founded 1897 vol. cxvii romanian journal of no. 1 …...vol. cxvii • new series • no. 1-2/2014...
TRANSCRIPT
• Reconsidering the importance of military medicine at the level of National Ministry of
Defence and into society
• Clostridium difficile – emergent hospital flora
• Stress management for optimization of organizational activity
• New quaternary ammonium salts based decontaminants
• News and perspectives on treatment of normal pressure internal hydrocephalus
• Nonalcoholic fatty liver disease – an etiological approach
• An unusual cause for cerebellar syndrome
• Past and future
www.amfmr.ro
Founded 1897 • Vol. CXVII
New series • No. 1-2/2014
REVISTA DE MEDICINĂ MILITARĂ
Military Medicine
Romanian Journal of
Editorial Board of Romanian Journal of Military Medicine
Under the patronage Romanian Association of Military Physicians and Pharmacists
Honorary Editor Victor Voicu MD, PhD
Editor-in-Chief Daniel O. Costache MD, PhD, MBA Dragoș Cuzino MD, PhD
Executive Editor Florentina Ioniță Radu MD, PhD, MBA
Associate Editors Mariana Jinga MD, PhD, MBA Silviu Stanciu MD, PhD
Advisory Board Dan Mischianu MD, PhD Dragoș Vinereanu MD, PhD, EC, FESC
Redactors Doina Baltaru MD, PhD – Cluj Napoca Ovidiu Bratu MD, PhD – Bucharest Ciprian Constantin MD, PhD – Balkan Military Medical Committee Florin Miclea MD, PhD – Timișoara Constantin Ștefani MD – Bucharest
Editorial Assistants Dan Dobre MD Cristina Solea Claudia Țiglea
Technical Secretary Oana Ciobanu
International Editorial Board
Natan Bornstein (Israel) Raluca Ciornei MD (UK)
Mihai Coculescu MD, PhD (Romania) Cris S. Constantinescu MD, PhD, FRCP (UK)
Daniel Dănilă MD, PhD (USA) Mihai Moldovan (Denmark)
Ioan Opriș BS, PhD (USA) Gerard Roul MD, PhD (France)
Adrian Săftoiu (Denmark)
Ioanel Sinescu MD, PhD (Romania) Ionescu Târgovişte MD, PhD (Romania)
Radu Ţuţuian (Switzerland) Victor Voicu MD, PhD (Romania)
Scientific Publishing Committee
drian Barbilian MD, PhD Anda Băicuş MD, PhD
Cristian Băicuş MD, PhD Andra Bălănescu MD, PhD
Silviu Brad MD, PhD Daciana Brănișteanu MD, PhD
Marian Burcea MD, PhD Sofia Colesca PhD, MBA
Gabriel Constantinescu MD, PhD Dan Corneci MD, PhD
Raluca S. Costache MD, PhD, MBA Mircea Diculescu MD, PhD Cosmin Dobrin PhD, MBA
Gabriela Droc MD, PhD Silviu Dumitrescu MD, PhD Cristian Gheorghe MD, PhD Mihai E. Hinescu MD, PhD Codorean Ioan MD, PhD
Florentina Ioniţă Radu MD, PhD Mariana Jinga MD, PhD
Viorel Jinga MD, PhD Ruxandra Jurcuţ MD, PhD Dan Mischianu MD, PhD Ovidiu Nicodin MD, PhD Tudor Nicolaie MD, PhD
Emilian A. Ranetti MD, PhD Corneliu Romanițan MD, PhD
Carmen Adella Sîrbu MD, PhD, MPH Sorin Țiplică MD, PhD
Dragoş Vinereanu MD, PhD, EC, FESC
REDACȚIA Str. Institutul Medico-Militar nr. 3-5, sector 1, București, R-010919, Tel/fax 021.321.5386
Romanian Journal of Military Medicine (RJMM) is included in Romanian College of Physicians Medical Publications Index and
credited with 5 CME credits. RJMM is recognized by CNCSIS in the category C.
www.amfmr.ro
Romanian Journal of Military Medicine, vol. CXVII, New Series, No 1-2/2014
ISSN 1222-5126
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
1
Founded 1897 • Vol. CXVII
New Series • No. 1-2/2014
Edited by the Romanian Army Medical Directorate and Romanian Association of Military Physicians and Pharmacists.
Contents
EDITORIAL Ioan Sîrbu
Reconsidering the importance of military medicine at the level of National Ministry of Defence and into society 3
REVIEW ARTICLE Gabriela V. Dumitrescu, Viorel Ordeanu, Simona Bicheru, Lucia Ionescu, Diana Popescu, Marius Necşulescu
Clostridium difficile – emergent hospital flora 5
SYSTEMATIC REVIEWS, META-ANALYSIS Iuliana Guiţă – Alexandru
Stress management for optimization of organizational activity
Diana M. Popescu, Viorel Ordeanu, Lucia E. Ionescu, Gabriela V. Dumitrescu, Simona N. Bicheru, Marius Necşulescu
New quaternary ammonium salts based decontaminants
13
18
ORIGINAL ARTICLES Cristian Năstase, Marian Mitrică, Cristian Popescu
News and perspectives on treatment of normal pressure internal hydrocephalus
Florentina Ioniță Radu, Mariana Jinga, Petruț Nuță, Raluca S. Costache, Sandica Bucurica, Bogdan Macadon, Vasile Balaban, Mihăiță Pătrășescu
Nonalcoholic fatty liver disease – an etiological approach
24
33
CLINICAL PRACTICE Carmen A. Sîrbu, Octavian M. Sîrbu, Anca M. Sandu, Cristina P. Sandu, Marian Ștefănescu
An unusual cause for cerebellar syndrome
39
VARIA Andrei Necșulescu
Past and future 42
ADMINISTRATIVE ISSUES Guidelines for authors 45
RJMM Romanian Journal of Military Medicine
2
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
3
Reconsidering the importance of Military
Medicine at the level of National Ministry of
Defense and into society
Ioan Sîrbu
This goal can be achieved through the
implementation of a modern management both of
the Medical Directorate and of the subordinate units,
which basically involves a reform of these
institutions, keeping them out of the incertitude of
annual budgetary provision, looking for contractual
stability with National Defence, Internal Affaires,
National Security and Justice Authority Health
Insurance Company (C.A.S.A.O.P.S.N.A.J) and placing
them on the right path for institutional performance.
The reform of the military medical institution is an act
of courage that has to be accomplished with great
determination.
The first step would be submitting to the Supreme
Council of National Defence (CSAT) the concept of the
modernization of the military medical system
including elements of innovative vision on the
military medical phenomenon. One of these issues is
the need for modernisation of medical equipment
and hospital infrastructure in order to allow the
treatment in national military hospitals of soldiers
injured in combat theaters and of civilians after
natural disasters or industrial accidents with multiple
victims.
Another goal is to create a fully equipped base for
physical and neuropsychological recovery of military
personnel executing missions in operation theaters
and of their family members, allowing a fast and
complete social and family reintegration.
A particular attention
should be paid to hero
combatants, wounded in
combat theaters; they will
take benefit from the best
specialists in health care in
the new social-medical
edifice which will be
available since 2015.
In 2015 also, the construction of the new Emergency
Universitary Central Military Hospital will begin in
Bucharest in Garrison 867, part of the Ministry of
National Defense estate patrimony, under
Government Decision no 1594/04.12.2008.
This investment is the natural consequence of the
need to be aligned with the realities of modern
medicine promoted by North Atlantic Alliance
through ROL 4 level hospital units, covering all
medical and surgical specialties required for complete
rehabilitation and recovery of military personnel
wounded in the operation theaters or in the current
training activities, on national territory.
In the same time with updating of the clinical basis,
we should concentrate our attention on improving
the continuous training of our healthcare staff
regarding the achievement of new treatment
techniques and solutions. Continuous professional
training is an asset that our physicians are providing
to the military personnel in distress.
EDITORIAL
Major General IOAN SÎRBU
Chief of Medical Directorate, Ministry of National Defence,
Romania Professor, Head of Oral
Implantology Department of the Faculty of Dental
Medicine, Bucharest, Romania
4
From the experience of some colleagues, who have
chosen to leave the system, the main reasons for
discontent were: the working environment and the
lack of modern investigation means; to the surprise of
many, the financial reason was the last one.
Promoting team spirit and preserving the values in
the system has been a permanent concern of the
Medical Directorate Management.
All these contribute to achieving outstanding results
in our activity, leading to increasing satisfaction for
patients and doctors.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
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Article received on October 1, 2013 and accepted for publishing on December 13 2013.
Clostridium difficile – emergent hospital flora
Gabriela V. Dumitrescu, Viorel Ordeanu, Simona Bicheru, Lucia Ionescu, Diana Popescu, Marius Necşulescu1
Abstract: Clostridium difficile (C. difficile) is a Gram-positive sporogenous bacillus strictly anaerobic, which in the last decade has became the most important anaerobic bacterium in nosocomial human pathology. Cl.dificile is the etiological agent of more than 20% of diarrhea postantibiotics, over 95% of pseudomembranous colitis and the first cause of nosocomial infectious diarrhea in adults. Although this bacterium usually colonizes the intestine of vertebrates (the normal microbiota), the toxinogenic strains (tcdA and tcdB) are pathogenic in the digestive tract. Given the excessive use of antibiotics and the increased spores resistance, it is possible an environment contamination, with strains which may already be resistant to antibiotics. The main causes of this infection are decreased resistance to antibiotic-induced colonization, contamination with a pathogenic strain of Cl.difficile, secretion of A and/or B toxins and deficient immune response. Due to the increasing worldwide incidence of infections with C. difficile on one hand and to the discovery of new ways of transmitting the infection according with some studies regarding the genetic diversity of bacterium strains on the other hand, a new approach is necessary for C. difficile related topics..
Keywords: antibiotics, Clostridium difficile, epidemiology, nosocomial infection, toxins.
INTRODUCTION
Clostridium difficile (C. difficile) is a Grampositive
sporogenous bacillus strictly anaerobic, which in the
last decade has became the most important
anaerobic bacterium in nosocomial human pathology.
Cl.dificile is the etiological agent of more than 20% of
diarrhea postantibiotics, over 95% of pseudo-
membranous colitis and the first cause of nosocomial
infectious diarrhea in adults.
Although this bacterium usually colonizes the
intestine of vertebrates (the normal microbiota), the
toxinogenic strains (tcdA and tcdB) are pathogenic in
the digestive tract. Given the excessive use of
antibiotics and the increased spores resistance, it is
possible an environment contamination, with strains
which may already be resistant to antibiotics.
The main causes of this infection are decreased
resistance to antibiotic-induced colonization,
contamination with a pathogenic strain of Cl.difficile,
secretion of A and/or B toxins and deficient immune
response.
Microbiological diagnosis is made by several methods
and techniques for bacteria or toxins identification.
Cytotoxicity test reveals the cytopathic effect of fecal
filtrate with pg sensitivity. Immunoenzymatic assay
REVIEW ARTICLE
1 Military Medical Research Center (CCSMM), Bucharest
6
enables a rapid diagnosis, first generation with ELISA,
the second generation by immuno-enzymatic or
immuno-chromatography cassette. Molecular biology
techniques based on quantitative real-time PCR
detect tcdA and tcdB genes in stool, responsible for
toxigenesis with very good sensitivity and specificity.
Through cultivation and microscopy Cl. difficile can be
revealed in the stool or on contaminated surfaces;
spores are resistant in the environment and are
found in nosocomial flora. A characteristic enzyme,
glutamate dehydrogenase (GDH) can be revealed in
stool by immuno-enzymatic assay correlated with the
outcome of cultivation, or latex agglutination test
with antiGDH antibody.
Due to the increasing worldwide incidence of
infections with C. difficile on one hand and to the
discovery of new ways of transmitting the infection
according with some studies regarding the genetic
diversity of bacterium strains on the other hand, a
new approach is necessary for C. difficile related
topics.
CLINICAL
Clostridium difficile (C. difficile) is a Grampositive,
spore forming bacteria, spread by the fecal-oral
route. It is non-invasive, produces toxins A and B,
which cause disease, ranging from asymptomatic
carriage, to mild diarrhea, to colitis, or pseudo-
membranous colitis. Clostridium difficile infection
(CDI) is defined as the acute onset of diarrhea with
toxigenic C. difficile or its toxin and no other cause for
diarrhea.
Since 2000 the rate of CDI has been increasing,
especially in the elderly with a recent hospitalization
or residing in long-term care facility (LTCF).
Carriage of C. difficile occurs in 5– 15% of healthy
adults, up to 57 % in residents in LTCF and can reach
84.4 % in newborns and healthy infants.
In simple diarrhea cases, the classic symptoms may
not occur and the endoscopic examination shows
normal or ulcerated mucous; in 25% of cases ending
the antibiotic therapy was followed by clinical
recovery in 2-3 days. Further on antibiotheraphy is a
prolonging factor of diarrhea relapse.
Pseudomembranous colitis represent up to 9% of CDI
and starts with abundant watery diarrhea, over 7
stools a day, with heterogenic no bleeding aspect.
They are accompanied by fever in 75% of cases and
abdominal pains in 70% cases. The symptoms are
non-specific, leukocytolysis up to ex 80.000 PMN/I¼l,
extracellular dehydrating caused by exudative
enteropathy.
Digestive endoscopy confirms the diagnosis, allowing
canker yellowish sores visualization, named
pseudomembrane, on mucous colon membrane. In
the first stage they are isolated, afterwards they
come together. In CDI forms with severe onset and
no obvious etiology of diarrhea an endoscopy is
recommended, but this test is difficult to perform on
aged and fragile patients. Complications such as
septic shock and toxic megacolon may occur, septic
shock and toxic megacolon occur and provoke the
colon perforation (colectomy required) and even
death.
The ratio of severe forms differs (7-18%), depending
on the studies we consider. Consecutive mortality
with C. difficile varies 0,6-3% and when complications
occur is 35-50%. Some studies show increased
mortality in North America, a double no. of cases in
EU, heading to 24/milion, C. difficile being involved in
death cases three times more frequent than
Staphilococcus aureus MRSA. In 20% of cases,
relapses appear in the first two months after the
initial episode. In over 50% of cases they are
connected with the persistence of pathogen strain
(spores) inside digestive tract; a new stain could
appear and provoke reinfection especially during
hospital admission. Multiple strains have been
identified during one episode of infection.
