group B streptococci (subtypes III which normally inhabit

the vagina and are mainly a cause during the first week of life) and those that normally inhabit the digestive

tract such as Escherichia coli (carrying K1 antigen).Listeria monocytogenes (serotype IVb) may affect the

newborn and occurs in epidemics. Older children are more commonly affected by Neisseria

meningitidis (meningococcus),Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five

by Haemophilus influenzae   type B  (in countries that do not offer vaccination, see below).[1][3] In adults, N.

meningitidis and S. pneumoniae together cause 80% of all cases of bacterial meningitis, with increased risk

of L. monocytogenes in those over 50 years old.[3][4] Since the pneumococcal vaccine was introduced, however,

rates of pneumococcal meningitis have declined in children and adults.[11]

Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space.

Similarly, individuals with a cerebral shunt or related device (such as anextraventricular drain or Ommaya

reservoir) are at increased risk of infection through those devices. In these cases, infections

with staphylococci are more likely, as well as infections bypseudomonas and other Gram-negative bacilli.[3] The

same pathogens are also more common in those with an impaired immune system.[1] In a small proportion of

people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to meningitis.[3] Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal meningitis.[12]

Tuberculous meningitis, meningitis due to infection with Mycobacterium tuberculosis, is more common in those

from countries where tuberculosis is common, but is also encountered in those with immune problems, such

as AIDS.[13]

Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired,

or by disorders of the immune system.[14] Anatomical defects allow continuity between the external environment

and the nervous system. The most common cause of recurrent meningitis is skull fracture,[14] particularly

fractures that affect the base of the brain or extend towards the sinuses and petrous pyramids.[14] A literature

review of 363 reported cases of recurrent meningitis showed that 59% of cases are due to such anatomical

abnormalities, 36% due to immune deficiencies (such as complement deficiency, which predisposes especially

to recurrent meningococcal meningitis), and 5% due to ongoing infections in areas adjacent to the meninges. [14]

[edit]Aseptic

The term aseptic meningitis refers loosely to all cases of meningitis in which no bacterial infection can be

demonstrated. This is usually due to viruses, but it may be due to bacterial infection that has already been

partially treated, with disappearance of the bacteria from the meninges, or by infection in a space adjacent to

the meninges (e.g. sinusitis). Endocarditis(infection of the heart valves with spread of small clusters of bacteria

through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection

withspirochetes, a type of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia

burgdorferi (known for causing Lyme disease). Meningitis may be encountered incerebral malaria (malaria

infecting the brain). Fungal meningitis, e.g. due to Cryptococcus neoformans, is typically seen in people with

immune deficiency such as AIDS. Amoebic meningitis, meningitis due to infection with amoebae such

as Naegleria fowleri, is contracted from freshwater sources.[2]

[edit]Viral

Viruses that can cause meningitis include enteroviruses, herpes simplex virus type 2 (and less commonly type

1), varicella zoster virus (known for causing chickenpox and shingles),mumps virus, HIV, and LCMV.[9]

[edit]Parasitic

A parasitic cause is often assumed when there is a predominance of eosinophils in the CSF. The most

common parasites implicated are Angiostrongylus cantonensis and Gnathostoma

spinigerum. Tuberculosis, syphilis, cryptococcosis, and coccidiodomycosis are rare causes of eosinophilic

meningitis that may need to be considered.[15][16][17]

[edit]Non-infectious

Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges

(malignant meningitis)[18] and certain drugs (mainly non-steroidal anti-inflammatory

drugs, antibiotics and intravenous immunoglobulins).[19] It may also be caused by several inflammatory

conditions such as sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such

as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel

wall) such as Behçet's disease.[2] Epidermoid cysts  and dermoid cysts may cause meningitis by releasing irritant

matter into the subarachnoid space.[2][14] Mollaret's meningitis is a syndrome of recurring episodes of aseptic

meningitis; it is now thought to be caused by herpes simplex virus type 2. Rarely, migraine may cause

meningitis, but this diagnosis is usually only made when other causes have been eliminated. [2]

[edit]Mechanism

The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect

the brain and spinal cord (the central nervous system). The pia mater is a very delicate impermeable

membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid

mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater.

