healthmed vol03-no1

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EDITORIAL BOARD

Editor-in-chief Mensura Kudumovic Editorial assistant Jasmin Musanovic Secretaries Dzenana Jusupovic Azra Kudumovic Technical editor Eldin Huremovic Lectors Mirnes Avdic

Adisa Spahic Members Farah Mustafa (Islamabad) Maizirwan Mel (Kuala Lumpur) Bakir Mehic (Sarajevo) Farid Ljuca (Tuzla) Emina Nakac-Icindic (Sarajevo) Ago Omerbasic (Sarajevo) Slavica Ibrulj (Sarajevo) Fatima Jusupovic (Sarajevo) Aida Hasanovic (Sarajevo) Dijana Avdic (Sarajevo) Selma Alicelebic (Sarajevo)

Address of the Sarajevo, Bolnicka BB Editorial Board phone/fax 00387 33 640 407

[email protected] http://www.healthmed_bih.org Published by DRUNPP, Sarajevo Volume 3 Number 1, 2009 ISSN 1840-2291

HealthMEDVolume 3 / Number 1 / 2009

Journal of Society for development of teaching and business processes in new net environment in B&H

Sadržaj / Table of Contents

Profile of Venous Thromboembolism at the Pati-ents with Non-Small Cell Lung CarcinomaProfil venskog tromboembolizma kod pacijenata sa nemikrocelularnim karcinomom pluća ................. 3-7Bakir Mehić, Hasan Žutić, Amina Mehić

* * *In a way to treat addiction; is therapeutic outco-mes effective?Načini tretmana ovisnosti; koliko jeterapija efikasna? .................................................... 8-16Wasif S., Azhar S., Tahir MK., Amir HK., Hadi A., Forouzan Bayat Nejad

* * *Use of mathematical modeling in predicting the impact of a disease: An example of measlesdynamic modelMatematsko modeliranje u predvidjanju kretanjabolesti: dinamicki model morbila ....................... 17-23Semra Čavaljuga, Mladen Čavaljuga, Mira Čavaljuga

* * *Health Promotion in Silicon Valley: A Study of 11 CorporationsPromocija zdravlja u Silikonskoj dolini: Studijaprovedena u 11 korporacija ............................... 24-27Yann A. Meunier

* * *The most frequent reasons for visits to patients in Emergency Medical Care Center SarajevoNajčešći razlozi za kućne posjete u ZHMP Sarajevo .................................................28-32Enes Slatina

* * *The most frequent congenital cardiovascular anomalies Najčešće kongenitalne anomalije kardiovaskularnog sistema ............................................................. 33-37Selma Aličelebić

HealthMEDSadržaj / Table of Contents

Volume 3 / Number 1 / 2009


* * *Flock level risk factors for ovine brucellosis in se-veral cantons of Bosnia and HerzegovinaRiziko faktori na nivou stada za pojavuovčije bruceloze u nekoliko KantonaBosne i Hercegovine ......................................... 38-44Sabina Seric Haracic, Mo Salman, Nihad Fejzic,Brian J. McCluskey, Thomas J. Keefe

* * *Hypertension as leading cardiovascular illness among minnersHipertenzija kao vodeća kardiovaskularna bolestrudara ............................................................... 45-50Muvedeta Lemeš, Belma Pojskić

Dependence of lower extremies amputations tocaracteristics of Diabetes Mellitus Ovisnost amputacija donjih ekstremiteta u odnosuna osobine dijabetes melitusa .......................... 51-54Dijana Avdić, Džemal Pecar, Mensura Kudumović,Mirela Avdić

* * *De Quervain’s tenosynovitis occurence in patients with u Repetitive Stress Injurys treated at the basic rehabilitation ‘’PRAXIS’’ centerEfikasnost tretmana teniskog lakta (Epicondylitis hu-meri radialis)u ambulanti CBR -“PRAXIS“ .... 55-60Džemal Pecar, Dijana Avdić

* * *Influence of early physiotherapy to recovery after Paresis N. FacialisUticaj rane fizikalne terapije na oporavak nakon pareze n. Facialisa ................................................ 61-65Edina Tanović

* * *Intrathoracic metastases of a breast cancer treated in Clinic for pulmonary diseases and tb „Podhrastovi“- Sarajevo in the four-year period from 2004.–2007.Intratorakalne metastaze karcinoma dojke tretirane na klinici za plućne bolesti i tuberkulozu „Podhrastovi“ u četvorogodisnjem periodu od 2004. do 2007. godine ........................................................................... 66-70Vesna Čukić

* * *Treatment of elderly patients with rectal prolapse with modified anal cerclage methodTretmana starijih pacijenata sa prolabiranim rektu-mom metodom modificirane analne serklaže .... 71-79Nedžad Šehović, Amela Sofic, Adnan Zećo

* * *Alpha-lipoic acid and quercetin protectagainst methotrexate induced-hepatotoxicityin rats ............................................................... 80-89Hebatallah A. Darwish, Amina Mahdy

PREVIEW PAPERSNew classification of epidermolysis bullosagroup of blistering disorders ........................ 90-93Naima Mutevelic Arslanagic, Rusmir Arslanagic,Selma Arslanagic

* * *Instructions for the autors ................................. 94-95

HealthMED - Volume 3 / Number 1 / 2009

Journal of Society for development of teaching and business processes in new net environment in B&H 3

Profile of Venous Thromboembolism at the Patients with Non-Small Cell Lung CarcinomaProfiL VeNSkog TromboemboLizma kod PaCijeNaTa Sa NemikroCeLuLarNim karCiNomom PLućaBakir Mehic1, Hasan Zutic1, Amina Mehic2

1 Clinical Centre University of Sarajevo, Clinic of Lung Diseases and TB, Bosnia and Herzegovina2 University of Sarajevo, Faculty of Medicine, Bosnia and Herzegovina

Summary

Although lung cancer incidence has increased during the last decades and non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung tumors, few reports exist on the incidence of (venous thromboembolism) VTE in NSCLC. The purpose of this paper is to try to make definition of predictive parameters for onset of VTE at the patients with NSCLC.

Clinical records of all NSCLC patients with VTE, treated at Clinic of Lung Diseases and TB, Clinical Centre University of Sarajevo, from 2006 - 2008 were retrospectively reviewed. In total the-re were 1563 patients with NSCLC.

Results of the research: Among 1563 hospi-talized patients with NSCLC during three years period, 92 (5.88%) were diagnosed with VTE and 0.58% with pulmonary embolism (PE). Mean age of our patients with VTE was 62.8 ± 8.6 ye-ars (range 36 – 86), and male sex was 3.6 time more frequent than female. After calculating the correlation coefficient, it is evident that there is strong correlation between performace status (PS) and the time of onset of VTE, and low correlati-on between the location and the time of the onset VTE, as well as low correlation between PS and the location of the VTE.

Conclusion: As predictive parameters for onset of VTE at the patients with NSCLC we could in-

clude adenocarcinoma as the most frequent histo-logy type of NSCLC at the cases of VTE (65.2%). Advanced cancer stage (84.8%) could be the si-gnificant predictor of appearance of VTE. The bi-ggest percent of patients with VTE (44.56%) had this vascular event before the start of chemothera-py and during the first line treatment with chemot-herapy. The most frequent location of VTE was on the veins of legs. Diseases of the heart were the most frequent comorbidity, in 39.13% of cases.

Key words: venous thromboembolism, non-small cell lung cancer, predictive parameters, re-trospectively reviewed.

Sažetak

Mada je incidencija raka pluća u toku posljed-nje decenije u porastu, a na nemikrocelularni rak pluća (NSCLC) otpada odprilike 80% svih tumo-ra pluća, posatoji samo nekoliko radova kada je u pitanju incidencija venoznog tromboembolizna (VTE) u slučajevima NSCLC. Svrha ovog rada je da pokuša da definiše prediktivne parametre za na-stanak VTE kod pacijenata sa NSCLC.

Rad je retrospektivni pregled kliničkih podata-ka svih pacijenata sa NSCLC i VTE tretiranih na Klinici za plućne bolesti i TB, Kliničkog Centra Univerziteta u Sarajevu od 2006 – 2008 godine. Ukupno je bilo 1563 pacijenta sa NSCLC.

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Rezultati istraživanja: u trogodišnjem periodu, kod 92 (5.88%) pacijenata sa NSCLC dijagnostici-ran je VTE, a 0.58% njih je imalo emboliju pluća (PE). Prosječna dob pacijenata sa VTE bila je 62.8 ± 8.6 godina (raspon 36 – 86), muškarci su 3.6 puta bili zastupljeniji u odnosu na žene. Nakon izraču-navanja koeficijenta korelacije, našli smo da posto-ji jaka korelacija samo između performan statusa (PS) i vremena nastanka VTE, te slaba korelacija između vremena nastanka VTE i njene lokacije, kao i slaba korelacija između PS i lokacije VTE.

Zaključak: kao prediktivne parametre za na-stanak VTE kod pacijenata sa NSCLC mogli bi smo smatrati adenokarcinom kao najčešći histo-loški tip NSCLC jer je u 65.2% slučajeva VTE bio prisuutan. Odmakli statdij NSCLC (84.8%) mo-gao bi biti značajan prediktor pojave VTE. Naj-veći procenat pacijenata sa VTE (44.56%) imao je razvoj ove bolesti prije početka kemoterapije, te za vrijeme prve linije tretmana kemoterapijom. Najčešća lokacija VTE bila je na venama nogu. Najčešći nalaz komorbiditetnih bolesti otpadao je na bolesti srca, 39.13% slučajeva.

Ključne riječi: venski tromboembolizam, ne-mikrocelularni rak pluća, prediktivni parametri, retrospektivni pregled

Introduction

Thromboembolism is a well recognized com-plication of malignant disease with a spectrum of clinical manifestations varying from venous thromboembolism (VTE) and Trousseau’s syn-drome to disseminated intravascular coagulation.[1] The link between activation of the blood coagu-lation system and malignancy dates back to 1865.[2] Thereafter venous thrombosis has been reported to be a common complication in patients with ma-lignancy,[3,4] but although lung cancer is the second most common cancer in western countries and the leading cause of cancer death in men and women[5] strikingly few papers on the phenomenon of VTE in lung cancer patients are found and data on mor-tality due to VTE are limited.

Utilizing a Medicare database, Levitan et al. [6] found that the incidence of VTE is high among cancer patients, and lung cancer belonged to the group of malignancies with the highest inciden-

ce rates. More recently, the overall risk of venous thrombosis was found to be increased seven-fold in patients with a malignancy vs. persons without malignancy.[7] Although lung cancer incidence has increased during the last decades and non-small cell lung cancer (NSCLC) accounts for approxi-mately 80% of all lung tumors, few reports exist on the incidence of VTE in NSCLC.

The purpose of this paper is to try to make de-finition of predictive parameters for onset of VTE at the patients with NSCLC.

The goals of this paper are to give answers to the next questions: what pathological type of NSCLC and what stage of NSCLC is most frequ-ently followed by VTE, what performance status (PS) is most frequently affected by VTE? What time during of treatment the onset of VTE is most frequent? What’s the common venous location and what is the role of comorbidity and level of platelets during the onset VTE?

Patients and Methods

Clinical records of all NSCLC patients with VTE, treated at Clinic of Lung Diseases and TB, Clinical Centre University of Sarajevo, from 2006 - 2008 were retrospectively reviewed. In total there were 1563 patients with NSCLC. To be eligible for this study, patients were to have histologicaly con-firmed diagnosis of NSCLC with evidence of way of treating methods till the onset of VTE. Histolo-gical types of tumors were classified according to the 1999 World Health Organization classification.

The diagnosis of VTE has been made set ba-sed on clinical signs, spiral computed tomography scan and ventilation-perfusion gamma scans for pulmonary embolism (PE), or Doppler ultrasono-graphy for confirmation of thromboses in periphe-ral veins.

Statistical analysis was performed using the SPSS software system (SPSS for Windows versi-on 11.0, Chicago, IL).

After analysis of distribution of frequency for nonparametric data and mean values for parame-tric data, we performed a correlation test to analy-ze rate of linkage between the observed variables, and for showing the curve of regression we used a model of simple regression.



Results

Our retrospective review identified 92 NSCLC patients with confirmed VTE (Table 1). The most frequent histological type was adenocarcinoma (65.2%), and 74% of patients had a good perfor-mance status (PS) at the moment of onset of VTE.Table 1. Patient’s characteristics

Patients, no. (%) 92 (100)Sex, no (%) Male 72 (78.2) Female 20 (21.8)Age, yr. Mean ± SD 62.8 ± 8.6

Range 36 – 86

Pathology, no. (%) Adenocarcinoma 60 (65.2) Squamous 25 (27.2) Large cell 7 (7.6)Clinical stage, no. (%) I 1 (1.1) II 4 (4.3) IIIA 9 (9.8) IIIB 26 (28.3) IV 52 (56.5)Performance status, no. (%) 0 27 (29.35) 1 25 (25.17) 2 16 (17.39) 3 20 (21.74) 4 4 (4.35)

The majority of patients (78.2%) were males, and 56.5% of patients had stage IV disease. Cha-racteristics of VTE (the time and location of onset, number of platelets) and chronic medical comor-bidities are shown in table 2.

There were 50 cases of VTE (54.34%) with the onset before the second line of treatment of NSCLC. More than 20% of VTE happened befo-re the beginning of causal treatment of NSCLC. 40.22% VTE were located in veins of legs too. The most frequent comorbidity in our population of patients with NSCLC and VTE was the heart diseases (36 patients vs. 39.13%).

Table 2. Characteristics of VTETime of the onset, no. (%)

Before treatment 19 (20.65)During the first line of treatment 22 (23.91)During the time free from disease 9 (9.75)During the second line of treatment 5 (5.43)During the third line of treatment 8 (8.70)During the palliation 8 (8.70)During the best supportive care 21 (22.83)

Location of onset, no. (%)

Brain veins 7 (7.61)

Carotid veins 8 (8.70)

Pulmonary arteries 9 (9.78)

Veins of upper arm 9 (9.78)

Veins of forearm 7 (7.61)

Intestinal veins 3 (3.26)

Renal veins 3 (3.26)

Iliac veins 9 (9.78)

Iliac-femoral veins 8 (8.70)

Femoral veins 10 (10.87)

Femoral and shin veins 7 (7.61)

Shin veins 12 (13.04)

Medical comorbidities, no. (%)

No comorbidities 12 (13.04)

COPD 11 (11.96)

Liver metastasis 11 (11.96)

Heart failure 10 (10.87)

Arterial hypertension 13 (14.13)

Arrhythmias 13 (14.13)

Diabetes mellitus 14 (15.22)

After stroke 1 (1.09)

Peripheral vascular diseases 7 (7.61)

Platelets, no.

Mean ± SD 466.73±140.47

Range 210 – 812

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After calculating the correlation coefficient (Ta-ble 3), it is evident that there is strong correlation between PS and the time of onset of VTE, and low correlation between the location and the time of the onset VTE, as well as low correlation between PS and the location of the onset of VTE. This is better shown by the model of simple regression curve (Fig 1). PS is followed by the time of the onset of VTE.

Fig 1. Model of simple regression curve for vari-ables PS and the time of the onset VTE

The simple regression curves for the location of the onset of VTE to time of the onset of VTE and the PS to the location of the onset of VTE are shown on Fig 2 and Fig. 3.

Fig 2. Model of simple regression curve for va-riables: location of the onset of VTE and time of the onset of VTE

Fig 3. Model of simple regression curve for vari-ables: PS and location VTE of onset VTE

Discussion

VTE contributes to morbidity and mortality in cancer patients and is a frequent complication of anticancer therapy. In the current study, the frequ-ency, risk factors, and trends associated with VTE were examined among hospitalized cancer patients.

Among 1563 hospitalized patients with NSCLC during three years period, 92 (5.88%) were dia-gnosed with VTE and 0.58% with PE. In study Khorana AA et al [8] on 1,015,598 cancer patients 4.1% were diagnosed with VTE. Mean age of our patients with VTE was 62.8 ± 8.6 years (range 36 – 86), and male sex was 3.6 time more frequent than female. In the same study Khorana AA et al, age ≥65 years, female sex and black ethnicity were risk factors associated with VTE. Adenocarcinoma was the most frequent histology type of NSCLC fo-llowed with VTE (65.2%). This is the same result like Bloom at al [12]: “Patients with adenocarcinoma of the lung had a three-fold higher risk (incidence: 66.7 per 1000 years) than patients with squamous cell carcinoma of the lung incidence: 21.2 per 1000 years)”. Advanced cancer stage patients (84.8%) could be the significant predictor of developing VTE. Even that, in our cancer patients with VTE,

Table 3. Correlation coefficient for variables of VTE in population patients with NSCLC

Variables VTE Correlation coefficient One-sided significance

Time of the onset – PS 0.873890309 3.06793E-30

Location of the onset – Time of the onset -0.27692448 0.0003766367

PS – Location of the onset 0.263892037 0.005514431



vascular events were the most frequent in PS 0 and 1 (54.5%). There were very similar opinions in stu-dies of Chew HK et al [9] and Tesselaar ME et al [10].

In studies Tesselaar ME at al [10], Numico G et al [11], and Bloom et al [12] authors finding chemot-herapy as a risk factor for VTE, and Khorana AA et al [8] said that patients receiving chemotherapy were disproportionately at risk. In our study the bi-ggest percent of patients with VTE (44.56%) had this vascular event before the start of chemotherapy and during the first line of chemotherapeutical tre-atment. Also, we found that most frequent location of VTE were on the leg veins. In this population of patients we found heart comorbidity as the most frequent, in 39.13% of cases, besides that the 12 cases (13.4%) stay without registered comorbidity. Also, we found a higher average number of plate-lets 466.73±140.47 range 210 – 812, but there was no correlation between the higher average number of platelets and other observing variables, besides results of Korana et al.[13] who found an elevated prechemotherapy platelet count was associated with a three-fold increased rate of VTE.

Conclusions

As predictive parameters for onset of VTE at the patients with NSCLC we could include adeno-carcinoma as the most frequent histology type of NSCLC followed with VTE (65.2%). Advanced cancer stage patients (84.8%) could be the signi-ficant predictor of developing VTE. The biggest percent of patients with VTE (44.56%) had this vascular event before the start of chemotherapy and during the first line treatment with chemothe-rapy. The most frequent location of VTE was on the leg veins. Diseases of the heart were the most frequent comorbidity, in 39.13% of cases. There was no correlation between registered a higher average number of platelets (466.73±140.47) and the other observing variables.

Literature

1. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107(23 Suppl 1):I17-I21.

2. Trousseau A. Phlegmasia alba dolens. In: Clinique medicale de l’Hotel-dieu de Paris. Paris: JB Balliere et Fils; 1865. pp. 654-715.

3. Mao C, Domenico DR, Kim K, et al. Observations on the developmental patterns and the consequences of pancreatic exocrine adenocarcinoma. Findings of 154 autopsies. Arch Surg 1995; 130:125-134.

4. Sallah S, Wan JY, Nguyen NP. Venous thrombosis in pa-tients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87:575-579.

5. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55:10-30.

6. Levitan N, Dowlati A, Remick SC, et al. Rates of ini-tial and recurrent thromboembolic disease among patients with malignancy versus those without ma-lignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78:285-291.

7. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Ma-lignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293:715-722.

8. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110(10):2339-46.

9. Chew HK, Davies AM, Wun T, Harvey D, Zhou H, White RH. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost. 2008; 6(4):601-8.

10. Tesselaar ME, Osanto S. Risk of venous thromboem-bolism in lung cancer. Curr Opin Pulm Med. 2007; 13(5):362-7.

11. Numico G, Garrone O, Dongiovanni V, Silvestris N, Colantonio I, Di Costanzo G, Granetto C, Occelli M, Fea E, Heouaine A, Gasco M, Merlano M. Prospec-tive evaluation of major vascular events in patients with non-small cell lung carcinoma treated with cis-platin and gemcitabine. Cancer 2005; 103(5):994-9.

12. Blom JW, Osanto S, Rosendaal FR. The risk of a ve-nous thrombotic event in lung cancer patients: higher risk for adenocarcinoma than squamous cell carcino-ma. J Thromb Haemost 2004; 2:1760-1765.

13. Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104:2822-2829.

Corresponding author: Bakir Mehic Clinical Centre University of Sarajevo, Clinic of Lung Diseases and TB, Bardakčije 90, 71000 Sarajevo, Bosnia and Herzegovina e-mail: [email protected]

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Summary

Background: Despite the use of methadone for the treatment and management of Addiction, still there are controversial theories in dose setting. Aim of the study describes the clinical outcomes of the Methadone maintenance treatment program in the Penang state of Malaysia. Reason to select Penang is the highest prevalence of drug addiction in this region of Malaysia known as drug hub. A way to ensure the sustainability in the harm reduction plan.

Methodology: A descriptive data collection form was used to collect the prospective and re-trospective information from the medical profile of out-patients of methadone clinics in Pinang. The data was collected from all of three methado-ne clinics of Pinang state governed by Ministry of Health, Malaysia. Universal sampling technique was employed for data collection. Following are the some concern criteria employed in the study.

- Patients active on methadone therapy- Registered during Jan 2007 – May 2008.- Evaluation of National Protocol (methadone

maintenance guideline)The reason for above mention time frame was

selected because Ministry of Health Malaysia of-ficially started methadone treatment in the middle – end of 2006.

Results and discussion: The mean age of ma-les admitted in methadone clinic was 41.0 years while it is slightly lowers in female 39.5 years.

Majority 97.4% respondents on three methadone clinics were male, only 2.6% females. Ethnic dis-tribution showed no significant difference between Chinese and Malays (39.8% ; 44.4%). While upon religion 45.1% were Muslims and 39.5% were Buddhists. Majority of them were single (57.9%), remaining married (32.3%) and few were divorced (9.8%). Baseline information on withdrawal and intoxication showed 57.3% respondents of metha-done experiencing withdrawal symptoms, 15.1% experiencing intoxication signs only 27.6% with no evidence. The most frequent withdrawal symp-toms found were yawning, lacrimation, mydriasis, perspiration and anxiety. The findings showed that only 30.6% active respondents were on therape-utic comfort dose (TCD) while remaining 69.4% were on ineffective therapeutic setting and pertai-ning a risk of relapse. Therapy response shows that 71.2% subjects were on maintenance dose, 21.9% on stabilization stage while 7.0% were subsequent to withdrawal stage. Tabulated data showed the methadone dosing and description of management found in methadone clinic of Pinang. The resul-ted revealed that 72.5% respondents were experi-encing the dose plan inconsistent to the National guidelines of Malaysia.

Recommendations: The above study revealed the need to review the National guidelines on evi-dence based management. Also there is a strong need for the training of practitioners for achieving and designing the therapeutic comfort dose plan.

in a way to treat addiction; is therapeutic outcomes effective?NačiNi TreTmaNa oViSNoSTi; koLiko je TeraPija efikaSNa?Wasif S.1, Azhar S.2, Tahir MK.1, Amir HK.4, Hadi A.3, Forouzan Bayat Nejad5

1 Lecturer in Island college of technology (ICT), Balik Pulau, Pulau Pinang, Malaysia2 Dean of School of Pharmaceutical Sciences, USM, Pulau Pinang, Malaysia.3 Lecturer in University technology Malaysia (UITM), Shahalam, Selangor, Malaysia4 PhD fellow in clinical Pharmacy, University Sains Malaysia (USM), Malaysia. 5 MD student, Tehran University of Medical Scienses (TUMS), Iran



The results showed that to crop the drug abuse problem in the present situation more strategic in-formations will be needed as to better control on the drug addiction and achieve 20-20 Vision of Malaysia to make the country as a drug-free zone and a step ahead to harm reduction.

Key words: Methadone Maintenance Trea-tment (MMT), Drug addiction, Addiction, Nar-cotics addiction, drug dependency, addiction and dependency.

Introduction

In context to make Malaysia a drug – free soci-ety, 2015 vision was created (Sattler, 2004), so to ensure the time being harm reduction in term of treatment and educational settings a lot of resear-ches were done on such topic (Mazlan, 2007; Mu-haamda Mazlan, 2006; Reid, 2007; Viknasingam, B et al., 2007 and Viknasingam, B ., Navaratnam, V, 2006 etc..). Such studies were mainly empha-sized on the risk assessment of sexually transmi-tted infections as well as blood-borne infection among drug addicts. In the time span of 2001 to 2006 various studies were done by Naveratnaam to identified the respective medical – health rela-ted problems in the treatment of addiction. Metha-done maintenance program was officially started in mid - end of 2006, so far the outcomes were not properly identified on such large scale application

The Aims of this study was to evaluate the setting settings and methadone dose titration re-garding to the medical outcomes of the methadone maintenance program (MMT). As a common con-cept that Quality of Health among the methadone receiving respondents was a important factor per-taining to relapse or drop-out.

Methodology

All of three registered methadone clinics of Penang state, Malaysia were selected to identify the methadone dosing & therapy management for drug addiction. A year retrospective (Jan 2007 to Dec 2007) with six month prospective (Jan 2008 to may 2008) study was designed to collect the necessary information from the methadone cli-

nics. All the respondents registered to methado-ne during this mentioned period was included in the study while exception was made on those being defaulted or drop-out from the methadone program. Approvals were made from Ministry of health Malaysia, Local authorities of the concern hospital and ethical committee. Universal sam-pling technique was used in this study.

A self designed data collection form was used to collect the information from the medical profi-les of MMT patients. A descriptive statistical re-port was generated after the complete analysis of data collected from the methadone centers. All the analysis was made through the statistical software (SPSS) version 13.0.

Results

A total of 283 respondents from three different methadone maintenance clinics of Penang state participated in the study. Total of 215 (76.0%) were accepted for the study because of active on MMT program, while remaining of 68 (24.0%) were exc-luded after being defaulted from MMT program.

Complete descriptive data is available in table 1 & table 2. Forty-seven about (70.1%) relapse cases were detected in Pinang hospital. There was only 1 (1.9%) patient who had successfully followed to MMT program and was free from drugs. Figure 1 contains the %-age relapse from last 1½ year (Jan 2007- May 2008) among three methadone clinics of Pinang state. Table 3 contains the information regarding the therapy module of MMT program, 116 (54.0%) taking methadone from 7 -12 mont-hs only 26 (12.1%) >12 months of treatment. The findings showed high rate of relapse and it was significant with Chinese as mentioned in table 4.

Baseline data on withdrawal sign & symptoms indicated that 57.3% of patients who undergone the treatment experienced some adverse sign & symptoms during the treatment with methadone (figure 2). Majority of respondents 65 (30.2%) had evidence of withdrawal and intoxication sig & symptoms on 3rd day during the first week of treatment plan (table 4). while table 5 contains the information regarding the withdrawal sign & symptoms commonly observed during the MMT program.

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Table 1. Methadone maintenance treatment (MMT) program

Methadone clinics of Penang state Gender

Total MaleN (%)

Female N (%)

a. Centre Pulau Pinang General Hospital (P.P)a 145(96.0) 6 (3.9) 151

Bukit Mertajam Hospital (BM)b 83 (98.6) 1 (1.4) 84

Butterworth Health Clinic (B.W)b 48 (100.0) - 48

Total 276 (97.5) 7 (2.5) 283

b. MMT treatment activePulau Pinang General Hospital 99 (95.2) 6 (4.8) 105

Bukit Mertajam Hospital 68 (97.1) 1 (2.9) 69

Butterworth Health Clinic 41 (100.0) - 41

Total 208 (96.7) 7 (3.3) 215a patient consensus from march 2007 to May 2008.b patient consensus from Jan 2007 to May 2008.

Table 2. Frequency of related outcomes of the MMT program

Characteristics N (%)

P.P BM B.WDefaulted casesa. Prison 9 (15.7) 9 (13.4) 3 (4.5) b. Untraceable 39 (76.5) - 2 (2.9)c. Rehabilitation centre - 2 (2.9) -

Successful treatment cases - 1(1.9) -

Deaths: a. Abnormal liver function

- - 1 (1.9)

b. Aspirated Pneumonia - 1(1.9) -

c. Overdose of methadone - - 1 (1.9)

Total N = 68 (24.2) 47 (70.1) 13 (19.4) 7 (10.4)

Table 3. Duration of treatment among the out-patients of MMT program

Duration of Treatment

MMT clinics N %Total

P.P B.M B.W

≤ 6 moths 24 (11.1) 28 (13.0) 21 (9.8) 73 (33.9)

7 – 12 months 71 (33.0) 33 (15.3) 12 (5.6) 116 (54.0)

> 12 moths 9 (11.2) 9 (4.2) 8 (3.7) 26 (12.1)

Total 104 (48.4) 70 (32.6) 41 (19.1) 215



Table 6 describes the complete information re-garding the dose setting and titration on each level of treatment (initial, maintenance, withdrawal). The comparison was made with the per mg dose of methadone on each stage to that of the Nati-onal Protocol Guidelines of Ministry of Health Malaysia. The results were identified that 72.5% of out-patients taking DOT therapy in addiction treatment methadone centers were in the inconsi-stent dosing practice with the National Guideline of Ministry of Health Malaysia.

Figure 1. Percentage relapses during (Jan 2007 – may 2008) MMT program

Figure 2. Baseline data for the withdrawal and intoxication sign & symptoms

Table 4. Evidence of withdrawal and intoxication sign and symptoms during first week of MMT tre-atment among out-patients

Characteristics N (%)

Evidence of withdrawal signsand symptoms

2nd day 54 (25.1)

3rd day 65 (30.2)

4th day 7 (3.3)

No evidence 89 (41.4)

Evidence of intoxication signand symptoms2nd day 1 (0.5)3rd day 1 (0.5)4th day 3 (1.4)5th day 6 (2.8)6th day 1 (0.5)7th day 11 (5.1)No evidence 192 (89.3)

Table 5. Listed withdrawal sign & symptoms fo-und among out-patients

Sign & symptoms N (%)

Observed among (N = 126)

Yawning 112 (88.9)

Rhinorrhoea 54 (42.8)

Piloerection 47 (37.3)

Perspiration 82 (65.1)

Lacrimation 121 (96.0)

Mydriasis 107 (84.9)

Vomiting 27 (21.4)

Muscle twitches 41 (32.5)

Abdominal cramps 79 (62.7)

Anxiety 98 (77.8)

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Table 6. Dose schedule for MMT program in out-patients

Characteristic N (%) Dose level

Maintenance dose:Std dose(30–60 mg per day)

42 (27.5)

Practice dose : Consistent

40 mg 1 (4.2)

45 mg 3 (1.4)

50 mg 5 (2.3)

55 mg 13 (7.0)

60 mg 20 (9.3)

65 mg 17 (12.6) 111 (72.5)

70 mg 11 (5.1) Inconsistent

75 mg 4 (1.9)

80 mg 19 (18.1)

85 mg 22 (11.2)

90 mg 6 (7.4)

95 ≥ 32 (19.5)Withdrawal dose:↓ 10 mg / week 10 (66.7)↓ 5 mg / week 3 (20.0)

↓ 10 mg / month 2 (13.3) Consistent 13 (86.7)

Retention to 40 mg 14 (93.3)Retention on > 40 mg 1 (6.7)

Chart 1 represent the diagrammatic presentati-on of the basic issues of therapeutic comfort dose (TCD), while chart 2 showed that 149 (69.4%) have ineffective TCD plan and pertaining to risk of relapse on MMT program.