Approximately 3% of adults are asymptomatic
carriers and often with toxin-free strains and
sometimes specific toxins may be identified in some
asymptomatic patients stool. The asymptomatic
transmission of toxinogen strains in neonates is 5-
70%, but there is no explanation what so ever.
Although nosocomial infections are the most
frequent, some of them could be communal. There
are recorded 17.5% postantibiotics diarrhea in EU,
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
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from which 66% have one day manifestation. After
two weeks antibiotherapy, the frequency becomes
3.8%, from which 70% are toxic. In North America
were identified a lot of cases but no strain high
pathogen 027 had been isolated in communal
infectious. Differential diagnosis will be made with
other infectious diarrhea: bacterial, viral, fungus and
parasitic or non-infectious causes; for example, the
outcome of some ”cool” drugs is in reality laxative
ones (supplements for straitening the immunity,
sugar free sweets, food with magnesium and decaf
products) with no connection with CDI etiology.
[Duker Freuman T., 2014]
Figure 1. Pathogenesis of Clostridium difficile – associated disease
(http://bioweb.uwlax.edu/bio203/s2009/kumm_jakl/pathology.htm)
MICROBIOLOGICAL DIAGNOSTIC
CDI diagnostic is based on revealing the toxins in
stool or isolating a toxinogenic strain of Cl.difficile,
this being the only pathogenic strain. Diagnostic
testing for C. difficile has rapidly evolved in the past
decade. Previously, toxin A + B EIAs were the most
widely used diagnostic tests because of ease of use
and objective interpretation.
However, EIA tests have substantially reduced
sensitivities compared with reference standards.
Moreover, toxin A immunoassays (without toxin B)
lack detecting the small number of pathogenic strains
that only produce toxin B. Two major advances in the
laboratory diagnosis are the use of GDH detection in
stools as a means of screening for CDI and the
development of Nucleic acid amplification tests
(NAATs) such as PCR to detect toxigenic strains of C.
difficile. Glutamate dehydrogenase (GDH) screening
tests for C.difficile can be used in two- or three-step
algorithms with subsequent toxin A + B EIA testing,
but the sensitivity of such strategies is lower than
NAATs [Surawicz et al., 2013] (fig 2).
Testing the toxigenic C. difficile should be limited to
patients with > 3 nonformed stool specimens per 24
hr period, unless ileus (obstruction) is suspected.
Repeat testing following a positive test (test of cure)
is not recommended since patients may carry
toxigenic C. difficile for months after clinical cure.
Repeated testing following a positive test is
appropriate if the patient improves with therapy and
relapses after the completion of a treatment regimen
(clinical relapse). Testing a second specimen from a
negative patient is more likely to be a false positive
[American Society for Microbiology, 2010].
The optical microscopy swab is pathognomonic,
revealing long gram-positive bacilli with a bulge at
8
terminal ends, with long terminal and isolated spores,
visible with Gray coloration. While the presence of C.
difficile can be suspected, we cannot differentiate the
pathogencal strains from the nonpathogencal ones,
therefore the examination should be supplemented
with toxigenical and molecular biology tests. In the
last years, a very pathogenical and virulent strain, C.
difficile 027, has been identified, that causes severe
epidemic episodes (Fig 3).
Figure 2. Diagnostic algorithm of Clostridium difficile (Surawicz et al., 2013)
The epidemic strain currently described in North
America and EU, has the following features: PCR
ribotype 027 in accordance with Anaerobe Reference
Laboratory surveillance data [ECDC, 2006], pulsotype
NAP 1 on pulsed-field electrophoresis, enzymatic
restriction-profile BI, toxinotype III by Rupnik
toxinotyping method, positive for binary toxin actinia-
specific ADPribozyltransferase, deletion of 18 bp in
tcdC gene controlling the expression of toxins A and
B, hyperproduction of toxins A and B (Ax16 and Bx23)
in comparison with strains of other genotypes,
resistant to macrolides (erythromycin) and la
flororquinolones (moxifloxacin, gatifloxacin and
levofloxacin).
Only specialised laboratories are able to perform the
techniques for identifying these features and a two
weeks period is required for confirmation [INVS,
2006].
In practice, CDI diagnostic is based on toxin B
detection in stool or revealing the toxigen strain. A-
and B+ strains cannot be detected by current
imunoenzymatic assays which detect only A stain.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
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Figure 3. Analysis of anaerobic bacterial isolates in the microbiology laboratory of CCSMM
The strain isolation through culture is a necessary
stage for epidemic clone 027 characterisation; PCR
profile identification provides the certainty diagnosis.
This clone presence is clinically suspected if a severe
form of the disease is diagnosed, epidemiologically
suspected if several cases occur, or microbiologically
suspected if the isolated strain is resistant to new
fluoroquinolones (moxifloxacin CMI > 4 mg/l) or to
erythromycin (CMI > 256 mg/l).
These characteristics are not specific to clone 027,
but justify the stool culture in anaerobiosis in order to
isolate the responsible stain and to send it to a
specialised reference laboratory for further
examination.
The genes encoding TcdA and TcdB, tcdA and tcdB,
respectively, have been sequenced and are found in
single open reading frames located within a 19.6-kb
pathogenicity locus (8, 38).
As expected, both open reading frames are large,
with tcdA found within an 8,133-nucleotide region
and tcdB is 7,098 nucleotides in length (fig. 4).
Both tcdA and tcdB are low-G C (28%) genes, which
are comparable to the G C content (29%) of the C.
difficile genome, and the toxins exhibit a high degree
of overall similarity (66%).
Given the proximal locations of tcdA and tcdB and the
high sequence and functional homology between the
two proteins, it has been proposed that the two
genes may have arisen as the result of a gene
duplication event.
Furthermore, the similarity in the biochemical activity
of TcdA and TcdB, wherein both toxins use a highly
conserved N-terminal domain to modify identical
substrates, supports the notion of gene duplication.
The major regions of homology between TcdA and
TcdB fall within the enzymatic and receptor-binding
domains of the two toxins. The N-terminal domains
of TcdA and TcdB show 74% homology, and this
homology provides a basis for the similar substrate
specificity of these two toxins.
The C terminus of TcdA and TcdB show a number of
short, homologous regions termed combined
repetitive oligopeptides (CROPs). TcdA encodes five
groups of CROPs, which range in size from 21 to 50
residues and can be repeated throughout the C
terminus of the protein. TcdB also encodes five
groups of CROPs, four of which show homology to the
CROPs of TcdA.
Yet the CROPs found in TcdB are more divergent and
less frequent than those found in TcdA. CROPs
appear to play a putative role in initial target cell
interaction and receptor binding, but the mechanism
explaining the necessity for these repeats in cell
binding remains unclear [Daniel E. Voth, 2005].
10
Figure 4. Genetic arrangement of the C. difficile pathogenicity locus and proposed protein domain structures of TcdA and TcdB. Both TcdA and TcdB are encoded on the 19.6-kb pathogenicity locus. In addition to the two toxin genes tcdA and tcdB,
three additional regulatory open reading frames are located on this island. tcdD is a proposed positive regulator, tcdE is a putative holing protein, and tcdC is a proposed negative regulator of toxin gene expression. Through deletion mutagenesis, research combined from multiple research groups has revealed a three-domain structure of the large clostridial toxins. The glycosyltransferase activity is located at the N terminus of the protein, and the C terminus is involved in receptor binding.
Located in the middle domain of the protein is a putative transmembrane segment that is thought to be involved in membrane translocation. [Daniel E. Voth, 2005]
EPIDEMIOLOGY
C. difficile transmission is made by fecal-oral route, by
hands and contaminated objects or environment. The
fast transmission in healthcare environments is a
result of several factors: strain dissemination in CDI
patients, half of samples from patients rooms being
positive; high resistance of spores on inert supports
for several months; too many patients crowded in
common healthcare settings; numerous healthcare
maneuvers creating a high possibility of
contamination by the medical personnel hands;
inadequate usage of antibiotics which diminishes the
resistance to colonization and facilitates C. difficile
development.
The main individual risk factors are the advanced age
and antibiotherapy. There are several studies which
correlate the consumption of some classes of
antibiotics with CDI incidence: clindamicyn, 3-rd
generation cephalosporins, macrolides, and
amoxicillin with clavulanic acid, 1-st generation
cephalosporins and fluoroquinolones. It seams that
the role of fluoroquinolones in C. difficile 027strains
emergence and spreading is connected to the
resistance level towards them [INVS, 2006].
All factors stimulating the digestive ecosystem
alteration, like laxatives, antacids, antisecretors,
transit retarders, baritosis transit, gastrointestinal
surgery, etc. may facilitate this infection [Duker
Freuman, 2014].
In March 2014, an epidemic episode with 31 cases of
postantibiotic C. difficile infection was recorded in
Ploiesti Emergency Hospital (Romania) and the
patients were isolated and treated. Most of them
were aged people from Neurology, Nephrology and
Intensive Care Unit [Libertatea newspaper, 2014].
In May 2014 the Ministry of Health of Romania gave
the alert for C.difficile in Vaslui and Bucharest
hospitals. The beginning of the year is worrying, in
only 4 months, in Bucharest health facilities were
registered 462 infected patients [Pro TV, 22 Mai
2014].
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
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In accordance with Annual epidemiological report:
Reporting on 2011 surveillance data and 2012
epidemic intelligence data, 2013, uttered by
European Centre for Disease Prevention and Control
(ECDC), 48% cases of HAI (Healthcare-Associated
Infections) associated with gastro-intestinal infections
were connected with C. difficile, and from all HAI
(15.000 cases) in 3 only 5,4% of cases the Clostridium
difficile has been isolated. Taking into consideration
that in Romania over 92.3% of patients were the
beneficiary of an antimicrobial prophylaxis during
more than a day surgeries, the HAI risk associated
with C. difficile is very high [ECDC, 2013]
TREATMENT
There is worldwide observed natural resistance
and/or acquired to the medicines of the quinolone
group.
A mild CDI can usually be controlled by withdrawing
treatment with the antibiotics causing the infection
(25% of patients could recover in 2-3 days). More
severe cases can be treated using an oral specific
treatment with metronidazole (1 g/day) or
vancomycin (1-2 g/day) for 10 days. The
metronizadole is a better choice, being a less
expensive treatment with no risk of selecting
glycopeptides resisting germs like golden
enterococcus and staphylococcus.
Failure to respond to metronidazole therapy within 5
– 7 days should prompt consideration of a change in
therapy to vancomycin at standard dosing. For mild-
to-moderate CDI in patients who are intolerant/
allergic to metronidazole and for pregnant/
breastfeeding women, vancomycin should be used at
standard dosing. In patients in whom oral antibiotics
cannot reach a segment of the colon, such as with
Hartman’s pouch, ileostomy, or colon diversion,
vancomycin therapy delivered via enema should be
added to treatments (500 mg in 100 – 500 ml of
normal saline every 6 h) until the patient improves.
However, relapse is common and requires further
treatment with repeated series of metronidazole or
vancomycin, in high doses first and smaller doses
associated with probiotics (i.e. Saccharomyces
boulardii) after improvement. Severe cases may need
intensive care for maintaining the vital functions and
even surgical treatment for colectomy (in case of
toxic megacolon or colon perforation).
CT scanning is an important technique for perforation
diagnosis in comparison with colonoscopy technique
which presents a perforation risk due to gas inflation.
The antibiotic treatment for healthy individuals
colonized with C. difficile is not recommended, being
inefficient for eradicating for good this bacteria in
digestive tract. [Ordeanu, 2010; Ordeanu 2012]
Considering the antibiotherapy limitations, there has
been designed the fecal bacteriotheraphy, known as
“stool transplant”/fecal microbiota transplant (FMT)
of bacterial flora acquired from the feces of a healthy
donor to reverse the bacterial imbalance responsible
for the recurring nature of the infection, with good
results [ASGE, 2013].
This “synthetic stool” is a super-biotic obtained using
several cultures of saprophyte intestinal culture
[Allen-Vercoe, 2013]. Studies show that patients with
recurrent CDI (RCDI) have abnormally proportioned
colon microbiota, and that reintroduction of normal
bacteria via donor feces corrects this imbalance,
restoring phylogenetic richness and colonization
resistance.
There is no international consensus for defining and
surveillance CDI, but we have to consider local
(regional and national) epidemiology conditions and
possibilities. ECDC created a working group for early
detection and monitoring the CDI. They have
suggested recorded signals criteria for severe and
grouping cases of CDI.
C. difficile infectious can usually be prevented by
practicing good hygiene in healthcare environments,
such as: individual bed space, washing hands
regularly (mechanical action of washing after gloves
removal), using gloves, protection mask, glasses and
gown in bed space area and in contact with patients,
using medical supplies for one usage only, cleaning
surfaces using bleach wipes of sodium hypochlorite
containing 0.5 % active chlorine, and patient removal
limitation. [CCLIN, 2013]
12
COMMENT
Due to the increasing worldwide incidence of
infections with C. difficile on one hand, and to the
discovery of new ways of transmitting the infection
according with some studies regarding the genetic
diversity of C. difficile strains on the other hand,
(http://www.pharmacypracticenews.com) a new
approach is necessary for C. difficile related topics It
is important to adopted NAAT testing alone or a 2 or
3 step algorithm for CDI diagnosis.
If the C. difficile is confirmed and classified as a
severe form or in an epidemic context it should be
reported to Public Health Territorial Authorities and
to The Anaerobe Reference Laboratory from INCDMI
Cantacuzino, for a clear diagnosis and adequate
measures.
CONCLUSION
Due to the increasing worldwide incidence of
infections with C. difficile on one hand and to the
discovery of new ways of transmitting the infection
according with some studies regarding the genetic
diversity of bacterium strains on the other hand, a
new approach is necessary for C. difficile related
topics.