The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with cerebrospinal

fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the

arachnoid membrane and the skull.

In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or

through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis

follows invasion of the bloodstream by organisms that live upon mucous surfaces such as the nasal cavity. This

is often in turn preceded by viral infections, which break down the normal barrier provided by the mucous

surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where

theblood-brain barrier is vulnerable—such as the choroid plexus. Meningitis occurs in 25% of newborns with

bloodstream infections due to group B streptococci; this phenomenon is less common in adults.[1] Direct

contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the

nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above);

occasionally, congenital defects of the dura mater can be identified.[1]

The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of

bacterial infection but can rather largely be attributed to the response of theimmune system to the entrance of

bacteria into the central nervous system. When components of the bacterial cell membrane are identified by the

immune cells of the brain (astrocytesand microglia), they respond by releasing large amounts of cytokines,

hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune

response. The blood-brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling

of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF,

causing inflammation of the meninges, and leading to "interstitial" edema (swelling due to fluid between the

cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads

to a decreased blood flow and a third type of edema, "cytotoxic" edema. The three forms of cerebral edema all

lead to an increased intracranial pressure; together with the lowered blood pressure often encountered in acute

infection, this means that it is harder for blood to enter the brain, and brain cells are deprived of oxygen and

undergo apoptosis (automated cell death).[1]

It is recognized that administration of antibiotics may initially worsen the process outlined above, by increasing

the amount of bacterial cell membrane products released through the destruction of bacteria. Particular

treatments, such as the use of corticosteroids, are aimed at dampening the immune system's response to this

phenomenon.[1][4]

[edit]Diagnosis

CSF findings in different forms of meningitis[20]

Type of meningitis Glucose Protein Cells

Acute bacterial low highPMNs,often > 300/mm³

Acute viral normalnormal or high

mononuclear,< 300/mm³

Tuberculous low highmononuclear andPMNs, < 300/mm³

Fungal low high < 300/mm³

Malignant low highusuallymononuclear

[edit]Blood tests and imaging

In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-

reactive protein,complete blood count), as well as blood cultures.[3][21]

The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid

through lumbar puncture(LP, spinal tap).[22] However, lumbar puncture is contraindicated if there is a mass in

the brain (tumor or abscess) or theintracranial pressure (ICP) is elevated, as it may lead to brain herniation. If

someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem,

localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended

prior to the lumbar puncture.[3][21][23] This applies in 45% of all adult cases.[4] If a CT or MRI is required before LP,

or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to prevent

delay in treatment,[3] especially if this may be longer than 30 minutes.[21][23] Often, CT or MRI scans are

performed at a later stage to assess for complications of meningitis.[1]

In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is

common in bacterial meningitis, due to a combination of factors including dehydration, the inappropriate

excretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.[4][24]

[edit]Lumbar puncture

A lumbar puncture is done by positioning the patient, usually lying on the side, applying local anesthetic, and

inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When

this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is

normally between 6 and 18 cm water (cmH2O);[22] in bacterial meningitis the pressure is typically elevated.[3]

[21] The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF

indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest

bacterial meningitis.[3]

Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs

The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content

and glucose level.[3] Gram stainingof the sample may demonstrate bacteria in bacterial meningitis, but absence

of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced

by a further 20% if antibiotics were administered before the sample was taken, and Gram staining is also less

reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it

identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available.[3] The type

of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually

neutrophil-predominant) or viral (usually lymphocyte-predominant),[3] although in the beginning of the disease

this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal

etiology, among others.[16]

The concentration of glucose in CSF is normally above 40% that in blood. In bacterial meningitis it is typically

lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A

ratio ≤0.4 is indicative of bacterial meningitis;[22] in the newborn, glucose levels in CSF are normally higher, and

a ratio below 0.6 (60%) is therefore considered abnormal.[3] High levels of lactate in CSF indicate a higher

likelihood of bacterial meningitis, as does a higher white blood cell count.[22]

Various more specialized tests may be used to distinguish between various types of meningitis. A latex

agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria

meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not

encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic.

Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of

limited use unless other tests have been unhelpful.[3] Polymerase chain reaction (PCR) is a technique used to

amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal

fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required.

It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral

meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this).[9] Serology (identification of antibodies to viruses) may be useful in viral meningitis.[9] If tuberculous meningitis

is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low sensitivity, and tuberculosis

culture, which takes a long time to process; PCR is being used increasingly.[13] Diagnosis of cryptococcal

meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal

antigen in blood or CSF is more sensitive, particularly in persons with AIDS.[25][26][27]

A diagnostic and therapeutic conundrum is the "partially treated meningitis", where there are meningitis

symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may

resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive

positive evidence of a viral cause (e.g. a positive enterovirus PCR).[9]

[edit]Postmortem

Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a

widespread inflammation of the pia mater and arachnoid layers of the meninges covering the brain and spinal

cord. Neutrophil leucocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along

with cranial nerves and the spinal cord, may be surrounded with pus—as may the meningeal vessels.[28]

[edit]Prevention

For some causes of meningitis, prophylaxis can be provided in the long term with vaccine, or in the short term

with antibiotics.

Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their

routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis

in young children in those countries. In the countries where the disease burden is highest, however, the

vaccine is still too expensive.[29][30] Similarly, immunization against mumps has led to a sharp fall in the number

of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps. [9]

Meningococcus vaccines exist against groups A, C, W135 and Y.[31] In countries where the vaccine for

meningococcus group C was introduced, cases caused by this pathogen have decreased substantially. [29] A

quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y vaccine

against four strains is now a visa requirement for taking part in the Hajj.[32] Development of a vaccine against

group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to

make a vaccine) only elicit a weak response from the immune system, or cross-react with normal human

proteins.[29][31] Still, some countries (New Zealand, Cuba, Norway and Chile) have developed vaccines against

local strains of group B meningococci; some have shown good results and are used in local immunization

schedules.[31] In Africa, the current approach for prevention and control of meningococcal epidemics is based

on early detection of the disease and emergency reactive mass vaccination of the at-risk population with

bivalent A/C or trivalent A/C/W135 polysaccharide vaccines.[33]

Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV),

which is active against seven common serotypes of this pathogen, significantly reduces the incidence of

pneumococcal meningitis.[29][34] The pneumococcal polysaccharide vaccine, which covers 23 strains, is only

administered in certain groups (e.g. those who have had a splenectomy, the surgical removal of the spleen); it

does not elicit a significant immune response in all recipients, e.g. small children. [34]

Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of

tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine. [29]

Short-term antibiotic prophylaxis is also a method of prevention, particularly of meningococcal meningitis. In

cases of meningococcal meningitis, prophylactic treatment of close contacts with antibiotics

(e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not

protect against future infections.[21][35]

[edit]Treatment

[edit]Initial treatment

Meningitis is potentially life-threatening and has a high mortality rate if untreated; [3] delay in treatment has been

associated with a poorer outcome.[4] Thus treatment with wide-spectrum antibiotics should not be delayed while

confirmatory tests are being conducted.[23] If meningococcal disease is suspected in primary care, guidelines

recommend that benzylpenicillin be administered before transfer to hospital.[7] Intravenous fluids should be

administered if hypotension (low blood pressure) or shock are present.[23] Given that meningitis can cause a

number of early severe complications, regular medical review is recommended to identify these complications

early,[23] as well as admission to an intensive care unit if deemed necessary.[4]

Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence

of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure may

be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to

decrease the intracranial pressure with medication (e.g.mannitol).[4] Seizures are treated with anticonvulsants.[4] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device,

such as a cerebral shunt.[4]

[edit]Bacterial meningitis[edit]Antibiotics

Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the initial treatment of

bacterial meningitis.

