Israel Medical Association Journal

The incidence of invasive uterine cervical cancer in Israeli Jewish women is persistently lower than in many other countries, although the frequency of premalignant lesions is similar to that in other populations. Most characteristics, except certain traditional habits, are similar to those in other populations. The incidence among women born in North Africa and their Israeli born descendants is significantly higher than in those born in other continents, possibly due to genetic factors. In view of the similarities to other populations the reason for the low incidence in Israel remains obscure, and whether it may be attributed to genetic reasons or to some traditional habits remains to be confirmed
 

Background: Traditionally, medication dosage was based on clinical and demographic parameters, but drug metabolism was recently recognized as an important factor for proper dosing and prediction of side effects. Metabolic considerations are crucial when administering drugs with a narrow therapeutic index, such as those of the thioguanides family (azathioprine and 6-MP). These can cause life-threatening myelosuppression due to low activity of a critical metabolic enzyme, thiopurine S-methyl transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies.

Objectives: To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the thioguanide family due to enzymatic variants.

Methods: DNA analysis was performed using polymerase chain reaction methods. We tested TPMT[1] allelic variants TPMT*3A (G460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpopulations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews.

Results: The Druze (P = 0.0002) and Ethiopian Jewish (P = 0.015) subpopulations had a significantly unique distribution of allelic variants compared to the rest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote for TPMT*3A/ *3A was detected.  Ethiopian Jews were found to carry mainly the TPMT*3C variant, also observed in other studies of African populations.

Conclusions: It is advisable that Druze patients be tested for the TPMT enzyme before starting treatment with 6-MP or azathioprine. Such testing may also be considered for other Israeli ethnic subgroups.

Background: Hypovitaminosis D has been shown to be extremely common in various regions around the world, mostly at high latitudes. Israel is characterized by certain features – cultural (e.g., ethnic isolates) and geographic (e.g., sunny climate) – that have been identified for their possible association with vitamin D status.

Objectives: To conduct an ecological study on a representative sample of the population of Israel, testing vitamin D status across age groups, genders, ethnic groups, and seasons.

Methods: We obtained serum samples from 195 healthy Israeli volunteers representing a broad demographic spectrum. Serum concentrations of 25(OH)D were measured with the commercial kit Liaison 25(OH)D Assay (DiaSorin, Italy).

Results: The mean vitamin D level for the entire cohort was surprisingly low (22.9 ± 10.1 ng/ml), with 149 subjects (78%) suffering from vitamin D insufficiency (< 30 ng/ml). Vitamin D status was better in infants than in older age groups. Differences by gender were significant only in the infant age group (i.e., vitamin D status was worse among females) and were not prominent across older ages. Israelis of Ashkenazi origin had higher vitamin D mean levels than those of Sephardic origin, who, in turn, had higher vitamin D levels than Arab subjects (31.4 ± 12, 24.1 ± 10, and 17.6 ± 9 ng/ml respectively). With regard to season, there were no differences between the samples collected in winter and the samples collected in summer.

Conclusions: The results suggest that hypovitaminosis D is common across all ages, genders and seasons in Israel, a country characterized by a sunny Mediterranean climate. Specific ethnic groups may be at especially high risk.

Background: The incidence of stroke varies among ethnically and culturally diverse groups.

Objectives: To examine the ethnic-geographic patterns of stroke incidence in men and women with coronary heart disease in Israel, focusing on the extent to which this variability can be explained by known differences in risk factors for stroke.

Methods: Patients with documented coronary heart disease were followed for 6–8 years for incident cerebrovascular events. Baseline medical evaluation included assessment of vascular risk factors and measures of blood lipids. Among 15,052 patients, a total of 1110 were identified with any incident ischemic cerebrovascular event by ICD-9 codes, of whom 613 had confirmed ischemic stroke or transient ischemic attack.

Results: A major excess of ischemic cerebrovascular events among Israeli Arab women as compared to males, and an inverse finding among Israeli born Jews, were noted. The high risk in the Arab population in Israel reflected an unfavorable risk profile, since predicted rates by multivariate analysis and observed rates were 69 and 68 per 1000, respectively. High ischemic cerebrovascular event rates were identified among patients born in the Balkan countries and North Africa (89 and 90 per 1000) but unfavorable risk factor levels of these individuals did not explain them. Most trends appeared similar in male and female patients. A comparison of observed and accepted-according-to-risk-profile rates of ischemic cerebrovascular events yielded significant differences (P = 0.04), consistent with an additional role of geographic/ethnic origin, resulting from factors that remain unrecognized,or with variables unassessed in this study.