References:
1. Allen-Vercoe E. “Syntetic stool can cure clostridium difficile infection” University of Guelph, Science Daily, 2013
2. Coignard B., Barbut F. “Conduite a tenir: diagnostic, investigation, surveillance, et principes de prevention et de maitrise des infections a Clostridium difficile” INVS, RAISIN, France, 2006
3. Duker Freuman T. “Surprise! It’s a laxative” blog www.tamaraduker.com, 2014
4. Hemker Oliva, Hourigan Suchitra “Fecal Microbiota Transplantation” www.news-medical.net/health, 2014
5. Ordeanu V. et all. “Elements of pharmaceutical microbiology” 2nd edition, Universitary Publishing House “Carol Davila” Bucharest, 2010
6. Ordeanu V. “ Antibiotheraphy individualisation” UMF conference, 2012
7. Ordeanu V. et all. “Clostridium difficile a threat emerging in zooantroponotic pathology”, Book of abstracts, Scientific Conferences, 2nd Edition 2014, Timisoara, pg. 112-113”
8. Stoica O. “31 cases of postantibiotic C. difficile infection recorded in Ploiesti” Libertatea newspaper, 7 March 2014
9. Surawicz Christina M., Brandt Lawrence J., Binion David G., Ananthakrishnan Ashwin N., Curry Scott R., Gilligan Peter H., McFarland Lynne V., Mellow Mark, and Zuckerbraun Brian S. “Guidelines for Diagnosis, Treatment,
and Prevention of Clostridium diffi cile Infections”, The American Journal of GASTROENTEROLOGY, Guidelines for CDI, 2013
10. Voth Daniel E. and Ballard Jimmy D. “Clostridium difficile Toxins: Mechanism of Action and Role in Disease”, Clin. Microbiol. Rev. 2005, 18(2):247.
11. http://www.pharmacypracticenews.com/ViewArticle.aspx?d=Clinical&did=50&i=January+2014&iid=1029&aid=24792
12. *** American Society for Microbiology “A Practical Guidance Document for the Laboratory Detection of Toxigenic Clostridium difficile”, September 21, 2010
13. *** CDC “Clostridium difficile - information for healthcare providers”, Atlanta, USA, 2005
14. *** CCLIN “Conduite a tenir devant un ou plusieurs cas de diarhee a Clostridium difficile” France, 2013
15. *** ECDC “027 Clostridium difficile - An emerging epidemic in European Health Care”, Stockholm, Sweden, 2006
16. *** ECDC ’’Annual epidemiological report: Reporting on 2011 surveillance data and 2012 epidemic intelligence data”, 2013
17. *** Pro TV, 22 May 2014.
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Article received on August 12, 2013 and accepted for publishing on October 9 2013.
Stress management for optimization of organizational
activity
Iuliana Guiţă – Alexandru1,2
Abstract: Stress is a constant presence in our lives, whether we analyze it in professional, social or family terms. This daily reality creates a state of tension, strain and discomfort, causing significant changes in physical and mental health. Stress at work can affect anyone, at any level, in any sector and in organizations of any size. Stress affects health and safety of individuals and also organizations’ welfare and national economies. There is a definite correlation between the level of stress at work and the changes in organization’s productivity.
Keywords: stress management, organizational optimization, occupational stress, organizational culture, psychological contract
STRESS: DEFINITION, TYPES AND CAUSES OF ITS
OCCURRENCE
We meet every day people who are overworked,
overwhelmed or underpaid. We wonder what to do
to cope with the stress in our life. Often we forget to
put on paper all the endless tasks we have to do
during the day, and paradoxically we receive other
new tasks to fulfill.
According to Peter Drucker, we have to make a clear
distinction regarding those who are accomplishing an
intellectual work today, the situation being more
complicated for them than for production line
workers of the past, who knew what they have to do.
Instead, those involved in intellectual work should
not only execute the plan, but also to conceive it. This
puts an important pressure on the human brain so in
case you see a doctor, one of the question is: “How
stressed are you?” Certainly, stress at work can affect
anyone at any level. It is produced in no matter what
do main and in organizations of any size. Stress
affects the health and safety of individuals and also
welfare of organizations and national economies.
Stress was introduced by Hans Hugo Bruno Selye,
professor of histology, who sets up the foundation of
International Institute of Stress with Alvin Tofler in
1977. He believes that stress is related to adaptation
syndrome as a reaction of individual against
environmental aggressions. Hans Selye defines stress
as “the set of reactions of the body to the external
action of the causative agents (physical, chemical,
biological and psychological) consisting in
morphofunctional changes, most often endocrine”.
According to the Romanian Language Explanatory
Dictionary (1998), stress is “the name given to any
environmental factor (or set of factors) causing an
SYSTEMATIC REVIEW
1 Military Emergency Hospital “Dr. Ion Jianu “, Pitești, Romania 2 Researcher in the Research Center for the Promotion of Excellence in Training - University of Pitești
14
abnormal reaction to human body; adverse effect on
the human body produced by an environmental
factor.”
According to Terry Looker, Olga Gregson (2009, p.
31), “Stress is seen as a reaction of the organism
against changes occured in our environment.”
All mentioned authors consider that “stress can be
defined as the condition that we feel when we
perceive a discrepancy between perceived demands
and ability to cope with them.”
Lazarus and Folkman (1984) define stress as “a
cognitive and behavioral effort (with obvious
emotional expression) to reduce, control or tolerate
external or internal demands that exceed personal
resources.”
Ioan Bratu Iamandescu (2002) believes that mental
stress is a syndrome consisting of exacerbation
beyond the level of simple homeostatic adjustments,
certain psychic reactions and their somatic
connections (affecting almost all body components),
in connection with external and internal excitement
exerted by triggering factors (stressor factors) acting
intense, surprisingly, sudden and/or persistent and
having a symbolic nature, “threating”, or, othertime,
extremely favorable to the subject (perceived or
anticipated by the subject). In other cases, stressor
factors could be psychical excitants with major
affective resonance (positive – eustress or negative –
distress) or overloading factors of cognitive
(attention, thinking, etc) and volitional process,
mentioning that mental stress is mainly based on a
major emotional involvement.”
The definition given by Golu M. (1981) should also be
taken into consideration: “state of tension, tightness,
discomfort, caused by affective agents with negative
significance (or positive, in case of eustress),
frustration or repression of some motivations (needs,
desires, aspirations – including underloading),the
difficulty or impossibility of solving problems”.
However, Paul Popescu Neveanu, in the “Dictionary
of Psychology “ (1978), defines stress in terms of two
meanings: “a) situation, stimulus which puts the body
into a state of tension ; b) the special tension state,
itself, of the body as an activation of all its resources
to cope with physical or psychical aggression (strong
emotion)”.
“Stress is an individual reaction and the result of
interaction between environmental demands on one
hand and the resources, capabilities and
opportunities of the individual on the other hand.”
It is certain that stress is characterized by intense
hormonal changes, massive secretion of adrenaline.
There are also morbid changes (hypertension, gastric
ulcer etc). Psychical stress is caused by prolonged
emotions primarily mainly due to frustration, conflict
and anxiety. There is stress of overload and also
stress of underload. A moderate stress boosts and
stimulates the body vitality. The harmful feature of
stress occurs when the damage is too large,
exceeding the individual adaptive capacity.”
Doctor Ioan Bratu Iamandescu, in his book “Psychical
stress and internal diseases” (1993), believes that
stress can be positive (eustress) or negative (distress).
Eustress (“positive stress“) has beneficial effects on
the human body, occurring when the stress agents
have positive significance for the individual.
These triggers positive emotions (intense joy, ecstasy,
triumph, laugh out loud), and positively affect the
body’s organs and apparatus. Eustress appears in the
course of positive emotional states or coupled with
moderate exercise (eg sex or jogging). Eustress is
essentially acute. Frequent repetition of eustress
contributes to increase antiinfection and antitumor
immunity, becoming a longevity premise.
Distress (“negative mental stress“) is widely
recognized as pathological. It usually produces pain
and inadaptation as a result of contact with a stressor
agent.
Situations generating mental stress:
• the existence of unusual circumstances for the
individual, which find him unprepared to deal with
them
• the significance of an event
• engaging the individual into an exaggerated action
or relation
• peculiarities of the social context
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15
• lack of internal conditions
• subjective way of perceiving environmental
demands
• underload / overload
• existing conflictual situations in the family,
profession or intellectually related
• lack of time
• isolation
• the emergence of a physical or mental obstacle in
the way of a goal that leads to frustration
• disturbing circumstances arising from physical
agents (noise, vibration, temperature fluctuations).
STRESS AND HEALTH AT WORKPLACE
MANIFESTATIONS OF STRESS AT WORKPLACE
Stress at work can affect anyone, at any level.
It is produced in every sector and in organizations of
any size. Stress affects the health and safety of
individuals and also welfare of organizations and
national economies.
Workplace stress occurs when job demands exceed
the available resources of human beings. Stress is not
only the result of major adverse events, but also is
the result of stress and daily pressures. The latter, by
their frequency, have an important role in the
professional environment and affect more individuals
than major adverse events, which are rare.
Andreescu Anghel, Liţă Ştefan (2006), states that
“sometimes, professional stress is considered as a
positive, beneficial factor on performance.
This refers to eustress which means activation,
mobilization of individual resources. It is important to
distinguish between eustress and distress, one as a
state of stress with beneficial effects, the other with
adverse health effects.”
Today’s world, more dynamic in work field
perspective, brings in the foreground workers,
personnel reductions and services externalization,
increased flexibility in terms of position and
competencies, the growth in number of determined
time job contracts, growing uncertainty of jobs and
intensity of work (overload and higher pressure), and
unstable balance of life and work.
That is why stress can bring disease and pain to
individuals, both at work and at home.
Stress can compromise safety at work too, thus
contributing to other health issues related to work,
such as musculoskeletal disorders.
Stress greatly affects the image of an organization.
Reducing stress associated with work and
psychosocial risks is not only a moral imperative but
also a legal one. It is also an important problem of
economic efficiency. The good news is that stress
associated with work can be approached in the same
logical and systematic way as other health and safety
issues.
There is an abundance of practical examples to cope
this problem in the area of Eurpean Union countries.
Using the appropriate method, workers may be stress
protected.
Considering the example of a person who feels great
pressure meaning job demands (work time, liability)
larger than individual capabilities and corroborated
by conflicts with colleagues/leaders, frequent
changes or threats on job security – such as the
possible personnel downsizing; all these could be
perceived as a stressful situation by someone or
challenging by another. What makes the difference in
perception depends on job nature, the psychological
profile of individuals, as well as physical health or
health, in general.
Manifestations of stress at workplace can lead to:
depression, anxiety, feelings of being overwhelmed
and unable to cope with them, a decrease in
professional performance, an increase in the number
of days for sickness treatment, absenteeism,
insomnia, cognitive difficulties (reduced ability to
concentrate or make decisions), fatigue, headache,
palpitations, gastrointestinal problems, increased
aggressivity, etc.
All these lead to the following consequences:
• a decrease in productivity
• an increased risk of having an accident at work
• damage in personal relationships
• an increased risk of health problems (cardiovascular
disease, digestive problems, cervical pain, etc.)
16
STRATEGIES TO ELIMINATE AND PREVENT
STRESS AT WORK
Recent studies of the so-called “healthy
organizations” suggest that policies for employee
health lead to benefits for organizations.
A healthy organization is defined as an organization
with a low rate of illness or disability in working
personnel.
That means an increased competitivity. Researchers
have identified that a minimum stress at work leads
to a higher level of productivity as definition for a
healthy organization.
These relate to:
• Recognizing employee’s performance
• Opportunities for career development
• Organizational culture that values employee
• Managerial actions in concordance with the values
of the organization.
Strategies to reduce stress at work include:
a) psychological assistance for employees is an
occupational health service; that is provided by
organization in order to reduce or eliminate the
decreasing performance at workplace;
b) training services for employees: performance
management, time management, stress
management, career management, etc. ;
c) educational workshops: parenting, work life
balance, time management, stress management,
emotional control, anger management, decision
making and problem solving, alertness,
communication in couple, smoking quittance, weight
control, etc.;
d) online educational resources: newsletter, access to
educational information for the employee and his
family (web resources, brochures);
e) career management services;
f) services for managers and professionals in human
resources departments are:
- management of critical incidents ;
- assistance for enhancing skills in control of
inadequate behaviors of employees;
- assistance and training in management of
employees capabilities;
- development and implementation of employee
assistance programs in the company.
STRESS PREVENTION AT WORKPLACE
There is no standardized approach or a manual for
developing stress prevention programs. Design
programs and solutions will be influenced by many
factors: the size and complexity of the organization,
available resources, and in particular the type of
problems the organization faces.
For example, in some companies the main problem is
overloading employees and others, an inflexible
program or lack of communication with the public. In
other words, it is not possible to find a universal
prescription for stress prevention in the workplace,
but it is possible to provide some guide lines for the
prevention of stress in organizations.
In all cases, the process of stress prevention
programs involves three distinct approaches:
problem identification, intervention and evaluation.
Organizations must be prepared properly to lead this
process successfully.
A minimum level in preparing a stress prevention
program should include the following:
• workplace stress awareness (causes, costs, control);
• ensuring a quality management and support for the
program;
• employee involvement in all phases of the program;
• establishing the technical capability of program
management (specific training for members or
consultants involvement).
Assembling employees or employers and managers in
the same committee or “solving problem group” can
be a very useful approach for developing a stress
prevention program.
Researches show that these participatory efforts
were successfully achieved on ergonomic issues in
the workplace, partialy due to the capitalization of
direct knowledge of employees about the problems
encountered in their workplace.
The “psychological contract” as a mean of preventing
and combating stress is today a frequent approach. In
the literature the term “psychological contract” is
commonly used in the sense of mutually shared set of
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
17
expectations between the employee and the
organization.
The author Denise Rousseau defines the
psychological contract as “individual beliefs shaped
by an organization, in terms of exchange between the
individual and the organization”.
Psychological contract can be accepted as a mental
model that employees use to inframe and interpret
organizational phenomena. Its terms shall constitute
a reference system to which employees report their
work and the attitude of employers towards
employees is also very important.
Characteristics of the psychological contract:
• represents, essentially, a subjective perception that
differs from one individual to another;
• psychological contract is dynamic, that means it is
changing over time, during the relationship between
employer and employee;
• refers to the mutual obligations based on
investment in promises made by both parties, with
the hope of a positive outcome for each party;
• is closely linked to the context of labor relationship,
the psychological contract can not be created by
individual or organization only.
