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עמוד בית
Fri, 14.06.24

October 2002

Original Articles
Arie Figer, MD, Yael Patael Karasik, MD, Ruth Gershoni Baruch, MD, Angela Chetrit, MSc, Moshe Z. Papa, MD, Revital Bruchim Bar Sade, MSc, Shulamith Riezel, MD and Eitan Friedman, MD, PhD

Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients.

Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls.

Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212-sporadic and 56 carriers of either a BRCA1:or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent auloradiography,

Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only {3/536, 0.6%).

Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.

Judith Barash, MD, Doron Dushnitzky, MD, Dalia Sthoeger, MD, Rita Bardenstein, MSc and Yigal Barak, MD,

Background: Human parvovirus B19 is responsible for a variety of clinical syndromes, such as erythema infectiosum, non-immune hydrops fetalis, transient aplastic anemia, and arthropathies. HPV is also suspected of playing a role in the pathogenesis of various chronic inflammatory and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Kawasaki disease and multiple sclerosis.

Objectives: To study the age distribution and clinical presentation of patients hospitalized for human parvovirus B19 infection.

Method: We reviewed the case records of all pediatric patients with serologic evidence of HPV infection who were admitted during a 20 month period to a major community hospital

Results: Of 128 children tested for HPV, 48 had evidence of acute infection based on the presence of immunoglobulin M antibodies; 8 patients who also had positive IgM for other viruses were excluded, thus 40 case records were studied. The mean age of the patients was 5.21 years, but 22 patients were under 4: The clinical presentations included 25 patients with fever, either recurrent or prolonged, accompanied in some by enlarged spleen, liver and lymph nodes, skin rash and arthropathy; the remaining patients were investigated for anemia, skin rash, joint complaints and hepatitis. In addition; HPV infection was documented in several well-defihed clinical conditions, such as SLE, vasculitic skin lesions, acute lymphoblastic leukemia, pure red cell aplasia, and optic neuritis.

Conclusions: In a group of 40 pediatric patients exhibiting anti-HPV IgM antibodies, a younger age and less common clinical presentations were observed, furthermore 5 patients had clinical syndromes in which the causative role of HPV infection was not clear.

Yehuda Neumark, PhD, Yechiel Friedlander, PhD and Rachel Bar-Hamburger, PhD

Background: Various studies support the concept of an inherited vulnerability to drug dependency, while emphasizing the importance of social and environmental influences and their interactions

Objectives: To compare the characteristics of heroin-dependent Jewish men in Israel with those of the general population, focusing on the nature of family history of substance abuse.

Method: This case-control study compares 64 heroin-dependent Jewish male residents of Jerusalem with a community sample of 131 randomly selected Jerusalem residents with no drug use disorder. Univariate and mulbvariate moderns were employed to appraise the independent associations between heroin dependence and exposure variables such as family history of substance misuse and exposure to legal psychoactive substances.

Results: The case group is characterized by heavy tobacco and' alcohol involvement. Nearly 70% of the cases report an alcohol and/or drug problem in at least one first-degree relative compared with 10% of controls (odds ratio 14.5, adjusted for sociodemographic and other potential confounders). Cases with a positive family history have, on average, higher alcohol consumption levels and higher heroin-use severity scores, as compared with cases with no such history.

Conclusions: Familial aggregation of drug and alcohol problems, along with smoking at a young age, is the strongest predictor of heroin dependence in this population. Better understanding of the components underlying this familial aggregation can lead to improved prevention and treatment strategies.

Eytan Cohen, MD, Shlomo Almog, PhD, Daniel Staruvin, MD and Moshe Garty, MD, MSc

Background: Acarbose has become an important adjuvant therapy for diabetic patients. Many of these patients are also treated with digoxin for congestive heart failure or chronic atrial fibrillation

Objective: To evaluate a possible drug interaction between acarbose and digoxin.

Methods: An open-label, analyst-blind, randomized, crossover, two-period study was conducted in 11 healthy subjects. In period I, each subject received one single oral dose of 0.75 mg digoxin. In period ll, they were given acarbose tablets., 60 mg-3 times a day for 12 days. On day 8, one hour after acarbose administration, a single oral dose of 0.75 mg digoxin was administered. The study periods were separated by a 3 week washout interval: Serum. digoxin levels., over. time, in the two periods were compared by standard techniques;

Results: There were no differences in the pharmacokinetic parameters of digoxin in the two periods, apart from a significant increase in the mean maximum serum concentration (Cmax) when digoxin was given with acarbose (5.97 compared to 4.67 g/L, P = 0.02). Simulated steady-state peak levels of digoxin (Cmax,ss) achieved with a daily dose of 0.25 mg digoxin, in the presence.and absence of acarbose, were 2.89 and 2.40 g/L respectively (P =0.05); Simulated steady-state trough (Cmin,ss) and average (Cave,ss) concentrations were similar and within the therapeutic window.

Conclusion: There was no significant pharmacokinetic interaction between digoxin and acarbose at current therapeutic doses in the healthy volunteers. This interaction should be further studied with higher doses of acarbose and at steady-state conditions.