Conclusions: We identified an ethnic diversity in stroke risk among Israeli born in different parts of the world beyond what could be expected on the basis of differences in known risk factors. These findings call for detailed research aimed at identifying additional differences in the risk profile of patients with atherothrombotic disease exposed to an increased risk of stroke.
 

Background: Dupuytren’s disease is a fibroproliferative disorder of the palmar fascia that can cause disabling digital contractures. The pathogensis of the disease is still unclear, and it afflicts predominantly white males of northern European origin. Gender-related differences of Dupuytren's disease and the distinctive characteristics of the disease in females are not yet well defined.

Objectives: To evaluate and illustrate the distinctive characteristics of Dupuytren's disease in females.

Methods: A retrospective study was performed of all female patients with Dupuytren’s disease seen and followed at our Hand Surgery Unit over a 20 year period. The study group consisted of 48 women (56 hands). The collected data included clinical and epidemiological features on admission, and outcome of surgical intervention.

Results: Of the 48 women (56 hands) with Dupuytren's disease, 23 (26 hands) underwent limited fasciectomy. The average age at presentation was 60.1 years. A few of the patients originated from Asia and Africa. Manifestations and pattern of the disease were nearly comparable to those observed in the male group, except for a slightly higher incidence of proximal interphalangeal joint contracture in female patients. Generally, females expressed less severe contractures on presentation, and a slow progression thereafter. A favorable functional postoperative outcome was observed. Seven patients had minor complications including local hematoma and painful scars. Two patients developed moderate signs of complex regional pain syndrome.

Conclusions: Further investigations are needed to assess the potential role of androgens in the pathogenesis of Dupuytren's disease, and a possible protective role of estrogenic hormones, rendering Dupuytren’s contracture a postmenopausal affliction.
 

Background: Parental fear and misconceptions about fever are widespread in western society. Ethnicity and sociodemographic factors have been suggested as contributing factors.

Objectives: To test the hypothesis that undue parental concern about fever is less in traditional than in western cultural-ethnic groups.

Methods: Bedouin (traditional society) and Jewish (western society) parents of children aged 0–5 years with fever were interviewed in a pediatric emergency unit. Interviews were conducted in the parents' most fluent language (Hebrew or Arabic). A quantitative variable (a 9 item “fever phobia” scale) was constructed.

Results: The parents of 101 Jewish and 100 Bedouin children were interviewed. More Bedouin parents were unemployed, had less formal education and had more and younger children than the Jewish parents. Parents of both groups expressed erroneous beliefs and practices about fever; quantitative but not qualitative differences in fever phobia variables were documented. Compared with their Jewish counterparts, more Bedouin parents believed that fever may cause brain damage and death, administered antipyretic medications for temperature ≤ 38ºC and at excessive doses, and consulted a physician within 24 hours even when the child had no signs of illness other than fever (all P values < 0.001). The mean fever phobia score was higher in the Bedouin than in the Jewish group (P < 0.001). By multivariate analysis, only the cultural-ethnic origin correlated with fever phobia.

Conclusions: A higher degree of fever phobia was found among parents belonging to the traditional Bedouin group as compared to western society parents.
 

Background: Age-related macular degeneration is the most common cause of legal blindness in the developed world including Israel. Ethnic background is a risk factor for advanced AMD[1] in several populations, however the relative prevalence of this disease in different ethnic groups in the Middle East is unknown.

Objectives: To compare the prevalence of advanced AMD in Arabs and Jews in Israel.

Methods: We performed a retrospective analysis of two independent groups of patients: the first group comprised a sequential series of Jerusalem residents who underwent photodynamic therapy for neovascular AMD (PDT[2] group), and the second group consisted of all individuals in Jerusalem who received a blind certificate due to AMD (legal blindness group). Control groups were assessed to exclude inherited ethnic associated bias in the two study groups.

Results: The PDT group included 146 patients: 142 were Jews (97.3%) and 4 were Arabs (2.7%). The legal blindness group included 340 Jerusalem residents: 326 Jews (96%) and 14 Arabs (4%). The number of Arab AMD patients in the two groups was lower than expected based on the ethnic composition of the age-matched Jerusalem population (P = 0.0002 for the PDT group, and P < 0.0001 for the legal blindness group). By contrast, the number of non-AMD Arab patients who were treated in the same clinic and the number of Arabs who received a blind certificate for diabetic retinopathy was not different from expected based on their relative number in the Jerusalem population.