Chart 1. Clinical feature adherence to therapeu-tic dose setting in MMT program

Chart 2. Evaluation of MMT outcomes related to therapeutic comfort dose (TCD)

Table 4. Percentage of relapse among races in MMT Program

Race

Methadone clinicP.P B.M B.W

N (%) N (%) N (%)enroll active sig enroll active sig enroll active sig

Malay 52 (34.5)

40 (26.5) 37 (44.0) 35 (41.6) 29 (60.4) 26 (54.2)

Chinese 70 (46.3)

43 (28.5) 0.001 31 (36.9) 31 (36.9) 0.000 10 (20.8) 8 (16.7) 0.024

Indian 28 (18.5)

21 (13.9) 16 (19.1) 4 (4.8) 9 (18.8) 7 (14.6)

Other 1 (0.7) 0 (0.0) - - - -Total 47 (31.1) 14 (16.7) 7 (14.5)Sig: chi-square



Discussion

The treatment of opioid addiction was a contro-versial issue since late 70’s. A lot of clinical studi-es were carried out in this span of time to analyze the therapeutic effectiveness of the methadone tre-atment and majority of them have modest results (Einat Pele, 2005; Kreek M.J, 1992; Leavitt S.B et al., 2000; Ward, J., 1995; Sarz Maxwell, 1999; Jeff ward, 1999; Lubmir Okruhlica, 2002; Icro Maremmani, 2007; Yasukazu Ogai et al., 2007; Jason Luty, 2003).

The effectiveness of Methadone maintenance treatment in this study was observed by:

1. Checking the rate of relapse among the MMT patients

2. Medical complication found during the treatment

3. Life quality (medical complication before the treatment and medical complication found during the treatment). Chronic disease and subsequent supportive pharmacotherapy and therapeutic comfort dose setting correlation with urine analysis and psychotherapy session during the treatment.

Findings of this study showed high controver-sial practices in the implementation of MMT pro-gram that were found inconsistent to the National guidelines of methadone maintenance treatment protocol of Ministry of Health Malaysia (2006).

Relapse and Defaulted percentage

A total of 283 drug addicts were registered in the three registered methadone clinics of Penang state during Jan 2007 to May 2008. The mean S.D age was 41.0 (9.32), majority of them were males (97.5%) and they also formed the majority (53.4%) of admission were found in Hospital Pu-lau Pinang. The total of 54.6% relapsed cases were identified from all three registered methadone cli-nics among them 70.1% relapse cases were found in Hospital Pulau Pinang, 19.4% in Butterworth methadone clinic and 10.4% in Bukit Meratajam Hospital. Majority of relapses were identified in the first six month of MMT program, few relapse cases were found after the completion of 1 year

treatment. Majority of relapse cases were reported in Chinese least in Indian.

Currently only 12.1% patients were successfu-lly completed the 1 year of treatment, while majo-rity of them only followed the treatment program for a period of 7 – 12 months of treatment. Few studies identified that craving for drugs, emotio-nal pressure and boredom were the main reasons found among relapsed cases (Research report No. 31, 1997; Yasukazu Ogai et al., 2007). As Ame-rican National consensus Development panel (1998) reported 50% common drop-out from the MMT studies.

Yasukazu Ogai and his collegues worked in Japan for the development and validation of re-lapse prevention technique through risk scale assessment for drug abusers in Japan, while his basis emphasize were focused on craving, quality of life experience by drug addicts and time frame spent in the treatment program. Modest findings and outcomes were associated with his study but the limitation was applied for Opioid users as the validation was done on cocaine users alone. Such model may help the Ministry of Health Malaysia to control the relapse cases of drug addiction. As certain reliability was found in the study to esta-blish such a model as a preventive measure to re-duce relapse cases.

Baseline data evidence that 57.3% patients were experienced withdrawal sign & symptoms, while 15.1% suffered with intoxication symptoms and only 27.6% MMT patients showed no eviden-ce of any sign & symptoms during the treatment of methadone. Majority of withdrawal symptoms were yawning and anxiety. The reason behind these findings represent the low dose setting of methadone which would revealed the withdrawal symptoms and cravings that will also associated with the risk of relapse.

The current study showed that 89.8% of drug addicts were pre-suffered with different types of medical complications before starting the methado-ne treatment, while after the completion of 3 mont-hs therapy 95.9% of drug addicts among them still carrying the medical complication only 4.1% drug addicts improved, predominantly in Malays.

Majority of patients were experiencing General complications (like; fatigue, trouble sleep, loss of appetite, teeth problem and eye/vision problem),

14



musculo-skeletal problem (joint pain and stiffne-ss), neurological disorder (headache, numbness, dizziness, forgetting things), gastro-intestinal pro-blems (constipation, stomach pain, diarrhea) and cardio-respiratory disorders (persistent cough, wheezing, chest pain). These findings could be the possible cause of psycho-disturbance which may lead to depression. It could be the predictive factor for relapse; similar findings were reported by Icro Maremmani (2007) in his study in Italy.

Therapeutic comfort dose (TCD)

The therapeutic comfort dose (TCD) is ter-med as “the effective dose plan that will suppress the withdrawal sign & symptoms while will not show any sign of intoxication”. The objective wi-thdrawal sign & symptoms can be suppressed by increasing the potency dose of methadone while subjective intoxicated symptoms can be overco-me by decreasing the potency dose. So TCD is the middle dose setting between objective and subjec-tive sign & symptoms. The findings of the study reported only 30.6% of all the patients were on TCD setting while remaining 69.4% seemed to be on ineffective dose setting.

Urine analysis for the drug of abuse is one of the reasonable marker to determine the therapeu-tic effectiveness of the dose. Several studies sug-gested that with an increase in the average dose of methadone could possibly lower down the number of drop-out cases and also a lower proportion of urine tested positive for opioid (Maxwell S, Sc-hinderman, 1999; Strain E. C., Stitzer M. L., Lie-bson I. A., Bigelow G. E, 1998; Strain E.C et al., 1999; Ceplehorn J.RM., Bell J., 1991).

Findings of our study showed that 93.5% of total 215 patients induce positive urine analysis for opioid. Majority reports were positive from 8 to 16 month of therapy. Surprisingly 98.8% were on maintenance dose setting of 30 – 80 mg / day. Similar findings were explained in several studies (Einat Peles et al., 2005; Maxwell, Shin-derman, 1999; levit S. B., et al., 2000; Ward. J., 1995; Lubomir. Okruhlica. et al., 2002 and Jason Lutty., 2003). They reported the direct proporti-on of methadone dose and urine positive results. Their findings were preliminary based on Serum

methadone level (SML), majority of them repor-ted that to achieve an effective therapeutic dose it is necessary to adopt a methadone serum level of 600ng/ml or higher for the completely suppressi-on of opioid withdrawal symptoms. Overall all the above researchers suggested that effective thera-peutic treatment was achieved with 100mg dose of methadone and above.

Cepelhorn & Bell (1991) did a research on drug respondents in Italy, the results of this study con-cluded that patients who were on methadone dose less than 60 mg have five times more risk of dro-pping out as those receiving doses of 80 – 100mg. Similarly a double-blind trials done by Strain et al. (1999) revealed that 53% positive urine results were found after 30 weeks in patients receiving methadone dose 80 – 100 mg as compared to 62% of those on 40 – 50 mg of methadone dose setting.

In view the results of this study and the stan-dard MOH (Ministry Of Health, Malaysia) guide-lines of MMT and other dose optimizing studies conducted all over the World, following were the important issues found in the protocol;

No therapeutic monitoring of methadone as SML value. Maintenance dose range was between 30 – 80 mg.

Highly Urine positive results were found even after the 14 months of treatment.

Increase relapse rate was found during the first six months of treatment.

Increased evidences of withdrawal and intoxi-cated sign & symptoms.

Low percentage of improve quality of life in term of medical conditions in the treatment with methadone. In those who follow the therapy.

Conclusion & Recommendations

Overall management of drug addiction in three methadone clinics are quiet satisfactory, as consi-derable number of drop-outs are observed in past one and half year. While dose setting and few ot-her practices are found “inconsistent to protocol”, although inconsistent practices in the dose setting found satisfactory adherence of patients to MMT program over one year. There are still sizeable gaps in everyday practices of methadone maintenance treatment in Hospital Pulau Penang and Butterwor-



th clinic; like patient follow-up, and counseling par-ticularly emphasizing on addiction education.

The study found no improvement in the quality of life among drug addicts as far as medical com-plications are concerned. Almost every respondent receiving methadone has developed chronic infec-tion. Surprisingly no supportive therapy is added in combination to methadone. Study strongly un-derlines to highlight this issue because greater risk of relapse is found in such risky group. This can adversely impact on transmission of infection to the other parts of community.

There is a strong need to update national gui-delines for the management of Drug addiction and to reassure the national addiction control strategy & policy. The aims of this strategy should have to include- reducing the incidence of clinically ap-parent and ensure the treatment for addicts never been treated before, also reducing the social sti-gma associated with drug abuse as it is a elemen-tal factor for relapse. Few targets have to set in this policy as; providing clear information to the general public especially the village site, to ena-ble people to make informed decisions about di-agnosis, treatment and prevention of transmission of infection, providing a range of easily accessible screening and management options (including ge-neral practices), setting secondary poly setting for screening and management, and establish practi-ces for future research thereby improving the evi-dence base information for providing good practi-ces in management of addiction.

Educational programs for practitioners are strongly recommended as to increase the thera-peutic outcome of the MMT program by adop-ting evidence-based treatment in IVDUs. Future researches are required to evaluate practitioners’ belief, attitudes and practices. Approaches should be optimize HIV/AIDS counseling and promote behaviors that will prevent future drug practices.

In order to improve the quality of care and optimize the management of addiction, there is a need to increase the knowledge of nursing staff, development and evaluation of strategies to ensure that the majority of general practitio-ners have the skills, knowledge and confidence to treat drug addicts and counsel them to adopt a responsive behavior. Alternatively pharmacists’ expertise in counseling and assessing the effec-

tiveness of pharmacotherapy can be practiced in the methadone clinics to optimize the quality of management of addiction.

It is strongly suggested to initiate methadone maintenance program during the rehabilitation period of drug addicts, as they will get a social support as well as better control on drugs during the treatment (urine positive).

Literature

1. Sattler, G. (2004), Harm reduction among injecting drug users: Malaysia. Mission report. Manila, Phi-lippines: Regional Office for the western Pacific, World Health Organization.

2. Viknasingam, B and Navartnam, V, 2006. The use of Rapid Assessment methodology to compliment existing national assessment/surveillance system: A study among injecting Drug users in Kepala Batas, Penang, Malaysia, International journal to Drug policy, doi:10.1016/j.drugpro.2006.11.004

3. Vicknasingam, B et al., 2007, ‘Malaysia’s evolving response to heroin dependence, injecting drug use and HIV/AIDS – initial experience with buprenorp-hine maintenance treatment’. Abstract submitted to NIDA international conference, Quebec city, Cana-da, june 15- 18, 2007.

4. Mazlan, M et al., 2007, ‘Injecting buprenorphine in malaysia: demographic and drug use characteristi-cs of Buprenorphine injectors’: Abstract submitted to NIDA international conference, Quebec City, Canada, June 15-18, 2007.

5. Mahmud Mazlan et al., 2006, ‘New Challenges and opportunities in managing substance abusers in Malaysia’. Drug and Alcohol review, 25, 473-478.

6. Einat peles, Shaul Schreiber, Miriam Adelson., (2006). “ Factors predicting retension in treatment: 10-year experience of a methadone maintenance treatment (MMT) clinic in Israel”. Drug and Alco-hol dependence, 2006, volume 82, issue 3, pp: 211-217.

7. Kreek M.J., (1992), “Rationale for maintenance pharmacotherapy of opiate dependence”, In: O’Brein, C.P., Jaffe, J.H. eds. Addictive states. Re-search publications: Association for research in Nervous and mental disease. Ravan Press, New York: 210.

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8. Levitt S.B et al., (2000), “When Enough is not Enough: New perspectives on optima methadone maintenance dose”, Mt Sinai J Med. 67(5-6): 404-411.

9. Ward, J., (1995), “Factor influencing the effec-tiveness of methadone maintenance treatment: An evaluation of change and innovation in the metha-done program in New South Wales, Australia 1985-1995”, PhD thesis. National Drug and Alcohol Re-search Centre.

10. Jeff ward, Wayne Hall, Richard. P. Mattick., (1999). “Role of maintenance treatment in opioid dependence”, The Lancet, vol. 353. issue: 9148. pp. 221-226.

11. Lubomir Okruhlica et al., (2002). “Does thera-peutic threshold of methadone concentration in plasma exist?”, Heroin Addiction & Rehabilita-tion Clinical Problems, 4(1): 29-36.

12. Icro Maremmani, Pier Paolo Pani, Matteo Pacini, Giulio Perugi., 2007. “Substance use and qual-ity of Life over 12 months among buprenorphine maintenance-treatment and methadone mainte-nance-treatment heroin-addicted patients”., Jour-nal of Substance Abuse Treatment 33. 91-98.

13. Yasukazu Ogai et al., (2007), “Development and validation of the stimulant relapse risk scale for drug abusers in Japan”, Drug and Alcohol De-pendence, 88: 174-181.

14. Jason Luty., (2003), “What works in drug addic-tion?”. Advance in Psychiatric treatment, vol.9, 280-288.

15. Research Report No.31, (1997). “A Follow-up study on Drug addicts after treatment and Reha-bilitation”, Centre of Drug research, University Sains Malaysia (USM).

16. American National consensus Development pa-nel, 1998., Advisory council on the misuse of the drugs, Drug misuse and the environment. London: Home office.

17. Strain EC, et al.,1999. Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA; 281:1000–1005

18. Saraz Maxwell, Marz Shinderman., (1999). “Op-timizing Response to methadone maintenance treatment: Higher Dose Methadone”, Journal of Psychoactive Drugs: Vol-31(2)

19. Strain E.C., Stitzer M.L., Liebson I.A., Bigelow G.E., (1998), “Useful predictors of outcome in methadone-treated patients: Results from a con-trolled clinical trial with three doses of metha-done”, Journal of Maintenance in the addiction, 1(3): 15-28.

20. Ceplehorn J.R.M., Bell J. (1991), “Methadone dosage and retention of patients in maintenance treatment”, Med J Aust, 154(1): 195-199.

Corresponding author:

Forouzan Bayat Nejad H/p: + 98-9355491159 No. 45, 2nd Floor, Gisha 33th St., Tehran, Iran E-mail: [email protected], [email protected]



Summary

Protecting children from vaccine-preventable diseases, such as measles, is among primary go-als of public health professionals worldwide. Sin-ce vaccination turned out to be the most effective strategy against major childhood diseases, develo-ping a mathematical model that would predict an optimal vaccine coverage level needed to control the spread of these diseases becomes a challenge for various experts Worldwide as well designed mathematical model could be extremely helpful for the daily routine practice. Elaborating a mat-hematical models for monitoring of measles with its vaccination coverage and predicting the impact of this disease in a population is the basic objec-tive of this paper. The model was elaborated with the population of B&H as at the census of 1971 -- just before the obligatory vaccination was intro-duced -- used as a theoretical population. The epi-demiological classification of the population was performed for all of the age groups. In this paper we assume that all vaccinated individuals develop antibody following vaccination. Known varia-bles of susceptible, sick and immune population to create a mathematical model of the dynamics of measles showing spread within a population to design this model were used. A dynamic model expressed by a global model with its sub-model based on the dynamics of measles infection was created. The model, which fully incorporates ele-ments of measles dynamics relevant for the spread

of the disease is quantitative and dynamic. It faci-litates long-term projections of the spread of the disease and identifies the possibilities for an effici-ent protection. The model shows percentage of the immune persons at any given immunisation level and morbidity and lethality that can be expected at that level of immunisation.

Key words: mathematical models, measles, disease dynamics, vaccination, Bosnia and Herze-govina

Sažetak

Među najvažnijim ciljevima svih zaposlenih u sektoru javnog zdravstva je i prevencija djece od zaraznih bolesti kao što su morbili. Pošto se pokazalo da je vakcinacija najefikasnija strategi-ja u prevenciji dječijih zaraznih bolesti pravljenje matematskog modela koji predviđa optimalan procenat obuhvata vakcinacijom potreban da bi se kontrolisalo širenje ovih bolesti u nekoj po-pulaciji je, ne samo postao izazov za eksperte u ovoj oblasti širom svijeta, nego bi takav model bio i vrlo koristan u svakodnevnoj praksi. Osnovni cilj ovoga rada je dizajniranje matematskog mo-dela monitoringa morbila sa procentom obuhvata vakcinacijom u predviđanju kretanja ove bolesti u populaciji. Ovaj model je napravljen na popu-laciji Bosne i Hercegovine prema popisu stanov-ništva iz 1971. godine, odnosno neposredno prije uvođenja obavezne vakcine protiv ove bolesti u

use of mathematical modeling in predicting the impact of a disease: an example of measles dynamic modelmaTemaTSko modeLiraNje u PredVidjaNju kreTaNja boLeSTi: diNamiCki modeL morbiLaSemra Cavaljuga, Mladen Cavaljuga, Mira Cavaljuga

Institute of Epidemiology and Biostatistics, Faculty of Medicine, University of SarajevoBosnia and Herzegovina

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program imunizacija, koja je uzeta kao teoretska populacija. Epidemiološka klasifikacija popula-cije je napravljena za sve dobne grupe. U ovom radu je pretpostavljeno da su svi vakcinisani ra-zvili antitijela nakon dobivene vaccine, odnosno da je svaka vakcinacija i imunizacija. Pri dizajni-ranju matematskog modela dinamike morbila koji pokazuje širenje bolesti u populaciji korištene su poznate varijable: osjetljivih, bolesnih i imunih. Dinamički model baziran na dinamici infekcije morbilima je predstavljen kao globalni model sa svojim sub-modelom. Ovaj model, koji u potpu-nosti uključuje sve elemente dinamike morbila važnih za širenje bolesti, je kvantitativan i dina-mički. On uključuje dugoročnu projekciju širenja bolesti i identificira mogućnosti za efikasnu pre-venciju. Model pokazuje procenat imunih osoba za bilo koji nivo obuhvata vakcinacijom, kao i koji se morbiditet i letalitet mogu očekivati za taj pro-cenat obuhvata.

Ključne riječi: matematički modeli, morbili, di-namika bolesti, vakcinacija, Bosna i Hercegovina

Introduction

Diseases that motivated the development of modern epidemiological theory are arguably tho-se of childhood infections, most notably measles. This arose predominantly from their large public health importance in the late 19th and early 20th century (5). In middle 19th century England’s sophisticated system of vital statistics was initi-ated by William Farr, and data series relating to several childhood infections became available that were both reliable enough and long enough to ge-nerate hypotheses about the mechanisms underl-ying epidemic spread. It was only at this time that the microbe theory of infection - the notion that certain infections are caused by living organisms multiplying within the host and capable of being transmitted between hosts – replacing the miasma-tic theory of infection - became firmly established, due to the work of Pasteur and others.

Many facts are widely known about Measles: it is an acute, highly communicable viral disea-se -- highly contagious through person-to-person transmission with > 90% secondary attack rates among susceptible persons -- caused by the Me-

asles virus, a member of the genus Morbillivirus of the family Paramyxoviridae. It is the first and worst eruptive fever occurring during childhood. It produces also a characteristic red blotchy rash which appears on the third day to seventh day. The disease is more serious in infants and adults then in children. Complications may result from viral replication or bacterial superinfection and include mild form as Otitis media, but can lead to serious and even fatal including pneumonia, croup, di-arrhea and encephalitis. Many infected children subsequently suffer blindness, deafness or im-paired vision. Measles confer lifelong immunity from further attacks. The case fatality rates in the developing countries are estimated to be between 3-5%, but commonly 10-30% in some localities (1). Prior to widespread immunization, measles with its contagionity index over 95% was common in childhood (2). The first measles vaccine was introduced by Edmonston 1963 (2). Worldwide today, measles vaccination has been very effecti-ve, preventing an estimated 80 million cases and 4.5 million deaths annually (3). Although global incidence has been significantly reduced through vaccination, measles remains an important public health problem. Since vaccination coverage is not uniformly high worldwide, measles stands as the leading vaccine-preventable killer of children worldwide; it is estimated to have caused 614,000 global deaths annually in 2002, with more than half of measles deaths occur in Sub-Saharan Afri-ca (4). The World Health Assembly in 1989 and the World Summit for Children in 1990 set goals for measles morbidity and mortality reduction of 90% and 95%, respectively, compared with pre-vaccine levels (3). Therefore, vaccination against measles with one dose is one of the components of WHO’s EPI (World Health Organisation’s Expan-ded Programme on Immunization) implemented from the 1970’s in most countries. The fundamen-tal characteristic of vaccination is that it reduces the incidence of disease in those immunized, the susceptible. Also, vaccination protects indirectly non-vaccinated susceptibles against infection by producing herd immunity. Since the introduction of the vaccination incidence of measles has been decreasing worldwide.



Mathematical modeling of measles

The most striking aspect of measles epidemi-cs (particularly observed prior to vaccination era), i.e. their regular cyclic behavior, was noticed first by Arthur Ransome around 1880 (5). Cyclic occu-rrence was observed in Bosnia and Herzegovina as well. Speculation about the underlying cause centered on the availability of a sufficient number of susceptible individuals of the right age in close enough proximity to each other; hence precursory ideas of critical community sizes for sustaining endemic measles were present. A factor that com-monly occurs in many mathematical models of a disease - particularly measles - is the age structu-re of the population. The age of a population and seasonality linked to school season were recogni-zed as important as early as 1896. William Hamer published a discrete time epidemic “model” for the transmission of measles in 1906. The work of W.H. Hamer was continued some decade after with H.E. Soper and this model today is known as Hamer-Soper model. Their observation can be reformulated as stating that the incidence of new cases in a time interval is proportional to the pro-duct SI of the (spatial) density S of susceptibles and the (spatial) density I of infectives in the po-pulation. This assumption of mass action - in ana-logy to its origin in chemical reaction kinetics – is fundamental to the modern theory of deterministic epidemic modeling. The popularity of mass action is explained by its mathematical convenience and the fact that at low population densities it is a re-asonable approximation of a much more complex contact process (10, 11). Following Hamer and Soper, many measles mathematical models have being created.

Measles in Bosnia and Herzegovina Prior to introducing mandatory vaccination in

1970 for all children of 12 months, average morbi-dity rate for the period 1952-1970 was 252.0 0/0000. In the period following 1970, from 1970 to 1976, measured average morbidity rate was 138.5 0/0000. Maintaining rather high incidence rate even after introduction of the immunization program was the leading reason that in Bosnia and Herzegovina

single-dose revaccination with Measles vaccine was introduced 1976 for all children age 7 (2). Morbidity rate following this period was signifi-cantly lower than recorded previously – 57.5 0/0000 in average from 1977 until 1992 (8, 9). Graph 1 shows measles morbidity rate per 100.000 popula-tions in Bosnia and Herzegovina 1952-1992.

Data on any communicable disease after 1992 due to the 1992-1995 war, followed by the heal-th system restructuring in the transition and post-transition period are not taken into this paper as they are considered unreliable.

Despite very good vaccine with high coverage level, measles persist.

Oscillation in a fight against measles remain present regardless all efforts. In this paper we tri-ed to give a method of prediction of magnitude of a future epidemic based on a population age struc-ture and vaccination level. The basic objective of this paper is a discussion of an adequate theoreti-cal model for monitoring of measles and predic-ting the impact of measles in population.

Sources & Methods

From the data collected from standard, official sources, such as Statistical yearbooks for populati-on (age and sex structure) [(7)]; and other relevant epidemiological and official sources such is e.g. the PhD thesis of R. Mulić, MD, MSc, from 1990 (8) who refer to the major relevant official sources: Annual analyses on outcome of immunization (8); Central contagious diseases register of the Public Health Institute (8); Records on immunization sta-tus of the affected population groups (8); etc., a general mathematical model was formulated, and definitions found for several major variables:

- Key variables - Assumptions on relations among the key

variables, - Course of events the epidemiological

process (changes occurring in the key variables),

- Dynamics of the disease.

The presented model is quantitative, but it cle-arly reflects the transition of the population from one epidemiological category into another.

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The population is classified according to the fo-llowing criteria:

- Demographic, based on the age groups: - Newborns (0-1 years)- Preschool children (1-7 years)- Remaining population (7 and more years)

- Epidemiological, based on the health status: - Population at risk - Affected population - Immune population

The classifications were combined, and the epi-demiological, health status categories were deter-mined in each age group. The global model and its sub-model are presented graphically as block-diagram showing clear flow from one demograp-hic as well as epidemiological category to another in Charts 1 and 2. Charts 3 and 4 show empirical model for the given population with calculated si-tuation in year t based on theoretical population of Bosnia and Herzegovina, according to the census in 1971 as presented in Tables 1 and 2.

Results and discussion

Simulation models for the year t and for a the-oretical population and input are shown in charts 3 and 4. The age structure of the theoretical po-pulation (Table 1) is the same as the structure of population of Bosnia and Herzegovina as at 1971 census which overlaps with the very first year of measles vaccination, while the theoretical morbi-dity (Table 2) was based on the official records of B&H Public Health Institute for the period before the immunization became mandatory (1961 - 70) and after the introduction of revaccination.

Although model is hypothetical and theoreti-cal it is empirical too as the basis for prediction is a real population of BiH virgin of any Measles immunization strains as it is prior to introducing Measles immunization program in the 1970/1971 season.

Quantitative, mathematical models of measles can be:

1) Empirical, created for the purpose of investigating and elimination of an epidemic for a specific country for a given time-

frame such as: Hamer-Soper (10,11); chain binomial Reed-Frost model (12); discrete time model known as S-I-R or Suspect -Infectious-Removed (13), which can be considered as continuation of the Reed-Frost model as it uses the same base of stochastic contagious index;

or:2) Theoretical, based on the time series analysis

for creation of a quantitative frame for an epidemic and - when possible – for the basic strategy for its elimination. Examples of this group are: Box-Jenkins model, which uses existing data on a disease and hence belongs to autoregressive models; model using moving averages in addition to auto-regression method is known as STARMA model or Space-Time-Autoregressive-Moving-Average (14); MacDonald uses stochastic model with exact population data and several assumptions (15); mathematical model for dynamics of directly transmitted viral and bacterial infections, or Anderson & May model, which was used to estimate that about 96% of a population should be vaccinated against measles in order to eradicate the disease, assuming that each vaccination is immunization. One of their conclusions from analysis of measles data for England and Wales since 1968 is that the risk of new measles outbreaks is present if herd immunity falls below 94% (16).

Unlike the mentioned models, model presented in this paper represents an attempt of creation of a simple tool, flexible enough to take into account epidemic process with all its phases and to serve as an empirical model if needed. The empirical model should be based on the available data and formulated goals of measles eliminations strategy and should provide precise indicators and results. This model combines approaches developed by the models which monitor epidemic process and time flow of a disease and models allowing mo-nitoring of a disease among different age groups and it provides an option for quantitative analysis of both aspects.

The model incorporates and defines all phases of an epidemiological process and also serves as



an empirical foundation for predicting concrete indicators and results. The flexibility of the model allows:

Simple introduction of additional age groups (e.g. school children 7-14 years and/or 14-18, stu-dents, adults, etc.),

Simple introduction of additional epidemiolo-gical categories along a logical chain of newborns, maternal immune, persons at risk, latent, infectio-us or a combination of categories,

Simple monitoring of seasonal variations, even in specifically set time-intervals of particular inte-rest (e.g. school year starts 1 September, ends on 1 July. In between those two dates there are high de-gree of likelihood that school children will come into contact with infected persons, and that period can be incorporated in this model)

With the presented model, based on dynamic quantitative analysis, changes of indicators in any period of time, most significantly during the epi-demics, can be easily taken into account. If fixed-indicators time-series analysis is used, however, the variations will on a long run be smoothed.

The other quantitative approach to measles epidemic modeling could be statistical. However, there are two reasons why in our case a statistical model would not be acceptable:

1) Statistical approach does not view the problem from the same angle;

2) Statistical model would not predict vaccination coverage drop in Bosnia and Herzegovina to 57% during 1992-1995 (17).

Conclusions

This model facilitates long-term projections of measles morbidity and lethality for any given le-vel of immunization. Based on the actual immu-nization level, it is possible to predict immunity, morbidity and lethality figures for any given pe-riod of time, as well as the outcome of any future immunization campaign.

The model presented in this paper cannot be understood as a simple application of quantitati-ve methods in medicine. It should be seen as an instrument in understanding of a problem, and not an answer to it. It allows the measles problem to be reviewed from many angles: clinical, epidemi-ological and population-based, as well as opera-tional - simultaneous, dynamic, statistical, etc. It also provides for creation of instruments for sol-ving the problem.