Abraham Benshushan, MD, Avi Tsafrir, MD, Revital Arbel, MD, Galia Rahav, MD, Ilana Ariel, MD and Nathan Rojansky, MD

Background: Although Listeria monocytogenes is widely distributed in nature, it rarely causes clinical infection in previously healthy people. This microorganism. however, may cause severe invasive disease in pregnant women and newborns.

Objectives: To investigate – in our pregnant population – the impact, severity and outcome of listeriosis on both mother and fetus.

Method: The study was carried out at a level III, university two-hospital complex, In a retrospective chart review of 65,022 parturients during a 10 year period (1990-1999), we identified and: evaluated 11 pregnant patients and their offspring with Listeria infection;

Results: Chorioamnionitis with multiple. placental abscesses were observed in all five placentae examined. Clinically 4 of 11 parturients had a cesarean section for fetal distress (36.3%), as compared to the 14% mean CS rate in our general population. Two of 11 had a fate abortion (18.1%), as compared with the 4% rate in our hospital. Four of 11 had premature labor (36%), which was about four times the rate in our population. Finally, although no intrauterine feta1 death was recorded in our series, there was one neonatal death of a term infant. (1/11, 9%), which is about 10 times higher than our corrected perinatal mortality rate.

Conclusions: If not promptly and adequately treated, listeriosis in pregnancy may present serious hazards to the fetus and newborn through direct infection-of the placenta and chorioamnionitis.

Ze'ev Korzets, MBBS, Eleanora Plotkin, MD, Jacques Bernheim, MD and Rivka Zissin, MD

Background: Acute renal infarction is an oft-missed diagnosis. As a result; its true incidence, although presumed to be low, is actually unknown. Surprisingly, the medical literature on the subject, other than anecdotal case reports, is scarce.

Objectives: To increase physician awareness of the diagnosis and to identify predictive clinical and laboratory features of the entity.

Method: Between 1 November 1997 and 31 October 2000, 11 cases of acute renal infarction in 10 patients were diagnosed in our center by contrast-enhanced computerized tomography. The medical charts of these patients were reviewed regarding risk factor, clinical presentation, possible predictive laboratory examinations, and out-come.

Results: During the 36 month observation period, the incidence of acute renal infarction was 0.007%. The mean age of the patients (5 men and 5 women) was 67.4 + 21.1 (range 30-87 years). In four cases the right and in five the left kidney was involved; in the other. two cases bilateral:involvement was seen. In 7/10 patients, an increased risk for thromboembolic events was found. Six had chronic atrial fibrillation and one had a combined activated protein C resistance and protein S deficiency, Three patients had suffered a previous thromboembolic event. Two cases were receiving anticoagulant therapy with an INR of 1.6 and 1.8, respectively. On admission, flank pain was recorded in 10/11, fever in 5 and nausea/vomiting in 4 cases. Hematuria was detected in urine reagent strips in all cases; Serum lactate dehydrogenase and white blood cell count were elevated in all cases (1,570 + 703 IU/L and 12,988 + 3,841/ l, respectively). In no case was the diagnosis of acute renal infarction  initially entertained. The working diagnoses were .renal colic in 2 pyelonephritis in 3, renal carcinoma, digitails intoxication, and suspected endocarditis in one patient each, and an acute abdomen in 3. Time from admission to definitive CT diagnosis ranged from 24 hours to 6 days; Three patients were treated with intravenous heparin and another with a combination of IV heparin and renal intra-arterial urokinase infusion with, in the latter case, no recovery of function of the affected kidney. With the exception of this one patient (with a contralateral contracted kidney) who required maintenance dialysis, in all other cases serum creatinine levels. remained unchanged or reverted to the baseline mean of 1.1 mg/dl (0.9-1.2).

Conclusions: Acute renal infarction is not as rare as previously assumed. The entity is often misdiagnosed. Unilateral flank pain in a patient with an increased risk for thromboembolism should raise the suspicion of renal infarction. In such a setting, hematuria, leuaocytosis and an elevated LDH level are strongly supportive of the diagnosis.

Mark J. Yaffe, MD, CM, M, MCISc, CCFP, FCFP and Jacqueline Klvana, MD, CM, CCFP

Background: Eldercare often necessitates the presence of a family caregiver at the senior's visit to a doctor’s office. Studies indicate that some caregivers are not satisfied with these encounters or with as An understanding of the dynamics of these complex interactions is required.

Objectives: To explore family physicians’ attitudes to interfacing family caregivers of the elderly, to identify factors within the family patient-caregiver encounters in the office setting that for physicians,  to ascertain factors that might be problematic for physicians, to ascertain factors that might contribute to doctors’ behaviors and concerns, and to propose possible solutions for optimizing the outcomes of these visits.

Method: A questionnaire for self-administration was mailed to 200 family physicians in Montreal, Canada who are affiliated with two community secondary care and one tertiary care hospital and involved in geriatric office practice. The survey focused on family physician attitudes, concerns and observations on the interactions among themselves, elderly patients and their family caregivers during office visits.