Empiric antibiotics (treatment without exact diagnosis) must be started immediately, even before the results of

the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of

bacteria that cause meningitis in a particular place. For instance, in the United Kingdom empirical

treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone.[21][23] In the USA, where

resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment

is recommended.[3][4][21] Empirical therapy may be chosen on the basis of the age of the patient, whether the

infection was preceded by head injury, whether the patient has undergone neurosurgery and whether or not a

cerebral shunt is present.[3] For instance, in young children and those over 50 years of age, as well as those

who are immunocompromised, addition of ampicillin is recommended to cover Listeria monocytogenes.[3]

[21] Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be

possible to change the antibiotics to those likely to deal with the presumed group of pathogens. [3]

The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric

therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its

sensitivities to antibiotics.[3] For an antibiotic to be effective in meningitis, it must not only be active against the

pathogenic bacterium, but also reach the meninges in adequate quantities; some antibiotics have inadequate

penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been

tested directly on meningitis patients in clinical trials. Rather, the relevant knowledge has mostly derived from

laboratory studies in rabbits.[3]

Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically

treated for six months, those with tuberculous meningitis are typically treated for a year or longer. [13] In

tuberculous meningitis there is a strong evidence base for treatment with corticosteroids, although this

evidence is restricted to those without AIDS.[36]

[edit]Steroids

Adjuvant treatment with corticosteroids (usually dexamethasone) has been shown in some studies to reduce

rates of mortality, severe hearing loss and neurological damage in adolescents and adults from high income

countries which have low rates of HIV.[37] The likely mechanism is suppression of overactive inflammation.[38] Professional guidelines therefore recommend the commencement of dexamethasone or a similar

corticosteroid just before the first dose of antibiotics is given, and continued for four days.[21][23] Given that most

of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that

dexamethasone be discontinued if another cause for meningitis is identified.[3][21]

Adjuvant corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids

has been demonstrated in adults as well as in children from high-income countries, their use in children

from low-income countries is not supported by evidence; the reason for this discrepancy is not clear.[39] Even in

high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of

antibiotics, and is greatest in cases of H. influenzae meningitis,[3][40] the incidence of which has decreased

dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are recommended in the treatment

of pediatric meningitis if the cause is H. influenzae and only if given prior to the first dose of antibiotics, whereas

other uses are controversial.[3]

A 2010 analysis of previous studies has shown that the benefit from steroids may not be as significant as

previously found. The one possible significant benefit is reduction of hearing loss in survivors. [41]

[edit]Viral meningitis

Viral meningitis typically requires supportive therapy only; most viruses responsible for causing meningitis are

not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial

meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such

as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is effective.[9] Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and

analgesics.[42]

[edit]Fungal meningitis

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of highly dosed antifungals,

such as amphotericin B and flucytosine.[25][43]

[edit]Prognosis

Untreated, bacterial meningitis is almost always fatal. Viral meningitis, in contrast, tends to resolve

spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends on

the age of the patient and the underlying cause. Of the newborn patients, 20–30% may die from an episode of

bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again to

about 19–37% in adults.[1][4] Risk of death is predicted by various factors apart from age, such as the pathogen

and the time it takes for the pathogen to be cleared from the cerebrospinal fluid, [1] the severity of the

generalized illness, decreased level of consciousness or abnormally low count of white blood cells in the CSF.[4] Meningitis caused by H. influenzae and meningococci has a better prognosis compared to cases caused by

group B streptococci, coliforms and S. pneumonia.[1] In adults, too, meningococcal meningitis has a lower

mortality (3–7%) than pneumococcal disease.[4]

In children there are several potential disabilities which result from damage to the nervous

system. Sensorineural hearing loss, epilepsy, learning and behavioral difficulties, as well as decreased

intelligence, occur in about 15% of survivors.[1] Some of the hearing loss may be reversible.[44] In adults, 66% of

all cases emerge without disability. The main problems aredeafness (in 14%) and cognitive impairment (in

10%).[4]

[edit]Epidemiology

Demography of meningococcalmeningitis.       meningitis belt       epidemic zones      sporadic cases only