Table 1. Age Structure of Population of Bosnia and Herzegovina 1971

Population %

Less than 1 year 2,210 2.21

1 – 7 years 13,350 13.35

More than 7 years 84,440 84.44

Total 100,000 100.00

Table 2. Measles Morbidity in Bosnia and Herzegovina

Mb 0/00001961 – 1970

Mb 0/00001981 - 1992

Less than 1 year 601 160

1 – 7 years 1,959 301

More than 7 years 59 132

22



Chart 1. Global model block diagram

Chart 2. Measles dynamics sub-model withvaccination

Chart 3. Global simulation model block diagram (situation in year t)

Chart 4. Simulation sub-model (vaccinationsuccess 95 %)



Graph 1. Measles morbidity rate per 100.000 populations in Bosnia and Herzegovina 1952-1992

Source: Mulić PhD Thesis 1990 (8); Epidemiological Bulletin 1992 IPH BiH (9)

Literature

1. Heyman DL. (Ed.) Control of Communicable di-seases Manual. 18th Edition. APHA, Washinghton DC. 2004; (347-354),

2. Gaon JA, Borjanović S, Vuković B, et al. Specijalna epidemiologija akutnih zaraznih bolesti. Svjetlost, Sarajevo 1982. (25-33) ,

3. World Health Organization, Department of vacci-nes and biological. Measles Technical Working Group: strategies for measles control and elimina-tion. Report of a meeting, Geneva, 11-12 May 2000. Geneva, Switzerland: World Health Organization, 2001.,

4. Moussa Tessa O. Mathematical model for control of measles by vaccination. Mali Symposium of Applied Sciences - MSAS Aug 2006. http://www.maliwatch.org, 18 Dec 2008,

5. Roberts MG, Heesterbeek JAP. MATHEMATICAL MODELS IN EPIDEMIOLOGY, in Mathematical Models, [Eds. Filar JA, Krawczyk JB.] in Encyc-lopedia of Life Support Systems (EOLSS), Develo-ped under the Auspices of the UNESCO, Eolss Pu-blishers, Oxford ,UK, 2003. http://www.eolss.net, 20 Dec 2008,

6. Čavaljuga S. Predviđanje kretanja morbila u po-pulaciji (Dinamički model). Magistarski rad. Me-dicinski fakultet Univerziteta u Sarajevu, Sarajevo 1997.

7. SZZZ. Statistički godišnjaci o narodnom zdravlju i zdravstvenoj zaštiti u SFR Jugoslaviji. Savezni za-vod za zdravstvenu zaštitu, 1961.-1990.

8. Mulić R. Epidemiološke karakteristike morbila na području SR Bosne i Hercegovine u period prije i poslije uvođenja obavezne vakcinancije. Doktorska disertacija. Medicinski fakultet Univerziteta u Sa-rajevu, Sarajevo 1990.

9. ZZZBiH. Epidemiološki bilten. Zavod za zdravstve-nu zaštitu Bosne i Hercegovine, 1992. God. II; Br. 10,

10. Hamer WH. Epidemic diseases in England – the evidence of variability and persistency of types. Lancet, 1906. 2: (733-739),

11. Soper HE. Interpretation of periodicity in disease prevalence. Journal of the Royal Statistical Soci-ety A, 1929.92: (34-73),

12. Greenwood M. On the statistical measure of in-fectiousness. Journal of Hygiene. 1931. 31: (336-351),

13. Enderle JD. A Discrete-Time Communicable Di-sease Model with a Stochastic Rate for Nonhomo-geneus Population. ISA, 1991. Paper#91-010,

14. Cliff AD. Statistical modeling of measles and in-fluence outbreaks. Statistical Methods in Medical Research. 1993; 2: (43-73),

15. Thacker SB and Millar DJ. Mathematical mode-ling and Attempts to Eliminate Measles: A Tribute to Late Professor George Macdonald. American Journal of Epidemiology, 1991. 133; 6: (517-525),

16. Anderson RM, May RM. Directly transmitted in-fectious diseases: control by vaccination. Science, 1982. 215: (1053-1060),

17. Čavaljuga S. Evaluacija programa obaveznih imunizacija u ratnom periodu u BiH. Specijali-stički rad. Medicinski fakultet Univerziteta u Sa-rajevu. 1995.


Semra Cavaljuga Institute of Epidemiology and Biostatistics Faculty of Medicine, University of Sarajevo Cekaluša 90, 71 000 Sarajevo Bosnia and Herzegovina email: [email protected]

24



Summary

A study was conducted with 11 organizations from Silicon Valley by the Stanford Health Pro-motion Network in December 2008 to assess the extent and quality of their corporate health pro-motion programs. It showed that in the sample No organization had a totally integrated science-based approach to health promotion, Organizations have a wide array of common issues in this area. The main topics of interest are how to measure return on investment and benchmark against the industry and demographics and there is a role to play for entities such as the Stanford Health Promotion Network to galvanize, enable and serve as a reso-urce center for health promotion.

Key Words: Health Promotion, Study, Silicon Valley, Stanford Health Promotion Network

Introduction

A study was conducted in December 2008 by the Stanford Health Promotion Network on heal-th promotion programs in Silicon Valley. Its main purposes were:

- To identify the top 4 health promotion issues that employers have relating to health plans and vice versa.

- To have a profile of the extent and quality of corporate health promotion programs in these corporations.

Methodology

11 companies from Silicon Valley were studied in December 2008, including 5 cutting-edge global leaders. Their size varied from 120 to 20,000 pe-ople. Their spokespersons held the following po-sitions: General Manager, Director (2), Regional Vice-President, Senior Manager (Benefits), Senior Benefits Analyst, Senior Account Manager, Corpo-rate Health and Safety Manager, Employee Health Services Manager, Fitness Operations Manager, Principal. Two methods were used, as follows:

a) An intensive and dynamic brain storming session with corporation representatives, which aimed at identifying the top 8 health promotion issues that they faced

b) Gathering answers to the following 12 questions:

1. How would you rate support from your management to corporate health promotion programs?

2. Does your corporation have full-time health promotion employee(s)?

3. Does your corporation outsource its health promotion programs?

4. Is your corporation working with health plans regarding health promotion programs?

5. Does your corporation use a health risk assessment?

6. Did your corporation have an initial operating budget for health promotion programs?

Health Promotion in Silicon Valley: a Study of 11 CorporationsPromoCija zdraVLja u SiLikoNSkoj doLiNi: STudija ProVedeNa u 11 korPoraCijaYann A. Meunier

Stanford Health Promotion Network



7. How would you rate your corporation health promotion programs efficiency?

8. Does you corporation measure return on investment in its health promotion programs?

9. Does your corporation have fitness programs?

10. Does your corporation have health promotion success stories?

11. What are the best aspects of your corporate health promotion programs?

12. What are your wishes for improving your corporate health promotion programs?

Results

The top 8 health promotion issues were as fo-llows:

- Performance guarantees for health outcomes / engagement

- Benchmarking against industry and demographics

- Communication to health plan members so that they know what is available to them

- Providing incentive for healthy behavior- Senior management support- Internal committee- Budget incentives- Goals / objectivesThe answers to the above questionnaire were

as follows:

1. Support from management to corporate health promotion programs: 4.1/5 (average)

2. Full-time health promotion employee(s): No: 2 / Yes: 6

3. Outsourcing of health promotion programs: No: 2 / Yes: 6

4. Working with health plans: No: 3 / Yes: 55. Health risk assessment: No: 3 / Yes: 76. Operating initial budget for health promotion

programs: No: 3 / Yes: 87. Health promotion programs efficiency

rating: 3.2/5 (average)8. Return on investment assessment: No: 6 /

Yes: 29. Fitness programs: No: 3 / Yes: 7

10. Health promotion success stories: No: 3 / Yes: 7

11. Best aspects of health promotion programs: Some programs from carriers are fee

of charge, fitness group challenges, incorporation of employee and community programs, input of employees, cutting-edge fitness classes and programs, innovative web-based offerings to maximize employee reach and engagement, diversity and flexibility, qualified service provider, employee steering and implementation, variety, comprehensiveness, leadership buy-in, communication, integrated approach, executive commitment

12. Wishes for improving health promotion programs:

On-site classes, weight management meetings, full complement of programs, HRA with labs available to all employees, more numerous and more accessible educational sessions

Discussion

Although drawn from a limited number of companies the survey data identified some com-mon tendencies, as follows:

* It is remarkable that regarding health promo-tion programs employers and health plans face many identical challenges among themselves. Before the study a plausible assumption was that small and medium size organizations had mostly different issues than large multinational corporati-ons. Our results show that it is not the case. This finding has tremendous implications on the design and implementation of corporate health promotion programs1,2,3,4,5,6.

* Most companies stated that they support cor-porate health promotion programs a lot (average: 4.1/5). However, the vast majority (6/8) outsour-ces them, which shows that their commitment is not to the point of integrating them into their DNA. The discrepancy between perception and reality confirms that health promotion is not anchored in the workplace concept of corporate leaders. It also outlines the need for sensitization of corporate le-adership to health promotion issues. This can be

26



done best by third parties with no vested interest such as the Stanford Health Promotion Network7.

* No company has a comprehensive health promotion program i.e., including science-based health risk assessment, motivation rating, behavi-or change program, efficiency evaluation, return on investment determination, etc. Moreover, the notion that a science-based foundation is neces-sary in order to guarantee quality, consistency and results is not widespread. This calls for and educational approach to health promotion in the workplace8,9,10.

* 37.5% of companies are not working with health plans. This fact is particularly interesting concerning small and medium enterprises. Indeed, health plans have some free corporate health pro-motion programs. In forums like the ones organi-zed by the Stanford Health Promotion Network employers can learn from one another and from health plans, consultants and specialists. The inte-raction between these professionals hopefully will lead to a harmonization of best practices which will result in decreased health costs.

* Most companies have health promotion su-ccess stories. This affirmation carries hope for the future of health promotion programs. The showca-sing of such successes among co-workers can go a long way in advocating healthy behavior change.

* The best aspects of corporate health promoti-on programs are multiple. It is important that these features be shared with others so that everybody can learn best practices and save time and money in the creation and implementation of corporate health promotion programs.

* The best wishes for health promotion pro-grams are varied. Therefore, there is much to be done and lots of room for improvement for corpo-rate health promotion programs11,12,13.

* The health promotion programs efficiency rating was relatively low (average: 3.2/5). The re-asons for the poor performance in the efficiency of these programs must be determined on a case by case basis and ideally they should be shared with others to avoid repeating the same mistakes14,15,16.

* Return on investment is a big issue to the vast majority of corporations (6 don’t or can’t measure it). This crucial topic must be addressed thoroug-hly at various levels in order to get the buy-in from upper management for corporate health promotion

programs and incite managers to champion health promotion initiatives17,18,19,20,21. The fact that some corporations sent their benefit executives reveals that they consider health promotion as a benefit to employees and not as a profit generating inves-tment in their human capital.

* Finally, for health promotion purposes, collaboration and team building are essenti-al22,23,24,25,26,27,28.

Conclusion

The extent and quality of corporate health pro-motion programs in Silicon Valley varies greatly. However, corporations have several common issues. These can be better uncovered and addre-ssed in catalytic think tanks such as the Stanford Health Promotion Network. The ability of these entities to produce positive outcomes can result in an overall improvement of healthcare not only in Silicon Valley but also at the state and national levels. Although this survey sheds some valuable new light on many issues, further work is needed on a wider scale to establish more reliable data in the same field.



Literature

1. Design of Workplace Health Promotion Programs, Michael P. O’Donnell. 1995. Published by the American Journal of Health Promotion.

2. Hunnicutt, D., Deming, A., and Baun, B., Health Promotion Sourcebook for Small Business. Wellne-ss Councils of America, 1998.

3. Wellness Councils of America (WELCOA): www.welcoa.org

4. National Business Coalition on Health (NBCH): www.nbch.org

5. Health Enhancement Research Organization (HERO): www.the-hero.org

6. 7 Steps to Health Promotion, Daphne Woolf and Veronica Marsden. Group Healthcare Manage-ment. February 1996.

7. Chapman, Larry S., Securing Support From Top Management. The Art of Health Promotion, Vol. 1: No. 2, May/June 1997, pp. 1-7.

8. Chapman, L., What Newer Forms of Health Mana-gement Technology Can Be Used in Programming? The Art of Health Promotion, September/October 1997, Vol. 1, No 4.

9. Chapman, L.S., Planning Wellness Getting Off to a Good Start. Seattle, WA; Summex Corporation, 1996.

10. McGinnis, J.M., Worksite Health Promotion Acti-vities Summary Report, U.S. Department of Heal-th and Human Services. Office of Disease Preven-tion and Health Promotion, 1992.

11. U.S. Preventive Services Task Force (USPSTF) in Agency for Healthcare Research and Quality (AHRQ): www.ahrq.gov

12. Pacific Business Group on Health (PBGH): www.pbgh.org

13. Estes Park Institute: www.estespark.org

14. Health Promotion: Sourcebook for Small Busine-sses published by the Wellness Councils of Ameri-ca and Canada.

15. Green, L.W., and Kreuter, M.W., Health Promoti-on Planning, An Educational and Environmental Approach, (2nd ed.). Mountain View, CA; Mayfi-eld Publishing Company, 1991.

16. Allen, Judd, Culture Change Planner, available online at www.healthyculture.com

17. Chapman, Larry S. Program Evaluation: A Key to Wellness Program Survival, 1996.

18. McKenzie J. and Smeltzer J. Planning, Implemen-ting, and Evaluating Health Promotion Programs: A Primer, 2nd Edition Allyn and Bacon, 1997.

19. Schaloc, R. Outcome-Based Evaluation. Plenum Press, 1995.

20. Integrated Benefits, Inc. (IBI): www.ibionline.com

21. Healthcare Effectiveness Data and Information Set (HEDIS) in National Committee for Quality Assurance (NCQA): www.ncqa.org

22. Kanter, Rosabeth M., Successful Partnerships Manage the Relationship, not just the Deal. Co-llaborative Advantage, Harvard Business Review, July/August 1994.

23. Meyer, C., How the Right Measures Help Teams Excel, Harvard Business Review, May/June 1994.

24. Rapaport, R., To Build a Winning Team: An Inter-view with Head Coach Bill Walsh, Harvard Busi-ness Review, January/February 1993.

25. Wetlaufer, S., The Team That Wasn’t, Harvard Bu-siness Review, November/December 1994.

26. Social Marketing by Philip Kotler and Eduardo Roberto.

27. Center for Disease Control and Prevention (CDC): www.cdc.gov

28. Consumer Assessment of Healthcare (CAHPS): www.cmc.hhs.gov/caps

Corresponding author: Yann A. Meunier * Program Manager Stanford Health Promotion Network 1070 Arastradero Road, Rm 3C03G Palo Alto, CA 94304-1334 Tel: (650) 721 2802 Fax: (650) 723 6450 E-mail: [email protected] http://shpn.stanford.edu

28



Summary

The Institute of Emergency Medical Care Sa-rajevo is the institution which deals, in organized way, with rendering the emergency medical care at the level of Canton of Sarajevo. Rendering the medical care is carried out through the Central Outpatient Department of Emergency Medical Care and there exists the General Outpatient De-partment with four receiving boxes. There exists also the Pediatric Department as well as Surgical Department with additional diagnostic services. Aiming at faster and easier accessibility of emer-gency medical care, rendering help is carried out through the (*Emergency Medical Care) branches at the level of the municipality of Ilidža during 24 hours, while the other branches work only during the evening/night hours and it is in function in: Hadžići, Saraj polje (Novi Grad), Vogošća, Ili-jaš and Trnovo. It is very specific for the work of Emergency Medical Care to work fast in the field which is carried out upon citizen’s phone call to Dispatch Centre on phone numbers: 124 and 611 111. While serving the purpose of justifiability and urgency, the ambulance goes to perform visits to homes, and along with it, depending on urgency level, we possess also differently equipped teams and ambulance vehicles for rendering emergency medical care. In this work, there are analyzed two weeks of emergency medical care teams going to the field. By random selection, these are first two weeks of the month of December, 2004, and, we wished to establish level of urgency of visits

to homes, justifiability of visits depending on the level of urgency, most frequent reasons for inter-ventions, as well as patients’ gender and age, also, which are usual problems of emergency medical care in the field.

Key words: emergency medical care, Dispatch Centre, visits to homes.

Sažetak

Zavod za hitnu medicinsku pomoć Sarajevo je ustanova koja se organizovano bavi pružanjem hitne medicinske pomoći na nivou Kantona Sara-jevo. Pružanje pomoći se obavlja preko centralne ambulante hitne pomoći gdje postoji opšta ambu-lanta sa četiri prijemna boksa. Postoji i pedijatrij-ska ambulanta kao i hiruška ambulanta uz prateće dijagnostičke službe. Radi brže i lakše dostupnosti hitne pomoći, pružanje pomoći se obavlja i preko punktova na nivou općina Ilidža 24 sata dok osta-lu punktovi rade samo u večernjim časovima i to Hadžići, Saraj polje (Novi Grad), Vogošća, Ilijaš i Trnovo. Ono što čini specifičnost rada Hitne po-moći je brzi rad na terenu koji se obavlja na poziv građana u dispečerski centar na tel: 124 i 611 111. Svrsishodno opravdanosti i hitnosti, odlazi se u kućne posjete, s tim da ovisno o stepenu hitnosti posjedujemo i različito opremljene ekipe i sanitet-ska vozila za pružanje hitne medicinske pomoći. U ovom radu su analizirane dvije sedmice rada ekipa hitne pomoći koje odlaze na teren. Slučaj-nim odabirom to su prve dvije sedmice mjeseca

The most frequent reasons for visits to patients in emergency medical Care Center SarajevoNajčešći razLozi za kućNe PoSjeTe u zaVodu za HiTNu mediCiNSku Pomoć SarajeVoEnes Slatina

Institute of Emergency Medical Care (IEMC) Sarajevo, Bosnia and Herzegovina



decembra 2004., sa željom da utvrdimo stepen hit-nosti kućnih posjeta, opravdanost posjeta ovisno o stepenu hitnosti, najčešći razlozi za intervencije, kao i spol i uzrast pacijenata; takođe, koji su to uobičajeni problemi hitne pomoći na terenu.

Ključne riječi: hitna pomoć, dispečerski cen-tar, kućne posjete.

1. Introduction

The IEMC Sarajevo is the institution which of-fers help, in organized way, to all the citizens in the Canton of Sarajevo 24 hours or 365 days per year. Offering help is carried out in the outpatient departments of the Institute as well as by means of emergency medical care teams offering help in the field. In the Institute, the help is offered by staff members who are trained and qualified for all the possible situations either in the outpatient depar-tment or in the field. In this work, there is analyzed the field work of emergency medical teams. The experienced dispatchers receive the phone calls for visits to homes on phone numbers 124 or 611 111. The staff members receiving the phone calls in the Dispatch Centre, which usually represents the key part of the service, have several years of work experience, and, their duty is to be kind and to calm down the person asking for help, while gi-ving them useful instructions. After having recei-ved the phone call, the dispatcher carries out triage of call depending on the level of urgency, while directing the calls, by communication system, to the field teams. By good communication system, there is enabled sending promptly the information on urgent case as well as organized management of service and field teams. When receiving the phone call, the dispatcher poses certain questions.

1. What did happen – type of injury or illness and number of injured persons?

2. Where did that occur? 3. When did it happen? 4. When it is about the first degree of urgency,

s/he asks if the person is conscious and if the person breathes?

5. What is the name of person (if possible to find out) and address?

6. Who does call and from which phone number (in case of need of subsequent contact)?

Depending on urgency degree, in the IEMC, there exist three degrees of urgency for work of field teams:

The first degree is the degree for which it is a must to intervene, if possible, within first five minutes; usually it is about sudden heart disease or sudden failure of previously sick heart, CVI, traffic accidents, fights, falls, consciousness crises, delivery, profuse bleeding and all other situations when the life is directly endangered.

The second degree of urgency represent usually the patients with chronic diseases in the phase of exacerbation when the life is not directly endangered and which can wait for the arrival of an ambulance for up to 30 minutes. The examples are: hypertension, chronic obstructive bronchitis (COB), febrile conditions, hypotention etc.

The third degree of urgency represents usually giving the regular therapy in the field (for instance, imovable patients or patients who are movable with a lot of difficulty) or solving by therapy against pain for persons with verified cancer, lumbar sciatica when it is possibe to wait up to 1 hour.

2. Goal of work

The goal of work is to establish the most frequ-ent reasons for visits to homes of IEMC Sarajevo.

3. Material and methods

This retrospective research comprises the emergency medical interventions in the field du-ring first two weeks in the month of December, 2004. In the analysis, there were used the working protocols from the Dispatch Centre. There was analyzed the total of 688 patients.

4. Statistical analysis

In the statistical analysis, there were used com-puter programs Microsoft Word and Excel.

30



5. Results

Table 1. From the table, it is visible that the am-bulance in the field intervened the most in cases of patients who are 70 years of age and over 70.

Graph 1. It shows he ratio of patients by gender and it is visible that the women seek help more in the field

Graph 2. The most frequent CNS disease in the field is the CVI ac.

Graph 3. The most frequent respiratory disease in the field is COB

Graph 4. The most frequent CVS diseases in field are myocardiopathies

Graph 5. The most frequently the injuries in the field are caused by falls

Graph 6. The most frequent intoxications are ca-used by ethyl-alcohol

Table 1.

AgeO 10 20 30 40 50 60

70 + Unknown9 19 29 39 49 59 69

Gender M F M F M F M F M F M F M F M F M FTotal 2 4 3 5 11 5 3 6 5 10 7 19 32 41 37 84 188 215



Graph 7. The most frequent diseases requiring visit to home are CVS diseases

Graph 8. The most of cases in the field are of II degree of urgency

Graph 9. The largest number of patients stay at home or is sent home after offered emergency medical care

6. Discussion

From graphic and tabular analysis of informati-on, it is visible that out of 688 patients, the largest

number of interventions in the field were carried out due to the persons who suffer cardiovascular diseases, then respiratory ones, then CVS dise-ases etc. (graph 7.). The cardiovascular diseases are the first reasons of mortality in the world as well as in our country. The table 1 shows the ratio of patients by age and it is visible that the largest number of interventions (visits to homes) is for the patients who are 70 years old and older than that. The number of interventions grows as the persons are older. The graph 1 shows the relation of pa-tients by gender and it is visible that the women (58%) ask for help more often. The graph 2 shows the most frequent cardiovascular diseases when the ambulance intervened and it is visible that the most frequently the patients suffer myocardiopt-hy. The graph 3 shows the CVS diseases and the cases of acute stroke are the most frequent ones. The graph 4 shows the most frequent respiratory diseases and it is visible that it is COB. The graph 5 shows the most frequent injuries in the field and it is visible that these are the falls due to winter period, icy pavements from which the ice and snow were not removed. The teams intervened when 5 traffic accidents occured and there were 7 injured persons. The graph 6 shows the most frequent reasons of intoxication in the field and it is the intoxication with ethyl-alcohol, while there was a significant number of drug overdose. The graph 8 shows the percentage-related relation of urgency of interventions at home and it is visible thate there are the most of interventions of second degree of urgency, then of the first one. The graph 9 shows where the patients are sent after the inter-vention of emergency medical care. It is visible there that the majority of patients are sent home or they stay at home and the reason for that is the fact that the majority of patients are of II and III degree of urgency. The basic issue which influenced the results and made difficult the work of Emergen-cy Medical Care is a huge number of phone calls made by citizens. Unlike the Emergency Medical Care in Zagreb, the Sarajevo Emergency Medical Care have five times more interventions. The rea-son for that is a large number of uninsured patients who ask for help in the Emergency Medical Care. There is certain number of unjustified phone calls which cannot be sanctioned. Also, the reason is the fact that scheduling appointment in the outpa-

32



tient departments of Health Centres, which takes a lot of time, influences the increased number of patients, especially of second degree of urgency. Poor cooperation between the Emergency Medi-cal Care teams and family medicine in the field also influences the increased number of interven-tions which are not of the first degree of urgency.

7. Conclusions

1. The most frequent diseases that occupy the work of team in the field are the cardiovascular diseases.

2. From the results, it is visible that a large number of visits to homes and the majority of visits are of second degree of urgency.

3. There is indispensible better cooperation of Emergency Medical Care teams and family medicine in order to decrease the number of interventions of II and III degree of urgency and to direct one part of these patients to the Health Centres.

4. To educate the population by means of media regarding the place where and why the need to ask for help.

5. Due to enormous stress and frequent carrying of patients, it is necessary to change more often the teams working on special vehicles (cardio-vehicles) where mainly the help of I degree of urgency is offered.

6. Considering that the ambulances and equipment are in function during 24 hours, it is necessary to change them regularly and to renew due to safety of teams and better efficiency.

Literature

1. Mulaomerović A., Elco H.Dykstra.: (Reform and Modernization of Emergency Medical Care Sy-stem in FBiH) Reforma i modernizacija sistema hitne medicinske pomoći u FBIH, Medicinski arhiv, 2000; 54(4): 197-200.

2. Softić S,.: (Unique Dispatch Centre System of Com-munications) Jedinstven dispečerski centar sistem veza, Medicinski arhiv, 2000; 54(4): 227-230.

3. Smajkić A., Nikšić D., Jelaća P.: (Bases of Resear-ch in Public Health) Osnove istraživanja u javnom zdrastvu, Sarajevo,1996.

4. Vlasta Jasprica-Hrlec i sar.: (Emergency Medical Care in Out-of Hospital Conditions) Hitna medi-cinska pomoć u izvanbolničkim uvjetima Zagreb: Jaspra, 2003.

5. Vnuk, V.: (Emergency Medicine – Pre-hospital Pro-cedure) Urgentna medicina- prehospitalni postu-pak, I izdanje,Alfa Zagreb,1990.

6. Zlatko Puvačić: (Statistics in Medicine) Statistika u medicini, Sarajevo, 1997.


Enes Slatina Institute of Emergency Medical Care (IEMC) Sarajevo, Bosnia and Herzegovina e-mail:



Summary

The cardiovascular system is the first system that beginns to function in the embryo and blo-od already begins to circulate by the end of the third week of embryonal development. The cri-tical period of heart development is from day 20 to day 50 after fertilization. Numerous critical events occur during cardiac and great vessels de-velopment and because of that the cardiovascular system anomalies are realtively common. In Bo-snia and Herzegovina there is no existent unique evidence of congenital anomalies and registries. The aim of this study was to obtain the frequency of different types of cardiovascular anomalies, as the most frequent ones, among cases hospitalized in a Pediatric Clinic, University of Sarajevo Cli-nics Center, Bosnia and Herzegovina, during the period from January 2002 to December 2006. Re-trospective study was carried out on the basis of clinical records. Standard methods of descriptive statistics were performed for the data analysis. Eleven different types of cardiovascular system anomalies were found among 539 patients that were hospitalized during the investigated period. In our country should be given more attention to the birth defects prevention programms. EURO-CAT is a network of population-based registries for the epidemiologic surveillance of congenital anomalies that is active in Europe over last 25 years, covering 1,2 million births per year. The establishment of the Bosnia and Herzegovina registry and the Referral Centre of the Ministry of Health for the surveillance of Birth Defects

would improve the quality control and enhance the planning of the health care programmes for pregnancy and early childhood.

Key words: congenital anomalies, cardiovas-cular system, frequency

Sažetak

Kardiovaskularni sistem je prvi sistem koji u embriju počne funkcionirati i već krajem treće sed-mice embrionalnog razvoja počne cirkulacija krvi. Kritični period za razvoj srca je od 20. do 50. dana nakon oplodnje. Za vrijeme razvoja srca i velikih krvnih žila brojni su kritični momenti zbog čega su anomalije kardiovaskularnog sistema relativno če-ste. U Bosni i Hercegovini ne postoji jedinstvena evidencija i registar kongenitalnih anomalija. Cilj ovoga istraživanja bio je ustanoviti učestalost razli-čitih tipova kongenitalnih anomalija kardiovasku-larnog sistema, kao jednih od najčešćih anomalija, među pacijentima hospitaliziranim na Pedijatrijskoj Klinici Kliničkog Centra Univerziteta u Sarajevu, Bosna i Hercegovina, u periodu od januara 2002. do decembra 2006. godine. Podaci za ovo retros-pektivno istraživanje dobiveni su iz kliničkih prije-mnih protokola i historija bolesti. Za analizu poda-taka primijenjene su uobičajene statističke metode. U istraživanom periodu ustanovljeno je jedanaest različitih tipova anomalija kardiovaskularnog siste-ma kod 539 pacijenata koji su zbog istih hospitalizi-rani. U našoj se zemlji mora posvetiti više pažnje za programe prevencije urođenih poremećaja. EURO-CAT je evropska mreža registara za epidemiološko

The most frequent congenital cardiovascular anomalies Najčešće koNgeNiTaLNe aNomaLije kardioVaSkuLarNog SiSTema Selma Alicelebic

Institute of Histology and Embryology, University of Sarajevo, School of Medicine, Bosnia and Herzegovina

34



praćenje kongenitalnih anomalija, koja je aktivna preko 25 godina i godišnje pokriva 1,2 miliona no-vorođenih. Uspostavljanje takvoga registra u Bosni i Hercegovini kao i referalnih centara za praćenje urođenih poremećaja pri Ministarstvima zdravstva osiguralo bi kvalitetan nadzor i napredak u plani-ranju programa zdravstvene zaštite u trudnoći i ra-nom djetinjstvu.

Ključne riječi: kardiovaskularni sistem, ra-zvoj, kongenitalne anomalije, učestalost

Introduction

Congenital anomalies are defined as structural defects, chromosomal abnormalities, inborn errors of metabolism, and hereditary disease diagnosed before, at, or after birth (1). Con genital anomali-es represent a significant problem because of their frequency, unclear origin and the consequences for the society. The data of congenital anomalies in the different parts of the world are different due to dif-ferences in ecological, socio-economic, geographic and other conditions of living. The surveillance of congenital anomalies serves two main purposes: to facilitate the identification of teratogenic (malfor-mation causing) exposures and to assess the impact of primary prevention and prenatal screening po-licy and practice at a population level. European Economic Community’s Committee on Medicinal and Public Health Research established in 1979 to improve “the methodology of population studies throughout the Community”. Congenital anoma-lies chosen as first topic for concerted action. The European Economic Community’s Committee on Medicinal and Public Health Research started alre-ady in 1979. a multicentric epidemiological study of congenital anomalies through the project called EUROCAT (acronym derived from its original name “European Concerted Action on Congenital Anomalies and Twins”) (2). Congenital anomalies are registered in almost every country all over the world on special designed questionnaires which management and outcome, however, vary conside-rably between the different countries. Due to the si-gnificance of congenital malformation in perinatal morbidity and mortality and its various types and diverse incidences in several countries, it is impor-tant for each population, even on regional basis, to

know the distribution and incidence of congenital malformations (3). In Bosnia and Herzegovina there is no existent unique evidence of congenital anomalies and registries (4). According to the lite-rature data, birth defects involving the brain are the largest group all over the world at 10 per 1000 live births, compared to heart at 8 per 1000, kidneys at 4 per 1000, and limbs at 1 per 1000. All other de-fects have a combined incidence of 6 per 1000 live births (5). Hovewer, birth defects of the heart are the most common birth defect leading to death in infancy, accounting for 28% of infant deaths due to birth defects, while chromosomal abnormaliti-es and respiratory abnormalities each account for 15%, and brain defects about 12% (6). The aim of this study was to obtain the frequency of different types of the cardiovascular system anomalies, as the most frequent ones, among the cases hospitalized at the Paediatric Clinic of the University of Sarajevo Clinics Centre, Bosnia and Herzegovina, during the period from January 2002 to December 2006.