The main functions of the psychological contract:
• reduces incertitude, because not all possible
aspects of the employment relationship may be
covered by a formal written contract between the
two parts: employer and employee;
• dictates employee behaviors - like a system, the
employee weighs their commitment to the
organization and the organization’s obligations to
themselves and change their behavior in relatation
with critical company outcomes;
• the third function of psychological contract, gives to
employee a sense of influence on what happens to
him, in the organization.
To conclude, stress is a “disease” of our time,
affecting people no matter of their lifestyle.
Stress is found everywhere, more obvious and more
frequent in advanced countries. To find the way to
manage stressful situations is up to each of us.
References:
1. Labor Safety and Health Agency – https://osha.europa.eu/ro/topics/stress index_ html
2. Anderson, N.; Schalk, R., The psychological contract in retrospect and prospect. Journal of Organizational Behavior, vol. 19, 1998, p. 640
3. Aradavoaice Gheorghe, (2010), Stres, eustres, distres, Antet Publishing House, Bucharest
4. Băban, A. (1998), Stress and personality, Dacia Publishing House, Cluj-Napoca
5. Charly, C. (2003), How to face stress, Polirom Publishing House, Iași
6. Cocoară, Mihai (2005), Stress-definition, manifestation, prevention, Category: Medicine for all. ISBN: 973-87431-2-5
7. Derevenco, P., Anghel, I., Baban, A. (1992), Stress in health and illness – from theory to practice, Dacia Publishing House, Cluj-Napoca
8. Floru, R. (1974), Mental stress, Enciclopedic Publishing House, Bucharest
9. Gherman L., Pănoiu, L., Răcăşan M (2010), Human resource and career management, “Independenţa Economic” Publishing House, Piteşti
10. Holdevici, I. (1995), Autosuggestion and relaxation, Ceres Publishing House, Bucharest
11. Holdevici, I. (1995), Suggestion and suggestive psychotherapy, Victor Publishing House, Bucharest
12. Horney, K. (1998), Our inner conflicts, IRI Publishing House, Bucharest
13. Iamandescu, I.B. (1993), Psychical stress and internal diseases, All Publishing House, Bucharest
14. Iamandescu, I.B. (1995), Manual of Medical Psychology, InfoMedica Publishing House, Bucharest
15. Iamandescu, I.B. (2002), Mental stress, InfoMedica Publishing House, Bucharest
16. Ionescu, G. (1980), Normal and pathological mental life, Academic Publishing House, Bucharest
17. Lacombe F. (2005), Solving communication difficulties, Polirom Publishing House, Iasi
18. Lăzărescu, M. (1994), Clinical psychopathology, Helicon Publishing House., Timisoara
19. Rousseau, D. M.( 1996), Psychological Contracts in Organizations: Understanding Written and Unwritten Agreements. Newbury Park, CA: Sage
18
Article received on October 1, 2015 and accepted for publishing on October 9 2015.
New quaternary ammonium salts based decontaminants
Diana M. Popescu1, Viorel Ordeanu1, Lucia E. Ionescu1, Gabriela V. Dumitrescu1, Simona N. Bicheru1, Marius
Necşulescu1
Abstract: Decontamination after terrorist attacks or industrial accidents with biological and/or chemical agents („bio-chem“) must be fast and efficient, in order to reduce the number of victims and to eliminate the consequent damages. The decontamination of living biological agents (bacteria, viruses) or nonliving ones (toxins, regulators) and toxic chemicals could be accomplished by reactions of hydrolysis in various experimental conditions, in particular in alkaline medium, reactions with amines or ammonia, alcohols, phenols etc. and by their transformation into less toxic degradation products. “Bio-chem” intentional or unintentional contamination is a real risk, towards which an effective management must be available to prevent and control it. Decontamination is an essential measure to protect the personnel and the environment. Synthesis and testing of new „bio-chem“ decontaminants, based on quaternary ammonium salts, complete the arsenal of protection against chemical and biological agents. The most effective selected substances could be produced and used for decontamination in accordance with legal procedures.
Keywords: „bio-chem“ contamination, decontaminants, disinfectant, quaternary ammonium salts, chemical synthesis
DECONTAMINATION
After terrorist attacks, biological and/or chemical
attacks or industrial hazards with bio-chem agents,
the decontamination must be prompt and efficient, in
order to reduce the number of victims and to
eliminate the consequent damages. The
decontamination of the living biological agents
(bacteria, viruses, fungus, and parasites) or of the
nonliving agents (toxins, regulators) and of the toxic
chemicals could be accomplished by hydrolytic
reactions in various experimental conditions
(especially in alkaline medium), reactions with amines
or ammonia, with alcohols and phenols etc. or by
their transformation in less toxic degradation
products.
The biological contamination refers to bacteria and
viruses generating diseases as anthrax, plague,
smallpox, botulism etc. From the chemical structure
point of view, the range of the products used in
microbial decontamination is wide but very few fulfill
the conditions of a good decontaminant.
In this paper there are taken into account the
quaternary ammonia salts obtained by treating the
tertiary amines with alkyl halogen, particularly alkyl
chlorides or benzyl chlorides. These compounds are
SYSTEMATIC REVIEW
1 Military Medical Research Center (CCSMM), Bucharest
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
19
the most important agents having a biocide action.
Synthesis and conditioning decontaminant by
Mechanical Engineering and Research Institute,
Bucharest (ICTCM) in different forms with the
chemical structure of quaternary ammonium salt
soluble in water was carried out in accordance with
national and European Union legislation related to
ecology and environmental protection.
Figure 1. Microbiological testing of decontaminating substances, in vitro, in CCSMM microbiology laboratory
Figure 2. Microbiological testing of decontaminating substances in various materials, CCSMM minipolygon biological testing
Spectrum of activity and penetrating ability of
decontaminating substance is enhanced by a
surfactant that is designed to reduce surface tension
thus facilitating contact between the microbian cell
and decontaminant compound.
Decontaminant qualities of each product are
determined by the choice of the active substance and
should take account of its antimicrobial qualities, the
purpose, and the conditions that will be used in.
Decontamination efficiency is determined by the
contact time of each decontaminant product,
decontaminating solution concentration, the amount
of solution used per unit area and, not the last, by the
decontaminant agent application mode.
SCREENING TEST
Screening of potential decontaminating substances
was performed in the Laboratory of Microbiology-
20
Epidemiology, in diagnosis laboratory for biological
agents, ranked by P2+ biosafety level for the
pathogen microorganisms.
Bacterial sensitivity assays were performed (the
antibiotic disc diffusion method on several lots),
according to the following parameters: cultivation on
solid culture medium Mueller-Hinton, 72 hours
aerobic incubation at 37° C, with daily reading.
The following bacterial species were tested:
Staphylococcus aureas, Bacillus anthracis, Escherichia
coli, Pseudomonas aeruginosa, Vibrio cholerae.
Results were quantified by measuring with 0.1 mm of
accuracy (caliper and magnifier), comparatively, on
many tests, to calculate the average of each
substance on each species.
Product code DC-3 and code DC-7 was carried out on
quaternary ammonium salts and Nalkylpyridinium
basis. Their testing revealed that the best
microbiological activity was recorded in the product
code DC-7. The possible synergistic effect with
oxidizing compounds was tested in order to achieve
possible decontaminating mixtures.
The bactericidal effect of the substance was tracked
for a set of standard bacterial (gram-positive and
gram-negative, anaerobic bacterial and spores) and
other pathogenic microorganisms; bacterial
sensitivity results were read after 24 and 48 hours of
incubation and then, after storage at room
temperature 48 hours, to watch the effect in time.
The antimicrobial effect was quantified by calculating
the average diameter of bacterial inhibition zone and
bactericidal concentration (g/liter), calculated as the
quantity of substance (20 mg) divided by the volume
in which the antimicrobial diffusion was effective.
(figure 1, 2).
Figure 3. Microbiological testing of decontaminating substances in various materials, CCSMM minipolygon biological testing
TOXICOLOGICAL TESTING
Toxicological screening for acute toxicity aimed to
confirm that these substances are not highly toxic
and are not dangerous to operators.
To demonstrate, 0.5 ml of each substance was
injected in mice (approx. 20 g weight, young adult),
tracking morbidity and mortality for three days. The
test results have enabled experiment achievements
under conditions of a specially arranged experimental
minipolygon.
Experiencing decontaminating products
Representative microbial strains were used for the
main groups of pathogenic bacteria: gram-positive
cocci: Staphylococcus aureus, Streptococcus
pneumoniae, Enterococcus fecalis; gram-positive
bacilli: Bacillus anthracis (vaccine strain), Bacillus
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21
cereus, Bacillus subtilis; gram-negative bacilli:
Escherichia coli, Proteus vulgaris, Klebsiella
pneumoniae, Pseudomonas aeruginosa; vibrio: Vibrio
cholerae.
The experimental contamination and
decontamination have been carried out on an out of
service military vehicle, representing the “target”
(figure 3, 4) marked with numbered areas of
approximately 0.1 square meters on which have been
implemented operating procedures for CBRN
(chemical, biological, radiological and nuclear)
contamination control.
Areas were chosen as follows: vertical painted metal
sheet, for aqueous solution decontaminants; glass
window for aqueous solution decontaminants; rubber
tires for aqueous solution decontaminants and
horizontal painted metal sheet for supplied powder
decontaminants as a positive control.
Microbial contamination was done by spraying the
allocated surface, separately, with every microbial
strain and with a mixture of them also. A microbial
suspension culture in a liquid medium was used, with
approximately 1 million live bacteria per ml. Also, it
was sprayed 1 ml of suspension per square
decimeter, enough to create a uniform contaminant
film. For liquid decontaminating substances, the
aqueous solution (conc. 10%) was sprayed to cover
the contaminated area until the excess liquid begun
to tear, about, 10 ml/sqdm on smooth surfaces (glass,
metal sheets) and about 20 ml/sqdm on rough
surfaces (peeling metal sheet, tires).
Figure 4. Microbiological testing of decontaminating substances on combat vehicle with Biological Mobile Intervention Team of CCSMM in CBRN training area from Campulung
Microbiological samples were collected by means of
hygienic-sanitary pad, as follows:
0. before contamination (to establish a baseline level
of natural contamination);
1. immediately after contamination (to check the
level of contamination experiment);
2. after decontamination for each decontaminant
upon each biological agent within 10 min (as required
for military using decontaminant);
3. at every 45 min (as for general household
disinfectant).
In addition, at the end of the experiment, samples
were collected from different parts of the operator’s
protective equipment and from the environment to
detect any residual contamination. All samples were
immediately transported under biosafety conditions
and tested in the microbiology P2+ laboratory.
Decontamination achieved results after 45 min are
shown in Table 1.
22
Table 1. Contamination level after decontamination by 10% aqueous solution
No. Decontaminant Biological
agent Surface
Time (min.)
Growth (tube)
Growth (pane)
Remarks
1 DC 17 ICTCM Mixture Glass 45 - ++hem. Contaminated
2 DC 17 ICTCM B. cereus Glass 45 - - Uncontaminated
3 DC 17 ICTCM Mixture vertical
metal sheet 45 +dep. - Contaminated
4 DC 17 ICTCM B. cereus vertical
metal sheet 45 +/- - Uncontaminated
5 DC 18 ICTCM Mixture Glass 45 - - Uncontaminated
6 DC 18 ICTCM B. cereus Glass 45 +/- - Uncontaminated
7 DC 18 ICTCM Mixture vertical
metal sheet 45 +dep. - Contaminated
8 DC 18 ICTCM B. cereus vertical
metal sheet 45 +dep. - Contaminated
9 DC 19 ICTCM Mixture Glass 45 - - Uncontaminated
10 DC 19 ICTCM B. cereus Glass 45 +/- - Uncontaminated
11 DC 19 ICTCM Mixture vertical
metal sheet 45 +dep. - Contaminated
12 DC 19 ICTCM B. cereus vertical
metal sheet 45
+veil, dep.
+ Contaminated
- or +/-: no microbial growth; dep.: bacterial deposit at medium bottom; veil: bacterial population at medium top; hem.: hemolytic colonies.
COMMENTS
The antimicrobial effect remains and is more obvious
after 45 min, suggesting that these products can be
proposed as potential disinfectants for medical or
hygienic-sanitary use, according with Drug Law.
The decontamination with powder is less effective in
all cases, compared with the laboratory control
sample, because of weak contact between micro-
organism and decontaminant, so a residual
contamination remains on surfaces.
In all cases, the final stage of decontamination should
be washing with water because the substances used
can be corrosive upon certain materials or irritating
for personnel.
After the final washing action, a microbiological
analyze was made to determine residual
contamination of surfaces, waste water or protection
equipment, but a significant contamination was not
recorded, so it can be concluded that there is no risk
to the environment.
CONCLUSIONS
A number of potential decontaminating substances
were synthesized and tested, eight of which were
selected and recommended as decontaminating
agents because these can be characterized by high
chemical stability. These products are soluble in
water and various organic solvents. These biocidal
products have bactericidal and fungicidal capabilities,
with a large spectrum of usability. The substances are
characterized by low toxicity on animals.
Theoretical and experimental scientific research has
been made to design and implement polyvalent “bio-
chem” decontaminants for destruction of biological
and toxic chemical agents, hazardous to health.
Technologies have been developed for obtaining
polyvalent decontaminants, selected by efficiency
assays, in laboratory. The experimental polyvalent
model for chemical and biological decontamination
with decontaminants of quaternary ammonium salts
types was developed.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
23
Among the tested products, the best antimicrobial
activity is achieved by products based on mixture of
oxidizing compounds and quaternary ammonium
salts, which also have a synergic effect when used,
expanding the action spectrum.
References:
1. Ordeanu V., Luta N., Voicu V., Taralunga Gh., Mircioiu Ctin., Neamtu Ctin., Andries A., Irimia Adriana, Alkyl-Phosphates as New Substances for Disinfection and Decontamination “Bio-Chem”, Chemistry Mag. Bucharest, 59, no. 6, 2008.