Disability-adjusted life year for meningitis per 100,000 inhabitants in 2002.[45]

      no data       ≤ 10      10-25      25-50      50-75      75-100      100-200      200-300      300-400      400-500      500-1000      1000-1500      ≥ 1500

Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown.[9] Bacterial

meningitis occurs in about 3 people per 100,000 annually in Western countries. Population-wide studies have

shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often in the summer. In

Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually. [6] Sub-Saharan Africa has been

plagued by large epidemics of meningococcal meningitis for over a century,[46] leading to it being labeled the

"meningitis belt". Epidemics typically occur in the dry season (December to June), and an epidemic wave can

last two to three years, dying out during the intervening rainy seasons.[47] Attack rates of 100-800 cases per

100,000 are encountered in this area,[48] which is poorly served by medical care. These cases are

predominantly caused by meningococci.[6] The largest epidemic ever recorded in history swept across the

entire region in 1996–1997, causing over 250,000 cases and 25,000 deaths. [49]

Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as

army barracks during mobilization, college campuses[1] and the annual Hajj pilgrimage.[32]Although the pattern

of epidemic cycles in Africa is not well understood, several factors have been associated with the development

of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the

population), demographic conditions (travel and large population displacements), socioeconomic conditions

(overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent

infections (acute respiratory infections).[48]

There are significant differences in the local distribution of causes for bacterial meningitis. For instance,

while N. meningitides groups B and C cause most disease episodes in Europe, group A is found in Asia and

continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt,

accounting for about 80% to 85% of documented meningococcal meningitis cases.[48]

[edit]History

Some suggest that Hippocrates may have realized the existence of meningitis,[6] and it seems that meningism

was known to pre-Renaissance physicians such as Avicenna.[50] The description of tuberculous meningitis, then

called "dropsy in the brain", is often attributed to Edinburgh physician Sir Robert Whytt in a posthumous report

that appeared in 1768, although the link with tuberculosis and its pathogen was not made until the next century.[50][51]

It appears that epidemic meningitis is a relatively recent phenomenon.[52] The first recorded major outbreak

occurred in Geneva in 1805.[52][53]Several other epidemics in Europe and the United States were described

shortly afterward, and the first report of an epidemic in Africa appeared in 1840. African epidemics became

much more common in the 20th century, starting with a major epidemic sweeping Nigeria andGhana in 1905–

1908.[52]

The first report of bacterial infection underlying meningitis was by the Austrian bacteriologist Anton

Weichselbaum, who in 1887 described themeningococcus.[54] Mortality from meningitis was very high (over

90%) in early reports. In 1906, antiserum was produced in horses; this was developed further by the American

scientist Simon Flexner and markedly decreased mortality from meningococcal disease.[55][56] In

1944,penicillin was first reported to be effective in meningitis.[57] The introduction in the late 20th century

of Haemophilus vaccines led to a marked fall in cases of meningitis associated with this pathogen, [30] and in

2002 evidence emerged that treatment with steroids could improve the prognosis of bacterial meningitis. [38][39][56]

Spina bifidaFrom Wikipedia, the free encyclopedia

Spina bifida cystica

Classification and external resources

ICD-10 Q 05. , Q 76.0

ICD-9 741, 756.17

OMIM 182940

DiseasesDB 12306

eMedicine orthoped/557

MeSH C10.500.680.800

Spina bifida (Latin: "split spine") is a developmental birth defect caused by the incomplete closure of

the embryonic neural tube. Somevertebrae overlying the spinal cord are not fully formed and remain unfused

and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through the

opening in the bones. There may or may not be a fluid-filled sac surrounding the spinal cord. Other neural tube

defects include anencephaly, a condition in which the portion of the neural tube which will become

the cerebrum does not close, and encephalocele, which results when other parts of the brain remain unfused.

Spina bifida malformations fall into four categories: spina bifida occulta, spina bifida cystica

(myelomeningocele), meningocele andlipomeningocele. The most common location of the malformations is

the lumbar and sacral areas . Myelomeningocele is the most significant form and it is this that leads to disability

in most affected individuals. The terms spina bifida and myelomeningocele are usually used interchangeably.