Patients and methods

Retrospective study was carried out on the ba-sis of the clinical records of the Paediatric Clinic of the University of Sarajevo Clinics Centre, Bosnia and Herzegovina. Standard methods of descripti-ve statistics were performed for the data analysis.

Results

During the period from 1st January 2002 to 31st December 2006, a total of 539 patients with cardi-ovascular system anomalies were hospitalized and out of that num ber 288 (53,4%) were male pati-ents, while 251 (46,6%) were female (Table 1.).

TABLE 1. Total number and gender of treated cardiovascular sytem anomalies

GENDER N° %

MALE 288 53,4%

FEMALE 251 46,6%

TOTAL 539 100%



Eleven different types of cardiovascular system anomalies were found in this study.

The most frequent were ventricular and atrial septal defects, patent ductus arteriosus and com-plex congenital cardiovascular anomalies of the heart and great vessels. (Figure 1.).

FIGURE 1. Frequency of particular types of cardiovascular system birth defects

Congenital heart defects were more frequent than great vessels anomalies and the combined anomalies of heart and great vessels were the least frequent (FIGURE 2.).

FIGURE 2. Frequency of different kinds of car-diovascular system anomalies

Figure 3. shows a total apsolute number of each cardiovascular anomaly found in the investigated period according to the sex.

FIGURE 3. Sex distribution of cardiovascular system birth defects cases

About 10% patients with cardiovascular ano-malies have some of the chromosome abnormali-ties in this investigation (FIGURE 4.).

FIGURE 4. Frequency of chromosome abnor-malities in cardiovascular system birth defects

Trisomy 21 (Down syndrome) were the most frequent (94%) chromosome abnormality associa-ted with cardiovascular anomalies but Turner syn-drome and Edwards syndrome were considerably less (FIGURE 5.).

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FIGURE 5. Frequency of particular types of chromosome abnormalities in cardiovascular system birth defects

FIGURE 6. shows that heart septal defects were the most frequent anomalies associated with Down syndrome and the other were considerably less.

FIGURE 6. Frequency of particular types of cardiovascular system birth defects in Down syndrome

Discussion

In the period from 1st January 2002 to 31st De-cember 2006 a total number of 539 patients with congenital cardiovascular system anomalies were hospitalized at the Paediatric Clinic of the Univer-sity of Sarajevo Clinics Centre. Out of that num-ber 288 were males (53,4%) and 251 were females (46,6%); sex ratio-1,2:1. These findings corres-pond with literature ones (7). In this study eleven different types of cardiovascular system anomali-es were found and their frequency in both sexes varried from 21,52% (ventricular septal defect) to 0,55% (pentalogy Fallot). Anomalies of the heart

were more frequent (56,3%) than the great vessels anomalies (34,1%) and the complex heart and great vessels anomalies were the least frequent (9,6%) what corresponds with the data from the li-terature (7,8,9). From the total number of 539 pati-ents with congenital cardiovascular anomalies, 56 patients or 10,4% had some of the chromosome abnormalities and that: 53 patients or 94,6% had Down syndrome, 2 patients or 3,6% had Turner syndrome and one patient or 1,8% had Edwards syndrome. The most frequent cardiovascular ano-maly associated with Down syndrome was atrio-ventricular septal defect (24 patients or 45,3%), followed with ventricular septal defect (14 pati-ents or 26,4%), atrial septal defect (6 patients or 11,3%), tetralogy Fallot (4 patients or 7,5%) and combined cardiovascular anomalies (3 patients or 5,7%) what corresponds with the data from the li-terature (10).

Conclusion

According to this study, congenital cardio-vascular system anomalies, were higher in males (53,4%). Congenital heart defects were more frequent (56,3%) than great vessels anomalies (34,1%). Ventricular septal defect was the most frequent anomaly found both in males (22,2%) and in females (20,7%). Cardiovascular system anomalies were associated with chromosomal abnormalities in 10,4% cases, the most frequent with Down syndrome (94,6%). The most fre-quent cardiovascular anomaly (45,3%) associated with Down syndrome was atrioventricular septal defect, followed with ventricular septal defect (26,4%) and atrial septal defect (11,3%).



Literature

1. Dastgiri S., Stone D.H., Le-Ha C., Gilmour W.H. Prevalence and secular trend of congenital anoma-lies in Glasgow. UK Archives of Disease in Child-hood 2002;86:257-263

2. Eurocat European Surveillance of Congenital Anomalies. www.eurocat.ulster.ac.uk

3. Biri A., Onan A., Korucuoğlu U., Taner Z., Tıraş B., Himmetoğlu O. Distribution and Incidence of Congenital Malformations in a Universitiy Hospi-tal. Perinatoloji Dergisi 2005; 13(2): 86-90

4. Dinarević S. et al. Kongenitalne anomalije u KCUS Sarajevo. Materia socio medica 2005; 17 (1-2):39-41

5. Connor JM, Ferguson-Smith MA. Essential Medi-cal Genetics, 2nd ed. Oxford, Blackwell Scientific Publications, 1987.

6. Congenital abnormality. http://en.wikipedia.org/wiki/Congenital abnormality (last accessed July 9, 2008)

7. Mesihović-Dinarević S. i sar. Pedijatrija za studen-te medicine, Sarajevo: SaVart 2005;99-199.

8. Mardešić i sar. Pedijatrija, Zagreb: Školska knjiga 2003; 685-763.

9. Mesihović-Dinarević S. Dječija kardiologija (od fe-tusa do adolescenta), Sarajevo: Medicinski fakultet 2000; 99-199.

10. Novosel V. Citogenetička analiza kariotipa djece sa urođenim srčanim manama, Sinopsis, UDK 575.11:613.12


Selma Alicelebic Institute of Histology and Embryology, University of Sarajevo, School of Medicine, Cekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina e-mail: [email protected]

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Summary

Brucellosis has been recognized during the past five decades as an important infectious disease in ruminants in Bosnia and Herzegovina. Disease re-ports in recent years indicate an increase in the num-ber of reported outbreaks in ruminants, especially sheep. The objective of this study was to investigate risk factors associated with the brucellosis status of sheep flocks in several cantons of Bosnia and Her-zegovina. A cross sectional study was conducted on 138 sheep flocks during the period of July-Septem-ber 2005. The brucellosis status of the flocks was established through serological testing of serum samples using Rose Bengal and complement fixati-on tests applied in series. Data on risk factors were obtained through a study questionnaire. Risk factor analysis was performed using logistic regression analysis. The brucellosis risk factors identified are those usually associated with traditional manage-ment of small ruminant flocks in this region.

Key words: Brucellosis, small ruminants, risk factors

Introduction

Brucella melitensis, the primary causative agent for caprine and ovine brucellosis, is highly pathogenic to humans capable of causing one of the most significant zoonosis- inflicted disease syndromes known (Corbel, 1997). Brucellosis has been recognized during the past five decades as an important infectious disease of ruminants in Bosnia and Herzegovina (B&H). A government program currently in effect to control the disea-se is based on a test and slaughter policy. Disea-se detection comes through serological testing of routinely collected serum samples and samples obtained from reported clinical cases. Rose Ben-gal (RB) and complement fixation (CF) tests are applied in series for serological testing. Vaccinati-on against brucellosis is prohibited.

When the existing brucellosis detection system and control measures were instituted, reports on disease occurrence documented sporadic outbre-aks occurring predominantly in small ruminants after importation of new animals into the flock (Kolar, 1989). In recent years however, disease reports indicate a persistent increase in the num-ber of reported outbreaks in ruminants, especi-

flock level risk factors for ovine brucellosis in several cantons of bosnia and Herzegovinariziko fakTori Na NiVou STada za PojaVu oVčije bruCeLoze u NekoLiko kaNToNa boSNei HerCegoViNeSabina Seric Haracic1*, Mo Salman2, Nihad Fejzic1, Brian J. McCluskey3, Thomas J. Keefe4

1 Animal Health Economic Centre, Faculty of Veterinary Medicine, Sarajevo, Bosnia and Herzegovina2 Animal Health Population Institute, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, United States of America3 Department of Environmental Health, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, United States of America4 Centers for Epidemiology and Animal Health, Fort Collins, United States of America



ally sheep, along with a significant increase in the number of human cases. According to the State veterinary office of B&H animal health reports, the number of outbreaks reported in small rumi-nants in 2001 was increased more than ten-fold in 2006. Approximately the same level of increase was reported in human cases during the same pe-riod. These factors have had a profound influence on public health and animal production, and they have caused disruption in relations between far-mers, consumers and the B&H veterinary service.

Several authors suggest that, in the cased of en-demic brucellosis it is important to assess many epidemiological characteristics of the disease, since these factors may be useful in defining al-ternative tools for more efficient and practical control (Mikolon et al., 1998; Robinson, 2003; Lithg-Pereira et al., 2004). The most important risk factors for small ruminant brucellosis, such as transhumance and the introduction of new animals into a flock, are universally recognized and well documented (MacPherson, 1995; Reviriego et al., 2000; Kabagambe et al., 2001). However, with a specific animal husbandry method, production type, climate or habitat, a risk factor may have a unique role that may be differently important.

The objective of this study was to identify and investigate risk factors associated with the bruce-llosis status of the sheep flock in several cantons of Bosnia and Herzegovina.

Materials and methodsStudy design

Bosnia and Herzegovina has two administrati-ve units or “entities”, the Federation of Bosnia and Herzegovina (FB&H) and the Republic of Srpska (RS). FB&H is further divided into ten cantons (Map 1). A cross-sectional study was conducted of 138 sheep flocks from five cantons within the entity of FB&H. We used the formula for the estimation of proportion in an infinite population for the cal-culation of the sample size. The expected proporti-on of brucellosis infected flocks was 10%, and the

allowed error rate for required sample size was 5%. (Fleiss, 1981). The participating cantons and their contribution to the overall sample were as follows:

- Hercegovina-Neretva Canton (HNC) with 16 flocks, - Srednja- Bosna Canton (SBC) with 34 flocks, - Zenica-Doboj Canton (ZDC) with 32 flocks, - Una-Sana Canton (USC) with 35 flocks and - Tuzla Canton (TC) with 21 flocks.

Map 1: Administrative division of Bosnia and Herzegovina where yellow areas represent the study sampling area; five cantons in north (can-ton III or Tuzla Canton), northwest (canton I or Una– Sana Canton), center (cantons IV and VI or Zenica– Doboj and Srednja– Bosna Cantons, res-pectively) and south (canton VII or Hercegovina- Neretva Canton ) of Bosnia and Herzegovina

Data used in this study were collected during the period July-September 2005. Data collection was conducted as a collaborative project between the Animal health economics centre (Veterinary faculty Sarajevo), Veterinary institute Bihać and cantonal veterinary inspectors. Flocks included in this study came from the work areas of 23 veteri-nary practices, each participating in proportion to their work area size. Flocks tested were selected by participating local veterinarians who chose an

Table 1. Sample size for each individual flock at estimated within flock prevalence of 15%Flock size <50 animals 50-100 animals >100 animals

Sample size 15 17 19

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equal share of small (up to 50 animals), medium (from 50 to 100 animals) and large (more than 100 animals) flocks from their work areas. Participa-tion by the farmers and local veterinarians in the study was on a voluntary basis.

The brucellosis status of the flocks was esta-blished through serological testing of serum sam-ples. A flock was considered infected when one or more individual samples from the flock tested brucellosis positive. In order to calculate the num-ber of individual animals to be sampled from each flock we assumed brucellosis prevalence within a flock to be 15%. The number of serum samples taken from each flock was based on the flock size (Robinson, 2003) (Table 1).

A questionnaire was developed to obtain data on risk factors related to animal husbandry, introducti-on of new animals, and the occurrence of abortion as a primary symptom of disease. Data were collec-ted on flock size, the occurrence of multiple rumi-nant species farming, housing of animals, seasonal animal movement practices, sources of rams, and housing and group sizes for ewes during lambing. We collected further data on new animal origin, gender, the existence of health certificates for new introductions, and the length of time new introduc-tions were quarantined prior to their introduction to the flock. Data were also collected on abortion ra-tes. Questionnaires were reviewed by collaborating veterinary officials prior to their use in this study. For the study, the questionnaires were administe-red through personal interviews with flock owners during sampling visits. In order to ensure the con-sistency in the information collected through the questionnaires, only one person was involved in questionnaire administration.

Serological testing

Blood samples were collected from adult ani-mals (more than 1 year old) through venipuncture, using a single use vakutaner system. Once collec-ted, samples were transported to the laboratory, where they were stored at 4°C for a maximum of 2 days. Serological testing of the serum samples was accomplished using Rose Bengal and comple-ment fixation tests applied in series. After testing with the RB test, the extracted serum was separa-

ted from the blood clot in the tubes and stored at -20°C. Frozen serum samples were thawed over-night in the refrigerator prior to further testing.

Tests were carried out according to the OIE Manual of standards for diagnostic tests and vacci-nes (Garin-Bastuji and Blasco, 2004). The RB test was performed by mixing 25μl of the serum and an equal volume of antigen on a white, shallow welled, enamel plate. The mixture was rocked gently for 4 minutes at room temperature and then observed. Any sign of agglutination was conside-red positive. The CF test was performed using the ¨warm¨ procedure described by Alton et al. (1975) on standard 96-well micro-titre plates. The serum was considered positive if it showed at least 50% haemolysis at a given dilution (i.e. ≥20 ICFTU).

Data management and statistical analysis

The results from serological testing and the administered questionnaires were organized into a data base created specifically for this project (Microsoft® Access 2000). MINITAB 14, student version (Thomson learning ©2005), was used for logistic regression analysis.

The investigated risk factors were initially asse-ssed using univariable logistic regression analysis (Hosmer and Lemeshow, 2000). Prior to analysis, all continuous variables were categorized into qu-artiles in order to facilitate interpretation of the odds ratio. The chi- square (the likelihood ratio) or Fisher’s exact test (where observed cell frequenci-es were <5) were used to test for statistical signi-ficance of association between brucellosis flock status (1-one or more seropositive animal, 0- no seropositive animals) and categorical risk factors. In order to be considered eligible for multivariable logistic regression model, individual risk factor variables had to be significantly associated at the 20% significance level (i.e., p-values <0.2) in the univariable logistic regression analysis. Prior to multivariable analysis, selected individual varia-bles were tested for co-linearity using correlation analysis. In cases where two variables had correla-tion coefficients larger than 0.3, only the variable that had more biological relevance (larger odds ratio) was retained for further analysis. The same criterion was used in selecting between risk factor



variables that resulted from the same data but were defined using different criteria for categorization.

The multivariable logistic regression model was built using a stepwise approach described by Hosmer and Lemeshow (2000). A preliminary model contained all of the independent variables selected in the previous step of risk factor anal-ysis. A backward elimination procedure was used to determine the best model. All of the variables found to be associated at the 5% significance level (i.e. p-values <0.05) were retained in the multivari-able logistic regression model. Hierarchical models (at first with primary effects only and then later with two-way interactions terms) were also fitted.

Results

The median flock size for the 138 flocks in-cluded in this study was 86 (mean flock size 125 animals). The flock size was found to be quite va-riable, ranging from 9 to 526 animals. In regar-ds to farm management, 25.4% (35/138) of the flocks included in this study were managed as farm flocks, while the rest (103/138) were mana-ged as either fenced - range or range flocks. It is important to note that 71.4% (25/35) of the farm flocks in this study were composed of less than 50 animals. None of the owners of these flocks practi-ced seasonal movement of animals. Fenced- range

Table 2. Questionnaire results for risk factor variables significantly associated with flock status at the 20% significance level by univariable analysis (the likelihood ratio chi square probability or Fisher’s exact test (<5 observed cell frequencies))

Variable Number of flocks

% of brucellosis positive flocks OR P

Flock originSBC 34 23.5 3.6 0.031Other cantonsa 104 8.7 - -

Flock size >39 (Q1) 103 13.6 1.7 0.187b

>86 (median) 68 17.6 2.8 0.057>186 (Q3) 34 23.5 3.3 0.031

Cohabitation with goats Yes 17 23.5 2.6 0.097b

Noa 121 10.7 - -

Farm managementFenced range 50 20.0 2.9 0.043Farm 35 5.7 0.4 0.101b

Other/Combinedc 53 9.4 - -

Transhumance Yes 31 29.0 5.1 0.003Noa 107 7.5 - -

Transhumance to cantons where brucellosis is prevalent

Yes 13 46.2 8.9 0.001Noa 125 8.8 - -

Ratio rams to ewesd more than 1:20 45 17.8 2.9 0.0701:20 or lessa 73 6.8 - -

Housing during lambingd

Fences 24 37.5 7.9 <0.001Stables 103 5.8 0.1 <0.001Other/Combinedc 10 20 - -

Abortiond Yes 56 19.6 2.9 0.044Noa 77 7.8 - -

Abortion > 3 per flock (Q3)d Yes 25 36.0 7.0 <0.001Noa 108 7.4 - -

Previous history of brucellosisd Yes 8 62.5 14.7 <0.001Noa 118 10.2 - -

Legend: a- Reference category, b- Based on the Fisher’s exact test, c p>0.2 in the univariable analysis, not offered to the MLR model, d- Sample decreased due to the lack of data for some of the sample units

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flock management in B&H implies that animals are on pasture during the day and gathered inside fenced areas at night and during lambing. The fen-ces are usually mobile, allowing farmers to move their flocks in search of better pasture. The inve-stigated sheep farms were, for the most part, ori-ented towards meat production. Only in the canton Srednja- Bosna, is sheep farming primarily orien-ted towards dairy production. The destination for farm products is predominantly the local market. In this study, we determined that 22.5% (31/138) of farmers move their animals during the year in order to provide better pasture. These flocks are often pastured in minimally accessible mountai-nous areas, and consequently most animal heal-th problems are handled by a shepherd. It is not uncommon for these flocks to be the product of a merger between several flocks, thus promoting intermingling of flocks.

Of the 138 flocks, we identified 17 flocks with one or more infected animals yielding a proporti-on of brucellosis infected flocks in our sample of 12.3%.

Risk factors found to be associated with bru-cellosis occurrence in the flock at a level of sta-tistical significance of 20% based on univariable logistic regression analyses results are shown in the Table 2. These factors included: flock origin, flock size, cohabitation of sheep and goats, main-tenance of animals as fenced range flocks, seaso-nal movement of flocks, ratios between rams and ewes of more than 1:20, the housing ewes within fences during lambing, and histories of abortion or increased abortion frequencies within the flock.

Six of these variables were not considered for the multivariate logistic regression (MLR) anal-ysis due to their high co-linearity with one or more

of the other variables with higher biological plau-sibility (larger odds ratio). The final MLR model (Table 3) retained the following risk factors: sea-sonal movement of flocks into cantons with a high level of brucellosis occurrence, housing of ewes in fences during lambing and the occurrence of more than 3 abortions during the previous lambing sea-son (greater than the third quartile in the number of abortions in a flock used as continuous varia-ble). The sample size for the multivariate model was decreased from 138 to 132 flocks due to lack of the specific data for 6 of the sample units (in-cluding one brucellosis positive flock). First-order interactions of these risk factors were evaluated via MLR analysis, but none were found to be sta-tistically significant.

Discussion

This study represents the first epidemiological study with the aim to evaluate risk factors at the flock level for sheep brucellosis in Bosnia and Herzegovina. According to our results, the highest proportions of brucellosis positive flocks were fo-und in cantons where:

- producers were predominantly oriented towards dairy production (SBC),

- larger flocks were predominant (SBC, USC, ZDC) and

- seasonal movement of flocks was widely practiced among sheep farmers (SBC, ZDC).

Generally, differences in susceptibility for bru-cellosis in individual animals are dependent almost exclusively on the invasion site, stage of gesta-tion at the time of exposure and the infective dose

Table 3. Parameters of the final multiple regression model, that includes only those variables with p values for the odds ratios less than 0.05. Odds ratios and correspondent 95% confidence intervals are also provided for eligible variables.

VariableLogistic regression parameters

b SE (b) p OR 95%CI (OR)Constant -3.2 0.59 <0.001 - -Transhumance to cantons where brucel-losis is prevalent 1.9 0.84 0.023 6.6 1.3-34.2

Housing during lambing in fences 2.2 0.71 0.002 8.6 2.2-34.3Abortion >3 per flock (Q3) 2.31 0.7 0.001 10.1 2.5–40.1



(Crowford et al., 1990). However, according to Al-ton (1985), milking sheep also appear to be more susceptible to brucellosis than animals used for other products. Even though we found an associa-tion between the brucellosis status of a flock and a farmer’s orientation towards dairy production, this association was not statistically significant.

Based on the univariable logistic regression analysis results and findings of other authors (Lithg-Pereira et al., 2001), flock size appeared to be an important risk factor for brucellosis oc-currence in the flock. Simple animal numbers are clearly not the only contributor to increased disease risk, as shown by further analysis. Larg-er flocks are also predominantly maintained as fenced range flocks, and fenced range flocks are, in addition, more likely to be composed of no-madic flocks. These three variables were highly correlated. Therefore, only the destination and conditional nomadic practices of the flock owner were provided as risk factor variables in the MLR model in this study. Nomadic and semi- nomadic husbandry systems are well established risk fac-tors for brucellosis occurrence in sheep (MacP-herson, 1995; Omer et al., 2000; Reviriego et al., 2000; Al-Talafhah et al., 2003). Logically, not the practice itself, but the opportunity for contact with other potentially infected animals through seasonal movement of flocks creates the risk for establish-ment of brucellosis in a nomadic flock. Accord-ingly, seasonal movement of sheep in previously established brucellosis- prevalent areas amplifies the risk of potential contact with infected flocks. This was also confirmed by the results of multi-variate logistic regression analysis.

Independent and multivariable assessment of the fencing of ewes during lambing shows that this practice increases the risk of brucellosis infec-tion within a flock. The close contact that occurs between animals within fences, and the fact that aborted fetuses and placentas contain the highest concentrations of the agent, clearly support our findings (Garin-Bastuji and Blasco, 2004). Ani-mals managed as farm flocks have close contact during lambing and, therefore have equal opportu-nity for the spread of brucellosis within the flock. However farm flocks are generally housed in sta-bles and usually consist of smaller numbers of ani-mals. These flocks are pastured on private pastures

around households, and therefore are at a lower risk of contacting a diseased animal.

The practice of bringing new animals of unde-termined origin and health status into a flock might represent a window for introducing brucellosis (Mikolon et al., 1998; Lithg-Pereira et al., 2004). Also, the rearing goats along with sheep was shown to have an influence on brucellosis occurrence (Mikolon et al., 1998). These risk factors, although found to have an association, were not determined to be statistically significant in our study.

Even though, increased odds for brucellosis in-fection in flocks where ratio of rams to ewes was more than 1:20, were found to be almost statisti-cally significant in univariable analysis, they had to be excluded from MLR model since this vari-able had failed to meet established criteria on vari-able relevance. For the same reason variable on previous history of brucellosis was excluded from MLR model, although it was highly significant in univariable analysis.

Abortion occurrence is identified as a cause of suspicion for brucellosis by current control requirements in this country and in the OIE ter-restrial manual (Garin-Bastuji and Blasco, 2004). The odds ratio quantifying the risk of brucellosis infection in flocks with previous history of abor-tion was shown to be statistically significant at the 5% significance level through univariable analy-sis. However, this variable demonstrated a signifi-cantly increased association with brucellosis sta-tus of a flock when transformed so that not only abortion occurrence but abortion frequency were taken into account.

Conclusion

Mediterranean countries, such as B&H, provide the specific conditions, including extensive farming, communal pastures and uncontrolled animal move-ment that form the historical context for the per-sistence and spread of brucellosis infection among small ruminants. Many of the identified brucellosis risk factors are associated with the traditional way of managing small ruminant flocks in this area.

Planning of a targeted detection strategy should account for the established risk factors associated with brucellosis occurrence and spread. The risk

44



based approach to the disease surveillance would increase the overall sensitivity of the disease detec-tion and allow more effective allocation of limited resources for disease containment. However, in or-der to reach comprehensive and scientifically based disease detection program, further investigation of disease epidemiology are needed. Primarily, future studies need to reliably establish small ruminant brucellosis prevalence and incidence in the country and investigate specific relationship between bru-cellosis in humans in animals. This would impro-ve the market competitiveness of domestic sheep production by increasing consumer trust, and most importantly, help ih prevention of human cases.

Literature

1. Al-Talafhah, A.H., Lafi, S.Q., Al-Tarazi, Y. (2003): Epidemiology of ovine brucellosis in Awassi sheep in Northern Jordan. Preventive Veterinary Medici-ne, 60, 297-306.

2. Alton, G.G., Jones, L.M., Pietz, D.E. (1975): La-boratory techniques in brucellosis. In: WHO mo-nograph series No. 55, World Health Organization, Geneva, 163 pp.

3. Alton, G.G. (1985): The epidemiology of Brucella melitensis in sheep and goats. In: Verger, J.M., Plo-mmet, M. (ed.): Brucella melitensis, a CEC semi-nar. Martinus Nijoff, Dordrecht-Boston-Lancaster, 187-196.

4. Corbel, M.J. (1997): Brucellosis: an overview. Emerging Infectious Diseases, 3, 213-221.

5. Crawford, R.P., Huber, J.D., Adams, B.S. (1990): Epidemiology and surveillance, 132-148. In: Nielsen, K., Duncan, J.R. (ed.): Animal brucellosis. CRC Press, Boca Raton, Florida, USA, 301 pp.

6. Fleiss, J.L. (1981): Determining sample size needed to detect a difference between two proportions. Sta-tistical methods for rates and proportions. 2nd ed. John Wiley & Sons, Inc., New York, USA, 309 pp.

7. Garin-Bastuji, B., Blasco, J.M. (2004): Caprine and ovine brucellosis (excluding B. ovis). In: Man-ual of Diagnostic Tests and Vaccines for Terrestrial Animals. OIE, Chapter 2.4.2.

8. Hosmer, D.W., Lemeshow, S. (2000): Applied logis-tic regression. 2nd ed. John Wiley & Sons, Inc., New York, USA.

9. Kabagambe, E.K., Elzer, P.H., Geaghan, J.P., Opu-da-Asibo, J., Scholl, D.T., Miller, J.E. (2001): Risk factors for Brucella seropositivity in goat herds in eastern and western Uganda. Preventive Veterinary Medicine, 52, 91-108.

10. Kolar, J. (1989): Brucellosis in Eastern Europe-an countries. In: Young, E.J., Corbel, M..J. (ed.) Brucellosis; clinical and laboratory aspects. CRC Press, Inc., Boca Raton, Florida, SAD, 164-172.

11. Lithg-Pereira, P.L., Mainar-Jaime, R.C., Álvarez-Sánchez, M.A., Rojo-Vázquez, F.A. (2001): Evalu-ation of official eradication-campaigns data for investigating small-ruminant brucellosis in the province of Leon, Spain. Preventive Veterinary Medicine, 51, 215-225.

12. Lithg-Pereira, P.L., Rojo-Vazquez, F.A., Mainar-Jaime, R.C. (2004): Case-control study of risk fac-tors for high within-flock small-ruminant brucel-losis prevalence in a brucellosis low-prevalence area. Epidemiology and Infection, 132, 201-210.

13. MacPherson, C.N.L. (1995): The effect of trans-humance on the epidemiology of animal diseases. Preventive Veterinary Medicine, 25, 213-214.

14. Mikolon, A.B., Gardner, I.A., Anda, J.H., Hietala, S.K. (1998): Risk factors for brucellosis seroposi-tivity of goat herds in the Mexicali Valley of Baja California, Mexico. Preventive Veterinary Medi-cine, 37, 185-195.

15. Omer, M.K., Assefaw, T., Skjerve, E., Tekleghiorghis, T., Woldehiwet, Z. (2000): Prev-alence of antibodies to Brucella spp. in cattle, sheep, goats, horses and camels in the State of Er-itrea; influence of husbandry systems. Epidemiol-ogy and Infection, 125, 447-453.

16. Reviriego, F.J., Moreno, M.A., Dominguez, L. (2000): Risk factors for brucellosis seropreva-lence of sheep and goat flocks in Spain. Preventive Veterinary Medicine, 44, 167-173.

17. Robinson, A. (2003): Guidelines for coordinated human and animal brucellosis surveillance. FAO, Rome, 46.


Sabina Seric Haracic, Animal health economics centre, Veterinary faculty, Zmaja od Bosne 90, 71 000 Sarajevo, Bosnia and Herzegovina, Tel./fax: +387 33 66 35 51, e-mail: [email protected]



Summary

The aim: investigation of hypertension in mi-ners, depending on working conditions inside and outside of mine- pit, number of years of working and influence of smoking as a risk factor.

Methods: 828 miners or 40,66%, out of total number of employes, was covereed by this resear-ch. The control group consisted of 310 miners out of mine-pit or 15,2% out of total number o em-ployees. Blood preasure was measured at the beg-gining and ending of working process throughout the month, following the work in shifts.

Results: after complete examining and statisi-cal processing of recieved datas, a conclussion can be made that statistical significant case of hyper-tension among miners is evident, and it it caused by influence of working area and influence of smoking as additional risk factor.

Conclusion: The workers who worked in three shifts have had the hypertension evident more than those who worked outside the mine-pit, as well as increased smoking risk-factor in category up to 20 years in working process,and in both go-rups, in category over 20 years in working pro-cess, the smoking as risk-factor is more evident. Apart from the legal regulations concerning wor-king enviroment conditions and allowed negative factors in working enviroment, it is necessary to have better supervision of working conditions and better cooperation of service that controls protec-tion in working with team of doctors, as well as activities on introducing of smoking risk-factors, esspecially to those elderly employees.

Key words: hypertension, miners in mine-pits, working enviroment, cardiovascular dissease ( CVD)

Sažetak

Cilj: ispitati pojavu hipertenzije kod rudara ovisno o uslovima rada u jami i van jame, dužini radnog staža i uticaja pušenja kao faktora rizika.

Metode: Ispitivanjem je obuhvaćeno 828 ruda-ra ili 40,66% od ukupnog broja zaposlenih. Kon-trolnu grupu sačinjavalo je 310 rudara van jame ili 15,2% od ukupnog broja zaposlenih. Krvni pritisak je mjeren na početku i na kraju radnog procesa u toku mjesec dana prateći smjenski rad.

Rezultati: Nakon kompletnog ispitivanja i sta-tističke obrade dobijenih podataka može se kon-statovati da je dokazana statički signjifikantna po-java hipertenzije kod jamskih radnika što je uzro-kovano uslovima radne sredine i uticajem pušenja kao dodatnog riziko faktora.

