Israel Medical Association Journal

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.

______________________________________

[1] FACC = Fanconi anemia complementation group C

Background: One of the measures adopted in Israel since 1959 as part of the tuberculosis control program was screening children aged 12–13 years old. The screening comprised single-step tuberculin skin testing using the Mantoux method.

Objective: To assess the efficacy of tuberculin skin screening for TB[1] in schoolchildren in southwestern Israel as well as the compliance to treatment for latent tuberculosis infection.

Methods: We retrospectively reviewed the records of children in the Ashkelon region who underwent a tuberculin skin test during the period 1995–99.

Results: Of the 28,016 eligible children, 27,232 were tested. In 923 children, mostly from the former USSR and Ethiopia, an induration of 10 mm or more was found. Only 52 Israeli-born children tested positive. Tuberculosis was found in seven children with a positive test, five of whom were from Ethiopia. All children who tested positive were referred to the local TB clinic; only 266 children (28.8%) presented. Only 151 completed the recommended treatment of isoniazid for 6 months. Thus, although screening included most of the targeted children aged 13, only a third of them presented to a TB clinic, of whom only about half completed treatment of latent infection.

Conclusions: Our results indicate that the current policy of screening for latent TB in our region is ineffective in terms of implementation of the recommended treatment. We suggest that only high risk groups be screened, and that a concerted effort be made to implement treatment.

_______________________

Background: Epidemiological studies in different parts of the world have revealed controversial results on the association between hepatitis C virus infection and non-Hodgkin’s lymphoma. This discrepancy suggests that HCV[1] lymphotropism or its effect on host lymphocytes may be influenced by regional and racial factors, as well as by genomic variations.

Objective: To determine the prevalence of HCV infection in patients with lymphoproliferative disorders diagnosed and treated in our institute in Israel.

Methods: A total of 212 consecutive patients (95 males and 117 females) treated in our hematology outpatient clinic between August 1997 and September 1999 was screened for anti-HCV antibodies and hepatitis B surface antigen. HCV infection was confirmed by the presence of HCV RNA in the serum. The prevalence of HCV in patients with lymphoproliferative disorders was compared to a control group of patients with myeloproliferative disorders and myelodysplastic syndromes.

Results: HCV infection was more prevalent in the group of LPD[2] patients than in the control group, but this finding was not statistically significant. The prevalence of HCV among LPD patients was 7.8%, while that in the group with myeloproliferative and myelodysplastic disorders was 1.19% and in the general population 0.64%. Among the different classes of LPD, a significant association with HCV infection was established only in patients with diffuse large B cell lymphoma. Furthermore, HCV infection was significantly more prevalent than HBV infection in the LPD group, but not in the myeloproliferative and myelodysplastic disorders group.

Conclusions: Our finding of a significant association between HCV infection and diffuse large B cell lymphoma leads us to suggest that anti-HCV antibodies be performed routinely in such subjects.  

________________________

 [1]LPD = lymphoproliferative disorders

[2] HCV = hepatitis C virus

Background: Breast cancer is the most common malignancy among women in Israel and throughout the world. Israeli women aged 50–75 years are advised to undergo a mammographic screening examination every 2 years. However, the lack of a structured referral system is reflected in the low utilization rate of mammography.

Objectives: To describe an innovative program in which family physicians in an urban clinic developed a model framework for referrals, coordinated with radiologists and surgeons, aimed at increasing compliance among women referred for mammography.

Methods: A community-based study was conducted, outside of the regular reception hours, in a neighborhood practice with a population of 527 women aged 50–75. A referral system under the supervision of family physicians was designed, and the women received appointments for mammography at specified days and hours. The results of the examination were sent to the physician who used dedicated time to continue the diagnostic and/or therapeutic process, as appropriate. At the physician’s instructions a research assistant contacted the women who did not keep their appointments and scheduled a second appointment.

Results: In 1993, the year prior to the study, when women referred themselves for mammography, the utilization rate was 9%. During the study year the utilization rate was 77%. Women born in Europe or America had higher compliance rates than women born in Asia or Africa (81% vs. 72%, respectively). Married women were more compliant than unmarried women (81% vs. 70%, respectively). No correlation was found between compliance and age, family history of cancer in general, or breast cancer in particular. Six new cases of breast cancer were detected.

Conclusions: The initiative of family physicians increased the utilization of mammography among women under their care. Family physicians allocated time outside of their regular reception hours for the program. A relatively large number of new malignancies were found, but this impression should be confirmed or negated by a large-scale study using the same methods.
 

Background: Most of the published documents proposing teaching objectives for undergraduate clerkships were prepared by expert bodies. Seldom have the clinical teachers, who are critical to the learning process and to the implementationof the  teaching objectives, been the actual proponents of its core content.

Objective: To develop a national-scale proposal of teaching, objectives for the family medicine clerckship in medical school, using a consensus method and the actual, community-based teachers as the expert body.

Method: The Delphi method was chosen for that purpose. In the first round all 189 family medicine teachers in Israeli medical schools were asked to propose five teaching objectives. In the second round the objectives, which were generatedin the first round, were characterized by key words and were send to the participants as a second round for ranking according to their importance.

Results: A total of 116 family medicine teachers (61.38%) responded in the first round and 91 of the 116 (78.5%) in the second round. They formulated 51 teaching objectives listed in order of importance, covering a wide array of themes and including knowledge, attitude and skills objectives. The most important objectives were common problems in primary care, recognition of the biopsychosocial model, and understanding the importance of the doctor-patient relationship. The structure of the list provides a uniqe insight into the relative importance of each objective in the context of the whole core content of the clerkship.

Conclusions: Constructing a proposal for teaching objectives is feasible using the Delphi method and the field instructors as the selecting body. The process and its results can provide faculty with relevant and important suggestions on the content and structure of the family medicine clerkship.
 