Spina bifida can be surgically closed after birth, but this does not restore normal function to the affected part of

the spinal cord. Intrauterine surgery for spina bifida has also been performed and the safety and efficacy of this

procedure is currently being investigated. The incidence of spina bifida can be decreased by up to 75% when

daily folic acid supplements are taken prior to conception.

Contents

[hide]

1 Classification

o 1.1 Spina bifida occulta

o 1.2 Spina bifida cystica

o 1.3 Meningocele

o 1.4 Myelomeningocele

2 Signs and symptoms

3 Pathophysiology

4 Prevention

o 4.1 Pregnancy screening

5 Treatment

o 5.1 Fetal surgery clinical trials

6 Epidemiology

7 Society and culture

o 7.1 Media

o 7.2 Notable people

8 See also

9 References

10 External links

[edit]Classification

[edit]Spina bifida occulta

X-ray image of Spina bifida occulta in S-1

Unfused arch of C1 at CT.

Occulta is Latin for "hidden." This is one of the mildest forms of spina bifida.[1]

In occulta, the outer part of some of the vertebrae are not completely closed. [2] The split in the vertebrae is so

small that the spinal cord does not protrude. The skin at the site of the lesion may be normal, or it may have

some hair growing from it; there may be a dimple in the skin, alipoma, a dermal sinus or a birthmark.[3]

Many people with the mildest form of this type of spina bifida do not even know they have it, as the condition is

asymptomatic in most cases.[3] A systematic review of radiographic research studies found no relationship

between spina bifida occulta and back pain.[4] More recent studies not included in the review support the

negative findings.[5][6][7]

However, other studies suggest spina bifida occulta is not always harmless. One study found that among

patients with back pain, severity is worse if spina bifida occulta is present.[8][9]

[edit]Spina bifida cystica

In spina bifida cystica, a cyst protrudes through the defect in the vertebral arch. These conditions can be

diagnosed in utero on the basis of elevated levels of alpha-fetoprotein, after amniocentesis, and by ultrasound

imaging. Spina bifida cystica may result in hydrocephalus and neurological deficits. [citation needed]

[edit]Meningocele

The least common form of spina bifida is a posterior meningocele (or meningeal cyst).

In a posterior meningocele, the vertebrae develop normally, however the meninges are forced into the gaps

between the vertebrae. As the nervous system remains undamaged, individuals with meningocele are unlikely

to suffer long-term health problems, although there are reports of tethered cord. Causes of meningocele

include teratoma and other tumors of the sacrococcyx and of the presacral space, and Currarino syndrome,

Bony defect with outpouching of meninges.[10]

[edit]Myelomeningocele

Myelomeningocele in the lumbar area.

(1) External sac with cerebrospinal fluid.

(2) Spinal cord wedged between the vertebrae.

In this, the most serious and common[11] form, the unfused portion of the spinal column allows the spinal cord to

protrude through an opening. The meningeal membranes that cover the spinal cord form a sac enclosing the

spinal elements. Spina bifida with myeloschisis is the most severe form of spina bifida cystica. In this defect,

the involved area is represented by a flattened, plate-like mass of nervous tissue with no overlying membrane.

The exposure of these nerves and tissues make the baby more prone to life-threatening infections. [12]

The protruded portion of the spinal cord and the nerves which originate at that level of the cord are damaged or

not properly developed. As a result, there is usually some degree of paralysis and loss of sensation below the

level of the spinal cord defect. Thus, the higher the level of the defect the more severe the associated nerve

dysfunction and resultant paralysis. People may have ambulatory problems, loss of sensation, deformities of

the hips, knees or feet and loss of muscle tone. Depending on the location of the lesion, intense pain may

occur originating in the lower back, and continuing down the leg to the back of the knee. [citation needed]

Many individuals with spina bifida will have an associated abnormality of the cerebellum, called the Arnold