Zaključak: Radnici u jami radeći u tri smjene imali su pojavu hipertenzije znatno više nego rad-nici van jame, kao i povećani riziko faktor pušenja u kategoriji do 20 godina staža, a u obje grupe rad-nika u kategoriji preko 20 godina staža znatno je izraženo pušenje kao riziko faktor.

Pored zakonske regulative vezane za uslove radne sredine i dozvoljene štetnosti vezane za štet-ne faktore radne sredine potreban je veći nadzor nad uslovim rada i bolja saradnja službe zaštite na radu sa ljekarskim timovima, kao i aktivnosti na upoznavanju radnika o značajnom riziko faktoru pušenju posebno u kod starijih radnika.

Ključne riječi: hipertenzija, jamski radnici, radna sredina, kardiovaskularna bolest (KVB).

Hypertension as leading cardiovascular illness among minnersHiPerTeNzija kao Vodeća kardioVaSkuLarNa boLeST rudaraMuvedeta Lemes, Belma Pojskic

PZU “INTERMED“ Kakanj, County hospital of Zenica – internal department

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Introduction

CVD ( cardiovascular disseases) are primary cause of lethal outcome in the world. In USA, le-athal outcome of these disseases is 6 times larger than those of breast cancer. It is also the case in Europe, and we assume also in our country even though we do not have precise datas. There is no general register of cardiovascular disseases. In European congress of cardiologists in Stockholm, in 2005, the datas were given concerning neglec-ting of risk factors, esspecially to speciffic wor-king area conditions. ( disseases related to Marija Zavalić’s paper ).

One of conclusions was that the process of cu-rring shouldn’t be concentrated only on preventi-on of illness but also on „working place and en-viroment“ . according to WHO datas from 2004 cardio-vascular illnesses are the main reason of mortality in men and women, 44% in men and 55% in women. Regardless the fact that of male population and speciffic working enviroment whi-ch mostly has multiple risk factors, minners po-pulation is surelly the one with larger degree of cardiovascullar illnesses frequency.

The outlook of mine pits, weather conditions, humidity, dusting, bad gasses, noise, vibrations, hevy work, narrow working place...all these repre-sent risk factors that lead to cardiovascular illneses.

Th aim of work is to explore the appearance of hypertension in minners regarding the working conditions in mine pits and outside of it, smoking as additional risk factor as well as the lenght of working period.

The methods and the tested workers

Testing was conducted on 828 workers , out of which 518 were those who work in mine pits , and 310 who work outside of mine pits.

Hypertension is a state of increased systolic or diastoic blood preasure.according to directi-ves published in 2007 as a result of cooperation of European cardiological society and European society for hypertension (ESH/ECH), there are reccomendations based on evidences for diagno-sys determination, and for educative value among patients with hypertension.

According to most of the directives given, the bottom line for determination of diagnosis of hypertension is the level of blood preasure of 140/90mmHg.The preasure less than this is con-sidered normal but Europeans directives make the difference between optimal, normal and increased blood preasure, and the higher one is considered as first degree hypertension according to menti-oned directives with the level o blood preasure, systolic, from 140 to 159 mmHg and diastolic from 90 to 99 mmHg. As Second degree hyper-tension is considered systolic blood preasure from 160 to 179 mmHg, and diastolic from 100 to 109 mm, and third degree hypertenion is with blood preasure larger from 180 and diastolic larger from 110 mmHg.

Testings were conducted according to age, len-ght of work and smoking habitts.

All workers’ preasure was measured before en-tering the mine pit and after working day in three shifts, as well as workers who work outside of mine pit. The testing lasted for a month. All results were processed in statistical methods and presen-ted in tables.

Even though the working enviroment of miners is speciffic, with many proffessional risks and da-mges, still, it is unknown how and in what way, certain proffessional damages are related to hyper-tension.

Results

In this paper, 828 of workers were tested, out of which 518 of them were those who work in minnig pits or 40,66% and 310 or 15,2% of those who work outside of minning pits.Table 1. The number of employees and the num-ber of workers inside and outside of minnig pits

Workers ( Miners )on coal digging 828 36,9%

Mine – pit workers 518 23,1%

Surace–digging(outside of mine-pit) 310 13,8%

Other workers 1411 63,1%

Total number of employees 2.239



In table 2. the total amount of examined wor-kers inside and outside of mine pits is presented and relation to years of work, up to 20 yrs and over 20 yrs of total number of working years . Table 3. Number of those who suffer from hyper-tension according to working place

Examined workers Total HTA

Workers in mine pit 518 238 45,9%

Workers outside mine pits 310 56 18,1%

Total 828 294 35,5%

In table 3. 828 of workers were tested, out of which 518 of them were those who work in minnig pits or 40,66% and 310 or 15,2% of those who work outside of minning pits.

Picture 1. Graphic presentation of percentage of those who suffer from hypertension, working in mine pits.

Picture 2. graphic presentation of percentage of those who suffer from hypertension, working out-side of mine pits.

Regarding the years in work, up to 20 years, 118 of workers have been diagnosed with hyper-tension up to 20 years in work and 120 of them with over 20 years in work which is totaly 238 or 81% out of number of examined workers. In a gro-up of workers outside of a minning pit, up to 20 years in work , 22 workers are with diagnosys of hypertension and over 20 years in work - 34 wor-kers, what is 56 worers in total or 19 %.

Table 2. Examined workers according to years of work

Examined workers The years of work

Total0-20 yrs. More than 20 yrs

Workers in mine pits 360 158 518

Workers outside mining pits 180 130 310

Total 540 288 828

Table 4. The number of those who suffer from hypertension according to years in work.

Workers with hypertensionYears in work

TotalUp to 20 yrs. Over 20yrs.

Workers in minning pit 118 120 238 81%

Workers outside minning pits 22 34 56 19%

Total 140 154 294 100%

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Picture 3. Graphic presentation of those with hypertension who work in a minnig pit.

Picture 4. Graphic presentation of percentage of those who suffer from hypertension, working outside of mine pits

Using the χ2 test, the hypothesis on significant difference in total number of those with hyperten-sion is tested, regarding the working conditions. Three hypothesis were tested:

1. There is statistical signifficant difference in dignosing of hypertension regarding the working conditions (inside or outside the minnig pit). The final value of χ2 = 65,84, what is significantly above the limited value 3,841, and with probability of p less than 0,05, the mentioned hypothesis can be approved, i.e. miners working in minning pits, are more exposed to hypertension, and they make 81 % of total number of workers with hypertension.

2. There is statisticaly significant difference in diagnosing of hypertension according to age and years of work ( up to 20 and over 20 years of work) between the groups defined according to working conditions. The final values for the first and the second case are χ2 = 33,95 and χ2 = 19,06, what is signifficantly above the limit value of 3,841, and with probability of p less than 0,05, the hypothesis can be aproved. i.e. in first group ( up to 20 years of work ) and in second group ( over 20 years of work), those who are working inside the minning pits and they are the members of the first group 84,3% and 77,9% for second group of workers with hypertension in some other groups.

3. There is signifficant difference in diagnosing of hypertension dependable on age, regading the working conditions. there is sttisticaly signifficant difference in number of smokers. The value χ2 = 82,4 (for workers in minning pits) and χ2 = 9,90 ( for workers outside the minning pit ), which is significantly above the limited value of 3,841, and with probability of p less than 0,05,the hypothesis can be approved, i.e, in first ( inside minning pits ) and in second group ( outside the minning pits ), the workers above 20 years of work are under the larger risk of diagnosing of hypertension and, at the same time, it is possible to apply that the value x2 is signifficantly less, i.e. the difference is signifficantly larger among workers who work inside the minning pits as well as the risk of diagnosing of hypertension throughout the years of work in minning pit.

Table 5. Total number of smokers and nonsmokers according to working years.

Years of work Up to 20 years Over 20 years

Examined Smokers (%) Examined Smokers (%)

Workers in minning pits 360 252 (70) 158 138 (87)

Workers outside of minning pits 180 101 (56) 130 118 (90)

Total 540 353 (65) 288 256 (89)



In table 5, relation with smoking according to number of examined workers, is presented

Using the χ2 test, the hypothesis on signifficant difference in number of smokers related to wor-king conditions is also presented .

Three hypothesis were tested: 1. There is statisticaly signifficant difference

in number of smokers related to working conditions (inside and outside of minning pits). The final value χ2 = 2,15, what is less than limited value 3,841, and, with probability of p less than 0,05, the hypothesis can’t be approved or established, i.e. there is no statisticaly signifficant difference in number of smokers related to working conditions.

2. There is sttisticaly signifficant difference in number of smokers according to age (up to 20 and over 20 years of work) between groups deffined according working conditions. The final value for the first case χ2 = 10,23, and for the first group (up to 20 years of work) it means approval of hypothesis on existence of signifficant difference between those who work inside and outside of minning pits and the number of smokers who work inside minning pits is bigger. The final value for the second case χ2 = 0,85. and for the second group (over 20 years of work), it means that the hypothesis on existence of signifficant difference between those who work inside and outside of minning pits can not be approved.

3. There is sttisticaly signifficant difference in number of smokers according to age group regardles on working conditions. The final values χ2 = 17,75 (for workers in minning pits) and χ2 = 43,72 ( for the workers outside the minning pits), what is signifficantly above limited value of 3,841, and, with probability of p less than 0,05, the hypothesis can be approved or established, i.e. in first group (minners in minning pits) and in second group (minners ouotside minning pits), the number of smokers with more than 20 years in working process regardless working conditions what increases the risk factors for hypertension for both groups, regardless the age.

Discussion and conclusions

Minners’ working place has certain specifficiti-es, characteristic proffessional damadges and heal-th risks. The basic proffessional damadges in mines are: innapropriate metereological factotrs, dusting, noise, vibrations, hard work, working in shifts, narrow working space, innapropriate position, etc.

This group is directly related to process of coal digging, which means working at the front of the group where these risk factors are highest.

Increased physical effort, sensation activity, noise, vibrations, innapropriate position, all these factors lead to certain preasure of organism that leads to psychical preasure.

Surface coal digging as working enviroment has pfoffessional damadges but in a lot less level than under the surface. as most important factor, this area has natural ventilation and possibillity of decreasing of dusting by moisturing of this area, what is more comfortable than in a pitt. (9,7).

Constantly present feeling of tension has a di-rect influence on cardiovascular sytem and hyper-tension risks (5).

All these damadges individualy or in a group have influence on cardiovascular system and lead to hypertension of certain level. Along with ge-netic predisposition, risk factors and other men-tioned proffessional damadges, unless it’s detec-ted in a right time and curred, lead to progressive hypertension that can also produce different cardi-ovascular incidents. After testing, it is obvious that hypertension is a leading dissease among minners.

Based on research and sttistical processing, it is proved that there is signifficant difference in dia-gnosisng of hypertension regarding the age and no matter on working conditions. The research showed that those who work inside the minning pits are more exposed to hypertension regardless the years in work (in group up to 20 and over 20 years of work).

Out of 518 workers, who work in minning pits, 238 is with diagnosed hypertension or 45,9 %, and in comparing to years of working, the diffe-rence is not evident, which means that risk factors in working area are extremly influential on dia-gnosing of hypertension in minners.

In order to prevent these disseases in minners, an effort is made to decrease their exposure to bad influencess, primarly coal dust (3).

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National institute for proffessional safety and health of workers in USA (NIOSH-national In-stitute for Occupational Safety and Health ) in septembre 1995. has proclaimed proposition that exposure limit (REL.recommended exposure li-mit) does not breach over 1mg/m3 of air during average working time of 10 hours per day with 40 hour working week. (5).

Presented material shows tha factors of wor-king enviroment, primarly coal dust, tension, narrow working space without ventilation, leads to certain tension of organism and hypertension. (1).

Smoking is additional risk factor in working enviroment of minners. Irritation of vegetative ganglion leads to increase of cardio frequency , beating and minute volume and increase of artery preasure (10).

It is evident that great number of minners addi-tionaly increasses hypertension cases, esspecially in group over 20 years in work.

Research show the signifficant difference between the groups working inside and outside the minning pits, i.e. the minners inside minning pits are smokers in most cases and get hypertension diagnose more often.

The results of this paper show that these da-maging factors seem mostly cumulative and the most number of tested cases have been exposed to respirative coal dust and smoking.

In order to aplly these research results, it is ne-cesary to present it to subjects incharge, with reco-mondation of preventive-promotional work as the way to influence the quality of living of minners as well as guarancy o microclimatic working con-ditions what would provide respirative dust to allowed level.

This research should be used as reason for furt-her similar ang bigger researches in future.

There are no conditions of working enviroment without certain health risks on workers health. Proper evaluation of danger in work must include the work itself, working enviroment and total phi-sical and psychical markings of workers.

When all these markings are known, including proffessional and nonproffessional risk factors, we can provide adequate evaluation of health con-dition in order to protect employees’ health.

It is mandatory to educate family doctors rela-ted to illnesses that can dissapear or get worse in time becouse of innapropriate working conditions and establish good cordination between medical services in order to prevent premature disseases, consequential sick-leaves and premature invalidity.

Further on, it is mandatory to perform medical sistematic examinations in order to detect illness in proper time and to prevent progression of it, com-plications and to prevent invalidity This research should be used as influential for other bigger rese-arches in order to include team aproach to overvi-ewing and resolving of mentuioned problems.

Literature

1. Hearth Disease and Stroke Statisties 2004 Update. Dallas, Texas: American Hearth association; 2003.

2. Deborach D. Risk factors for atherosclerosis among coal miners.2003;12:23-45.

3. Newman B. Ankle-arm index as a predictor of car-diovasular disease and mortality in the cardiovas-cular health study. 2002; 3:538-545.

4. Nordsrom K.Work related sress and early atherosc-lerosis miners. Epydemiology 2001;2:180-185.

5. Schnell L. The workplace and cardiovascular dise-ase. OCCUP Med. 2000,1:12-23.

6. Gryn Y. Prevalence of silicosis at death in under round coal miners- Am. J Med. 2002;16:605-615.

7. Jensen H. Occupational miners diseases. Western Federation of miners. 2002; 1-54.

8. Institut za ocjenjivanjeradne sposobnosti. Radno angažovanje invalida rada i prijedlog mjera pre-vencije imnvalidnosti u rudnicima uglja u BiH. Sarajevo.1989g; 22-54.

9. Wang L. Clinical important FEV declines among coal miners. Ocup env Med J.1999,65:837-844.

10. Puvačić Z. Statistika u medicini. Sarajevo.1999.

Corresponding author: Muvedeta Lemes PZU “INTERMED“ Kakanj, Adress: ZPO br: 52, 72240 KAKANJ Telephone /fax: + 387 ( 032 ) 55 46 84 E-mail: [email protected]



Summary

Introduction: There are two types of Diabetes mellitus (DM) and each have different ocurrence of lower extremitates amputation.The most common reason for amputation is existance of diabetic foot.

Aim: Is to presentate occurrence of lower extremitates amputation in relation to DM type, when during the existance of DM is done the most of all amputations, type of antidiabetic therapy in the amputatet patients, number of dead outcomes among amputated patients by reason of additional complications.

Patients and methods: Retrospective study is done at Clinic for orthopedy and traumathology and at Institut for vascular diseases KCUS. Study includes 87 patients of which 60 are evaluated which endured lower extremitates amputation due to DM existance during 2 years period.

Results: Among amputated diabetic patients 91,7% were with DM type 2 and 8,3% with DM type 1.30% patients with DM for 5-10 years ,15 % less then 5 years , 13 % patients 16-20 years,13% 21-25 years,and 5% over 25 years. 88,3% patients were treated with Insulin therapy .11,7% were on oral antidiabetic therapy.Five patients died soon after amputation.

Conclusion: There is difference in DM type between. Amputations are more often at patients with duration of DM from 5 to 10 years and at patiens on insulin therapy.

Key words: Diabetes type,diabetic foot

Sažetak

Uvod: postoje dva osnovna tipa dijabetes me-litusa kod kojih je učestalost amputacija donjih ekstremiteta različita. Najčešći razlog za amputa-ciju kod dijabetičara jeste postojanje dijabetičnog stopala.

Cilj rada: prikazati učestalost amputacija do-njih ekstremiteta prema tipu dijabetes melitusa, u kojem periodu trajanja dijabetes melitusa je ura-đeno najviše amputacija, tip antidijabetične tera-pije kod amputiranih pacijenata, broj (procenat) pacijenata kod kojih je nakon urađene amputaci-je nastupio smrtni ishod kao posljedica dodatnih komplikacija.

Pacijenti i metode rada: istraživanje je prove-deno na Klinici za ortopediju i traumatologiju i In-stitutu za vaskularne bolesti KCUS u vidu retros-pektivne studije. U obzir je uzeto 87 pacijenata, a analizirano je njih 60 kod kojih je urađena ampu-tacija donjeg ekstremiteta kao posljedica dijabetes melitusa u dvogodišnjem periodu.

Rezultati: među amputiranim dijabetičari-ma 91,7 % pacijenata je imalo dijabetes melitus tip 2, a 8,3 % dijabetes melitus tip 1 (X²=0,343, p>0,05). Najviše pacijenata, 30 %, imalo je traja-nje dijabetesa 5 – 10 godina, 15 % pacijenata do 5 godina, 13 % pacijenata 16 – 20 godina, 13 % 21 – 25 godina i 5 % pacijenata trajanje dijabetes pre-ko 25 godina (X²=4,682, p>0,05). Na inzulinskoj terapiji bilo je 88,3 % pacijenata, dok je 11,7 % pacijenata bilo na terapiji oralnim antidijabeticima

dependence of lower extremies amputations to caracteristics of diabetes mellitus oViSNoST amPuTaCija doNjiH ekSTremiTeTa u odNoSu Na oSobiNe dijabeTeS meLiTuSaDijana Avdic1, Dzemal Pecar, Mensura Kudumovic, Mirela Avdic

Orthopedic Clinic, University Clinical Center Sarajevo, Bosnia and Herzegovina

52



(X²=3,672, p>0,05). Kod 5 (8,3 %) pacijenata je nastupio exitus letalis nakon urađene amputacije.

Zaključak: utvrđeno je da je kod amputiranih pacijenata postojala značajna razlika prema tipu dijabetes melitusa. Amputacije su bile najčešće kod pacijenata koji su imali trajanje bolesti 5 – 10 godina te kod pacijenata koji su bili na inzulinskoj terapiji.

Ključne riječi: tip dijabetesa, dijabetično sto-palo

1. Introduction

Diabetes mellitus is basiclly deficitary disease which is result of apsolute or relative insufficien-cy of insulin.There are two basic types of diabetes mellitus: type 1 –autoimmune disorder where im-mune system „attack“ beta pancreatic cells whi-ch produce hormon insulin and type 2 - where pancreatic cells insulin production is not sufficient and other cells receptors do not t recognize insulin (1,2).

Critical diabetic ishemic disease is the most complicated problem in vascular medicine Critical ishemia of extremity is definted as ishemia which endanger parts of extremity or whole exstremity. It is caracterised by persistent pain in pasive acti-ons, ulcers, feet gangrena and pedal arteries sisto-lic pressure < then 50 mm Hg.(3)

One of the most basic reasons for lower extre-mities amputation in diabetic patients is diabetic foot.Clinical signes are: ulcers, tipical foot defor-mations, occurrence of hronic oedema, ishemic changies leading to necrosis and gangrena.(4)

Lower extremities amputation in diabetic pa-tients can be resut of infection, neuropathia and microvascular disease. Analyse results show that 3,7% of amputated diabetic patients are with less then 45 years of age; 31,9% patients are in gro-up with 45-65 years of age and 64,4% are older than 65.(5,6) Medical rehabitation is one possibi-liy how to moderate phisical,psychical and social consequences of amputations. Rehabillitation aim is to prosthetic, to substitute amputated part of extremity with prosthesis and to train amputated person how to use prosthesis.(7)

2. AIMS

- to presentate occurrence of lower extremities amputation according to DM type;

- DM duration related to lower extremity amputations perfornance;

- type of antidiabetic therapy in the amputatet patients;

- number(and %) of dead outcomes among amputated patients by reason of additional complications.

3. Patients and methods

Retrospective study is done at the Clinic for orthopedy and traumathology and at Institut for vascular diseases CCUS. Study includes 87 pa-tients , 60 are evaluated which endured lower done by x2 test ( level of significancy ) and by Pearson correlation Coficient extremitates am-putation, 41 (68%) male and 19(32%) female, due to DM complications during 1 year period. Data assasment is.

4. Results

Chart 1. Patients division by DM typeX²= 0,343 p>0,05

As it is visible at chart above there is signifi-cant difference in lower extremity amputation occurrance in relation to DM type. 91,7 % patients were with DM type 2 but only 8,3% DM type 1.



Chart 2. DM duration ( years)X²=4,682 p>0,05

Chart showes that majority of patients, 30 %, had DM duration 5 – 10 years and that minority of patient only 5% had DM duration over 25 years.

Chart 3. Patient division by antidiabetic treatmentX²=3,672 p>0,05

There is evident difference among amputated patients regarding therapy. 88,3 % of patients were treated with insulin, 12% with oral therapy .

Chart 4. Patients with exitus letalis after lower extremity amputation by reason of additional complications

From 60 (69 %) amputated diabetic patients 5 (8,3 %) patients ended up with exitus letalis after lower extremity amputation by reason of additio-nal complications

5. Discussion

According to DM type ,55 patients were with DM 2 and 5 patients were with DM 1, ratio 92%: 8%. Tseng and Van Gilis and associates also found in their study that majority of amputated patients were with DM2(8,9).

Duration of DM is evaluated and we had 15 % of patients with DM less than 5 years; 30% 5-10 years; 13 % 16-20 years; 13% 21-25 years and 5% of patients with DM over 25 years. So in our study the majority of patients were diabetic from 5 to 10 years. Tseng and Van Gilis and associates got the same result in their study.

Antidiabetic therapy in the evaluated patients was various. 88% of patients were treated with insulin; 12% with oral therapy. Our findings are similar to other studies which we used for com-parisons .(8,9)

6. Conclusions

- According to DM type there is significant statistic difference beween amputated patients with DM type 1 and DM type 2;

- Duration of DM is not statisticly significant in the period from 5 to 25 years . We found that patients with DM duration over 25 years had less amputation occurrance then patients with shorter duration of DM;

- Five patients died soon after lower extremity amputation by reason of additional complications.

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7. Literature

1. Heljić B. i saradnici. Diabetes mellitus – klinički aspekti, Medicinska knjiga, Sarajevo, 2002. (121 – 149 str.)

2. Guyton A. Human physiology and mechanisms of disease, Published by N.B. Saunders, Philadelphia, Pennsylvania, 1991. (78 – 80 str.)

3. Levin M., O’Neal L., Bowker H. The Diabetic foot, Mosby year book, St. Louis, 1993. (57 – 59 str.)

4. Klein L., Lopes – Virela F. New concept about the pathogenesis of atherosclerosis and thrombosis in diabetes mellitus, Journal Article, St. Louis, 1993. (33 – 35 str.)

5. Nedvidek B. Osnovi fizikalne medicine i medicinske rehabilitacije, Medicinska knjiga, Novi Sad, 1986. (70 – 80 str.)

6. Dahl – Jorgensen K. Diabetic microangiopathy, Acta Paediatr Suppl, 1998, 31 (4) : 25

7. Pickup C., Williams G. Text book of Diabetes, Black well Scientific Publications: London, Edinburg, Boston, Melbourne, Paris, Berlin, Vienna, 1991. (45 – 48 str.)

8. Avdic, D., Buljugic, E. Osteophorosis, how prevent and how treat it. HealthMed, Dec2008, 2(4):305-306,

9. Avdic, D., Jusupovic, F., Kudumovic, M. Anthro-pometric values for boys aged 14 - 15 years who actively train basketball in comparing to boys of same age who do not train any sports HealthMed, Dec2008, 2(4): 253-264.

Corresponding author: Dijana Avdic Orthopedic Clinic, University Clinical Center Sarajevo, Bosnia and Herzegovina e-mail: [email protected]



Summary

Introduction: Among patients treated at clinic «PRAXIS» during past 15 years, there were 2422 patients treated for Repetitive stress injuries on upper and lower extremities. 18 diagnoses were included, among which there were 50 patients di-agnosed with De Quervain’s tenosynovitis. Only patients with De Quervain’s tenosynovitis who had vertebral symptoms were excluded from the study. Repetitive Stress Injuries represent epide-miological emerging serious and important disea-ses. Incidence of Repetitive Stress Injuries incre-ased from 14% to 56% in the period from 1978 to 1900 and has been associated with total increase in professional injuries.

Method: 50 patients with De Quervain’s teno-synovitis were treated using local injection of depo- corticosteroid with regular dosage. The treatment effects were evaluated on first and control examina-tion. Disease severity was assessed from 1 to 5 using same general scheme with functional ability test.

Results: Our results show that 96% of patients were treated sucsessfuly and the same effect was acomplished in 2 patients with recurent symtomes upon repeated injection. For complete recovery 3 patients received physical therapy during the pe-

riod of 3 weeks. Cost benefit and Cost efficiency analysis revealed that the above mentioned appro-ach in the treatment of these patients is efficient and 96% of patients regained work ability after one examination and concurrent intervention. Practi-cally the total expenses include: medication price, specialist examination and application without the loss of work engagement in active working popu-lation. Expressed in value points it amounts 50 po-ints (1 point represents relative value determined by Federal Health Insurance Institute norms).

Conclusion: Local instillation of corticostero-ids leads to almost 100 % treatment efficiency and functional work ability in patients.

Key words: De Quervain’s tenosynovitis, lo-cal application, depo-corticosteroid

Sažetak

Teniski lakat (Epicondylitis humeri radialis) je najčešći razlog zbog koga pacijenti, sa bolom u lakatnom zglobu, idu ljekaru. Egzaktni uzrok nastajanja bola u laktu je još uvijek nije razjašnjen u potpunosti, ali je u uzročnoj vezi sa vezivnim hvatištem mišića podlaktice,sa kostima podlaktice u području lakta.

de Quervain’s tenosynovitis occurence in patients with u repetitive Stress injurys treated at the basic rehabilitation ‘’PraXiS’’ centerefikaSNoST TreTmaNa TeNiSkog LakTa (ePiCoNdyLiTiS Humeri radiaLiS) u ambuLaNTi Cbr -“PraXiS“Dzemal Pecar*1, Dijana Avdic2

1 High Medical School, University of Sarajevo, Bosnia and Herzeegovina2 Orthopedic Clinic, University of Sarajevo Clinical Center, Bosnia and Herzegovina

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U ovom radu izvršena je analiza ukupnog uzorka pacijenata iz zdravstvene ustanove „Prax-is“ koji su se u toku petnaest godina javljali radi liječenja bolnog lakta (Epicondylitis humeri ra-dialis). Od ukupno 228 pacijenata bilo je 126 muškaraca, 101 žena i jedno dijete do 14 go-dina starosti. Početnim pregledom utvrđenoje je da zbirni prosjek početnog zdravstvenog stanja pacijenata valorizovan sa ocjenom 2,87, a nakon završenog liječenja, sa ocjenom 4,48.

Od ukupnog broja od 223 pacijenta liječenih kombinovanom metodom manipulacije i lokalne instilacije kortikosteroida, kod osam pacijenata je primjenjena i fizikalna terapija. Prema tome nije bilo potrebe da se primjeni operativni tretman ni kod jednog pacijenta.

Tretman pacijenata je uključivao 1. primjenu manipulacijkih metoda radi

uspostavljanja pokretljivosti „blokiranog“ radio-humeralnog i gornjeg radio-ulnarnog zgloba,

2. lokalnu instilaciju depo kortikosteroida radi liječenja upale (enthesitis-a), a time i eliminacije bola i uspostavljanja fizioloških uslova funkcionisanja zgloba i lokalnih sturktura.

Za razliku od konzervativne metode kojom se u početnoj fazi primjenjuje imobilizacija, radi spriječavanja iritacije i razvoja upalnog procesa, uz istovremeno analgetsku antireumatsku me-dikamentnu terapiju, početna primjena manipu-lacije, sa uspostavljenjem pokretljivost zgloba, a ne imobilizacije, naknadnom instilacija steroidnih preparata, postiže se, u pravilu, funkcionalna res-titucija i veoma brzo uspostavljanje pune radne sposobnosti.

Ključne riječi: Epicondylitis humeri radialis, manipulacija, medikamentnozna terapija.

Introduction

Repetitive strain injury (RSI), known also as a Cumulative Trauma Disorder (CTD) is a syndrome caused by profesional hand repetitive task, acompa-nied by nonspecific hand pain or disorder of upper extremities overuse is most common current disea-se manifestation caused by professional injury due to arms overuse or pathological alterations.

In typest a «typing cramp» often occurs. The main cause is typewriting machine, computer or musical instrument overuse which causes cumu-lative tissue damage, secondary inflammation and severe pain. Disorders such as repetitive strain injury are associated with both physical and psyc-hosocial stressors(1,2,3,4).

Statistical data from US Bureau of Labor Stati-stics for the year of 1980 show that the prevalence of RSI is 18% in total professional injuries, and the prevalence has increased during the period of eighteen years up to 66% in the year of 1998. It is estimated that for every reported RSI case there are 10 more which are unreported. In USA autho-rized institutions estimates that RSI expenses for the industry amounts up to 20 milliard US dollars on yearly bases measured in reimbursement and the additional 54 milliards US dollars in loss of working hours.

For the RSI diagnosis, typical complaints are: - pain in the arm which irradiates in several

directions,- pain worsens during the work,- weakness and reduction in endurance,- marked arm and shoulders muscles rigidness,- symptoms spread diffusely in nonanatomical

manner, do not follow nerve distribution

Patients believe that the pain is associated with the injury -. tissue damage. The cause for the beli-ef is strong «alarming pain» which predicts danger (4). Physical examination for objective abnorma-lities determination starts with tender, gentle mo-vements, without firm grip. Diagnostic, electrop-hysiological and radiological test are normal.

Pain intensity and loss of function is associated with work stress (5). There are three simple me-chanisms which can influence pain enhancement and pain related disability (6).

Psychological distress (depression or anxiety-tension) causes pain enhancement (decrease or increase in pain threshold susceptibility for pain-ful savors) Psychologist consider it «catastrophic pain» and believe it to be worse than standard pain sensation (7).

Patient sense it to be something serious and that it will not lessen with standard examination and professional services (8). Psychologist calls this «amplified anxiety» or «health anxiety».



There is evidence that the behavior affects he-alth perception. Active illness can amplify sense of a person not being healthy. On contrary, health is in a great manner dependant on persons behavi-or and thinking.