Conclusions: Advanced AMD is less common in the Arab than the Jewish population of Jerusalem. Genetic and environmental factors may account for this difference. A population-based study is required to assess the overall prevalence of AMD in Jews and Arabs.

Background: In the western world, trauma is the leading cause of disability and mortality in the 1–39 years age group. Road accidents constitute the most frequent cause of mortality among children older than 1 year and falls from a height are the most frequent cause of injuries requiring hospitalization.

Objectives: To analyze the epidemiology and characteristics of severe pediatric trauma due to falls from a height in northern Israel. This analysis should aid in planning an effective intervention plan.

Methods: This observational study included all patients aged 0–14 who died or were admitted to an intensive care unit in northern Israel following a steep fall. Demographic and clinical data were collected retrospectively for 3 years and prospectively for 1 year.

Results: A total of 188 children were severely injured or died following such a fall, with an annual rate of 11.4 per 100,000 children. Over 85% of severe injuries due to falls occurred among non-Jewish children, with an incidence rate 6.36 times higher than among Jewish children (20.17 and 3.17 per 100,000 children, respectively). In the non-Jewish sector 93.7% of the falls occurred at or around the child’s home, mainly from staircases, balconies and roofs.

Conclusions: A very high incidence of severe trauma due to domestic falls from a height was found among non-Jewish children in northern Israel. Domestic falls represent an important epidemiological problem in the non-Jewish pediatric sector, and an effective prevention plan should include measures to modify parents’ attitudes towards safety issues and the creation of a safe domestic environment.
 

Background: Studies have found ethno-cultural disparities in health care delivery in different countries. Minority populations may receive lower standards of care.

Objectives: To test a hypothesis that Jewish Ethiopian women may be receiving less preventive recommendations than other women in Israel.

Methods: A telephone survey was conducted using a structured questionnaire designed specifically for this study in Hebrew, Russian and Amharic (Semitic language of Ethiopia). The study group included 51 post-menopausal women of Ethiopian origin, aged 50–75. The control group included 226 non-Ethiopians matched by age, some of whom were immigrants from the former Soviet Union. The questionnaire dealt with osteoporosis and breast cancer screening and prevention.

Results: All the parameters measured showed that the general population received more preventive treatment than did Jewish Ethiopian women, including manual breast examination, mammography, osteoporosis prevention, bone density scans, and recommendations for a calcium-rich diet, calcium supplementation, hormone replacement therapy, biphosphonates and raloxifen. On a logistic regression model the level of knowledge of the Hebrew language, age, ethnicity and not visiting the gynecologist were significantly related to not having received any preventive medicine recommendations.
Conclusions: Differences in cultural backgrounds and language between physicians and their patients may become barriers in the performance of screening and preventive medicine. Recognizing this potential for inequity and using methods to overcome these barriers may prevent it in the future

Background: Ethnicity has been associated with variance in warfarin treatment regimens in various settings.

Objectives: To determine whether ethnicity is associated with variance in patient management in Israel.

Methods: Data were extracted from the electronic patient records of Clalit Health Services clinics in the Sharon Shomron region. The study group comprised all patients treated with warfarin who performed international normalized ratio tests for at least 6 months in 2003. The proportion of tests of each patient within the target range was calculated, as was the crude average rates and 95% confidence intervals for Jewish and Arab patients. The data were then stratified by patient's gender, specialty of attending physician, patient's age, and the country where the physician studied medicine.

Results: We identified 2749 Jews and 293 Arabs who met the inclusion criteria of the study. The crude average rate of patients’ INR[1] tests within the target range was 62.3% among Jews (95% CI[2] 61.5–63.1) and 52.7% (95% CI 49.9–55.5) among Arabs. When stratified by gender, age, and the treating physician's specialty and country of education, the stratum-specific rates among Jewish patients were consistently higher than among Arabs.

Conclusions: These results suggest that cultural differences regarding adherence to recommendations for drug therapy in addition to genetic factors may be associated with this variance.

Objectives: To evaluate factors that might influence the decision of pregnant women to choose chorionic villous sampling for prenatal testing.

Methods: The study group comprised 239 women referred for prenatal diagnosis who elected to undergo CVS[1]. The data were analyzed according to indication, ethnic group and religion.

Results: Among women undergoing CVS because of advanced maternal age and because of anxiety, we noted a significantly high proportion of unbalanced families, i.e., with three or more children of the same gender and deviated gender ratio. We found a significant excess of males among the Jewish families and a significant excess of females among the non-Jewish families. Jews were over-represented in the monogenic group while Christian Arabs were over-represented in the maternal age/anxiety group.