Chiari II malformation. In affected individuals the back portion of the brain is displaced from the back of the skull

down into the upper neck. In approximately 90 percent of the people with

myelomeningocele, hydrocephalus will also occur because the displaced cerebellum interferes with the normal

flow ofcerebrospinal fluid.[citation needed]

The myelomeningocele (or perhaps the scarring due to surgery) tethers the spinal cord. In some individuals this

causes significant traction on the spinal cord and can lead to a worsening of the paralysis, scoliosis, back pain,

or worsening bowel and/or bladder function.[13]

[edit]Signs and symptoms

Children with spina bifida often have hydrocephalus, which consists of excessive accumulation of cerebrospinal

fluid in the ventricles of the brain.[14]

According to the Spina Bifida Association of America (SBAA), over 73 percent of people with spina bifida

develop an allergy to latex, ranging from mild to life-threatening. The common use of latex in medical facilities

makes this a particularly serious concern. The most common approach to avoid developing an allergy is to

avoid contact with latex-containing products such as examination gloves, condoms, catheters, and many of the

products used by dentists.[2]

[edit]Pathophysiology

Spina bifida is caused by the failure of the neural tube to close during the first month of embryonic development

(often before the mother knows she is pregnant).

Normally the closure of the neural tube occurs around 28 days after fertilization.[15] However, if something

interferes and the tube fails to close properly, a neural tube defect will occur. Medications such as

some anticonvulsants, diabetes, having a relative with spina bifida, obesity, and an increased body temperature

from fever or external sources such as hot tubs and electric blankets can increase the chances a woman will

conceive a baby with a spina bifida. However, most women who give birth to babies with spina bifida have

none of these risk factors, and so in spite of much research, it is still unknown what causes the majority of

cases.[citation needed]

The varying prevalence of spina bifida in different human populations and extensive evidence from mouse

strains with spina bifida suggests a genetic basis for the condition. As with other human diseases such

as cancer, hypertension and atherosclerosis (coronary artery disease), spina bifida likely results from the

interaction of multiple genes and environmental factors.

Research has shown that lack of folic acid (folate) is a contributing factor in the pathogenesis of neural tube

defects, including spina bifida. Supplementation of the mother's diet with folate can reduce the incidence of

neural tube defects by about 70 percent, and can also decrease the severity of these defects when they occur.[16][17][18] It is unknown how or why folic acid has this effect.

Spina bifida does not follow direct patterns of heredity like muscular dystrophy or haemophilia. Studies show

that a woman who has had one child with a neural tube defect such as spina bifida, has about a three percent

risk of having another child with a neural tube defect. This risk can be reduced to about one percent if the

woman takes high doses (4 mg/day) of folic acid before and during pregnancy. For the general population, low-

dose folic acid supplements are advised (0.4 mg/day).[citation needed]

[edit]Prevention

There is no single cause of spina bifida nor any known way to prevent it entirely. However, dietary

supplementation with folic acid has been shown to be helpful in preventing spina bifida (see above). Sources of

folic acid include whole grains, fortified breakfast cereals, dried beans, leaf vegetables and fruits.[19]

Folate fortification of enriched grain products has been mandatory in the United States since 1998. The U.S.

Food and Drug Administration, Public Health Agency of Canada [20]  and UK recommended amount of folic acid

for women of childbearing age and women planning to become pregnant is at least 0.4 mg/day of folic acid

from at least three months beforeconception, and continued for the first 12 weeks of pregnancy.[21] Women who

have already had a baby with spina bifida or other type of neural tube defect, or are

taking anticonvulsantmedication should take a higher dose of 4–5 mg/day.[21]

Certain mutations in the gene VANGL1 are implicated as a risk factor for spina bifida: these mutations have

been linked with spina bifida in some families with a history of spina bifida.[22]

[edit]Pregnancy screening

Neural tube defects can usually be detected during pregnancy by testing the mother's blood (AFP screening) or

a detailed fetal ultrasound. Spina bifida may be associated with other malformations as in dysmorphic

syndromes, often resulting in spontaneous miscarriage. However, in the majority of cases spina bifida is an

isolated malformation.