2. Luta N., Ordeanu V., Taralunga Gh., Chiraleu E., Popescu M., Neamtu C., Hanganu M., Polyvalent decontaminants for the terrorist attacks combat BIO-CHEM, International Forum “The priorities of chemistry for a durable development”, 20-21 Oct. 2005, ICECHIM Bucharest, Romania.
3. Ordeanu V., Luta N., Voicu V., Taralunga Gh., Mircioiu C., Andries A., Neamtu Ctin., Irimia Adriana, New substances for disinfection and decontamination “bio-chem”, The XIII National Congress of Pharmacy, 28-30 Sept. 2006, Cluj-Napoca, Romania.
4. Stepan E., Neamtu C., Enascuta C., Ordeanu V., Necsulescu M., Andries A., Irimia Adriana, N,N,N’,N’-tetraacetyletylenedyamine (TAED) as an activator for persodiums, in modern compositions of detergents and
disinfectants, Chemistry Mag. (Bucharest) 59, No. 5, 2008, p.558.
5. Stoica L., Irimia Adriana, Oproiu G.C., Ordeanu V., Kinetic modeling of As(V) Separation by dissolved air flotation, Chemistry Mag. (Bucharest) 59, No. 4, 2008, p.379.
6. Craciunoiu S., Barbulescu Emilia, Raducanu Carmen, Ordeanu V., Necsulescu M., Decontaminants BIO-CHEM based on oxidizing compounds and quaternary ammonium salts, Innovative Technology Mag., No. 3, 2008.
7. Voicu V., Luta N., Ordeanu V., Andries A., Research for the development of decontaminating products to combat the effects of terrorist, chemical and biological attacks, Defense NBC Mag., No. 17, 2009, p. 31.
8. Jungerman E., Cationic Surfactants, Marcel Dekker Inc. New York 1970
9. Jackson J.B., Decontaminating solution, Brevet SUA no.3.079.346, 1963
10. *** Antiseptics and disinfectants, AFNOR, ed. 2, AFNOR 1989
24
Article received on December 10, 2013 and accepted for publishing on January 5, 2014.
News and Perspectives on Treatment of Normal Pressure
Internal Hydrocephalus
Cristian Năstase1, Marian Mitrică1, Cristian Popescu1
Abstract: Many patients, usually over 60 years old, presenting presenile dementia associated with marked gait disorders, impaired balance, urinary incontinence, have been shown to have enlarged ventricles associated with relatively small cortical atrophy. Intracranial pressure monitoring indicates normal values, or subject to only minor peaks, usually at night. Because some of these patients improve markedly after ventricular shunting procedures it has been suggested that their neurological dysfunction may be caused by a pressure effect on the brain from the increased internal surface of the ventricles. Many of these patients do benefit from surgery, and a lot of them have a history of subarachnoid hemorrhage, traumatic brain injury or meningitis which might have impaired the CSF absorption.
INTRODUCTION
We would like to present the experience of our clinic
over the last five years regarding the treatment of
normal pressure internal hydrocephalus (28 patients
operated between January 2009 and December
2013), to report our results and compare them with
the statistics and results from the international
literature. Normal pressure internal hydrocephalus
(NPIH) represents an increase of CSF volume, with
different etiology, that causes an enlargement of the
ventricular system as a consequence of the
hydrodynamic CSF circulation disorders.
The cause of this disease cannot be identified in 60%
of cases. It was described in 1965 with the Hakim &
Adams triad: gait disorders and impaired balance,
cognitive disorders (progressive dementia), sphincter
disorders (8). The imagistic explorations (CT scan)
indicate the size of hydrocephalus; ICP < 15 mmHg
and the pressure gradient between the ventricles and
subarachnoid space is very low. For treatment there
are extrathecal shunts (particularly ventriculo-
peritoneal shunt) and intrathecal shunts (particularly
endoscopic ventriculocisternostomy).
Both methods have been practiced successfully in our
clinic.
The ideal treatment method for hydrocephalus still
does not exist. None of the surgical techniques is
perfect and no shunting device gave total satisfaction
(4, 7).
Hydrocephalus represents the enlargement of one or
more parts of the CSF containing anatomic structures.
The CSF total volume is about 150 ml in adult; the
ventricular system contains 25-30 ml, the spinal
subarachnoid space contains 30 ml and the rest of
CSF is contained by the cranial subarachnoid space
ORIGINAL ARTICLES
1 Carol Davila Central Emergency Military Hospital, Bucharest
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
25
and basal cisterns (1).
Figure 1. The ventricular enlargement shown on CT scan
The total production of CSF is about 600 – 700 ml/24
hours, approximately 0,35 ml/min. The CSF
participates in maintaining the endocranial volume
constant by adjusting the production/absorption ratio
depending on the cerebral parenchyma volume and
the intracranial blood volume variations according to
the Monro-Kellie relationship. Changing the volume
of one of the three intracranial components (brain
tissue, blood, CSF) is followed by a compensatory
reaction from the other two components in order to
maintain inside an inextensible space the endocranial
volume constant (9).
Based on its underlying mechanisms, hydrocephalus
can be classified into obstructive and communicating.
The obstructive hydrocephalus is defined by any
condition that restricts the CSF flow to and from the
ventricular system. Any CSF flow interruption outside
the ventricular system defines the communicating
hydrocephalus (5).
Figure 2. Lateral ventricles puncture
The NPIH etiology is not fully known. There are many
possible congenital or acquired causes, but the most
important are the subarachnoid hemorrhages (20%),
meningitis (1%), parasite infections, traumatic brain
injuries, neurosurgical procedures with open
26
ventricular system, intoxications, Alzheimer disease
(15%).
Hydrocephalus of the adult patients is a
communicating, chronic and normal pressure
hydrocephalus (3).
DIAGNOSTIC
The CT scan and the MRI revolutionized the diagnosis
and the postoperative follow-up of the
hydrocephalus. The CT scan is the first stage of
diagnosis.
It highlights an obstructive cause, evaluates the
ventricular enlargement, appreciates the cerebral
parenchyma condition (periventricular hypodensity)
and the subarachnoid spaces condition (basal
cisterns, sylvian fissures, interhaemispheric fissure,
cortical sulci).
Bifrontal index measuring (the distance between
frontal horns / intracranial distance ratio, on the
same CT slice) > 50% is suggestive for a possible
decompensation of hydrocephalus.
The Evans index > 30% has the same meaning (the
frontal horns size/ the maximum biparietal diameter
ratio). It suggests an active hydrocephalus. The MRI
completes the CT scan by describing the obstructive
lesions accurately and obtaining dynamic information
over the CSF flow (the absence of CSF flow through
Sylvius aqueduct).
The preventing treatment is important because of the
existing risk of postoperative hydrocephalus after any
neurosurgical procedure. Cisternograms with
radioactive markers (99Tc-DTPA) remain
controversial and rarely used.
The radionuclide is injected into the subarachnoid
space by a lumbar puncture and serial images are
taken by planar scintigraphy 3, 6 and 24 hours after
the injection. In case of NPIH intraventricular
radioactivity can be obtained even 48 hours after the
injection. Serial lumbar punctures with repeated
evacuation of 15 – 30 ml CSF associated with clinical
improvement can predict a favorable response to
shunting procedures. Patients with initial measured
CSF pressure >15 mmHg responded favorably after
ventriculo-peritoneal shunting (6, 8, 9).
TREATMENT
The treatment of hydrocephalus depends on the
moment of diagnosis, etiology, age and clinical
condition of the patient (particularly the acute form)
and the complementary investigations results.
The treatment with acetazolamide, a carbonic
anhydrase inhibitor has favorable effects
predominantly by inhibiting the chorioid plexus
secretion and less by the diuretic effect.
The acetazolamide dose is 25 mg/kg/day with
simultaneously administration of furosemide 1
mg/kg/day.
The treatment of obstructive hydrocephalus is
removing the obstacle (excision of tumors). The
surgical treatment seeks not returning to normal size
of ventricles but regaining most of the lost
neurological functions.
The diuretic and corticosteroid therapies complete
the CSF evacuation by lumbar punctions. The CSF
lumbar drainage will be performed only after the
confirmation of communicating chronic
hydrocephalus by imagistic methods.
There are several types of extrathecal derivations of
CSF: controlled external ventricular drainage,
ventriculoperitoneal drainage, ventriculoatrial
drainage, ventriculopleural drainage.
The currently used valves are predetermined opening
pressure valves (low, medium and high pressure),
modular opening valves and programmable valves
with variable resistances, self-regulating valves etc.
The intrathecal derivation (particularly the
endoscopic ventricular cysternostomy) represents an
alternative treatment method. Both extra- and
intrathecal derivations have been successfully
performed in our clinic.
The intrathecal CSF derivations consist of endoscopic
ventriculostomy through the 3rd ventricle floor
aiming to restore the communication between
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
27
intraventricular and subarachnoid liquidian
compartments.
MATERIAL AND METHODS
We retrospectively studied 28 patients admitted to
our clinic between January 2009 and December 2013.
The patients were all neurological and imagistic
diagnosed with normal pressure internal
hydrocephalus.
Only in 18 cases, a cause for impaired CSF absorption
and ventricular enlargement could be detected. 8
patients had a history of traumatic brain injury, 4
patients had a history of subarachnoid hemorrhage
(First and second grade on Hunt and Hess scale) with
normal “4 vessels” cerebral angiogram, 2 patients
were diagnosed with Alzheimer disease prior to
admission and 4 patients had a history of ischemic
stroke.
3 of the patients with NPIH after subarachnoid
hemorrhage underwent endoscopic procedures with
intrathecal derivations (ventriculocisternostomy).
On the other 15 patients were performed ventriculo-
peritoneal shunts using various valves (most of them
were low pressure valves). The most frequently used
were the Delta (Medtronic), Spitz – Holter, Heyer –
Schulte, Pudenz, Cordis – Hakim valves. In 10 cases, a
cause for NPIH was not revealed and these patients
were diagnosed with idiopathic NPIH. They have also
been performed ventriculoperitoneal shunts with low
pressure valves.
Clinical improvement was significant in most patients,
but only partial in the patients diagnosed with
Alzheimer disease.
According to statistics from literature, urinary
incontinence is the main symptom that resolves after
shunting procedures.
Gait disorders and impaired balance are subsequently
remitted and dementia is the last that improves (3, 4,
8).
Black and collaborators established few criteria that
can predict the favorable clinical course after
shunting procedures:
- clinical: the presence of symptomatic triad;
approximately 77% of the patients presenting gait
disorders as primary symptom improve their
locomotor function after shunting; the patients with
dementia without gait disorders rarely improve after
drainage;
- patients with CSF pressure >18 mmHg on lumbar
puncture or continuous monitoring improve their
neurological status after ventriculoperitoneal
drainage;
- patients with CT or MRI showing large ventricles
with minimal cortical atrophy have favorable
evolution after shunting procedures.
The response to drainage is especially good as the
symptoms started recently (1, 5).
ILLUSTRATIVE CASES
Case 1.
66 year old male patient complaining of gait
disorders, impaired balance, cognitive impairment
(occasionally) and sphincter disturbances (imperious
need to urinate) which started about a year ago,
slowly progressive despite of conservative treatment.
We decided to install ventriculoperitoneal drainage
with self-regulating valve. Postoperative evolution
was favorable, symptoms thereby improving
considerably about 3 months after the procedure.
Case 2.
59 year old male patient complaining of headache,
nocturnal insomnia, depressive syndrome, cognitive
impairment, gait disorders and locomotor’s
instability.
Case 3.
68 year old female patient hospitalized for memory
disorders, sphincter disturbances (imperious need to
urinate), gait disorders, vertigo, occasional headaches
and depressive syndrome. The CT scan reveals
28
enlarged ventricular system. It was decided to install
VP drainage with Delta low pressure valve. The
symptoms improved partially after one month with
significant improvement 6 months after the
procedure.
Figure 3. The ventricular catheter placed inside the right lateral ventricle and the selfregulating valve placed in the right parietal region, under the scalp.
Figure 4. The ventricular catheter placed inside the frontal horn of the right lateral ventricle, near septum pellucid; VP drainage with Delta (Medtronic) low pressure valve.
Case 4.
64 year old male patient facing important balance
disorders, persistent vertigo, extremely difficult gait,
urinary incontinence (and incipient stercoral), onset
of Alzheimer disease (after neurological and
psychiatric examinations). It was inserted a Delta low
pressure valve. The symptoms improved partially
after 3-4 months; the gait has become easier,
sphincter disturbances have improved and the
cognitive impairment still exist, but more tolerable.
Case 5.
72 year old female patient hospitalized for walking
difficulties, balance disorders, persistent vertigo and
vomiting, dehydration. A central venous catheter was
inserted into the right subclavian vein and VP
drainage with a Delta low-pressure valve was inserted
on the left side; intraoperative CSF pressure was 15
mmHg.
Case 6.
66 year old male patient with memory disorders,
impaired balance and gait disorders, cognitive
impairment, urinary incontinence (occasionally),
started over a year ago, with progressive evolution.
Intraoperative measured ICP was 18 mmHg.
Ventriculoperitoneal drainage with Holter low
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
29
pressure valve was installed. The symptoms improved
after one month with the complete remission of gait
disorders, impaired balance and sphincter
disturbances.
Figure 5. The ventricular catheter placed inside right lateral ventricle (functional drainage).
CONCLUSIONS
The ventricular enlargement and the pressure on the
frontal lobes are probably responsible for the
occurrence of cognitive disorders and dementia.
The pressure on the regulator centers of the
sphincter functions located in the paracentral lobule
may be responsible for the urinary incontinence. The
ventricular dilatation may compress the internal
capsule and secondary the pyramidal tract,
responsible for the gait disorders, impaired balance
and pyramidal syndrome (4, 5, and 9).
To determine the surgical indication and to anticipate
the subsequent postoperative evolution, several
clinical and imaging criteria must be established:
• the obstructive causes for hydrocephalus must be
excluded; it must be a communicating form;
• a periventricular hypodensity on CT scan or
hyperintensity on T2 sequence (MRI) might be
transependimar CSF resorption and might anticipate
a favorable evolution after the shunt procedure;
• the rounding and symmetrical ballooning of the
frontal horns;
• dilated focal of convexity sulci may be revealed by
imaging studies and they are atypical CSF reservoirs
which subsequently decrease after drainage and they
should not be confused with cortical atrophy; typical
cortical atrophy (ex vacuo hydrocephalus) occurs
frequently with Alzheimer disease, and there is a
limited response to ventriculoperitoneal drainage
(11).