The term RSI is a term used for patients wit-hout specific related term with corresponding pat-hophysiology associated with the pain. It can also be used as an umbrella term incorporated in other discrete diagnoses that were related (usually wi-thout the reason) with the pain in the active arm such as:

- Carpal tunnel syndrome,- Cubital tunnel syndrome (Ulnar nerve

entrapment), - Thoracic Outlet Syndrome, - DeQuervain’s syndrome, - Stenosing tenosynovitis (Trigger finger/

tumb) - Intersection syndrome,- Golfer’s elbow (medial epicondylosis), - Tennis elbow (lateral epicondylosis), or- Focal dystonia.

RSI is also used as an alternative or umbrella term for other nonspecific diseases and as a gene-ral term which defines partially unaddressed pat-hology.

De Quervain’s tenosynovitis is a term for ten-don and sheet inflammation of the abductor po-llicis longus and extensor pollicis brevis muscles. Repeated ulnar deviation hand movements lead to inflammatory reaction which causes tendon and tendon sheet thickening additionally narrowing the canal with consequent irritation.

This overstress syndrome occurs in athletes, mu-sicians, tailors, physical workers and laundress in whom the activity of the thumb finger is frequent. Clinical pain dominates in the area of radial styloid process accompanied with crepitations which are amplified during the palpation. The most charac-teristic is a Finkelstein test which is performed so that the thumb is placed in the closed fist and the hand is ulnar deviated. If sharp pain occurs, the test is positive. The treatment is conservative in the be-ginning and includes rest, wrist immobilization and nonsteriodal antiinflammatory drugs.

If there is no relieve of the symptoms, local application of corticosteroids with anesthetics is

indicated. In the later stages of the disease if the stenosis and thickening of the tendon sheets is present, the remaining treatment option is surgi-cal with decompression and tendon sheet clean up. Physical rehabilitation begins two days later.

Tenosynovitis styloidei radii or De Quervain’s tenosynovitis is always accompanied with local swelling, pain in the wrist which irradiates in the forearm and distally towards the thumb.

Tendonitis is inflammation of the tendon or its bone connecting fibroses tissue composed of co-llagen bundle and blood vessels. Tenosynovitis is tendon sheet inflammation which can be caused by repetitive tension or microtraumatisation, calcium ions deposition, high blood cholesterol levels, rhe-umatoid arthritis or gout. De Quervain’s disease, an inflammatory disorder that can be caused by cumulative injury, is one of the most commonly diagnosed problems seen by hand surgeons, and is a major cause of lost workdays.

Movement is accompanied by crepitations with decreased amplitude of wrist and thumb maximal movements. De Quervain’s tenosynovitis symp-toms can be different only with involvement of a tendon. These symptoms are due to the inflam-matory reaction of the wrist affecting the surro-unding nerves, tendons, tendon sheets and fascia.

Diagnosis of De Quervain’s tenosynovitis is based on local swelling, painful sensations and de-creased hand function.

Symptomatological relief can be achieved with the rest or immobilization (wrist splints), topical heat or cold application (usually helps the patient) and nonsteroidal antiinflammatory medications (NSAIDs). Corticosteroid application between sheet and tendon helps the most. Surgical inter-vention is rarely used. Surgical intervention of de Quervain’s tenosynovitis can be complicated by neuroma formation or radial nerve damage.

Analyzing the demographical data from the Army medical databases in the period from 1998 to 2006 it was possible to find the data on de Quer-vain tenosinovitis prevalence. The prevalence was 11 332 cases in total population. Females were affected significantly more frequent (2,8 on 1000) compared with the males (0,6 on 1000). Risk fac-tor besides the gender is age. In patients older then 40 years of age prevalence of the disease is 2 on 1000 compared with the patients below the age

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of 20 (0,6 on 1000). Prevalence in African Ame-ricans is 1,3 on 1000, and in Caucasians 0,8 on 1000. Risk factors for the diseases in this study were gender, age and race (9).

Radial nerve superficial branch is vulnerable to trauma and iatrogenic injuries. There is a close rela-tionship between radial artery and this radial nerve branch, which can explain the pain during the ten-don sheet incision in surgical interventions (10).

In a prospective study which included two gro-up of patients with Trriger finger and de Quervain syndrome, patients were given steroid medicati-ons and anesthetics. Pain decreased in both groups during first seven days, and in one third of patients pain reoccurred (11).

The data indicates the efficiency of Triamcino-lone injection in patients with de Quervain syn-drome. Mixture of 1 ml Triamcinolone and 1 ml Lidocaine 1%, is usually given in two week inter-vals. This medication is instilled in a point abo-ve the induration as well as in the projection of extensor digiti brevis and abductor pollicis longus muscle tendon. Effectiveness is achieved in 89% of cases (12).

The Author of „Omega“ plastics accentuates the delicate surgery treatment procedure in rela-tion with the preservation of periosteal contact of osteofibrosis tunnel on radius styloid process (13). Successful surgical treatment is influenced by ana-tomical variations of abductor pollicis longus and extensor pollicis brevis muscle tendons, which needs to be accounted (14).

Material and methods

The study included 2 422 patients diagnosed with repetitive strain injury (RSI) in the «PRAX-IS» clinic for rehabilitation during the past 15 years. Retrospective analysis evaluated the occur-rence of the RSI disease and treatment effects of locally instilled depo-corticosteroid medications in patients with de Quervain’s tenosynovitis.

In patients with RSI syndrome the treatment ef-fect was evaluated in 50 patients diagnosed with tenosynovitis styloidei radi or De Quervain’s teno-synovitis. Clinical condition was assessed before and after the treatment in accordance with the fol-lowing common table:

Grade “0” : Immobile patient

Grade “1” : Hardly mobile with help from another

Grade “2” : Hardly mobile with the help of apparatus

Grade “3 ” : Independently mobile with the help of apparatus

Grade “4 ” : Good functional status with mini-mal consequences

Grade “5 ” : Preserved functional status

Grade “6 ” : Further medical treatment needed

Grade “7 ”: Treatment interrupted and contin-ued at another clinic

Synthetic depo Betamethasone medication (1 mL ampoule) was used for the therapy of this syn-drome in the dosage 2 + 5 mg, which has strong antinflammatory and secondary analgesic effects. The medication is injected locally between tendon and tendon sheet (intravaginally). Part of the me-dication is also instilled outside the tendon sheet between extensor pollicis brevis and abductor po-llicis longus muscle tendon for the possible occu-rrence of nonspecific tendon inflammation (and its sheets) and styloid process. Upon the medication application according to the observed data, pain relieve can be expected in 6 to 12 hours, and full recovery after 24 hours. Usually there is function recovery and pain reduction at the same time. The-refore it is possible to assess treatment effects with clinical examination on the first control check-up.


Prevalence of RSI was relatively high 11,51% or 2 422 patients out of which there were 50 (2%) patients diagnosed with tenosynovitis styloidei ra-dii or de Quervain’s tenosynovitis (Table 1). Table 1. Baseline characteristics of patients trea-ted in the past 15 years at the CBR PRAXIS

RSI Total2.422 21.042

Males 1.069 11.091Females 1.346 9.738Children -7 years 4 78Children 7-14 years 3 135



Figure 1. RSI gender differences

Figure 2. Total number treated at the CBR ‘’PRAXIS’’ clinic

Our study revealed that 56% of patients were females (Table 1 and Picture 1). It is specific for De Quervain’s tenosynovitis to affect more fema-les, over two thirds of patients with the disease are females (68%) and only 38% males.

Analising gender prevalence, greater prevalen-ce of females was observed also in other diseses which fall under RSI category and affect tendon-synovial tissue. It seems that the underlying pa-thophysiology in RSI diseases and greater occu-rences of active working females could be attribu-ted to longer repetitive movments of upper extre-mities including the hand.

Our results show that in patients with tenosyno-vitis styloidei radii or De Quervain’s tenosynovi-tis primary functional ability assesment, as well as

clinical symptoms grade (2,8) was lower than the general grade in RSI group.

Figure 3. Estimate primary functional ability pa-tients with tenosynovitis styloidei radii before and after treatment

In 96% patients, after the examination and locally medication application, already after 12 hours patients were feeling healthy and regained functional ability. Only two patients (4%) requi-red repeated injection, and after 7 day were com-pletely recovered.

Cost benefit analysis revealed that above men-tioned approach was far more efficient, conside-ring the fact that 96% of patients regained functi-onal ability after one application. Practically the total expenses include: medication price, specia-list examination and application without the loss of work engagement in active working population. Expressed in value points it amounts 50 points (1 point represents relative value determined by Fe-deral Health Insurance Institute norms), that is 24 times lesser than the using standard protocol.

Standard protocol for this disease would con-sist of following procedures: after initial examina-tion of general health practitioner and orthopedic specialist, patients would be given splint for 7 to 10 days, with analgesics and work absence.

Table 2. Estimate primary functional ability patients with tenosynovitis styloidei radii before and after treatment

Grade “0” nula “1” jedan “2” dva “3 ” tri “4 ” četiri “5 ” pet

Number patients:before traetment 0 0 17 26 7 0

Number patients:after treated 0 0 0 0 21 26

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Therefore, first two examinations - 30 points, two control examination - 20 points, splint appli-cation - 45 points and analgesic – 10 points totally 105 points. Furthermore, for 10 days of work disa-bility 1/3 of general LD=250 points, physical trea-tment 14 days =350 points, reimbursement for 14 day of absence= half of general LD=400 points. It sums up to 1210 points for three weeks treatment and rehabilitation.

This procedure does not include contribution on work in working hours since this variable does not have adequately estimated value in our settin-gs (In USA this loss would be 2 times more com-pared to personal income).

Conclusions

RSI represents growing problem for the man-kind. During the past 20 years RSI constitutes gre-at percentage in the diseases which leads to tem-porary work disability (Absentees).

Among the RSI diseases, tenosinovitis styloidei radii occurs more frequently in females (68:32).

Treatment of this disease with standard proto-col is inefficient and more costly (24 times more).

Local instillation of corticosteroids leads to al-most 100 % treatment efficiency and functional work ability in patients.

Literature

1. Pinsky, Mark A., The Carpal Tunnel Syndrome Book, Pinsky,Mark A.,The Carpal Tunnel Syndro-me Statistics U.S. Bureau of Labor Statistics Book Warner Books, 1993, p. 44.

2. Szabo R.M., King K.J.Repetitive stress injury: di-agnosis or self-fulfilling prophecy? J Bone Joint Surg Am. 2000 Sep;82(9):1314-22. Review.

3. Ring D., Guss D., Malhotra L., Jupiter J.B. Idiopa-thic arm pain. J Bone Joint Surg Am. 2004 Jul;86-A(7):1387-91..

4. Quintner J.L.The Australian RSI debate: ste-reotyping and medicine. Disabil Rehabil. 1995 Jul;17(5):256-62

5. Ring D., Kadzielsky J., Malhotra L., Lee S.P., Jupi-ter J.B. Psychological factors associated with idio-pathic arm pain. JBJS 2005 10; 87: 374-380.

6. Nahit ES, Pritchard CM, Cherry NM, Silman AJ, Macfarlane GJ. “The influence of work related psychosocial factors and psychological distress on regional musculoskeletal pain: a study of newly employed workers”. J Rheumatol (2001)28 (6): 1378–84.

7. Vranceanu AM, Safren S, Zhao M, Cowan J, Ring D. Disability and psychologic distress in patients with nonspecific and specific arm pain. Clin Orthop Relat Res. 2008 Nov;466(11):2820-6. Epub 2008 Jul 18.

8. Vranceanu A.M., Safren S., Zhao M., Cowan J., Ring D. Disability and psychologic distress in pa-tients with nonspecific and specific arm pain. Clin Orthop Relat Res. 2008 Nov;466(11):2820-6. Epub 2008 Jul 18.

9. Wolf JM, Sturdivant RX, Owens BD. Incidence of de Quervain’s tenosynovitis in a young, active popu-lation. J Hand Surg [Am]. 2009 Jan;34(1):112-5. Epub 2008 Dec 10.

10. Robson AJ, See MS, Ellis H. 2NApplied anatomy of the superficial branch of the radial nerve. Clin Anat. 2008 Jan;21(1):38-45.

11. Goldfarb CA, Gelberman RH, McKeon K, Chia B, Boyer MI. Extra-articular steroid injection: early patient response and the incidence of flare reacti-on. J Hand Surg [Am]. 2007 Dec;32(10):1513-20.

12. Sawaizumi T, Nanno M, Ito H -De Quervain’s disease: efficacy of intra-sheath triamcinolone injection. Int Orthop. 2007 Apr;31(2):265-8.

13. Bakhach J, Sentucq-Rigal J, Mouton P, Boileau R, Panconi B, Guimberteau JC. [The Omega “Ome-ga” pulley plasty: a new technique for the surgi-cal management of the De Quervain’s disease] Ann Chir Plast Esthet. 2006 Feb;51(1):67-73.

14. Bakhach J, Sentucq-Rigal J, Mouton P, Boileau R, Panconi B, Guimberteau JC. [The Omega “Ome-ga” pulley plasty: a new technique for the surgi-cal management of the De Quervain’s disease] Ann Chir Plast Esthet. 2006 Feb;51(1):67-73.

Corresponding author: Dzemal Pecar High Medical School, University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzeegovina e-mail:



Summary

Nervus facialis is the seventh cerebral nerve whi-ch stimulates mimic muscles and it is also sensory nerve for frontal two thirds of the tongue. Lesion of nervus facialis can be caused by: trauma, inflama-tory process on middle ear, with tumors, head or ear surgery. Paresis can be central and peripherial.

Aim of this paper is presentation of results after rehabilitation of damage to nervus facialis and comparison of level of remaining damages between patients who undertook physiotherapy and patients who did not.

In the study were treated two groups of pati-ents, each consisting of 30 patients with paresis n. facialis. The first group which was subject of this research was treated by general standards with medicaments and physiotherapy. Physiotherapy was conducted through electro-stimulation and kinetic therapy during one month period. Second group was control group. Patients were treated by general standards and with medications only du-ring one month period. Statistic data covers sex, age, coverage of n. facialis and treatment outco-me. In the estimate of clinical features we used House-Brackman scale.

Statistical data showed that there is no statisti-cally important difference in sex distribution, most of patients were aged 10-50, majority of patients had all three branches of n. facialis covered (70% in test group and 76,6% in control group). 13,3 % patients in test group were completely cured af-ter one month of physiotherapy, while the same result was shown in control group in only 3,33%

of patients. After one month of therapy recovery was noticed in 86, 6% of patients in the test gro-up and 83, 3% in control group. There were no patients who have not recovered in the test group while in control group the percentage was 13, 3%. After the research we can draw the conclusion that the patients who received physiotherapy alongside with standard measures and medications showed better results of rehabilitation than the patients who did not receive physiotherapy. Multidiscipli-nary approach to treatment of damage to n. facialis that includes physiotherapist from the beginning shows the best rehabilitation results.

Key words: paresis, physiotherapy, rehabilitation

Sažetak

Nervus facialis je sedmi moždani živac, koji inervira mimičnu muskulaturu i senzorni živac za prednje dvije trećine jezika. Lezija nervus fa-cialisa može nastati: traumatskim djelovanjem, upalnim procesom na srednjem uhu, kod tumora, operativnog zahvata područja glave ili samo uha. Pareze mogu biti centralne i periferne.

Cilj rada je prikazati rezultate rehabilitacije oštećenja nervus facialisa i komparirati stepen preostalog oštećenja kod pacijenata koji su proveli i koji nisu proveli fizikalni tretman.

U studiji su obrađene dvije grupe od po 30 paci-jenata sa paresom nervus facialisa. Prva grupa od 30 pacijenata, ispitivana grupa, je liječena primje-nom opštih mjera, medikamentoznom terapijom kao i fizikalnom terapijom. Fizikalna terapija je

influence of early physiotherapy to recovery after Paresis N. facialisuTiCaj raNe fizikaLNe TeraPije Na oPoraVak NakoN Pareze N. faCiaLiSaEdina Tanovic

Clinical Centar of the University of Sarajevo, Institute for Physiotherapy and RehabilitationBosnia and Herzegovina

62



ordinirana u vidu elektrostimulacije i kinezitera-pije u trajanju od mjesec dana. Druga grupa, kon-trolna je liječena opštim mjerama i medikamen-toznom terapijom također mjesec dana. Statistički su obrađeni spol, dob, zahvaćenost n. facialisa i ishod liječenja. U procjeni težine kliničke slike koristili smo se House-Brackmanovom skalom.

Na osnovu statističke obrade i dobijenih rezul-tata uočili smo da nema statistički značajne razli-ke u spolnoj zastupljenosti, većina pacijenata je u dobi između 10 i 50 godine Najviše pacijenata je imalo zahvaćene sve tri grane n. Facialsia ( 70% u ispitivanoj i 76,6% u kontrolnoj grupi). Nakon li-ječenjae u ispitivanoj grupi kod 13,3 % pacijenata došlo do potpunog izliječenja u roku od mjesec dana koliko smo ordinirali fizikalni tretman dok je kod kontrolne grupe takav rezultat bio samo kod 3,33%. Nakon mjesec dana terapije pokazalo se da su oporavljeni, kod ispitivane grupe 86,6% , a kod kontrolne grupe 83,3 % pacijenta. U ispitiva-noj grupi nije bilo neizlječenih pacijenata dok je u kontrolnoj grupi bilo 13,3 % pacijenata

Nakon istraživanja možemo zaključiti da su pacijenti kod kojih je uz opšte mjere i medikame-toznu terapiju ordinirana rana fizikalna terapija pokazali bolje rezultate rehabilitacije nego paci-jenti kod kojih fizikalna terapija nije primjenjena. Multidiciplinarni pristup u liječenju oštećenja n. facialisa u koji je od samog početka uključen fizi-jatar daje najbolje rezultate rehabilitacije.

Ključne riječi: pareza, fizikalna terapija, re-habilitacija

Introduction

Nervus facialis is the seventh cranial nerve that stimulates mimic muscles and frontal two thirds of the tongue. Lesion to n. facialis can be caused by: trauma, inflammatory process on middle ear, with tumors, after head or ear surgery. Paresis can be central and peripheral. (1, 2, 3).

Prevalence of disease and injury of nervus faci-alis in the rehabilitation processes is not rare, so it is necessary to conduct physiotherapy and kinetic therapy for three months in most cases, depending on the level of changes and causes sometimes even longer. (4, 5, 6).

Level of damage is the most important factor in the evaluation of level of reinnervation. With the use of this method, changes that indicate previous paresis or paralysis can be found even after 10 ye-ars, which confirms the fact that reinnervation is never complete, although we clinically determine full function of facial muscles (7,8,9,10).

Approach to rehabilitation has to be based on team work, which is in majority of cases based on cooperation between neurologist, maxillofaci-al surgeon, otorhinolaryngologist, traumatologist with physical therapist and physician (11, 12).

Therapy duration is in most cases three weeks, break after that and then repetition as long as the-re are signs of functional training. Muscle fatigue must not be caused because dysfunctional muscle does not have the ability to accommodate and its stress causes reinnervation to slow down.

Cooperation between patient, physician, physi-cal therapist and members of consulting team is necessary for directing the course of therapy and rehabilitation process.

Establishment of functional activity of facial muscles is not only functional aim but also aesthe-tical effect in the facial mimic. (13).

Diagnosis is set up after physical examination (inspection, palpation, sensibility and reflex test), electromyoneurography (EMNG), electro status and manual muscle test. (15, 16).

Therapy methods for rehabilitation of damage to nervus facialis consist of: general measures, conservative therapy (medications and physiothe-rapy) and surgery. In general measures we advise the patient to stay away from cold and wind, to wear dark protective glasses in order to prevent eye irritation, to shower the face with warm water several times a day or try to “churn”, which relea-ses the tension and enhances blood flow and fun-ctionality of mimic muscles, and to use the musc-les as often as possible. (17, 18, 19). Medication is performed through large doses of corticosteroids, pain killers, spasmolitics, anti-depressives, and al-most half of the patients were treated with injec-tion blockades. Physiotherapy aims to achieve muscle functionality through causing hyperemia, provoking the innervation, improvement of tonus and trofic, regaining of sensibility. For the purpose we use infrared radiation-solux lamp, galvanizati-on through Bergoni’s half-mask, electro stimula-



tion, biofeedback, acupuncture, manual massage and kinetic therapy.

Aims of the study

Aims of this paper are: presentation of impor-tance of physiotherapy in rehabilitation of patients after damage to nervus facialis and comparison of level of remaining damage in patients who did and who did not undertake physiotherapy.


Research sample consisted of two groups each consisting of 30 patients with paresis of nervus fa-cialis. First group, the test group, was treated by

general measures, medications and physiotherapy. Physical therapy was ordinated as electric stimu-li and kinesiotherapy and it lasted for one month. Second group, the control group, was treated by general treatment and medications also for one month. The research has been conducted as a re-trospective study. Patients were selected rando-mly.

Both groups were analyzed according to sex, age, type of disease and severity of clinical fea-tures. In the estimate of clinical features we used House-Brackman scale (19). In the scale cured pa-tients had first and second level of damage, third and fourth level patients who recovered and fifth and sixth level of damage to n. facialis patients who were not cured. All the data is presented in the tables using the method of descriptive statisti-cs: number of cases and percentage.

ResultsTable 1. Overview of patients according to sex

Groups ( 30+30) TotalTest ControlMale N 13 15 28

% 43,3 50 93,3Female N 17 15 32

% 56,6 50 106,6Total N 30 30 60

% 100,0 100,0 200,0Table 2. Overview of patients according to age

To 20 21-30 31-40 41-50 51-60 60 and moreTest group 2 (6,66) 8 (26,6) 7 (23,3) 6 (20) 5 (16,6) 2 (6,66)Control group 1 (3,33) 10 (33,3) 6 (20) 8 (26,6) 4 (13,3) 1 (3,33)Total 3 (10) 18 (60) 13 (43,3) 14 (46,6) 9 (30) 3 (10)

Table 3. Overview of coverage of n. facialis in both groups Groups TotalTest Control

All three branches symmetrically N 21 23 44 % 70 76,6 146,6

Primary upper branch (eye) N 7 6 11 % 23,3 20 43,3

Primary lower branch (mouth) N 2 1 3 % 6,66 3,33 10

Total N 30 30 60 % 100,0 100,0 200,0

Table 4. Overview of treatment results Group TotalTest Control

Cured N 4 1 5 % 13,3 3,33 16,6

Recovered N 26 25 51 % 86,6 83,3 170

Not cured N 0 4 4 % 0 13,3 13,3

Total N 30 30 60 % 100,0 100,0 200,0

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Discusion

Nervus facialis, seventh cranial nerve belongs to the group of motoric nerves. In its composition it has secretorial strains for salivary glands, lacri-mal and nasal glands and gustoreceptorial strains for sense of taste (16). Facial mimicry can express the mood, emotions, intentions and thoughts.

Function of nervus facialis and mimic muscles is obvious in expression of joy, grief, pain, hate, love, hope concern, happiness, horror, admiration, fear etc. (20).

Functions like speech, eating, drinking, suc-king, swallowing, whispering, laughing, crying, whistling can not be imagined without nervus fa-cialis. Functions where nervus facialis and mimic muscles participate are numerous. Patients with conditions in the facial area are disabled in every-day life, nutrition, speech and social contacts. (20).

It is difficult to conclude whether damage to nervus facialis is more common in male or fema-le population because results from various studies are controversial. Same number of studies gives advantage to men and women. (20). In our resear-ch groups were equal in terms of gender.

Data in the literature shows that damage to ner-vus facialis is most common between the age of 10 and 50 (although it can appear at any time in life) and that every year we have 20 cases on 100 000 people (7). Our results are consistent with this data.

In our research the largest number of patients had damage to all three branches of n.facialis (70% in test group and 76, 6% in control group) and the smallest number had damage to the lower branch of n. facialis. This is in favour of complexi-ty of treatment of such patients.

The condition starts suddenly and it culminates to its maximum within 48 hours. Gradual develo-pment of the condition with maximal development in the first week is rare. In majority of cases of damage to n. facialis certain level of spontaneous recovery can be expected. (3).

Overview of treatment results shows that in test group 13, 3 % of patients completely cured wit-hin a month of exposure to physiotherapy while in control group only one patient or 3, 33% of pati-ents showed such improvement.

After a month of therapy the largest number of patients were recovered, 86, 6% in test group and 83, 3% in control group. In the test group the-re were no patients who were not cured, while in control group there were 13,3% of such cases after a month of therapy.

In easier cases, recovery with paresis only starts in the end of second week and in case of pa-ralysis signs of recovery apper in the end of third and beginning of the fourth week from the start of condition.

Complete recovery, if it happens, takes place 3-6 months from the beginning of the condition and crucial factor that determines the level of re-covery is the level of paralysis or paresis. (3,5)

Conclusion

Based on the presented results and discussion in this research we can draw a conclusion that the pa-tients who received physiotherapy alongside with general measures and medications showed better rehabilitation results than the patients who did not have physiotherapy. Multidisciplinary approach in the treatment of damage to n. facialis with physi-cian involved from the beginning delivers the best rehabilitation results.



Literature

1. Chusid G. Joseph. Korektivna neuroanatomija i funkcionalna neurologija. Beograd: Savremena administracija, 1979: 210.

2. Grubor D. Ispitivanje vrijednosti kliničke procjene Bell-ove paralize. Magistarski rad. Sarajevo l988: 41-5.

3. Jajić I. Specijalna fizikalna medicina. Zagreb: Škol-ska knjiga l99l.

4. Jušić A. Klinička elektromioneurografija i neuromu-skularne bolesti. Zagreb: Jugoslovenska medicin-ska naklada. 1980.

5. Jančić-Stefanović J., Stefanović D. Jednostrane pa-ralize mimične muskulature sa akutnim početkom. Zbornik radova. Treći kongres fizijatara Srbije i Crne Gore, Igalo, 2002.

6. Jović N. Paraliza lica. VMA Beograd 2004: 84-85.

7. Lazić M. Zastupljenost rizikofaktora kod nastanka Belove paralize. Zbornik radova.

Treći kongres fizijatara Srbije i Crne Gore, Igalo, 2002.

8. Milorad R. Jevtić. Fizikalna medicina i rehabilitaci-ja. Univerzitet u Kragujevcu. 1999.

9. Majkić M. Klinička kineziterapija. Zagreb: Inme-dia, l997: 77-83.

10. Mihajlović V. Osnove fizikalne medicine. Titograd: Univerzitetska knjiga, 1983.

11. Mladenović Z. Maksilofacialna hirurgija. Sara-jevo 1984.

12. Zeković P. Fizikalna terapija sa rehabilitacijom. Beograd: Zavod za udžbenike i nastavna sred-stva, 1996: 172-176.

13. Poeck K. Neurologija. Zagreb: Školska knjiga, 1994: 151-84.

14. Pavićević-Stojanović M. Naša iskustva u liječen-ju bolesnika sa perifernom paralizom facijalnog nerva. Zbornik radova Jugoslovenski kongres lje-kara fizikalne medicine i rehabilitacije sa među-narodnim učešćem, Zlatibor, 1997.

15. Radojčić B. Bolesti nervnog sistema. Beograd- Zagreb: Medicinska knjiga, 1989: l83-85.

16. Semić N. Kaluđerović D. Kineziterapija i fizikal-nom liječenju periferne oduzetosti živca lica. Beo-grad: Drago, 1994.

17. Stanković I. Selektivni pristup u rehabilitaciji peri-ferne paralize facijalnog nerva, Zbornik radova. Treći kongres fizijatara Srbije i Crne Gore, Igalo, 2002.

18. Sobotta J. Atlas anatomije čovjeka. Sv. 1: glava, vrat, gornji ud. Zagreb: Naklada, Slap, 2003.

19. Vokomanović A. Testovi i skale za procjenu snage muskulature lica. Zbornik radova IV fizijatrijski dani Srbije i Crne Gore, Igalo, 2005: 76-8.

20. Šercer A.Otorinolaringologija. Zagreb: Jugoslo-venski Leksikografski zavod, 1965-1966. 65-73.


Edina Tanovic Clinical Center of the University of Sarajevo Institute for Physiotherapy and Rehabilitation -

Center for paraplegics Bolnička 25, 71 000 Sarajevo, Bosnia and Herzegovina; e-mail: [email protected]

66



Summary

Objective: The aim of this study was to des-cribe the patients with intrathoracic metastases of a breast cancer treated in Clinic « Podhrastovi» in the four-year period from 2004. to 2007.

Material and methods: Retrospective study was carried out on the basis of clinical records of the patients with intrathoracic metastases of a breast cancer treated in four-year period in Clinic „Podhrastovi“. For each case it was determined the time from the first diagnosis of breast cancer to the first diagnosis of its metastases, the previous tre-atment (operation, chemotherapy, radiotherapy...) and association of the breast cancer with primary lung and the other organs cancer. The final diagno-sis of each investigated case was established by lung and pleural biopsy.

Results: It was totally 19 patients: four in 2004., five in 2005., five in 2006., five in 2007. That is 1,05 % of the total number of cancer pati-ents treated in this period in Clinic «Podhrastovi». They were aged from 37 to 74 year. In four of them it was the first diagnosis of breast cancer although they already had metastases. Fourteen

patients were treated previously by operation, chemotherapy, radiotherapy and one patient was treated by alternative methods. About five years after the first diagnosis of the breast cancer its me-tastases were diagnosed. In four cases there were lung metastases and one of them had skin meta-stases, one liver, and one brain metastases too. In six patients there were pleural metastases and one of them had also pericard metastases and one had bone metastases too. Five patients had both lung and pleural metastases, and among them one had liver, one had bone, and one both: bone and liver metastases.Three patients had primary lung carci-noma, and one had primary lung and laryngeal carcinoma beside the previously diagnosed breast carcinoma.

Conclusion: Although there are very succe-ssful methods of early detection and treatment of breast cancer, there is a certain number of cases in which the diagnosis was late and therapy has no desirable results.

Key words: breast, cancer, lung, pleura, me-tastases

intrathoracic metastases of a breast cancer treated in Clinic for pulmonary diseases and tb „Podhrastovi“- Sarajevo in the four-year period from 2004.–2007.iNTraTorakaLNe meTaSTaze karCiNoma dojke TreTiraNe Na kLiNiCi za PLućNe boLeSTi i TuberkuLozu „PodHraSToVi“ u čeTVorogodiSNjem Periodu od 2004. do 2007. godiNe

Vesna Cukic

Clinic for pulmonary diseases and TB «Podhrastovi», Clinical Centre of University Sarajevo, Bosnia and Herzegovina



Sažetak

Cilj: Prikazati pacijentkinje sa intratorakalnim metastazama karcinoma dojke koje su tretirane na Klinici „ Podhrastovi“ u četvorogodišnjem perio-du od 2004. do 2007. godine.