Genetic counseling and further genetic testing, such as amniocentesis, may be offered during the pregnancy as

some neural tube defects are associated with genetic disorders such astrisomy 18. Ultrasound screening for

spina bifida is partly responsible for the decline in new cases, because many pregnancies are terminated out of

fear that a newborn might have a poor future quality of life. With modern medical care, the quality of life of

patients has greatly improved.[15]

[edit]Treatment

There is no known cure for nerve damage due to spina bifida. To prevent further damage of the nervous tissue

and to prevent infection, pediatric neurosurgeons operate to close the opening on the back. During the

operation for spina bifida cystica, the spinal cord and its nerve roots are put back inside the spine and covered

with meninges. In addition, a shunt may be surgically installed to provide a continuous drain for the

cerebrospinal fluid produced in the brain, as happens with hydrocephalus. Shunts most commonly drain into

the abdomen. However, if spina bifida is detected during pregnancy, then open fetal surgery can be performed.[citation needed]

Most individuals with myelomeningocele will need periodic evaluations by specialists including orthopedists to

check on their bones and muscles, neurosurgeons to evaluate the brain and spinal cord and urologists for the

kidneys and bladder. Such care is best begun immediately after birth. Most affected individuals will require

braces, crutches, walkers or wheelchairs to maximize their mobility. As a general rule, the higher the level of

the spina bifida defect the more severe the paralysis, but paralysis does not always occur. Thus, those with low

levels may need only short leg braces while those with higher levels do best with a wheelchair, and some may

be able to walk unaided. Many will need to manage their urinary system with a program of catheterization. Most

will also require some sort of bowel management program, though some may be virtually unaffected. [citation needed]

[edit]Fetal surgery clinical trials

Management of Myelomeningocele Study (MOMS)[23] is a phase III clinical trial to evaluate the safety and

efficacy of fetal surgery to close a myelomeningocele. This involves surgically opening the pregnant mother's

abdomen and uterus to operate on the fetus. This route of access to the fetus is called "open fetal surgery".

Fetal skin grafts are used to cover the exposed spinal cord, to protect it from further damage caused by

prolonged exposure to amniotic fluid. The fetal surgery may decrease some of the damaging effects of the

spina bifida, but at some risk to both the fetus and the pregnant woman.

In contrast to the open fetal operative approach tested in the MOMS, a minimally invasive approach has been

developed by the German Center for Fetal Surgery & Minimally Invasive Therapy at the University of Bonn,

Germany.[24] This minimally invasive approach uses three small tubes (trocars) with an external diameter of

5 mm that are directly placed via small needle punctures through the maternal abdominal wall into the uterine

cavity. Via this route, the unborn can be postured and its spina bifida defect be closed using small instruments.

In contrast to open fetal surgery for spina bifida, the fetoscopic approach results in less trauma to the mother as

large incisions of her abdomen and uterus is not required.

[edit]Epidemiology

Spina bifida is one of the most common birth defects, with an average worldwide incidence of 1–2 cases per

1000 births, but certain populations have a significantly greater risk.

In the United States, the average incidence is 0.7 per 1000 live births. The incidence is higher on the East

Coast than on the West Coast, and higher in whites (1 case per 1000 live births) than in blacks (0.1–0.4 case

per 1000 live births). Immigrants from Ireland have a higher incidence of spina bifida than do nonimmigrants. [25]

[26]

The highest incidence rates worldwide were found in Ireland and Wales, where 3–4 cases of

myelomeningocele per 1000 population have been reported during the 1970s, along with more than six cases

of anencephaly (both live births and stillbirths) per 1000 population. The reported overall incidence of

myelomeningocele in the British Isles was 2–3.5 cases per 1000 births.[25][26] Since then, the rate has fallen

dramatically with 0.15 per 1000 live births reported in 1998[15], though this decline is partially accounted for by

the fact that some foetuses are aborted when tests show signs of spina bifida (see Pregnancy

screening below).

Parents of children with spina bifida have an increased risk of having a second child with a neural tube defect.[25][26]

This condition is more likely to appear in females; the cause for this is unknown.[citation needed]