30
Figure 6. Preoperative MRI (T2 sequence) and postoperative CT scan; right ventricular catheter;prominent convexity sulci; incipient cortical atrophy
Figure 7. Preoperative and postoperative CT images; the catheter has been placed inside the left lateral ventricle because a central venous catheter was inserted into the right subclavian vein (functional drainage).
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
31
Figure 8. Important hydrocephalus with cortical sulcus persistent; catheter placed inside the left lateral ventricle (coronal section).
Maintaining good results depends on periodic
medical checks, immediate recognition and
treatment of complications (insufficient drainage
should be suspected first). There is no ideal method
for the treatment of hydrocephalus. None of the
surgical techniques is perfect and no device gave total
satisfaction.
The accelerated development of technology and the
practical experience in CSF intra- and extrathecal
drainage allow overcoming the current difficulties.
The world population undergoes a pronounced aging
process, the number of people aged over 60,
increasing to 400 million over the last 40 years. The
ratio of the elderly population has been modified,
representing over 50% in developed countries, with
the European zone being the aged (10).
References:
1 Black P., Kaye A. - Operative Neurosurgery. Churchill Livingstone. 2000, pp. 1235-1247.
2 Connelly S., Mc Khann G., Huang J., Chondhry T. – Fundamentals of Operative Techniques in Neurosurgery. Thieme 2001, pp. 345 - 355
3 Constantinovici A., Ciurea A.V. – Practical Guide of Neurosurgery, Medical Publishing House 1998, pp. 353-414
4 Jennett B., Lindsay K. – Neurosurgery; Fifth Edition; Springer-Verlag 1996 ; pp.283-289;
5 Greenberg M. – Handbook of Neurosurgery, fifth edition,
Thieme 2001, pp. 191-195;
6 Gorgan R. M. – Handbook of Surgery (Prof. Irinel Popescu), II, Romanian Academy Publishing House, 2007, pp. 114 – 120;
7 Kempe G. L. - Operative Neurosurgery, Springer – Verlag 1968, pp. 203-214;
8 Karaguiosov L. - Operative Neurosurgery, Medicina I Fizkultura, Sofia 1982, pp. 159-166;
9 Wilkins R.H. – Principles of Neurosurgery, McGraw Hill inc.1985.pp. 2341 – 2356.
32
10 Yasargil M.G. – Microsurgery vol II, Clinical Considerations Surgery of Intracranial Aneurysms and Results. New York. Georg Thieme Verlag 1984, pp. 232-295
11 Youmans J.R. - Neurological Surgery, Fourth Edition, W. B. Saunders Company, 2000.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
33
Article received on November 12, 2013 and accepted for publishing on December 15 2013.
Nonalcoholic fatty liver disease – an etiological approach
Florentina Ioniță Radu1, Mariana Jinga1,2, Petruț Nuță1, Raluca S. Costache1,2, Săndica Bucurică1,2, Bogdan
Macadon1, Vasile Balaban1,2, Mihăiță Pătrășescu1
Abstract: Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of fat in the liver (hepatic steatosis) either on imaging or on liver histology only after the exclusion of secondary causes of fat accumulation in the liver (e.g. high alcohol drinking, drugs and other medical ailments). Considering the fact that there are many causes of hepatic steatosis, the term NAFLD is reserved for the liver disease that is predominantly associated with obesity and metabolic syndrome. The presence of inflammation and cell injury defines steatohepatitis (NASH) which has the potential to evolve into cirrhosis and hepatocarcinoma, being, therefore, the stage of NAFLD most amenable to treatment. Among the treatments available, the most important are: weight loss, vitamin E and, last but not least, probiotics.
INTRODUCTION
Excessive alcohol consumption must be excluded
(>21 drinks per week in men and >14 drinks per week
in women over a 2-year period before the baseline
liver biopsy).
Insulin resistance (figure 1) is, therefore, central to
the development of NAFLD, as it is central to
metabolic syndrome (MS). The Adult Treatment Panel
III defines MS as the presence of three or more of the
following features:
1. Waist circumference greater than 102 cm in men
or greater than 88 cm in women,
2. Triglyceride level greater than or equal to 150
mg/dL,
3. High-density lipoprotein cholesterol level less than
40 mg/dL in men and less than 50 mg/dL in women,
4. Systolic blood pressure greater than or equal to
130 mm Hg or a diastolic pressure greater than or
equal to 85 mm Hg, and
5. Fasting plasma glucose level greater than or equal
to 110 mg/dL.
Patients with features of MS are at high risk for
NAFLD.
The gold standard for the diagnosis of NAFLD is
hepatic biopsy which further characterizes the
ailment deriving two stages of histological evolution:
nonalcoholic fatty liver (NAFL) (this may be the plain
hepatic steatosis) and nonalcoholic steatohepatitis
(NASH).
NAFL is defined as hepatic steatosis with no evidence
of hepatocellular injury in the form of hepatocyte
ballooning. NASH is defined as the presence of
hepatic steatosis and inflammation with hepatocyte
injury (ballooning) with or without fibrosis. Although
NAFL may be proportionally more common than
CLINICAL PRACTICE
1 Carol Davila Central Emergency Military Hospital, Bucharest
2 Carol Davila University of Medicine and Pharmacy, Faculty of Medicine, Bucharest
34
NASH, only patients with NASH have the potential to
progress to cirrhosis. The presence of the
characteristic ballooning injury is considered to be
the key to the diagnosis.
Figure 1: Insulin resistance – central to metabolic syndrome
Ballooning injury results in enlarged vacuolated cells,
classically containing Mallory-Denk bodies, which are
eosinophilic cytoplasmic inclusions near the nucleus.
The most important injury may be identified in zone 3
(around the central venule of the hepatic lobule) and
this pattern of distribution is also characteristic of
NAFLD.
The cardinal histologic feature of NAFLD is the
presence of an excessive accumulation of
triacylglycerols (TAG) and in hepatocytes. The
presence of obesity and insulin resistance lead to an
increased hepatic free fatty acid (FFA) flux creating an
environment appropriate for the development of
NAFLD/NASH.
The resultant net increase in hepatic FFA is
hepatotoxic unless it is converted to nontoxic
intracellular triglyceride (TG). When the synthesis of
TG is impaired, the level of FFA in the liver is
increased with subsequent augmentation of hepatic
fatty acid oxidation resulting in the overproduction of
reactive oxygen species (ROS) also known as free
radicals causing hepatocellular injury.
Based on this biochemical knowledge, a two-hit
hypothesis for the pathogenesis of NASH has been
proposed. The first hit involves the accumulation of
excess triglyceride and particularly FFA in
hepatocytes. The second hit is the generation of toxic
reactive oxygen species with the production of
hepatic injury and inflammation as a consequence of
FFA oxidation which ultimately leads to the initiation
and progression of fibrosis [1].
Hence, steatosis is mandatory for the diagnosis of
NAFLD but alcohol consumption and chronic hepatitis
C should be taken into account as two of the most
important alternative causes amenable to different
treatments.
The diagnosis of NAFLD requires the following:
(1) Hepatic steatosis according to imaging or
histology
(2) No significant alcohol consumption
(3) No competing etiologies for hepatic steatosis
(table 1)
and
(4) No coexisting causes for chronic liver disease.
NAFLD is the most common cause of abnormal liver
chemistry, so other causes, like those in table 1,
should be ruled out. The majority of patients with
NAFLD are asymptomatic. The most frequently
encountered symptoms are: vague right upper
quadrant dull ache or discomfort. Hepatomegaly is
the most common physical finding. Other clinical
symptoms and physical findings are, also, nonspecific:
general malaise, abdominal discomfort, nausea.
Celiac disease always should be ruled out in
suspected individuals considering the fact that this
disease is often underdiagnosed and seldom to be
taken into account as a differential diagnosis of
hipertransaminasemia.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
35
Table 1. Conditions associated with the risk of hepatic
steatosis
STEATOSIS
• Insulin resistance • Obesity • Type 2 diabetes mellitus • Dyslipidemia • Hypertension • Sedentary lifestyle • Corticosteroids • Estrogens • Amiodarone • Antiretroviral medications • Obesity surgery (e.g., jejunoileal bypass) • Rapid weight loss • Carbohydrate excess (e.g., diet and total parenteral nutrition) • Chronic hepatitis C virus, mainly genotype 3 • Hypothyroidism • Polycystic ovarian syndrome
Once NAFLD is diagnosed, the next step is to
determine the severity as it is necessary to establish
the prognosis. Clinical examinations and laboratory
and imaging studies in combination lack the
sensitivity and specificity for distinguishing NAFL from
NASH and for determining the presence and stage of
fibrosis, which is the most important determinant for
the severity and progression of disease.
Circulating levels of cytokeratin 18 fragments have
been investigated extensively as novel biomarkers for
the presence of steatohepatitis in patients with
NAFLD, but this testing is not routinely
recommended. Other noninvasive tests are emerging;
however, these are not yet ready for prime time. [1,
2, 3]
Liver biopsy still remains the most reliable approach
for identifying the presence of steatohepatitis and
fibrosis in patients with NAFLD.
The recommendations for liver biopsy are as follows
(figure 2):
1. Patients at increased risk for steatohepatitis and
advanced fibrosis according to the presence of
features of MS and possibly the NAFLD fibrosis score.
2. Patients with suspected NAFLD for whom
competing etiologies of hepatic steatosis and
coexisting chronic liver diseases cannot be excluded
without liver biopsy.
There is a general consensus that patients with NAFL
have a very slow progression (if any). On the other
hand, patients with NASH can exhibit histological
progression and can develop fibrosis (37%-41%) and
cirrhosis (Approximately 5%) [3]. Importantly, hepatic
cancer can occur in NASH in the absence of cirrhosis.
This is why every effort should be made to identify
patients with NASH as they are the ones to progress
to more severe forms of disease. The presence of
NASH can be associated with higher liver-specific
mortality in comparison with the general population.
Cardiovascular ailments associated with NASH (as
metabolic syndrome) contribute significantly to
mortality and morbidity. Patients with NAFLD are also
at increased risk for hepatocellular carcinoma, but
this risk is likely limited to those with advanced
fibrosis and cirrhosis (1%-42%) [2]. Furthermore, a
comparison of the natural history of NASH cirrhosis
with hepatitis C cirrhosis reveals that patients with
NASH cirrhosis have a significantly lower risk of
hepatocellular carcinoma. [2]
NAFLD is typically characterized by a hepatocellular
pattern of liver-related enzymes with mild elevations
(1-2 times the upper limit of normal) in serum alanine
aminotransferase (ALT) and aspartate amino-
transferase (AST). Up to 50% of NAFLD patients have
normal liver biochemistry. Therefore, several
biomarkers may aid in the diagnosis. The diagnosis of
NASH without a liver biopsy remains the most
significant clinical challenge in the evaluation of a
patient with hepatic steatosis. Several biomarkers
may distinguish between simple steatosis and NASH.
Some of the inflammatory markers include serum C-
reactive protein, interleukin-6, ferritin, hyaluronic
acid (HA), tumor necrosis factor a, leptin,
adiponectin, and resistin.
Apoptosis plays a key role in the pathogenesis of
NASH. Among the markers of apoptosis, plasma
cytokeratin 18 (CK-18) is emerging as one of the
promising biomarkers for the noninvasive detection
of NASH. Since oxidative stress also plays an
important role in the pathogenesis of NASH, several
biomarkers of oxidative stress have been
investigated. Among these, oxidized low-density
lipoprotein, thiobarbituric acidreacting substances,
superoxide dismutase, and glutathione peroxidase
36
dismutase have been examined. The NASH test
combined 13 variables [age, sex, height, weight, and
serum levels of triglycerides (TGs), cholesterol, a2-
macroglobulin, apolipoprotein A1, haptoglobin,
gammaglutamyl transpeptidase (GGT), ALT, AST, and
total bilirubin] to achieve positive predictive value,
and negative predictive value of 66%, and 81%,
respectively. [2, 3, 4]
Figure 2: Algorithm for liver biopsy in NAFLD
Two of the most promising tests for diagnosing
advanced fibrosis in NAFLD are the European Liver
Fibrosis (ELF) score and the NAFLD fibrosis score. The
ELF score includes HA, tissue inhibitor of
metalloproteinase 1 (TIMP1), aminoterminal peptide
of procollagen 3, and age. The NAFLD fibrosis score is
helpful in the clinical setting because it uses routinely
available variables in the clinical setting, including
age, BMI, hyperglycemia, platelet count, serum
albumin, and AST/ALT ratio. We use routinely
available models or markers that increase the pretest
likelihood of finding more advanced liver disease on
liver biopsy. These tests can aid in clinical decision
making for patients with NAFLD.
Some of these markers are a high AST/ALT ratio, a
high AST/platelet ratio, low albumin levels, and low
platelet levels. [2, 3]
TREATMENT LANDMARKS
Among patients suffering from NAFLD (more than
50% of them being asymptomatic) treatment is
mandatory only in NASH patients because only those
have the potential to evolve into more severe
diseases (cirrhosis, hepatocarcinoma) [5].
Because NASH is linked to excess body weight and
resulting insulin resistance, diet and lifestyle
measures are the recommended first-line therapy.