Materijal i metode: Ovo je retrospektivna analiza pacijentkinja sa intratorakalnim metasta-zama karcinoma dojke koje su tretirane u četvoro-godisnjem periodu . Određeno je vrijeme od prve dijagnoze karcinoma dojke do razvoja metastaza, prethodni tretman: operacija, kemoterapija, radio-terapija; postojala je udruženost karcinoma dojke sa primarnim karcinomom pluća i karcinomima drugih organa. Konačna dijagnoza je postavljena biopsijom pluća i pleure.

Rezultati: Ukupno je bilo 19 pacijentkinja: če-tiri u 2004., pet u 2005., pet u 2006. i pet u 2007.godini što predstavlja ukupno 1,05 % od ukupng broja pacijenata sa karcinomom koji su tretirani u ovom periodu na Klinici „Podhrastovi“. Pacijent-kinje su bile stare od 37 do 74 godine. Kod četiri od njih to je bila prva dijagnoza karcinoma dojke , iako je on već dao metastaze. Četrnaest od njih je prethodno tretirano : operacija, citoterapija, ra-dioterapija ili kombinacijom ovih metoda, a jedna je tretirana alternativnim metodama liječenja.Me-tastaze su dijagnosticirane u prosjeku pet godina nakon prve dijagnoze karcinoma dojke . Kod njih četiri postojale su metastaze u plućima : jedna od njih je imala i metastaze na koži, jedna i u jetri, a jedna i u mozgu. Kod šest pacijentkinja postojale su pleuralne metastaze: jedna od njih je imala i metastaze u perikardu, a jedna i metastaze u kosti-ma. Pet pacijenktinja je imalo zajedno i plućne i pleuralne metastaze, a među njima jedna je imala i metastaze u jetri, jedna u kostima, a jedna oboje: i koštane i jetrene metastaze. Tri pacijentinje su imale primarni karcinom pluća,a jedna primarni karcinom pluća i primarni karcinom laringsa po-red ranije dijagnosticiranog karcinoma dojk .

Zaključak: Iako postoje vrlo uspješne metode rane detekcije i tretmana karcinoma dojke, postoji izvjestan broj slučajeva gdje je dijagnoza kasno postavljena, a terapija nije dala željene rezultate.

Ključne riječi: dojka, karcinom, pluća, pleu-ra, mestastaze

Introduction

Breast cancer is the cancer that starts in the ce-lls of the breast (1). Worldwide, breast cancer is the second most common type of cancer after lung cancer (2) and the fifth most common cause of can-cer death (3). There are many prognostic factors associated with breast cancer: staging, tumour size and location, grade, whether the disease has me-tastased, recurrence of the disease, and age of the patient. Stage is the most important as it takes into consideration size, local involvment, lymph node status and presence of metastatic disease. Breast cancer can metastasise (spread) via lymphatics to nearby lymph nodes, usually those under arm. Breast cancer can also spread to other parts of the body via blood vessels or the lymphatic system. So it can spread to the lungs, pleura, liver, brain and bones (most commonly) (1). The higher the stage at diagnosis, the worse is the prognosis (2). Intrathoracic metastases present most common as solitary or multiple nodes in one or both lungs, uniltaral or bilateral pleural effusion, lymphangi-itis carcinomatosis ( which denotes involment of the pulmonary lymphatic network – result of the extension of tumour from lung capillaries to the lymphatics) in both lungs; all of these with or wi-thout involment of mediastinal lymph nodes. The aim of this study was to describe the patients with intrathoracic metastases of a breast cancer treated in Clinic «Podhrastovi» in four-year period from 2004. to 2007.


This is retrospective analysis of the patients with intrathoracic metastases of a breast cancer treated in four-year period ( from 2004. to 2007.) in Clinic for Pulmonary Diseses and TB „ Podhra-stovi“ Sarajevo. It was determined the time from the first diagnosis of breast cancer to the develo-pment of metastases, previous treatment: operati-on, chemotherapy, radiotherapy; there was asso-ciation of breast carcinoma with primary lung cancer and cancersof other organs. Final diagnosis was established by lung and pleural biopsy.

68



Results

They are shown on tables below.

Table 1. Patients treated in 2004

Name Age(years)

Time from first

diagnosis of breast cancer

Previous treatment of breast cancer

Type of metastases Other primary cancerLung Pleura Other

H.N. 65without previous diagnosis no treatment right left

right axill.lymph.

vertebra th

K.M. 50 five yearsago

right radical. mastectomia ,

chemoth.right

liver and right axill and.

supraclav lymph.

L. J. 56 six yearsago

right radical. mastectomia right, right

P. J. 37 eight yearsago

left radical. mastectomia,

radio th, chemoth..

both right


Name Age(years)

Time from first




B.E. 59without previous diagnosis

no treatment rightface and right arm

skin,

K.M. 50 five years ago

left radical. mastectomia,

chemoth., radio th

both liver and right orbita.

R.A. 66without previous diagnosis

no treatment both

S.F. 78 seven years ago

left radical. mastecomia ,

radio th.right right liver,

vertebra th

B.M. 67 two years ago right radical. mastectomia

Ca planocellleft lung




Name Age(years)

Time from first




B.F. 59 five years ago alternative medicine both brain

Č.M. 46 five years ago

right radical. mastectomia,

chemoth.,radio th

right pericardleft breast

two years ago (chemoth.)

J.A. 65 one year ago

left radical. mastectomia ,

chemoth., radio th

Ca planocell bronh.

principal. right

P.M. 59 16 years agoleft radical.

mastectomia, chemoth..

right

S.A. 53 19 years agoleft partial.

mastectomia , radio th

Ca microcellleft lung. Ca laryngis- ten

years ago

Table No4 patients treated in 2007

Name Age(years)

Time from first




Dž. M 55 four years ago

left radical. mastecomia,

chemoth., radio th

both both liver

D.A. 50 two years ago

right radical. mastectomia ,

chemoth. , radio th

Ca squamocelright lung

O.A. 60 one year ago left radical. mastectomia both

S.S. 74

without previous

diagnosis, both breasts

no treatment right mediastin.lymphnod.

S.A. 54 five years ago right radical. mastecomia left

70



It was totally 19 patients : four in 2004., five in 2005., five in 2006., five in 2007 year . that is 1,05 % of the total number of patients with cancer treated in this period in Clinic «Podhrastovi». They were aged from 37 to 74 year. In four of them it was the first diagnosis of breast cancer although it has already had metastases . Four-teen patients were treated previously: operation, citotherapy,radiotherapy, and one was treated by alternative methods. Metastases were diagnosed on average five years after the first diagnosis of breast cancer..In four of them there were lung me-tastases : one had and skin metastases, one had and liver, and one had and brain metastases. In six of them there were pleural metastases: one had and pericard metastases, and one had and bone metastases. Five of them had both lung and pleu-ral metastases,and among them one had liver,one had bone, and one both: bone and liver metastases. Three patients had primary lung carcinoma, and one had primary lung and laryngeal carcinoma beside the previously diagnosed breast carcinoma. All patients were treated wiht citotherapy or radi-otherapy or both (combinated cito and radiothe-rapy) with multidisciplinary approach (oncologist, radiotherapeutic ,pulmologist).

Discussion

Breast cancer is the second most common type of cancer after lung cancer [10,4% of all cancer incidence ,including both sexes (2)] and the fifth most common cause of cancer death (3). Worldwi-de, breast cancer is by far the most common can-cer amongst women, especially 35 to 64 years old (1) with an incidence rate more than twice of colorectal cancer and cervical cancer and about three times of lung cancer (3). However, breast cancer mortality all over the world is just 25% greater than that of lung cancer in women (2) . In 2005.,breast cancer caused 502 000 deaths in the world (7% of cancer deaths , almost 1% of all deaths) (3). The number of cases in the world has significantly increased since the 1970.s - a pheno-menon partly blamed on modern lyfestyles in the Western world with tendency for greater incidence in the next years (4). The incidence of breast cancer varies greatly in the world, being lower in

less developed countries and greatest in the more developed countries (4). However, the mortalty from breast cancer has been getting smaller in last decades owing to advance of radiologycal diagno-stic methods, programmes of early detection and new methods of adjuvant systemic therapy (1, 5).

Conclusion

In spite of all advances in diagnostics, scree-ning methods of early detection and new methods of therapy, breast cancer is still the most common cause of death of women in developed countries. There is a certain number of cases in which the diagnosis was late and therapy has no desirable re-sults. Some of them have intrathoracic metastases which require treatment in Clinic for pumonary diseases.

Literature

1. American Cancer Society, www.cancer.org, ( Sep-tember 26, 2007): What Is Breast Cancer ? . Re-trieved on 2008-02-03.

2. World Health Organization International agen-cy for Research on Cancer, www.who.int/, ( June 2003). World Cancer Report . Retrieved on 2008-02-03

3. World Health Organization, www.who.int/, ( Fe-bruary 2006). Fact sheet No 297: Cancer. Retrie-ved on 2007-04-26

4. Parkin D.M., Pissani P., Ferlay J. Global Cancer Statistics. CA Cancer J. Clin. 1999; 352:930-942

5. Cancer Facts and Figures – 1999,Atlanta Ga: American Cancer Society 1999.


Vesna Cukic Clinic for pulmonary diseases and TB “Podhrastovi” Clinical Centre of University Sarajevo, Bosnia and Herzegovina e-mail:



Summary

Method of anal cerclage with prolene ribbon nowadays is mostly use in case of very old pati-ents with rectal prolapse. Procedure is performed in manner that prolene net is placed orally, abo-ve anal sphincter, trough three to four incisions on skin of perianal region. Due to extreme pain surgery is done with general or spinal anesthesia depending on patient’s general health condition. Method is relatively rarely used due to pain it pro-duce. But there is a group of patients for which this surgery provides wanted results. In order to reduce pain and make post surgical recovery ea-sier, we made modification to this method using specially designed instrument in order to reduce tissue trauma and make placement of the net in adequate position easier.

Key words: Rectal prolapse, anal cerclage.

Sažetak

Metoda analne serklaže prolenskom trakom danas se primjenjuje najčešće kod izrazito stari-jih pacijenata sa rektalnim prolapsom.Operacija se sastoji u tome da se prolenska mrežica ubacuje oralno, iznad analnog sfinktera, kroz tri do četiri incizije perianalno na koži. Radi izrazite bolnosti operacija se vrši u općoj ili spinalnoj anesteziji u

zavisnosti od općeg stanja pacijenta.Metoda se relativno rijetko primjenjuje radi svoje bolnosti.Ipak postoji grupa pacijenata kod koje ova opera-cija daje željene efekte.U cilju smanjenja bolnosti i lakšeg postoperativnog toka uradili smo modifi-raciju ove metode koristeći naročito konstrisan in-strument sa ciljem što manje traumatizacije tkiva i lakšeg plasiranja mrežice na adekvatno mjesto.

Ključne riječi: Rectalni prolaps,anal cerclage.

Introduction

There is a group of patients with rectal prolapse which poor general health status does not allow the adequate surgical treatment, so often used are procedures which does not produce adequate re-sults but only relieve condition. Most often these are elderly patients with developed and long la-sting rectal prolapse, incontinence, which without doubt influence both on their functioning and soci-al life which eventually leads to mental disorders. Severe illness as this with poor general health state of the patient is very difficult to treat surgically. (1) That is why we use easier surgical procedures with satisfactory results.

Standard method of anal cerclage is done with four incisions after which subcutis is tunneled, and then under control pean is introduced. Homeosta-sis is usually done with compression or diather-

Treatment of elderly patients with rectal prolapse with modified anal cerclage methodTreTmaNa STarijiH PaCijeNaTa Sa ProLabiraNim rekTumom meTodom modifiCiraNe aNaLNe SerkLaŽeNedzad Sehovic, Amela Sofic, Adnan Zeco

Clinic of General and Abdominal Surgery, Clinical Center University of Sarajevo,Bosnia and Herzegovina

72



mia. Tunnels are made under raphe orally to pubo-rectal muscle and around the sphincter in ishiorec-tal space. After that rolled prolene net, previously measured is taken. With the instrument, it is pla-ced trough the cannel under the skin and continues with other instruments until we reach initial inci-sion. Ends are suturated with prolene 2-0 thread.

Before surgery to each patient is administered enema several hours before procedure. Patient is in laying position, at the gynecology table, with legs raised in leg holders.

After the cleaning of the surgical field injected is local anesthetic around the anal opening with intraluminal application of anesthetic in form of gel (if the surgery is performed under the local anesthesia). Each patient underwent rectal and rectoscopic examination, with the measurement and determining orientation of the anal opening as well as the size of the prolapsed part.

Modification is in fact that the prolene ribbon is placed perianally trough one incision on the skin, and most often ventrally due to easier dissection of the rectovaginal space. Everything is done with the specially designed net carrier, and it is placed at the same level as in case of standard method.

Goal

Today all available methods for treatment of these patients are mainly based on general ane-sthesia and more extensive surgeries which this group of patients is not able to withstand without high mortality risk. Our wish was to introduce a method which this group of patients can stand, as surgically as well as n term of anesthesia, and at the same time to retain efficacy of the method it-self on a high level, or close to the major surgeries under the general anesthesia.(2)

Toward that goal we modified standard method of anal cerclage.

Patients and methods

Group of patients participating in this resear-ch was randomly selected. For the purpose of this research we used two groups of 30 patients older than 70 years. All patients were before surgery

examined and answered the questionnaire. In case of all patients before the surgery rectal prolapse is proven. Duration of illness was not taken in consi-deration. All the patients from the first group were operated by the team which has routine, with the method commonly used. All patients had same conditions before the surgery, starting with prepa-ration, emptying of the colon, or enema, antibiotic prophylaxis, medications, anesthesia, cleaning of the surgery field and treatment after the surgery. Post surgical treatment involves therapy for pain, wound treatment, and diet in order to achieve sof-ter stool.

In case of patients with this disease we did not set any perquisites besides clinical finding which confirms prolapse. (3) Coming to surgeon because of the problems caused by this disease, after the examination they accepted the suggested surgery and voluntarily participated in research. All time they were divided into two groups.

Majority of patients were women, with multi-ple child births, older than 70 years and partially with deteriorated health. One part of the patients had very poor health and bringing these patients under the general anesthesia was not recommen-ded. Many patients had respiratory diseases which for sure contributed to prolapse development. (4)

Due to long lasting prolapse, and also beca-use patients earned to control it, changes on the rectum mucosa are inevitable. When we take in consideration that this area was for long time pe-riod exposed to different medical and non medical solutions, poorer nutrition due to compression and bacterial activity, anatomic changes and pre surgi-cal preparations were very different compared to normal.

Presentation of the net carrier and other necessary equipment

Net carrier is instrument with the handle and one part with spiral shape. It is made of flexible material, so it can adjust to the size of the anal opening, but still rigid enough not to bend when passing trough ishiorectal tissue. On one end is a handle in shape which enables rotation with use of force. At the same time, it is easy to sterilize the handle and it fits well into the hand so the slipping



is reduced. Distal part is little bit narrower than the profile of the complete carrier with the opening of 1mm and with blunt peak in order to avoid dama-ge of the surrounding tissue.

Carrier is mad of stainless material, simple for cleaning after the surgery, with average profile of 1.5–2 mm.

Beside the carrier we are using different types of catheters, usually silicone ones, single use, with different thickness – from 14 to 24 Ch, depending on thickness of the used net. Due to financial re-asons, we are usually use nelaton catheters, nose catheters and gastric probes. They can be easily found in all hospitals, so they do not require speci-al acquisition procedures.

Figure 1. Features of prolene net and suturated matherial

From antibiotic crèmes we used standard ones that are available. Usually those are the crèmes which are targeted on Gram + and Gram –, and if possible on fungus, such as Bacimycin (Baci-tracin) or Fucydin (acid. fusidici). In mixture with 2% of Xylocaine and this crème we have beside prophylaxis also analgesic effect – if the patient is under anesthesia which last shorter than the gel.

In this research we used nets VYPRO (II) ET-HICON, which are in everyday use in case of her-nioplastic surgeries due to its features.

These nets are made of approximately equal parts of absorptive and non absorptive multifila-ment fibers tangled together in form of macro po-res in net structure.

Absorptive part of fibers is polyglactine, or co-polymer, it is made of 90% of glycolide and 10%

lactide, which are also used in making Vicryl thre-ads. Polymer of the none absorbs polypropylene fibers (6) is identical to fibers from which prolene threads are made. Fibers of absorption polyglac-tine are used for easier manipulation with the net because of their flexibility and for the easier fixa-tion. Full resorption of these fibers last from 56 to 70 days.

Large pores of the non absorptive polypropyle-ne net structure retains its position permanently and in that manner act as a support for the tissue depending of the goal that we want to achieve with placing the net. These fibers act as isotropic in all directions, or to say that their biochemical features are very similar to abdominal wall tissue, so they act similar as the wall during mechanic and also pharmaco-kinetic induction. They don’t cause al-most any tissue reaction, and at the same time the tissue grows well into the net. Feeling of fling as well as rigidity that occurs with previous nets is avoided in case of this type thanks to the reabsop-tive part, and the tolerance on direct pressure is still equivalent and measures around 20 thanks to non absorptive part.

Most often tissue reaction on the net are sero-mas, which occurs after certain time. Although, cases of net removal due to infection are very rare because of it non irritating structure.

Fixing of the net to the surface is usually done with Prolene 2-0 suture. Non absorptive thread is mostly used in order to avoid migration or move-ment of the net during time.

Preparation of patients and post surgical recovery

Preparation of patients for surgery is done in two parts first is cleaning and the second one is antibiotic prophylaxis.

Preparation of patients for the surgery as well as for rectoscopy is done with enema and peranal laxatives. From enemas mostly used is mild soap solutions in warm water or oil based enema with castor oil, and among peranal laxatives used are Dulcolax, Medilax or Glycerol. Enemas are usu-ally administered one to two hours before proce-dure.

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All patients involved in study received antibi-otic prophylaxis because insertion of the foreign object, especially into anal area, has high risk of post surgery infection. Prophylaxis was in form of Bactrim 2tbl and Flagyl 3tbl orally two hours before surgery.

After surgery, patients were hospitalized for se-veral days due to pains, caused by aggressive of the surgical procedure, and because of fear from next stool. Everyday showering of the wounds and washing in mild soap water, with application of local analgesics, helps to faster recovery. Patient is discharged from the hospital after defecation and when the post surgical pain can be “covered” with orally administered analgesics.

Type of anesthesia

During these surgeries, in both groups different types of anesthesia were used. From local anesthe-sia in form of 1% Xylocain with Adrenalin com-bined with intravenous sedation (Midazolam), and if needed epidural and general anesthesia, depen-ding on general health state of the patient and ane-sthesiologist opinion.

Figure 2. and 3. Applying local anesthesia

After cleaning of the surgical field injected is the local anesthetic Xylocaine 1% with Adrena-lin around anal opening. Anesthesia is injected in two levels – first under the skin and then in dep-th of 5 CM pararectally. Besides classic pudenal application of local anesthetic, always 15 minutes

is injected gel with 2% of Xylocaine into the rec-tum. Usually anesthesia of the surgical field in this manner was satisfactory. Also, when needed other forms of anesthesia were used.

Initial incision of 1-2 cm is made usually from left or right side of the ventral raphe of m. levator anii also called “central point of perineum”. Su-bcutaneous tissue is dissected with scissors, and ligament is moved in order to ensure passage for net carrier. After tunneling under the raphe in rec-tovaginal space, we continue dorsally-pararectally tunneling on both sides. In this way minimal tra-uma is made to this very sensitive perianal area.

After that we take net carrier, which adjust to the size of anal opening or size of the rectum. Net carrier is inserted into the wound and with control of finger in rectum, with which we can feel every movement, we avoid every movement, and avoid possible rupture of the rectum when making rotati-on movement more laterally from the rectum until the end of the carrier does not reach the rectovagi-nal raphe. When the carrier makes rotation move-ment around rectum circumference, which means almost 360 degrees, silicone or Nelaton (cheaper) catheter is inserted with diameter of about 14 CH with previously removed top and greased with Fu-cydin, Bacimycin or Xylocaine crème for easier application. Depending on subcutaneous tissue af-ter the catheter of CH placed on carrier is catheter of 18 CH and then 22 CH. When the thickest ca-theter appears its proximal part is taken with two Kokher clamps and distal part is cut.

Rolled net is attached with one suture for the opening at the top of the carrier which is made for this purpose. With movement of the carrier trough the catheter, which at the same time pulls the net, if needed with antibiotic crème, we are taking the net to the incision. Proximal end of the net s taken with the instruments and released from the carrier, and pulling of the catheter from the wound we are placing the net into the wanted position.

Only remains to suturate ends of the net usually leaving anal opening transversally in size of two fingers. Next is rinsing of the wound with physi-ology solution, povidon solution and closing the wound in standard manner



Table 1. Photography and schematic review of the modified method of anal cerclage with application of net carrier

Figure 4. Rectal prolapse – before surgery

Figure 5. Rectal prolapse - incision

Figure 6. Rectal prolapse - tunneling

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Figure 7. Rectal prolapse – instrument placement

Figure 8. Rectal prolapse – instrument exit troug same incision

Figure 9. Rectal prolapse – fixing of net

Figure 10. Rectal prolapse – net extraction



Figure 11. Rectal prolapse – connecting net ends

Figure 12. Rectal prolapse –after net suture

Figure 13. Rectal prolapse – after surgery


Because modification is in technical procedure of easier placement of the net, and the principle of the surgery is the same, we thought that the me-dical results of the surgeries should be identical.

That is why we sis not analyzed possible medical benefits which obviously existed especially during the period after the surgery.

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Figure 14. and 15. Preoperative and postopera-tice case

On the figures we can see the rectal prolapse, be-fore surgery and state after the surgery (just after the end of the surgery, where still visible is one incision at 11 o’clock, which is used to place the net).

Our wish was to present the medical benefit. It is consisted of:

1. Duration of post surgical hospitalization

One part of the patients, treated with modified method, after the surgery felt so good that there was no reason for further observation and trea-tment. They were discharged earlier on home ba-sed treatment with agreed control periods.

At the same time, all patients were well infor-med before and after the surgery how to recognize complications symptoms, for example, wound in-fection and how to react.

Table 2. Duration of hospitalization of patients surgically treated with modified method (n1 = 30) and patients treated with standard method (n2 = 30). The difference is not statistically significant (one-way Mann-Whitney U-test: W = 862, p = 0.178).

Analysis of results which show that the diffe-rence in duration of hospital treatment for the pa-tients treated with these methods does not have a statistical significance. From the table no. 1 can be seen that much more patients treated with the modified method leaved on home treatment first day after the surgery (6) and that neither one pa-tient stay in hospital 4 days after the surgery, un-like standard method, in case of which 2 patients stayed four days after the surgery. It is also shown that the total duration of hospital stay in case of patients treated with modified method is shorter for 12 days compared to the standard method.

Based on this we can conclude that the modi-fied method have shorter hospitalization, or less difficult recovery after the surgery.

2. Economic benefit

Summarizing all analyzed results, we see that relatively large economic benefit lays on the side of modified method compared to the standard one.

From the results analyzed in the table we can see that:



Table 3. Benefit of modificated metod we used in comparing with standard metod we used before

Number of in hospital days for all the patients treated with the modified method was by 19.6% lower compared to other group, or it was 7 hospi-tal days shorter, which calculated today is 336€ .

On this economic benefit we can add the cost of treatment for patients which have repeated hos-pitalization, where the difference is 3 in hospital days in favor of modified method. Also, costs of the repeated surgery in case of standard method and orally administered antibiotics were for 7 hos-pital days longer than in case of modified method. In case of analgesics administered intravenously advantage was in 5 hospital days, but in case of orally applied therapy 3 days in favor of standard method. Explanation could be in probably longer intravenously administered analgesics in case of standard method, so that the need for oral analge-sia was lower.

Conclusions

From the previous analyses we can conclude that with the modified method of anal cerclage is more easy to place prolene net with much less ti-ssue trauma, which by itself leads to much shorter and easier recovery, lower percent of complicati-ons and by that economic benefit.

After the analyses, because of tolerability of surgery and easy post surgical recovery, we came to conclusion that we can treat almost all patients as day-surgery patients. This means that all pati-

ents after shorter observation, same day, and leave home or at the institutions from which they came. For these patients and relatives this is very impor-tant that the patients does not change environment and by that lifestyle.

That is why we think, that in case of patients with rectal prolapse at old age, high morbidity, which in majority of cases require care from ot-hers, this modification of surgical procedure can be recommended as better method that the stan-dard anal cerclage.

Regarding relapse of this illness after the surge-ry, results are identical with the standard method so we didn’t consider analysis of that as necessary.

Literature

1. Sainio AP Halme LE Husa AI. Anal encirclement with polypropylene mesh for rectal prolapse and in-continence.Dis Colon Rectum 1991 Oct; 34:905-8.

2. Pikarsky AJ Joo JS Wexner SD et al. Recurrent rec-tal prolapse: what is the next good option? Dis Co-lon Rectum 2000 Sep; 43:1273-6.

3. Herrera-Ramírez J, Andrade-Ibáñez A, González-Velásquez F, Morales-Guzmán MI, Martínez-Mier G. Rectal prolapse. Surgical experience with he-licoidal suture and anoplasty: short hospital stay. Cir Cir ; 75(6) :453-7.

4. Villanueva Sáenz E, Martínez Hernández-Magro P, Alvarez-Tostado Fernández JF. Helicoidal suture: alternative treatment for complete rectal prolapse in high-risk patients. Int J Colorectal Dis Jan 2003; 18(1) :45-9.

5. Mansilla JE, Bannura GC, Contreras JP, Barrera AE, Melo CL, Soto DC. Lomas-Cooperman tech-nique for rectal prolapse in the elderly patient.Tech Coloproctol Jul 2006; 10(2) :106-10.

6. Nat Clin Pract Gastroenterol Hepatol.Surgical ma-nagement of rectal prolapse.2007Oct;4(10):552-61.


Nedzad Sehovic Clinic of General and Abdominal Surgery, Clinical Center University of Sarajevo, Bosnia and Herzegovina. e-mail: [email protected]

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Summary

Background: Methotrexate (MTX), a folic acid antagonist, is widely used as cytotoxic che-motherapeutic agent for malignancies as well as in the treatment of various inflammatory diseases .The efficacy of this agent is often limited by seve-re side effects and toxic conditions. Regarding the mechanism of these side effects, several hypothe-ses have been put forward, among which oxidati-ve stress is noticeable.

Aims & Objectives: The present study was undertaken to determine whether α-lipoic acid or quercetin, potent free radical scavengers, could ameliorate MTX-induced oxidative liver injury and modulate immune response. The study also aimed to investigate the possible role of nitric oxi-de (NO) and tumor necrosis factor-alpha (TNF-α) in the pathogenesis of MTX-induced hepatoxicity.

Study design/Methods: Rats were randomly divided into four experimental groups beside a normal control group consisting each of 8 animals. Following a single injection of MTX (20 mg/kg; i.p), experimental groups were allowed to receive either α-lipoic acid (50 mg/kg/day; orally), quer-cetin (10 mg/kg/day; i.p in dimethylsulphoxide (DMSO)) or the vehicle DMSO alone. Treatment was carried out for 5 consecutive days. On the sixth day, blood serum was separated and used for the determination of TNF-α level as well as aspar-tate aminotransferase (AST) and alanine amino-transferase (ALT) activities to assess the hepatic function. Liver tissue samples were collected for the estimation of tissue malondialdehyde (MDA),

reduced glutathione (GSH) and nitric oxide (NO) levels, myeloperoxidase (MPO), superoxide di-smutase (SOD) and catalase (CAT) activities as well as for histological examination. Results obta-ined were statistically analysed by one way anal-ysis of variance (ANOVA) followed by Tukey-Kramer multiple comparison test. Significance was considered at p<0.05.

Findings: MTX caused a significant reducti-on in hepatic GSH level, SOD and CAT activities while MDA and MPO activities were significantly increased. Hepatic NO as well as serum TNF-α levels were markedly elevated following MTX treatment. Only ALT rather than AST activity was significantly increased. These changes were significantly reversed by either α-lipoic acid or quercetin treatment. Similarly, histological anal-ysis revealed that both treatments were effective in attenuating tissue damage. However, the effect of α-lipoic acid was more pronounced.

Conclusion: The study indicates that oxidati-ve stress, NO as well as TNF-α may play an im-portant role in the pathogenesis of MTX-induced hepatoxicity. α -Lipoic acid and quercetin have protective aspects in this process through their antioxidant and anti-inflammatory effects. These data imply that antioxidant therapy may be of the-rapeutic potential in alleviating hepatotoxicity in patients receiving MTX treatment.

Key words: methotrexate, α–Lipoic acid, qu-ercetin, nitric oxide, TNF- α, oxidative stress.

alpha-lipoic acid and quercetin protect against methotrexate induced-hepatotoxicity in ratsHebatallah A. Darwish1, Amina Mahdy2

1 Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt2 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Egypt



Introduction Anti-tumor drugs are being increasingly used as

adjuvant therapy for recurrent inflammatory dise-ase. It was suggested that reactive oxygen species (ROS) and hydrogen peroxides (H2O2) are asso-ciated with adverse effects of anti-tumor agents (Sugiyama et al., 1989; Zhang et al., 1992). Met-hotrexate (MTX), an antimetabolite drug widely used in cancer therapy or in various recurrent in-flammatory diseases, is known to have toxic effects due to oxidative reactions that take place during its metabolism in the liver (Chladek et al., 1997). Long-term MTX therapy has been associated with liver toxicity, including steatosis, cholestasis, fibro-sis, and cirrhosis (Tobias & Auerbach, 1973; Vonen & Morland, 1984; Hytiroglou et al., 2004).

The exact mechanism of MTX-induced hepa-totoxicity is as yet unclear. However, some mec-hanisms that could explain the toxicity have been suggested. MTX conversion to its major metabo-lite, 7-hydroxymethotrexate, takes place in the li-ver, where it is oxidized by a soluble enzymatic system (Chladek et al., 1997). Inside cells, MTX is stored in polyglutamated form (Galivan et al., 1983). Long-term drug administration can cause accumulation of intracellular polyglutamates de-creasing folate levels which has been suggested as a mechanism for MTX hepatotoxicity (Kamen et al., 1981; Kremer et al., 1986). Additionally, it was demonstrated that the cytosolic NAD(P)-depen-dent dehydrogenases and NADP malic enzyme are inhibited by MTX, suggesting that the drug could decrease the availability of NADPH in cells (Vogel et al., 1963; Caetano et al., 1997). NADPH is essential for glutathione reductase enzyme acti-vity that sustains the levels of reduced glutathione (GSH), which is an important cytosolic antioxi-dant substance. Thus the reduction in the levels of GSH due to MTX leads to a weakening of the ef-fectiveness of the antioxidant defense system pro-tecting the cell against ROS (Babiak et al., 1998).