Background: Low birth weight has been shown to be strongly related to hypertension in adult life.

Objective: To determine whether blood pressure is higher in children with intruterine growth retardation than in control subjects.

Methods: Blood pressure was measured in 58 children aged 4-6 years with IUGR and in 58 age-matched controls. The control children, whose birth weight was appropriate for gestational age, were also matched for gestational age.

Results: The children with IUGR had significantly higher mean values of systolic (p<0.05) and diastolic blood pressures (p<0.05) and mean arterial pressure (p<0.05). Significant differences in blood pressure values were found between preterm IUGR (n=21) and preterm controls (p<0.05).

Conclusion: These data indicate that children with IUGR may be at higher risk of hypertension already in childhood.

Background: Fibroadema, one of the most common benign breast lesions, has a characteristic age-specific incidence and is associated with other pathological entities in 50% of cases. The clinical or imaging diagnosis of fibroadenoma may be erroneous, and in some cases is found to be invasive cancer. The clustering of such entities, their correlation with age, and the risk of synchronous breast malignancy are uncertain.

Objective: To explore the possibility of any sigficant clustering of fibroadenoma-associated benign breast disease and to assess the possible risk of concomitant breast cancer.

Method: We analyzed the pathological results of 147 women undergoing excisional biopsies for fibroadenoma diagnosed pre-operatively either by clinical examination and imaging (n=117) or by radiology alone (n=30). The inter-relationships among all entities associated with fibroadenoma were studies by hierarchial cluster analysis. The correlation of the various pathologies with the risk of invasive breast cancer in relation to the patient’s age was also evaluated.

Results: Fibroadema-associated pathologies were found in 48% of the cases: sclerosing adenosis (23%), duct ectasia (17/7%), apocrine metaplasia (15.6%), florid fibrocystic disease (12.9%), duct papillomatosis (11.6%), infiltrating duct carcinoma (5.4%), duct carcinoma in situ (3.4%), and 1 case of lobular carcinoma in situ (0.6%). An orderly internal hierarchy and three significant clusters emerged: a) epithelial apocrine metaplasia, duct ectasia and sclerosing adenosis (similarity coefficients 16.0, 11.0 and 8.0 respectively); b) papillomatosis, florid fibrocystic disease and calcifications (similarity coefficients of 6.0, 4.0 and 2.0 respectively); and c) infiltrating duct carcinoma in situ (similarity coefficients of 1.8 and 1.6 respectively). Seven of the eight patients with breast cancer were older than 40 years.

Conclusions: In about half of the cases fibroadema was associated with other pathological entities clustered in an orderly hierarchy. The rarity of synchronous breast cancer in the younger age group and its more common association with fibroadema in the older age groups dictate a different approach to each. The finding of fibroadema in women older than 40 indicates the need for surgical excision.
 

Background: Recent studies have suggested a possible association between Chlamydia pneumoniae infection and coronary heart disease.

Objectives: To determine titers of antibodies to Chlamydia pneumoniae in patients with acute  myocardial infraction compared with titers in several control groups.

Methods: This prospective case-control study investigated 209 individuals. We assessed the serum IgG antibody titers to Chlamydia pneumoniae in 57 consecutive patients admitted with AMI to our intensive coronary care unit during a 4 month period. A serum sample was drawn upon admission after 6 weeks. Results were compared with those of four control groups: a) patients admitted with community-acquired pneumonia (n=18), b) patients with community-acquired urinary tract infection (n=42), c) patients with angiographically normal coronary artery disease (n=44), and d) patients with stable coronary artery disease (n=48). Serum immunoglobin G antibody titers to C. pneumoniae were determined using standard micro-immunofluorescene technology.

Results: Of 57 patients with AMI, 32 (56%) had a high lgG titer to C. pneumoniae (>=1:256) on the initial test, which remained unchanged (62%) after 6 weeks. The percentage of patients with high titers was significantly lower in the control groups: 5 of 18 patients (28%) in the pneumonia group (P<0.01), 11 of 42 (26%) in the urinary tract infection group (P<0.01), 11 of 44 (25%) with normal coronary arteries (P<0.01), and 17 of 48 (35%) with stable chronic ischemic heart disease (P<0.05).

Conclusion: The detection of high titers of lgG antibodies to C. pneumoniae in many patients with AMI, compared to control groups, suggest that chronic Chlamydia pneumoniae infection plays a role in the pathogenesis of atherosclerosis and acute ischemic events.

Background: Rectal administration of iodoacetamide induces colitis by blocking sulphhydryl groups and generating inflammatory mediators. Thalidomide, a non-barbiturate hyp­notic, also has an anti-inflammatory effect, presumably by suppressing the production of tumor necrosis factor alpha. In patients with Crohn’s disease, neutralization or suppression of TNFá reduces inflammation.

Objectives: To evaluate the effects of thalidomide in a model of experimental colitis.

Methods: Colitis was induced in rats by intracolonic administration of 3% iodoacetamide. In the treatment group, thalidomide 50 mg/kg was given daily by gavage and continued for 7 days until the rats were sacrificed. Their colons were then processed for wet weight, lesion area, weight of mucosal scraping, myeloperoxidase activity and histology. Serum levels of TNF were determined.

Results: Colonic wet weight, lesion area, myeloperoxidase activity and serum levels of TNFá were significantly lower (P<0.05) in the treatment group (iodoacetamide + thalido­mide) than the control group (iodoacetamide only). Histologi­cally, colonic inflammation in the treated group was markedly decreased.

Conclusions: Thalidomide effectively decreases colitis induced by iodoacetamide. The mechanism is probably associated with inhibition of TNFá, and should be further studied.