YES
Presence of any of the following (emerging): 1. Elderly (> 65 years old) 2. Family history of diabetes 3. Family history of cirrhosis
Elevated AST and/or ALT and evidence of steatosis on imaging
Presence of co-existing liver diseases or bio-chemical tests favoring an alternative diagnosis
NO
Presence of diabetes or metabolic syndrome
Work-up for co-existing liver diseases and liver biopsy if needed
YES NO
Liver biopsy Presence of any of the following: 1. AST > ALT 2. Low serum albumin 3. Low platelet count
YES
Liver biopsy
NO
YES NO
Consider liver biopsy Reassess every 6 months to 1 year
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
37
Optimal treatment begins with weight loss and
physical exercise. A tangible target for patients with
NAFLD is a weight loss of 5% to 10% of total body
weight over a 6- to 12-month period [6]. Those
measures may improve insulin sensitivity, increase
adiponectin expression, lipid profiles, and liver
biochemistry. The improvement in liver enzyme does
not always correlate with improvement in hepatic
histology, unfortunately. As it is already
demonstrated, weight loss by dietary changes may be
beneficial even without physical exercise; although
physical exercise may lead to further improvement in
insulin sensitivity. The initiation of increased physical
activity must be the first step to the treatment of
NAFLD; vigorous exercise and resistance training are
more helpful than aerobic exercises. The intensity
may be more important than the duration or total
volume of exercise. [7, 8, 9]
Current guidelines do not recommend the use of
hepaticopharmacological therapy in patients with
steatosis alone. Instead, patients with NASH and
significant liver disease (bridging fibrosis) are good
candidates for this type of therapy. According to the
clinical practice guidelines of the American
Association for the Study of Liver Diseases, the first
choice of therapy is vitamin E (preferably 800 IU/day).
A 2-year treatment in the PIVENS trial (800
IU/day) reversed steatohepatitis and improved all
histological features of NASH (except fibrosis) in
comparison with a placebo. This beneficial effect of
vitamin E was not associated with an improvement in
insulin sensitivity. Recent studies and meta-analyses
showed increased mortality, a risk of hemorrhagic
stroke, and a risk of prostate in long term vitamin E
treatments. [10, 11]
Animal studies have shown that omega-3
polyunsaturated fatty acids promote insulin
sensitivity, reduce intrahepatic triglyceride content,
and ameliorate steatohepatitis. [10, 11]
The drugs to increase insulin sensitivity (glitazone,
metformin) may be indicated as a treatment
alternative in NASH 16. Ursodesoxicholic acid and
pentoxifilin, which may benefit marginally. [6]
Probiotics and NAFLD
The newest topic in treatment of NAFLD is that of the
involvement of gut microbiota in the pathogenesis of
liver steatosis and inflammation.
Intestinal microbiota plays an important role in health
and disease. The gut-liver axis involves an interaction
between bacterial components like lipopolysaccha-
ride and hepatic receptors (Toll-like receptors). Our
gut has approximately 100 trillion (1014) microbes,
which make up approximately 1 to 2 kilograms of our
weight. Gut microbiota perform diverse immunologic,
digestive, and metabolic functions. [11]
Changes in microbiota may be involved in various
disease pathogenesis (nonalcoholic fatty liver disease
(NAFLD), hepatic encephalopathy, alcohol-related
liver disease, and hepatocellular carcinoma). Gut
microbiota may cause NAFLD by luminal ethanol
production by metabolization of carbohydrates, cau-
sing an increased intestinal permeability (“leaky gut”)
just like in alcohol associated steatohepatitis (ASH).
[12, 13]
In 2009 Miele was the first author to provide
evidence of increased intestinal permeability in
patients suffering from NAFLD and this fact was
associated with increased prevalence of small bowel
bacterial overgrowth (SIBO) in those patients [14].
The increased permeability appears to play an impor-
tant role in the pathogenesis of NAFLD. Loguercio
demonstrated in 2005 that probiotics may improve
NAFLD histology and biochemistry [15]. In October
2013 Yan-Yan Ma et al published a meta-analysis in
World Journal of Gastroenterology to conclude that
the treatment with probiotics and prebiotics may
definitely benefit patients with NASH [11].
Probiotics can inhibit the proliferation of harmful
bacteria, reduce SIBO, restore gastrointestinal barrier
function and modulate the immune system, all of
which contribute to the improvement of NAFLD. This
meta-analysis showed that probiotics significantly
reduced ALT, AST, T-chol, TNF-α and insulin resis-
tance, which are all related to the process and con-
sequences of NAFLD. Regular consumption of probi-
otics reduced, also, cholesterol levels which is part of
metabolic disturbances in NAFLD patients. [11]
38
A high fat diet that induces obesity, insulin resistance
and hepatic steatosis also leads to hepatic NKT cell
depletion. The hepatic NKT cell is the key mediator of
HF diet-induced metabolic abnormalities. Moreover,
recently, Cani and colleagues reported that a high-fat
diet increases plasma lipopolysaccharide (LPS) level,
which also contributes to the pathogenesis of insulin
resistance and increased liver triglyceride content. It
is possible that this bacterial endotoxinemia caused
by high fat diet reduces intrahepatic NKT cells and
leads to worsened or amplified insulin resistance. The
ability of probiotics to restore hepatic NKT cells and
improve HF diet-induced insulin resistance and fatty
liver are novel findings and intriguing. [12, 13]
These data suggest that strategies designed to down
regulate inflammatory mediators with probiotics
have promising potential in patients with NAFLD.
CONCLUSIONS
NAFLD/NASH is a prevalent health problem in general
population in close proximity with the same
increased rate of obesity, diabetus mellitus and
metabolic syndrome to which it is pathogenically
related. Proper management of insulin resistance by
diet, weight loss and physical exercise may provide
the patients with strong tools to fight the disease.
The increasing evidence of the role of gut microbiota
in disease pathogenesis and the role of probiotics in
decreasing hepatic steatosis and inflammation points
firmly towards new and handy solutions in the
nearest future.
References:
1. Sanyal AJ, Banas C., Sargeant C., Luketic VA et al; .Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006;43:682-689.
2. Adams LA, Lymp JF, St Sauver J, Sanderson SO et al; The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-121.
3. Bashar M. and David H. ; Van Thiel Current Concepts and Management Approaches in Nonalcoholic Fatty Liver Disease ScientificWorldJournal. 2013; 2013: 481893. Published online 2013 March 20
4. Rafiq N., Bai C., Fang Y., Srishord M., McCullough A., Gramlich T. Et al; Longterm follow-up of patients with non-alcoholic fatty liver. Clin Gastroentrol Hepatol 2009;7:234-238.
5. Ong JP, Pitts A, Younossi ZM.; Increased overall mortality and liver-related mortality in nonalcoholic fatty liver disease. J Hepatol 2008;49:608-612.
6. Zein CO, Yerian LM, Gogate P., Lopez R, Kirwan JP, Feldstein AE et al; Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610-1619
7. Huang MA, Greenson JK, Chao C., Anderson L., et al; One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005; 100:1072-1081.
8. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA.et al; Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology
2009;49:80-86.
9. Levy JR, Clore JN, Stevens W.; Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats. Hepatology 2004;39:608-616.
10. Williams CD, Stengel J, Asike MI, Torres DM, et al; Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population using ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140:124-131.
11. Yan-Yan Ma, Lin Li, Chao Hui Yu, Zhe Chen et al; Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis World J Gastroenterol. 2013 October 28; 19(40): 6911–6918. Published online 2013 October 28.
12. Cani P., Amar J, Iglesias M., Poggi M., et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. 2007;56:1761–1772.
13. Vishal Sh., Shashank G. , Sourabh et al ; Probiotics and Liver Disease Perm J 2013 Fall;17(4):62-67
14. Miele L, Valenza V, La Torre G, Montalto M et al; Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009 Jun;49(6):1877-87.
15. Loguercio C., Alessandro F., Tuccillo C., Terracciano F. et al; Beneficial Effects of a Probiotic VSL#3 on Parameters of Liver Dysfunction in Chronic Liver Diseases; J Clin Gastroenterol 2005;39:540–543
16. Boettcher E., Csako G., Pucino F., Wesley R., and Loomba R.; Metaanalysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis; Aliment Pharmacol Ther. 2012 January; 35(1): 66–75.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
39
Article received on January 12, 2014 and accepted for publishing on February 15 2014.
An unusual cause for cerebellar syndrome – case report
Carmen A. Sîrbu1, Octavian M. Sîrbu2, Anca M. Sandu2, Cristina P. Sandu1, Marian Ștefănescu1
Abstract: A male from rural area, S.M., aged 77 years, was admitted in our department for discontinuous headache. His medical history was irrelevant. He has been experiencing intermittent right parietal-occipital headaches during the last 3 months. Neurologic exam revealed a slight right limb ataxia. Initial laboratory findings revealed a white blood cell count of 6500/mm3 with 75% polymorphonuclear leukocytes, 15% lymphocytes and 8% monocytes. His serum glucose was 90 mg/dL. Non Gadolinium CT scan shows rounded, inhomogenous spontaneous hyperdense area (40-45 UH) between 5-12 mm diameter, localized frontal, temporal, occipital and cerebellar bilaterally. The question was whether the lesions were metastasis or parasitic infection?
Cerebral MRI showed unenhanced, well defined,
multiple lesions between 3-17 mm, with iso-
hyperintensity T1, T2, and FLAIR, spread out
periventriculary, subcortically, in frontal, temporal,
parietal lobes and subtentorially, right and left
cerebellum (figure 2). After serological tests from
blood and CSF the diagnostic of neurocysticercosis
was certified (an enzyme-linked immunosorbent
assay of the CSF was positive for immunoglobulin G
cysticercosis antibody, with 1.32 optical density units
(OD) (positive result > 0.50 OD); his serum IgG
cysticercosis antibody was positive with 5.12 OD).
CT findings are depending on the stage of evolution:
• Vesicular stage (viable larva): hypodense,
nonenhancing lesions
• Colloidal stage (larval degeneration): hypodense/
isodense lesions with peripheral enhancement and
edema
• Nodular-granular stage: nodular-enhancing lesions
• Cysticercotic encephalitis: diffuse edema, collapsed
ventricles, and multiple enhancing parenchymal
lesions
• Active parenchymal stage: the scolex within a cyst
may appear as a hyperdense dot
• Calcified stage: when the parasite dies, nodular
parenchymal calcifications are seen.
Our patient has multiple lesions in different phases of
evolution (active and calcified).
DISCUSSIONS
Neurocysticercosis is a parasitic brain infection,
caused by larval cysts of the tapeworm Taenia solium
by accidental ingestion of eggs.
It is the most common parasitic disease of the
nervous system and it is the main cause of acquired
epilepsy mainly in developing countries. Once in the
human intestine, Taenia eggs evolve to oncospheres
CLINICAL PRACTICE
1 Carol Davila Central Emergency Military Hospital, Bucharest
2 Carol Davila University of Medicine and Pharmacy, Faculty of Medicine, Bucharest
40
that cross the intestinal wall and lodge in the brain
where cysticerci develop.
Time from infestation until first symptoms is between
days and many years (30).This extremely long
incubation is due to hipnobiosis. They may be located
in subarachnoid space, ventricular system, or spinal
cord too, causing a clinical heterogeneity.
Figure 1. Non Gadolinium CT scan shows rounded, inhomogenous spontaneous hyperdense area (40-45 UH) between 5-12
mm diameter, localized frontal, temporal, occipital and cerebellar bilaterally.
Figure 2. Cerebral MRI showed unenhanced, well defined, multiple lesions between 3-17 mm, with iso-hyperintensity T1, T2,
and FLAIR, spread out periventriculary, subcortically, in frontal, temporal, parietal lobes and subtentorially, right and left
cerebellum
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
41
Onset of most symptoms is usually insidious to
chronic, with seizures (most common presentation),
headache, dizziness, stroke, neuropsychiatric
dysfunctions. Almost every neurological sign or
symptom may be present but physical findings occur
in less than 20% of the cases.
There is a pleomorphism of the immune response
against Taenia solium. In some cases, cysticerci are
destroyed by immunological attack, while in others,
parasites may live unchanged for years. CT scan
shows a rounded, homogeneous hyperdense area
with no enhancement with contrast medium. This
phase corresponds to the inactive parenchymal form
of the disease.
References:
1. Baccari P, Civilini E, Dordoni L, Melissano R: Celiac artery
compression syndrome managed by laparoscopy. Journal of
vascular surgery, vol. 50 pp.134-139 2009.
2. Muqeetadnan M, Amer S, Rahman A, Nusrat S, Hassan S:
Celiac artery compression syndrome. Case reports in
gastrointestinal Medicine, vol.2013, article ID 934052, 3
pages, 2013.
3. Radiopaedia.org (internet).UBM Medica network; c2005-
2015 rID:1143 Accesed at http://radiopaedia.org/articles/
coeliac artery compression syndrome.
4. Schaan de Quadros A, Sarmento-Leite R, Moraes C. Stent
Implantation in Critical Stenosis of Celiac Trunk: Enlarging
the Frontiers of Percutaneous Vacular Interventio. Arquivos
Brasileiros de Cardiologia, vol 83, no.5 pp. 445-447, 2004.
42
Past and future
Andrei Necşulescu1
Abstract: I was thinking a lot about choosing this title which at first glance doesn’t seem not to be related to the main topic of this article. However, I think these two opposites have the ability to describe in the most subtle form my journey in Istanbul, the city on two continents. The streets covered with history invites you to discover them step by step and the congress showed me a picture of my future when I will have the opportunity to present important projects in front of a selected audience.
The 18th edition of the Balkan Military Medical
Committee Congress was the start point. I can say
that it remains, so far, the most important scientific
event I have participated.
I also had the opportunity to visit Istanbul, a city like a
story that I truly recommend everyone to visit.
Novelty began for me at the military airport Baneasa
when, in a cold morning, I had
the chance to see a C17 Spartan
military transport aircraft for the
first time. I was curious because
that type of military aircraft had
to take me to destination
offering me a unique
experience. First flight was quiet and we were
greeted in Istanbul by friendly hosts and a beautiful
weather. Coach riding to the hotel in the bustling
metropolis gave me a chance to admire the
panorama for the first time especially because there
was quite a distance between the airport and our
hotel, the complex where we were accommodated
being in Asia. When I reached the destination I had
the honor to admire one of the most beautiful hotels
in Istanbul, a true pride of the Turkish army and also a
proof of their elite role in society. Beyond the luxury
and good taste I noticed again the perfect planning of
every detail, starting with accommodation. The
Congress began. In the first evening I started meeting
my colleagues from other countries during an elegant
and discreet reception.
That was the first time I
changed impressions with my
fellow military students from
the other participating
countries. We linked friendships
that I’m sure will be long-lasting
and we set up a future
collaboration for the upcoming congresses,
everything in a festive and friendly atmosphere.