Numerous experimental and clinical studies proved efficiency of treatment with α-lipoic acid (or thioctic acid) in diseases in which antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome, tumors, etc.). Efficiency of lipoate has been attri-buted to unique antioxidant properties of lipoate/

dihydrolipoate system manifested as ROS scaven-ging ability as well as enhancement of the tissue concentrations of other antioxidants, including one of the most powerful, glutathione (thus lipoa-te is called an antioxidant of antioxidants) (Bilska & Wlodek, 2005).

Flavonoids are phenolic phytochemicals that are important constituents of the nonenergetic part of the human diet and are thought to promote op-timal health, at least in part via their antioxidant effects in protecting cellular components against ROS (Hertog & Hollman, 1996). Quercetin is one of the most widely distributed flavonoids, present in fruits, vegetables, and many other dietary so-urces (Pawlikowska-Pawlega et al.,2003) .This compound was reported to scavenge superoxide in ischemia-reperfusion injury (Huk et al., 1998), to protect against oxidative stress induced by UV light (Erden Inal & Kahraman, 2000), spontane-ous hypertension (Duarte et al., 2001) or biliary obstruction-induced liver damage (Peres et al., 2000), and to inhibit angiogenesis (Igura et al., 2001), carcinogenesis (Yang et al., 2000) and por-tal hypertensive gastropathy (Moreira et al., 2004).

The present study was undertaken to determine whether α-lipoic acid or quercetin as potent anti-oxidant compounds, could ameliorate MTX-indu-ced oxidative liver damage and modulate immune response. The study also aimed to investigate the possible role of NO and/or TNF-α in the pathoge-nesis of MTX-induced hepatoxicity.

Materials & Methods

1. Chemicals: Methotrexate was purchased from Ebewe Pharma, Austria. Alpha-lipoic acid and quercetin were provided from Sigma-Aldrich chemicals Co., St. Louis, USA. All other chemi-cals were of analytical grade.

2. Animals: Male wistar rats weighing 140 – 160 g were obtained from the animal house of fa-culty of medicine, Cairo University, Egypt. They were kept at a constant temperature (22 ± 10C) with 12 hour light and dark cycles, fed a standard rat chow and allowed to accommodate for one week before performing the study.

3. Experimental design: Rats were randomly divided into five experimental groups, each of 8

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rats. The first group (Control group) was injected with saline. The second group (MTX group) was injected with a single dose of methotrexate in sali-ne (20 mg/kg; intraperitoneally) (Cetinkaya et al., 2006). The third group (MTX + lipoic acid) recei-ved MTX as mentioned in the second group along with α–lipoic acid in saline containing 2 mol/l NaOH and adjusted to pH 7.4 (50 mg / kg; orally) (Kishi et al., 1999; Abdel-Zaher et al., 2008). The fourth group (MTX + Quercetin) received MTX along with quercetin in dimethylsulphoxide (DMSO) (10 mg/kg; intraperitoneally) (Coldiron et al., 2002). The last group (MTX+DMSO) recei-ved MTX together with the vehicle DMSO alone. Treatment was carried out for 5 consecutive days.

4. Estimation of blood parameters: Blo-od samples were collected from the retro-orbital plexus, serum was separated for the determinati-on of tumor necrosis factor–alpha (TNF–α) level by enzyme linked immunosorbent assay (ELISA) (using kit provided by Assaypro, USA). Serum levels of alanine aminotransferase (ALT) and as-partate aminotransferase (AST) were estimated to assess the hepatic function (using kits provided by ProDia international, Germany).

5. Determination of oxidative biomarkers: Rats were sacrificed, the abdominal cavity of each animal was rapidly dissected, the liver was remo-ved, washed with ice-cold saline, weighed and blotted dry. The liver was then homogenized in ice cold saline (20% w/v) using potter-Elvejhem gla-ss homogenizer and the homogenate was divided into five portions.

The first portion of the homogenate was mixed with ice cold 2.3% KCl solution and centrifuged at 600 xg for 15 minutes at 40C. The supernatant was used for malondialdehyde (MDA) determination which has been identified as the product of lipid peroxidation that reacts with thiobarbituric acid to give a pink color. The absorbance was recorded at 535 nm and 520 nm using tetramethoxypropane as a standard (Uchiyama & Mihara, 1978). The diffe-rence between the two determinations was calcu-lated as TBA value and expressed as nmol/mg pro-tein. Another portion of the homogenate was trea-ted with 7.5% sulfosalicylic acid and centrifuged at 600 xg at 40C for 10 minutes. The protein free supernatant was used for the estimation of reduced glutathione (GSH) content based on the reaction

of GSH with 5,5-dithiobis-2-nitrobenzoic acid forming a product that has a maximal absorbance at 412 nm. The results were expressed as μmol/g wet tissue (Beutler et al., 1963). The third porti-on of the homogenate was mixed with ice cold 50 mM tris buffer containing 0.1 mM EDTA (pH 7.6) and centrifuged at 105.000 xg at 40C for 40 mi-nutes using Dupont survall ultracentrifuge, USA. The resulting cytosolic fraction was used for the estimation of both superoxide dismutase (SOD) and catalase (CAT) activities. SOD was measured by following the rate of autoxidation of pyrogallol at 420 nm. The change in absorbance was recor-ded and expressed in U/mg protein (Marklund & Marklund, 1974). CAT activity was assayed by fo-llowing the decomposition of its substrate, H2O2 at 240 nm. The change in absorbance was recorded and expressed in U/mg protein (Aebi, 1974).

6. Determination of nitric oxide (NO) level and myeloperoxidase (MPO) activity: A portion of the homogenate was mixed with ice–cold 50 mM phosphate buffer containing 0.5% hexadecyl-trimethyl ammonium bromide (pH 6). After three freeze and thaw cycles with sonication between cycles, the samples were centrifuged at 41,400 xg for 10 minutes and the supernatant was used for the determination of MPO activity. This was mea-sured spectrophotometrically using O-dianisidine dihydrochloride as a substrate for MPO-mediated oxidation by H2O2. The change in absorbance at 460 nm was recorded and expressed in U/mg pro-tein (Krawisz et al., 1984). The last portion of the homogenate was centrifuged at 17.000 xg at 40C for 15 minutes and the supernatant was used for the determination of NO level measured as total nitrites with the spectrophotometric Greiss reacti-on. Results were expressed as µmol/g tissue (Mi-randa et al., 2001). The protein content in liver fractions was measured by the method of Lowry et al. (1951).

7. Histopathological examination: Liver spe-cimens were fixed with 10% formaldehyde and processed routinely for embedding in paraffin. Sections of 5 μm were stained with hematoxylin and eosin (H&E) and examined under the light microscope.

8. Statistical analysis: Results were expressed as mean ± standard error of the mean (SEM). Di-fferences among means were tested for statisti-



cal significance by one–way analysis of variance (ANOVA). When differences were significant, Tukey-Kramer’s test was used for multiple com-parisons between groups. Statistical significance was considered when p < 0.05.

Results

1. Biochemical results: Testing of the hepatic function following a single injection of MTX

(20 mg/kg, i.p) in normal rats revealed a signi-ficant rise in ALT which was restored by either α-lipoic acid or quercetin treatment (table 1). AST was significantly unchanged among all the trea-tment groups.

A considerable elevation of lipid peroxides (MDA) in hepatic tissue was demonstrated fo-llowing MTX injection. This elevation was ame-liorated and completely abolished by treatment with quercetin and α-lipoic acid respectively (ta-ble 2). Further evidence for MTX-induced toxicity in the liver tissue was the profound reduction of

the antioxidant defense mechanisms as shown by a significant decrease in GSH content, SOD and CAT activities. Alpha-lipoic acid has demonstra-ted a powerful antioxidant effect as evidenced by restoring to normal the levels of GSH as well as SOD and CAT activities (table 2). Meanwhi-le, quercetin treatment normalized SOD activity, ameliorated GSH content and did not affect CAT activity in hepatic tissue (table 2).

Following MTX injection, MPO activity showed about three-fold increase. This rise was completely normalized while significantly ameli-orated by α-lipoic acid and quercetin respectively (table 2).

A two-fold increase in nitric oxide level in he-patic tissue of MTX-treated rats was observed in the present study. This marked rise was normali-zed by both antioxidant therapies (figure 1). Simi-larly, MTX injection in normal rats evoked a six-fold elevation in serum TNF-α level. Treatment with either α-lipoic acid or quercetin resulted in a beneficial restoration of normal level of this medi-ator in treated rats (figure 2).

Table 1. Effect of α-lipoic acid and quercetin on MTX-induced alterations liver enzyme activities Groups

Parameters

Control MTXMTX

+Lipoic acid

MTX+

Quercetin

MTX+

DMSO

ALT (IU/L) 71.6 ± 3.3 108.8 ± 11.02 a 70.2 ± 3.46 b 74.5 ± 7.49 b 92.2 ± 3 a

AST (IU/L) 179.9 ± 4.25 195 ± 7.52 175.9 ± 4.92 180 ± 5.26 184.2 ± 12.2

Values are expressed as mean ± SEM of 6-8 animals. a) significant difference from control group at p<0.05, b) significant difference from MTX group at p <0.05

Table 2. Effect of α-lipoic acid and quercetin on MTX-induced alterations in oxidant/antioxidant status Groups

ParametersControl MTX

MTX+

Lipoic acid

MTX+

Quercetin

MTX+

DMSO

MDA (nmol/mg protein) 2.53 ± 0.32 5.6 ± 0.41 a 4.07 ± 0.24 ab 2.69 ± 0.29 b 4.84 ± 0.3 a

GSH (µmol/g wet tissue) 3.03 ± 0.06 1.53 ± 0.75 a 2.61 ± 0.18 b 2.24 ± 0.06 ab 1.89 ± 0.08 a

SOD (U/mg protein) 15.5 ± 0.55 11.05 ± 0.84 a 15.2 ± 0.48 b 15.5 ± 0.5 b 12 ± 1.05 a

CAT (U/mg protein) 13.7 ± 1.09 9.54 ± 0.81 a 13.3 ± 1.14 b 10.8 ± 0.24 9.6 ± 0.52 a

MPO (U/mg protein) 2.53 ± 0.17 7.19 ±0.81 a 2.61 ± 0.25 b 4.85 ± 0.43 ab 6.11 ± 0.43 a

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Values are expressed as mean ± SEM of 6-8 animalsa) significant difference from control group at p<0.05, b) significant difference from MTX group at p<0.05

2. Histopathological results: As shown in fig-ure (3), the liver of normal control rats revealed no histopathological alteration. Normal histologi-cal structure of the central vein and surrounding hepatocytes were recorded (A). By contrast, liver sections from rats receiving MTX showed prolif-eration of Kupffer cells around the central vein, in association with focal inflammatory cells infil-tration in between the degenerated and necrosed hepatocytes (C). The portal area showed massive number of inflammatory cells infiltration with dilatation in both portal vein and bile ducts of MTX-treated rats (B). Concurrent administration of lipoic acid (D) and quercetin (E) improved the alterations in liver morphology as evidenced by moderate infiltration and vascularization. Howev-er, the hepatocytes showed fatty change in diffuse manner allover the hepatic parenchyma following quercetin (E) and in few manner following its ve-hicle DMSO (F).



Fig. 3. Photomicrographs of liver sections from (A) normal control rats (H&E, 64 x), (B & C) MTX-treated rats (H&E, 64 x and 160 x respecti-vely), (D) MTX + Lipoic acid, (E) MTX + Quer-cetin and (F) MTX + DMSO (H&E, 160 x).

Discussion

Several mechanisms may lead to oxidative stress in cancer patients. This may involve a non-specific chronic activation of the immune system accompanied by an excessive production of proin-flammatory cytokines leading in turn to increased ROS production (Mantovani et al., 1997). The use of antineoplastic drugs may additionally result in an excess production of ROS and may therefore lead to oxidative stress (Weijl et al., 1997). Thus, we can hypothesize that the body redox systems, which include antioxidant enzymes and low mole-cular weight antioxidants, may be down regulated in cancer patients as a function of the administrati-on of antineoplastic drugs just as it may be a result of the disease progression itself.

GSH plays an important role in the detoxification of xenobiotics and various chemicals. A reduction in the cellular GSH levels in response to MTX me-dication have been reported to be related to inhibi-tion of glutathione reductase activity, resulting in a failure to restore cellular GSH (Babiak et al., 1998). Moreover, Phillips et al. (2003) observed that mo-nocyte GSH levels decreased markedly after MTX administration. In an experimental study, MTX was ascertained to decrease GSH levels in hepatocyte cultures (Walker et al., 2000). In the present study, the significant reduction in GSH levels, promoted by MTX, lead to a reduction of effectiveness of the antioxidant enzyme defense system, sensitizing the cells to ROS (Babiak et al., 1998).

Decreased GSH levels were restored or signifi-cantly ameliorated by α-lipoic acid and quercetin respectively. Despite a rapidly growing interest in α-lipoic acid and its therapeutic potential as a pro-glutathione agent (Busse et al., 1992), information regarding the effect of its supplementation on the level of GSH in tissues is limited. Exogenously su-pplied α-lipoic acid is readily taken up by a variety of cells and tissues in which it is rapidly reduced by NADH- or NADPH-dependent enzymes to dihy-dro-lipoic acid (DHLA). DHLA was reported to im-prove cysteine availability within the cell, resulting in accelerated GSH synthesis (Sen, 1997). In view of this mechanism of action of α-lipoic acid, it may be expected that the effect of α-lipoic acid on tissue GSH would be most marked in organs that have a high activity of GSH-synthesizing enzymes as liver and erythrocytes in blood (Srivastava, 1971; Dene-ke & Fanburg, 1989). Moreover, DHLA is a strong reductant known to regenerate major physiological antioxidants of lipid and aqueous phases, such as vitamin E, and ascorbate (Packer et al., 1995). The-refore, the antioxidant power of DHLA contributes to the efficiency of α-lipoic acid in reservation of all the antioxidant defense mechanisms observed in the present study.

Similarly, quercetin, a member of the flavonoid family, has been shown to delay oxidant injury and cell death by scavenging ROS and free radicals, protecting against lipid peroxidation and thereby terminating the chain-radical reaction, and chela-ting metal ions (Silva et al., 2002). In particular, quercetin has been demonstrated to scavenge O2

., singlet oxygen (1O2) and .OH radicals, to prevent lipid peroxidation, to inhibit cyclooxygenase and lipooxygenase enzymes, and to chelate transition metal ions (Gordon & Roedig-Penman, 1998).

Lipid peroxidation, mediated by oxygen free radicals, is believed to be an important cause of destruction and damage to cell membranes (Jaho-vic et al., 2004) and this has been suggested to be a contributing factor to the MTX-mediated histo-pathological changes observed in hepatic tissue. Owing to their antioxidant activities, α-lipoic acid and quercetin reduced the MTX-induced oxidati-ve injury, and showed a cellular protective effect in this regards.

In addition to direct damaging effects on tissu-es, free radicals seem to trigger the accumulation

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of leukocytes in the tissues involved, and thus aggravate tissue injury indirectly through enhan-cement of the release of cytokines from activated neutrophils (Vaziri, 2004). It has been shown that activated neutrophils secrete enzymes such as MPO and liberate oxygen radicals (Sullivan et al., 2000). In turn, MPO plays a fundamental role in oxidant production by neutrophils. In our obser-vation, elevated cytokine TNF-α in the blood, and MPO levels in the liver, indicate that neutrophil accumulation contributes, at least in part, to MTX-induced oxidative organ injury. The results also revealed that both lipoic acid and quercetin have preventive effects through the inhibition of neu-trophil infiltration and cytokine release. This was evidenced by restoration of TNF-α level observed with both treatments along with either normali-zation or reduction of the elevated MPO activity following α-lipoic acid or quercetin respectively. Moreover, the significant increase in hepatic NO level following MTX was shown to be normalized by both antioxidant used in the study.

These beneficial effects of either lipoic acid or quercetin could be explained on the basis that; in the absence of an appropriate compensatory res-ponse from the endogenous antioxidant network, the system becomes overwhelmed (redox imba-lance), leading to the activation of stress-sensi-tive signaling pathways, such as nuclear factor kappa (NF-kB), and others. Under normal physi-ologic conditions, NF-kB forms a complex with its inhibitors and is maintained in the cytosol in an inactive state. NF-kB can be freed from its in-hibitors through the direct action of protein kina-ses, the IKKs that form a complex consisting of the catalytic subunits IKKα and IKKβ (Zandi et al., 1997). Freed from its inhibitor, NF-kB enters the nucleus and transactivates NF-kB–responsi-ve genes (Staal et al., 1990; Romics et al., 2004). It has been reported that α-lipoic acid and quer-cetin block NF-kB activation through inhibition of both IKKα and IKKβ in a dose-dependent ma-nner (Peet & Li, 1999). Moreover, lipoic acid and quercetin are also effective chelators of iron and copper (Ou et al., 1995; Lodge et al., 1998). It has been suggested that the metal chelating ra-ther than antioxidant properties, is responsible for such inhibitory effect on NF-kB activation (Bowie et al., 1997).

One major consequence of the activation of stress-sensitive signaling pathways (NF-kB) is the generation of gene products such as Nitric oxide. NO, a nontoxic mediator (vasodilator and neurotransmitter) under physiological conditi-ons, has been shown to contribute to cell and ti-ssue injury when it is formed at high rates and for prolonged periods by inducible NO synthase (iNOS). In cultured cells, induction of apoptotic and necrotic cell death and impairment of several metabolic functions such as mitochondrial energy production and DNA synthesis by NO have been described (Kroncke et al., 1998; Wink & Mitchell, 1998; Rauen et al., 2007). In addition to toxicity of NO itself, injury has been ascribed to oxidation products of NO such as NO2 or N2O3 (Grisham et al., 1999). Nitric oxide may react with superoxide radical to yield the highly reactive oxidant species peroxynitrite, leading to more aggressive oxidati-ve and nitrosative stress (Lorens & Nava, 2003). Moreover, NO or its oxidation products appeared to inhibit both cellular-H2O2 degrading systems; catalase and the glutathione/ glutathione peroxi-dase system. Catalase appeared to be inhibited rapidly by NO itself, hence, NO can bind to the heme moiety of native catalase, resulting in heme nitrosylation (formation of a complex between the heme iron and NO). This heme nitrosylation pre-vents the interaction of H2O2 with the iron center and thus H2O2 degradation (Rauen et al., 2007).

The observed normalization of TNF-α level by α-lipoic acid and quercetin could be correlated to suppression of the release of NF-kB. This correla-tion was previously demonstrated by Zhang and Freil (2001) in human aortic endothelial cells. Su-ppressed NF-kB in turn down regulated the expre-ssion of iNOS (Dias et al., 2005) providing a basis for the reduction achieved by these antioxidants in the encountered elevation of NO level caused by MTX administration.

In conclusion, the findings of the current study indicate that α-lipoic acid and quercetin effective-ly reduced oxidative and nitrosative stess caused by MTX. These data indicate that α-lipoic acid and quercetin may be of therapeutic use in preven-ting hepatotoxicity in patients receiving chemot-herapeutic agents. Hence, compensation of side effects, such as hepatotoxicity, affecting the con-tinuation of the use of chemotherapeutic agents



may enable the usage of those agents more effec-tively. However, our results warrant further inve-stigation with an adequate clinical trial to test the hypothesis that the supplementation of antioxidant agents may protect cancer patients from oxidative stress, occurring either spontaneously or enhanced by treatment with MTX or other oxidative dama-ge-inducing drugs.

Acknowledgement The authors are thankful to Dr. Adel Bakeer,

Histology Department, Faculty of Medicine, Ca-iro University, for performing the histopathologi-cal examination of the present study.

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Hebatallah A. Darwish Department of Biochemistry, Faculty of Pharmacy, Cairo University Egypt Phone: +2 011 2550300 e-mail: [email protected]

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Summary

This group of blistering disorders comprise the rare but serious group of mechanobullous disorders. They usually present at birth or in infancy, but ca-use problems thereafter throughout life. Categori-zations of the types of epidermolysis bullosa group of blistering disorders were controversial and often confusing because more than 20 types of these dise-ase have been described. This group of diseases are genetically determined and range from relatively mild problems to life threatening conditions. In this papaer we will shou new classification of epidermo-lysis bullosa group of blistering disorders.

Key words: epidermolysis bullosa, epidermol-ysis bullosa simplex, junctional epidermolysis bu-llosa, dystrophic epidermolysis bullosa

The present classification

Toward the end of last millenium, electron microscopy revealed abnormal keratin filaments ,diordered dermal anchoring fibril and defective hemidesmosomes, and discavered some of the major genes included those that encode keratins 5 and 14, collagen VII and laminin 5, and also genes responsible for the rare subtypes of epidermolysis bullosa blistering disorders (1).

The main varieties of epidermolysis bullosa EB gropu of blistering disorders are:

- Epidermolysis bullosa simplex - mainly autosomal dominant inherited

- Epidermolysis bullosa junctionalis - autosomal recessive inherited

- Epidermolysis bullosa dystrophica - both autosomal dominant, and autosomal recessive varieties.

Histopathology determines the level of cleava-ge, which is further defined by electron microsco-py and immunohistochemical maping.

A molecular technique including Western blot, Northen blot, restriction fragment length polymor-phism analysis and DNA sequences may then identify the mutated gene (2).

Epidermis, epidermodermal junction and the level places of cleavage are shematicaly shown on Shema 1

Shema 1.

Classification of the epidermolysis bullosa gro-up disorders, type inheritency and main clinical caractheristics are shown on Table 1.

Adopted Fine JD, Bauer EA, Briggman RA et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus re-port by the Subcomittee on Diagnosis and Classifi-cation of the National Epidermolysis Bullosa Regi-stry. J Am Acad Dermatol 1991 24 1 119 135 1.

In each of these groups there are several dis-tinct types of epidermolysis bullosa based on cli-nical, genetic, lighht microscopy, electron micros-copy and biochemical molecular evaluation(3).

These caractheristics are shown on Table 2.

New classification of epidermolysis bullosa group of blistering disordersNaima Mutevelic Arslanagic1, Rusmir Arslanagic2, Selma Arslanagic31 Department of Dermatology, Sarajevo, Bosnia and Herzegovina2 ORL Department, Sarajevo, Bosnia and Herzegovina3 Department of Plastic surgery, Sarajevo, Bosnia and Herzegovina



Adopted Fine JD, Bauer EA, Briggman RA et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus re-port by the Subcomittee on Diagnosis and Classi-fication of the National Epidermolysis Bullosa Re-gistry. J Am Acad Dermatol 1991 24 1 119 135 1

Epidermolysis bullosa simplex

Cytolisis causes blisters in the epidermis and causes blisters in the basal or spinous layers of the

epidermis, and keratinocytes often have abnormal density and organization of keratin filaments. Thus, there is true cell lysis . The pathological damage is based on split through the cytoplasm of the basal cells. The molecular defects lies in most cases on keratin gene mutations, genes which coding for keratin 5 and 14. Keratin 5 and 14 are found pre-ferentially in the basal layer. Different subgroups have considerable phenotypic variations. There are 11 distinc forms of epidermolysis bullosa simplex. Seven of which are autosomal dominant inherited and four autosomal recessive inherited (1).

TABLE 1. Type and subtype of the epidermolysis bullosa group of disordersType of disease

Number of verieties Inheritance Site of blister Specific defect Clinical features

EB simplex 11Mainly

autosomal dominant

Basal cells Keratin 5 and 14After friction

blisters on hands and feet

EB junctionalis 7 All autosomal

recessive Lamina lucida HemidesmosomesBlistering of

skin and mucosal membrane

EB dystrophica 11

Both, autosomal

dominat and recessive

Below basement membrane,

sublamina densa

Anchoring fibrilsType 7 collagen

Blistering of skin and mucosal

membrane, scaring and loss of nails

TABLE 2 TYPE OF EPIDERMOLYSIS BULLOSA AND ASSOCIATED CHARACTERISTICS

Type of EB Feature on light microscopy

Feature on electron microscopy Protein or antigen Gene

EB simplex Dowling Meara Epidermis Keratin filaments Keratin 5 KRT 5

EB simplex Weber Cockayne Epidermis Keratin filaments Keratin 14 KRT 14

EB with ectodermal dysplasis Epidermis Desmosome, attachment

plaque Plakophilin PKP 1

EB with muscular dystrophy Epidermis Hemidesmosome lamina

lucida, attachment plaque Plectin PLEC 1

EB junctionalis non Herlitz

Basement memebrane zone

Hemidesmosome lamina lucida, subbasal dense

plate,anchoring filamentsCollagen XVII BPAG 2

EB junctionalis with pyloric atresia

Basement membrane zone

Hemidesmosome lamina lucida, subbasal dense

plate, anchoring filamentsAlpha6beta4integrin ITGB6

ITBG 4

EB junctionalis Herlitz, rarely non

Herlitz

Basement membrane zone Lamina densa Laminin 5

LAMA 3LAMB 3LAMC 2

EB dystrophica Dermis Anchoring fibrils Collagen VII COL7A1

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Elewen variants of epidermolysis bullosa sim-plex are currently recognized and some of them are shown on Table 3.

Adopted Fine JD, Bauer EA, Briggman RA et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus re-port by the Subcomittee on Diagnosis and Classifi-cation of the National Epidermolysis Bullosa Regi-stry. J Am Acad Dermatol 1991 24 1 119 135 1.

Epidermolysis bullosa junctionalis

All seven currently recognized variants of this type are inherited by autosomal recessive transmi-ssion and the basic abnormality appears to lie in the hemidesmosomes. Defective genes normally co-ding for bullous pemphigoid antigen and laminin have recently been identified in the generalized , atrophic, benign variant of this epidermolysis bu-llosa subtype. This results in the development of a split at the level of the lamina lucida (4).

Some of clinical phenotype and mollecular de-fect correlations in epidermolysis bullosa junctio-nalis are shown on Table 4.Table 4. Clinical phenotype and mollecular defect correlations in epidermolysis bullosa junctionalis

ProteinEBJ Herlitz Laminin 5EBJ nonHerlitz Kolagen VIIEBJ with pyloric athresia Integrin alfa 6beta 4EBJ inversa Laminin 5EBJ started later Unnown

Adopted Fine JD, Bauer EA, Briggman RA et al. Revised clinical and laboratory criteria for subtypes

of inherited epidermolysis bullosa. A consensus re-port by the Subcomittee on Diagnosis and Classifi-cation of the National Epidermolysis Bullosa Regi-stry. J Am Acad Dermatol 1991 24 1 119 135 1.

Dystrophic epidermolysis bullosa

The abnormality cosists of defective anchoring fibrils connecting the basal lamina to the dermis and a subepidermal blister results. In the dominant vari-etie in later infancy or early childhood bullae form on friction sites and heal with scarring Figure 1 and 2. In the recessive types, there is also a defect of anchoring fibrils (5). Large bullae are present at bir-th, and they heal with scarring which is associated with the formation of webs between fingers Figure 3 a useless fist mucous membranes, hair, Figure 3, nails, Figure 3, and teeth may all be abnormal, Fi-gure 1, and there are reports of the development of squamous carcinoma on the scar sites (6,7).

Some of clinical phenotype and mollecular de-fect correlations in dystrophic epidermolysis bu-llosa are present on Table 5.Table 5. Clinical phenotype and mollecular defect correlations in epidermolysis bullosa dystrophica

ProteinEBD autosomal dominant inherited Kolagen VIIEBD autosomal recessive inherited Hallopeau Simens Kolagen VII

EBD autosomal recessive inherited non Hallopeau Simnes Kolagen VII

EBD autosomal dominant inherited, praetibialis Kolagen VII

EBD newborn transient Kolagen VIIEBD pruritic, autosomal dominant inherited Kolagen VII

Table 3. Clinical phenotype and mollecular defect correlations in epidermolysis bullosa simplexProteins Clinical features

EBS Weber Cockaine Keratin 5 and 14 Palms and solesEBS Kobner Keratin 5 and 14 Generalised

EBS Dowling Meara Keratin 5 and 14 Herpetiformic erythema and vesicles. Mucous membranes unaffected

EBS with muscular dystophy Plectin GeneralisedEBS with pathy hyperpigemnation Keratin 5 Keratinisation of palms and solesEBS, autosomal recessive without muscular dystrophy Keratin 14 Keratinisation and vesicles of palm and soles

EBS superficialis Unnown Erythema and vesicles



Figure 1. Bullae form on fricion sites and heal with scaring. The teeth are not normal

Figure 2. Generalised blistering, milia and scar formation

Figure 3. Large bullae heal with scaring which is associated with the formation of webs betwen fingers and scars alopecia

Literature

1. Fine JD,Bauer Ea,Briggman RA et al. Revised cli-nical and laboratory criteria for subtypes of inhe-rited epidermolysis bullosa.A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis bullosa Registry .J Am Acad Dermatol 1991; 24 (1) :119-1352

2. Pfeneder EG. Nakano A, Pulkkinen L,Christiano AM, UittoJ.Prenatal diagnosis for epidermolysis bullosa: a studz of 144 consecutive pregnancies at risk. Prenat Diagn. 2003;23(6):447-456

3. Uitto J, Richard G. Progress in epidermolysis bul-losa: from eponyms to molecular genetic classifica-tion. Clin dermatol 2005;23(1):33-40

4. Puvabanditsin S, Garrow E, Kim DU, Tirakitsoorn P, Luan J. Junctional epidermolysis bullosa associ-ated with congenital localized absence of skin, and pyloric atresia in two newborn siblings. J Am Acad Dermatol 2001;44(2 Suppl):330-335

5. Horn HM, Tidman MJ. The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol 2002;146(2):267-274

6. Mallipeddi R.Epidermolysis bullosa and cancer. Clin Exp Dermatol . 2002;27(8):616-623

7. Ayman T, Yerebacan O, Ciftcioglu MA, Alpsoy. A 13-year-old girl with recessive dystrophic epider-molysis bullosa presenting with squamous cell car-cinoma. Pediatr Dermatol.2002;19(5):436-4


Naima Arslanagic, Department of Dermatology, Sarajevo Bosnia and Herzegovina e-mail: [email protected]

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