Results: A total of 142 completed questionnaires were returned with a 71% response rate. Most family doctors felt that it was their responsibility to respond to caregiver concerns (90.6%) and that they were generally meeting their needs (94.2%). In contrast, 81% found this activity stressful and that as few as three such encounters per day were sufficient to generate stress. Causes of stress included: a) concern regarding misdiagnosis, b) different agendas or conflicting responses of patient and caregiver to doctors’ suggestions, and c) reluctance of the elderly or the caregiver to use community resources. A common physician strategy was reliance on acquired professional experience to solving problems of the elderly or of their caregivers.

Conclusions: Despite the stress involved, physicians are interested in assisting caregivers in the management of the elderly. Many doctors lack adequate knowledge about or confidence in community resources. Clinicians may require enhanced skills in conflict resolution necessary to achieve optimal outcomes.

Kosta Y. Mumcuoglu, PhD, Jacqueline Miller, PhD, Chen Zamir, MD, MPH, Gary Zentner, FRACP, Valery Helbin, MD and Arieh Ingber, MD

Background: Head louse infestations are prevalent worldwide. Over the past 20-25 years, 15-20% of all children in Israel between 4 and 13 years of age have been infested with head lice; This is mainly due to the existence of ineffective pediculicides on the market.

Objective: To examine the pediculicidal efficacy and safety of a natural remedy (”Chick-Chack") and to compare it in an open clinical study with a known pesticide spray.

Methods: The natural remedy, which contains coconut oil, anise ail and ylang ylang oil:, was applied to the hair of infested.children three times at 5 day intervals. Each treatment lasted for 15 minutes. The control pediculicide was a spray, formulation containing permethrin, malathion, piperonyl butoxide, isododecane and propellant gas, which was applied twice for 10 minutes with a 10 day interva1 between applications.

Results: Of 940 Children, aged 6-14 years, from six schools in Jerusalem who were examined for head louse infestastion,199 (21:.2÷/) were infested with lice and eggs, while 164 (17.4% ) were infested only  with nits. Altogether, 119 children were randomly treated with either the natural remedy or the control product. Treatment was successful with the natural remedy  in 60 children (92.3%) and with the control pediculicide in 59 children (92.2%). There were no significant side effects associated with either formulation.

Conclusions: The natural remedy was very effective in controlling  louse infestations under clinical conditions and caused no serious side effects.

Veronica Silva Vilela, MD, Nilson Ramirez de Jesus, MD and Roger Abramino Levy, MD, PhD
by Amir Karban, MD, Rami Eliakim, MD and Steven R. Brant, MD

The etiology of inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided limited insight into disease pathogenesis. There is ample evidence that these diseases are in part the result of genetic predisposition. The early search for candidate genes focused on genes involved in the regulation of immune function.

Recent genome wide searches reported several susceptibility loci for Crohn’s disease and ulcerative colitis. The recent identification of the IBD1 gene (NOD2) with mutations that are associated with susceptibility to Crohn’s disease will have a major impact on the understanding of the genetics of this disease.

Arie Bitterman, MD, Richard I. Bleicher, MD, Myles C. Cabot, PhD, Yong Y. Liu, MD, PhD and Armando E. Giuliano, MD
Molecular Biology Series
Hannah Tamary, MD, Raanan Bar-Yam, BSc, Michal Zemach, MD, Orly Dgany, PhD, Lea Shalmon, MSc and Isaac Yaniv, MD

Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far. The majority of affected patients belong to FA group A. Of the 32 unrelated Israeli patients with FA that we studied, 6 carried the FANCC mutations and 15 the FANCA mutations. Among the Jewish patients, ethnic-related mutations were common. Recent cumulative evidence suggests that the FA proteins are repair proteins. FANCC, FANCA and FANCG bind and interact in a protein complex found in the cytoplasm and nucleus of normal cells. FANCD2 exists in two isoforms; the long active form, FANCD2-L, is absent from FA cells of all complementation groups. FANCD2 co-localized with BRCA1 in unclear foci, probably as part of a large genomic surveillance complex. Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-g hypersensitivity and show progressive apoptosis. The definition of the molecular basis of FA in many affected families now enables prenatal diagnosis.

Clinical Views
Misha Witz, MD, Jonathan M. Lehmann, MB, BChir, Ali Shnaker, MD, Itamar Pomeranz, MD,George Leichtman, MD and Benthly Novis, MD, FRCP
Case Communications
Aharon Klar, MD, Ariel Halamish, MD, David Shoseyov, MD, Pascal Cassinotti, PhD, Gunter Siegl, Chaim Springer, MD, Gila Shazberg, MD and Haggit Hurvitz, MD
Ashraf Hamdan, MD, Dania Hirsch, MD, Pnina Green, MD, PhD, Avivit Neumann, Tamara Drozd and Yair Molad, MD
Craig Bjinderman, MA, Oren Lapid, MD and Gad Shaked, MD
The ECG of the Month
Bernard Belhassen, MD and Aharon Glick, MD
Medicus Judaicus
Arie Shifman, DMD, Shmuel Orenbuch, MA and Mel Rosenberg, PhD
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