Beyond the congress I ventured for the first time into
crowded Istanbul with my colleague Robert Popescu.
In the second day of the congress I went for the first
VARIA
1 Carol Davila University of Medicine and Pharmacy, Faculty of Military Medicine, Bucharest
Beyond the speeches from heads of delegations I was very happy to see
that the prize for the best project was awarded to Romania. It was a pride
for the whole delegation and we returned to the hotel very happy.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
43
time at the Military Museum from Istanbul where I
attended the opening ceremony. After visiting the
museum, my colleague and I were invited in the hall
where the presentations were kept. In front of a huge
picture of Mustafa Kemal Ataturk I attended military
medical exposures from Serbia, Greece, Turkey,
Bulgaria and Romania. I started to get ready for my
first speech in front of an audience composed mostly
of doctors.
Day three was the highlight of the congress for me.
Although I knew Robert Popescu was going to present
the project with doctors and university students, I
was told that my poster will be exhibited in the
museum lobby where I should provide clarifications
for the numerous questions that might be asked. I
admit that things for me were much more effortless
but I was kept up-to-date with the events of the
congress thank to my colleague who was getting
ready to present his project. I appreciated the
presentations of my colleagues from other countries
and together we agreed to collaborate in the
future and gather together at these conferences with
bigger projects that will integrate more teamwork. I
left there convinced that at the next congress I will
come with an oral presentation. I gathered the
minimum necessary experience to deal with future
congress work and I hope I managed to fit in that
great atmosphere provided by the hosts. The
presentation of my colleague was praised; his
experience at previous congresses he attended made
a difference. I left there thinking that I fulfilled the
task of coping with challenges and building the idea
that I can come up with a lot more and improve
myself.
Day four was great. It was time to visit the impressive
Dolmabahce, a true monument and one of the most
spectacular buildings in Istanbul. That day it was
warm, summer was definitely approaching. Many
people were gathered in front of the palace, a sign of
the importance of that particular place. Huge halls,
sophisticated architecture, historical significance and
opulence made me think about what many years ago
was considered absolute luxury. I recommend visiting
the palace along with other major sights of Istanbul.
The evening was one of the most important moments
of the congress due to the cruise on the Bosphorus.
The boat that was waiting for us was state-of-the-art,
impressive and equipped with a luxury dining room.
As already expected, we were welcomed aboard with
friendship. It was the last moment when I changed
impressions about congress with my colleagues from
other countries. There were five delegations in the
debut of the party but at the end we were a single
group with many things in common. That was the
moment when we had the chance to know us better
than we did before. Seen from the Bosphorus,
Istanbul was like a fairytale. I think one of the most
spectacular city’s overall images can be seen at night.
Picture of opulence was reflected in every detail
when I saw the most famous clubs from the city
during the cruise.
44
I went back to the hotel thinking that an experience
like that was unique and I rarely had the opportunity
to see so much luxury gathered in a single place. Last
day brought me back at the military museum which
hosted the closing ceremony. Beyond the speeches
from heads of delegations I was very happy to see
that the prize for the best project was awarded to
Romania.
It was a pride for the whole delegation and we
returned to the hotel very happy. Those were already
the last hours in Turkey. We started preparing to go
back home so we had lunch and then we started
packing the luggage. At the airport our plane was
waiting for us. After a turbulent flight we arrived back
in Romania on a cold and rainy weather, a lot
different than the sun and the heat from Turkey.
The experience was unforgettable. I recommend
everyone to take part in this kind of event even if
they have to deal with oral presentations. I think that
what matters the most is participation and the
numerous things that you can learn. Since little, brick
by brick, experience accumulates and allows
overcoming new limits. I hope I gave a good read and
I want to thank you for the time you have given me.
Vol. CXVII • New Series • No. 1-2/2014 • Romanian Journal of Military Medicine
45
Guidelines for authors
Thank you for your interest in Romanian Journal of Military Medicine. Please read the complete Author Guidelines carefully prior to submission, including the section on copyright. To ensure fast peer review and publication, manuscripts that do not adhere to the following instructions will be returned to the corresponding author for technical revision before undergoing peer review. Note that submission implies that the content has not been published or submitted for publication elsewhere except as a brief abstract in the proceedings of a scientific meeting or symposium. Once you have prepared your submission in accordance with the Guidelines, manuscripts should be submitted online at [email protected]. We look forward to your submission.
EDITORIAL AND CONTENT CONSIDERATIONS Aims and Scope Romanian Journal of Military Medicine (RJMM) is the official journal of the Romanian Association of Military Physicians and Pharmacists. The Journal publishes peer-reviewed original papers, reviews, metaanalyses and systematic reviews, and editorials concerned with clinical practice and research in the fields of medicine. Papers cover the medical, surgical, radiological, pathological, biochemical, physiological, ethical and historical aspects of the subject areas. Clinical trials are afforded expedited publication if deemed suitable. RJMM also deals with the basic sciences and experimental work, particularly that with a clear relevance to disease mechanisms and new therapies. Case reports and letters to the Editor will not be considered for publication. Editorial Review and Acceptance The acceptance criteria for all papers and reviews are based on the quality and originality of the research and its clinical and scientific significance to our readership. All manuscripts are peer reviewed under the direction of an Editor. The Editor reserves the right to refuse any material for review that does not conform to the submission guidelines detailed throughout this document, including ethical issues, completion of an Exclusive License Form and stipulations as to length.
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ADMINISTRATIVE ISSUES
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to the reader if the author responds to questions that follow from the images of the case, such as ‘What is your diagnosis? What are the features indicated on the CT scan? What is the differential diagnosis?’ Part 2 will briefly describe the imaging features, particularly those that lead to diagnosis or which are critical for management. Differential diagnosis should be mentioned. It will be useful to include either further images or pathological details that validate the imaging diagnosis. Occasionally, presentation of analogous cases or related images from a similar case might be appropriate. Please include between one and three references to definitive studies and appropriate reviews of the subject. The format of the Images page involves a brief background to and description of the disorder of interest together with two figures of high quality. Colored photographs are encouraged. The submission may take the form of a case report or may illustrate particular features from more than one patient.
MANUSCRIPT PREPARATION Style Manuscripts should follow the style of the Vancouver agreement detailed in the International Committee of Medical Journal Editors’ revised ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication’, as presented at http://www.ICMJE.org/. Spelling. The journal uses US spelling and authors should therefore follow the latest edition of the Merriam-Webster’s Collegiate Dictionary. Units. All measurements must be given in SI units as outlined in the latest edition of Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Royal Society of Medicine Press, London). Abbreviations should be used sparingly and only where they ease the reader’s task by reducing repetition of long technical terms. Initially use the word in full, followed by the abbreviation in parentheses. Thereafter use the abbreviation. Trade names should not be used. Drugs should be referred to by their generic names, rather than brand names. Parts of the Manuscript The manuscript should be submitted in separate files: title page; main text file; figures. Title page The title page should contain (i) a short informative title that contains the major key words. The title should not contain abbreviations; (ii) the full names of the authors (if possible, not more than 5 authors per title); (iii) the author's institutional affiliations at which the work was carried out; (iv) the full postal and email address, plus telephone number, of the author to whom correspondence about the manuscript should be sent; (v) disclosure statement; and (vi) acknowledgements. The present address of any author, if different from that where the work was carried out, should be supplied in a footnote. Disclosure statement The source of financial grants and other funding should be acknowledged, including a frank declaration of the authors’
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industrial links and affiliations. In the case of clinical trials or any article describing use of a commercial device, therapeutic substance or food must state whether there are any potential conflicts of interest for each of the authors: failure to make such a statement may jeopardize the article being sent out for peer-review. Acknowledgments The contribution of colleagues or institutions should also be acknowledged. Thanks to anonymous reviewers are not allowed. Main text As papers are double-blind peer reviewed the main text file should not include any information that might identify the authors. The main text of the manuscript should be presented in the following order: (i) abstract and key words, (ii) text, (iii) references, (iv) tables (each table complete with title and footnotes), (vii) figure legends. Figures and supporting information should be submitted as separate files. Footnotes to the text are not allowed and any such material should be incorporated into the text as parenthetical matter. Abstract and keywords Original articles must have a structured abstract that states in 250 words or less the purpose, basic procedures, main findings and principal conclusions of the study. Divide the abstract with the headings: Background and Aim, Methods, Results, Conclusions. The abstracts of reviews need not be structured. The abstract should not contain abbreviations or references. Three to five keywords should be supplied below the abstract and should be taken from those recommended by the US National Library of Medicine’s Medical Subject Headings (MeSH) browser—(http://www.nlm.nih.gov/mesh/meshhome.html). Text Authors should use subheadings to divide the sections of their manuscript: Introduction, Methods, Results, Discussion, Acknowledgments and References. References The Vancouver system of referencing should be used. In the text, references should be cited using superscript Arabic numerals in the order in which they appear. If cited only in tables or figure legends, number them according to the first identification of the table or figure in the text. In the reference list, the references should be numbered and listed in order of appearance in the text. Cite the names of all authors when there are six or less; when seven or more list the first three followed by et al. Names of journals should be abbreviated in the style used in MEDLINE. Reference to unpublished data and personal communications should appear in the text only. References should be listed in the following form: Number references in the order cited as Arabic numerals in parentheses on the line. Only literature that is published or in press (with the name of the publication known) may be numbered and listed; abstracts and letters to the editor may be cited, but they must be less than 3 years old and identified as such. Refer to only in the text, in parentheses, other material (manuscripts submitted, unpublished data, personal communications, and the like) as in the following
example: (Chercheur X, unpublished data). If the owner of the unpublished data or personal communication is not an author of the manuscript under review, a signed statement is required verifying the accuracy of the attributed information and agreement to its publication. Use Index Medicus as the style guide for references and other journal abbreviations. List all authors up to six, using six and "et al." when the number is greater than six. Tables Tables should be self-contained and complement, but not duplicate, information contained in the text. Number tables consecutively in the text in Arabic numerals. Type tables on a separate page with the legend above. Legends should be concise but comprehensive – the table, legend and footnotes must be understandable without reference to the text. Vertical lines should not be used to separate columns. Column headings should be brief, with units of measurement in parentheses; all abbreviations must be defined in footnotes. Footnote symbols: †, ‡, §, ¶ should be used (in that order) and *, **, *** should be reserved for P-values. Statistical measures such as SD or SEM should be identified in the headings. Figure legends Type figure legends on a separate page. Legends should be concise but comprehensive – the figure and its legend must be understandable without reference to the text. Include definitions of any symbols used and define/explain all abbreviations and units of measurement Indicate the stains used in histopathology. Identify statistical measures of variation, such as standard deviation and standard error of the mean. Figures All illustrations (line drawings and photographs) are classified as figures. Figures should be numbered using Arabic numerals, and cited in consecutive order in the text. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. Preparation of Electronic Figures for Publication: Although low quality images are adequate for review purposes, publication requires high quality images to prevent the final product being blurred or fuzzy.
SUBMISSION REQUIREMENTS Manuscripts should be submitted online at [email protected] A cover letter containing an authorship statement should be included. The cover letter should include a statement covering each of the following areas: 1. Confirmation that all authors have contributed to and agreed on the content of the manuscript, and the respective roles of each author. 2. Confirmation that the manuscript has not been published previously, in any language, in whole or in part, and is not currently under consideration elsewhere. 3. A statement outlining how ethical clearance has been obtained for the research, particularly in relation to studies involving human subjects, and animal experimentation. The institutional ethics committees approving this research
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must comply with acceptable international standards (such as the Declaration of Helsinki) and this must be stated. 4. For research involving pharmacological agents, devices or medical technology, a clear Conflict of Interest statement in relation to any funding from or pecuniary interests in companies that could be perceived as a potential conflict of interest in the outcome of the research. 5. For clinical trials, that these have been registered in a publically accessible database (see more under 'ETHICAL CONSIDERATIONS (Further Information)' later in these guidelines). If the above items are not included in the cover letter, manuscripts cannot be sent for review. Please also note that the cover letter does not require a detailed or lengthy description of the content or structure of the manuscript itself. Two Word-files need to be included upon submission: A title page file and a main text file that includes all parts of the text in the sequence indicated in the section 'Parts of the manuscript', including tables and figure legends but excluding figures which should be supplied separately. The main text file should be prepared using Microsoft Word, doubled-spaced. The top, bottom and side margins should be 30 mm. All pages should be numbered consecutively in the top right-hand corner, beginning with the first page of the main text file. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. For submission, low-resolution figures saved as .jpg or .bmp files should be uploaded, for ease of transmission during the review process. Upon acceptance of the article, high-resolution figures (at least 300 d.p.i.) saved as .eps or .tif files will be required.
PUBLICATION PROCESS AFTER ACCEPTANCE Accepted papers will be passed to production team for
publication. The author identified as the formal corresponding author for the paper will receive an email, being asked to complete an electronic license agreement on behalf of all authors on the paper. Accepted Articles The accepted ‘in press’ manuscripts are published online very soon after acceptance, prior to copy-editing or typesetting. Accepted Articles are published online a few days after final acceptance, appear in PDF format only, are given a Digital Object Identifier (DOI), which allows them to be cited and tracked. After print publication, the DOI remains valid and can continue to be used to cite and access the article. Given that copyright licensing is a condition of publication, a completed copyright form is required before a manuscript can be processed as an Accepted Article. Proofs Once the paper has been typeset, the corresponding author will receive an e-mail alert containing instructions on how to provide proof corrections to the article. It is therefore essential that a working e-mail address is provided for the corresponding author. Proofs should be corrected carefully; the responsibility for detecting errors lies with the author. The proof should be checked, and approval to publish the article should be emailed to the Publisher by the date indicated; otherwise, it may be signed off on by the Editor or held over to the next issue. Offprint A PDF reprint of the article will be supplied free of charge to the corresponding author. Additional printed offprint may be ordered for a fee.
COPYRIGHT, LICENSING AND ONLINE OPEN Details are on the Copyright Agreement Form that must be completed and signed when the Article is accepted.
Romanian Journal of Military Medicine
Vol. CXVII, New Series, No 1-2/2014
ISSN 1222-5126