Conclusions: The proportion of women who chose CVS for prenatal diagnosis varied according to indication, ethnic group and religion. The data in this study indicate that CVS may have been utilized for balancing families with ≥ 3 or more children of the same sex. Christian Arabs chose CVS more often than the other groups. Jewish women may have utilized CVS for family balancing of both sexes, while non-Jews may have utilized CVS for balancing families with ≥ 3 daughters. 

Background: Laron Syndrome, first described in Israel, is a form of dwarfism similar to isolated growth hormone deficiency caused by molecular defects in the GH[1] receptor gene.

Objective: To characterize the molecular defects of the GH-R[2] in Laron syndrome patients followed in our clinic.

Methods: Of the 63 patients in the cohort, we investigated 31 patients and 32 relatives belonging to several ethnic origins. Molecular analysis of the GH-R gene was performed using the single strand conformation polymorphism and DNA sequencing techniques.

Results: Eleven molecular defects including a novel mutation were found. Twenty-two patients carried mutations in the extracellular domain, one in the transmembrane domain, and 3 siblings with typical Laron syndrome presented a normal GH-R. Of interest are, on one hand, different mutations within the same ethnic groups: W-15X and 5, 6 exon deletion in Jewish-Iraqis, and E180 splice and 5, 6 exon deletion in Jewish-Moroccans; and on the other hand, identical findings in patients from distinct regions: the 785-1 G to T mutation in an Israeli-Druze and a Peruvian patient. A polymorphism in exon 6, Gly168Gly, was found in 15 probands. One typical Laron patient from Greece was heterozygous for R43X in exon 4 and heterozygous for Gly168Gly. In addition, a novel mutation in exon 5: substitution of T to G replacing tyrosine 86 for aspartic acid (Y86D) is described.

Conclusions: This study demonstrates: a) an increased focal incidence of Laron syndrome in different ethnic groups from our area with a high incidence of consanguinity; and b) a relationship between molecular defects of the GH-R, ethnic group and geographic area.

Background: It has been argued that arginine replacement in locus16 (Arg16) of ß₂ adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population.

Objectives: To investigate non-anglosaxic ethnic influences on ß₂AR[1] polymorphisms and its correlations to asthma severity.

Methods: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of ß₂AR and compared to matched controls. The Jewish patients included both Ashkenazi (of East European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis, and of non-asthmatic Anglo-Saxons described in the literature.

Results: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons.

Conclusions: The genetic distribution of ß₂AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal.

Background: Patient feedback is increasingly being used to assess the quality of healthcare.

Objective: To identify modifiable independent determinants of patient dissatisfaction with hospital emergency care.

Methods: The study group comprised a random sample of 3,152 of the 65,966 adult Israeli citizens discharged during November 1999 from emergency departments in 17 of the 32 acute care hospitals in Israel. A total of 2,543 (81%) responded to a telephone survey tht used a structured questionnaire. The ndependent variables included: hospital characteristics, patient demographic variables, patient perception of care, self-rated health status, problem severity, and outcome of care. The dependent variable was dissatisfaction with overall ED[1] experience on a 1–5 Likert-type scale dichotomized into not satisfied (4 and 5) and satisfied (1,2 and 3).

Results: Eleven percent of the population reported being dissatisfied with their emergency room visit. Univariate analyses revealed that dissatisfaction was significantly related to ethnic group, patient education, hospital identity and geographic location, perceived comfort of ED facilities, registration expediency, waiting times, perceived competence and attitudes of caregivers, explanations provided, self-rated health status, and resolution of the problem that led to referral to the ED. Multivariate analyses using logistic regressions indicated that the four most powerful predictors of dissatisfaction were patient perception of doctor competence and attitudes, outcomes of care, ethnicity, and self-rated health status.

Conclusions: Attempts to reduce dissatisfaction with emergency care should focus on caregiver conduct and attitudes. It may also be useful to improve caregiver communication skills, specifically with ethnic minorities and with patients who rate their health status as poor.

Background: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4+4A®T for Fanconi anemia complementation group C.

Objectives: To provide additional verification of the mutation rate of BLM and FACC[1] in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.

Methods: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto^TM kit to verify the results in 244 samples and there was an excellent match.

Results: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto^TM kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.

Conclusions: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS[2] and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

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[1] FACC = Fanconi anemia complementation group C