Israel Medical Association Journal

Southern Sinai, a mountainous desolated arid area, is inhabited by Bedouin nomad tribes composed of Arabic-speaking Moslems. Until the Six Day War between Egypt and Israel in 1967, healthcare services in the region were based on traditional medicine performed by the Darvish, a local healer. Over the course of Israeli rule (1967-1982) an elaborate healthcare service was established and maintained, providing modern, up to date, comprehensive medical services that were available to all free of charge.

Background: Recent years have brought significant progress to the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, among which is the new non-steroidal aromatase inhibitor, anastrozole, introduced for clinical use in Israel in March 1997.

Objectives: To evaluate the response rate and survival duration of patients treated with anastrozole for metastatic breast cancer, who had previously received at least one line of hormonal therapy.

Methods: Anastrozole was administered to 37 patients with metastatic breast cancer. The median age was 64 years. Estrogen receptor was positive in 20 patients, negative in 10 and unknown in 7. All patients were previously treated with tamoxifen in the adjuvant setting or as first-line hormonal therapy for metastatic disease. Anastrozole was given orally, 1 mg/day. Response was evaluated 2 months after the initiation of treatment and reevaluated every 2 months. Therapy was given until disease progression. Ten ER[1]-negative patients were excluded from the final analysis.

Results: Twenty-seven patients were eligible for response and toxicity analysis. The median follow-up was 20 months. One patient (3.7%) achieved complete response and remains free of disease 28 months after start of therapy. No partial responses were seen. Twenty patients (74%) had stable disease. Two year actuarial survival was 57%. Median survival was 26.5 months after starting therapy and median progression free survival was 11 months. The toxicity was mild: one patient (3.7%) complained of weight gain and one patient (3.7%) had mild fatigue.

Conclusion: Although the response rate was low, hormonal therapy with anastrozole seems to be beneficial in terms of disease stabilization, freedom from progression, and overall survival without serious toxicity.  

Recent data have shed significant new light on the structural and functional development of the kidneys, as well as on a rare congenital form of bilateral renal hypoplasia called congenital oligomeganephronia. In this renal disorder, few greatly enlarged and hard-working nephrons are found that will ultimately sclerose and lead to end-stage renal failure during early childhood. At the same time it has been recognized that the number of nephrons in the kidneys of various animal species and humans is correlated to renal mass. Therefore, premature babies and/or infants small for gestational age due to intrauterine malnutrition will be born with relatively small kidneys and a certain nephron deficit, a condition called congenital oligonephropathy. Extensive worldwide epidemiologic studies have now shown that these premature or SGA[1] infants have a high incidence of cardiovascular disease, hypertension, hyperlipidemia, diabetes and renal failure in adulthood. Although the pathophysiologic mechanisms responsible for these complications of premature birth are not entirely understood, it has become clear that the described association may pose a possible health problem in the adult population. This review describes the background of COMN[2] and CON[3] as well as the evidence that has accumulated on the adult complications of the latter. In addition, some thoughts are presented on the importance of identifying subjects possibly affected by CON, such that early recognition may alter the ultimate outcome.

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Background: Leptin is a 16 kDa hormone synthesized by adipocytes and involved in body weight regulation.

Objectives: To determine serum leptin concentrations in heart, liver and kidney transplant recipients.

Methods: We investigated 57 patients: 18 male heart transplant recipients (age 25-69 years) at 1-66 months after transplantation, 6 female and 8 male liver transplant recipients (age 33-70) at 11-73 months after transplantation, and 10 female and 15 male kidney transplant recipients (age 20-61) at 3-138 months after transplantation. All recipients were receiving immunosuppressive therapy, including prednisone 0-20 mg/day, azathioprine 75-125 mg/day, cyclosporin 100-250 mg/day or tacrolimus 2-10 mg/day. The results were compared to those of 10 female and 10 male healthy controls. Morning serum concentrations of leptin were measured with a commercial radioimmunoassay (Linco Research Inc., USA), and serum insulin and cortisol levels were measured by radioimmunoassay.

Results: Patients (both men and women) after heart, liver and kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/body mass index ratios than controls. Serum leptin concentrations were significantly higher in women than in men and correlated very significantly with BMI[1] in all cases. The multivariate stepwise analyses showed that among parameters including BMI, gender, age, time after transplantation, prednisone dose, hematocrit, serum concentrations of glucose, albumin, creatinine, cortisol and insulin, only BMI, gender, cortisol and insulin were significant independent determinants of serum leptin levels in these patients.

Conclusions: This is the first report showing that, in addition to body mass index and gender, basal cortisol and insulin levels affect the hyperleptinemia in transplant patients. The clinical relevance of hyperleptinemia in these patients will require further investigation.

Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only recently begun to be understood. A portion of these SCID patients bear a defect in either of the two recombination-activating genes, Rag-1 or Rag-2, while others have mutations in a newly identified gene, Artemis. Omenn syndrome is an unusual severe immunodeficiency with T cells but no B cells, and peculiar features also due to a defect in Rag-1 or Rag-2 genes. All these three forms are characterized by an impairment of the VDJ recombination, the process that insures the somatic diversification of immunoglobulin and T cell receptor-encoding genes. Recent findings have enabled us to better understand the pathophysiology of these three immunodeficiencies, which affect the V(D)J recombination process to a different extent and in different ways.

The notion of health used in medicine may have important implications, such as guiding the allocation of medical resources. This paper explores the notion of health through an overview and conceptual analysis of various notions of health found in modern medical and the philosophical literature. It argues that health is characterized either positively or negatively (per exclusion), and either mechanistically (as the set of common or ideal states of a species) or holistically (as unimpaired self-organization of organisms). The paper concludes that a sound notion of health characterizes health negatively and holistically, assimilating mechanism as a good approximation in simple cases.

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

Background: Trauma is viewed by many as a global problem. The phenomenon of similar outcomes within differing healthcare delivery systems can illuminate the strengths and weaknesses of various trauma systems as well as the effects of these characteristics on patient outcome.

Objectives: To compare and contrast demographic and injury characteristics as well as patient outcomes of two urban/suburban trauma centers, one in Israel and the other in the United States.

Methods: Study data were obtained from the trauma registries of two trauma centers. Demographic variables, injury characteristics and outcomes were compared statistically between registries.

Results: Significant differences between the registries were found in demographic variables (age), injury characteristics (Injury Severity Score and mechanism of injury), and outcome (mortality and length of stay). Age and Injury Severity Score were found to be significant predictors of outcome in both registries. The Glasgow Coma Score was found to contribute to patient outcomes more than the ISS[1]. Differences were found in the relative impact of injury and demographic factors on outcomes between the registries. After including the influence of these factors on patient outcomes, significant differences still remained between the outcomes of the trauma centers.

Conclusions: Despite possible explanations for these differences, true comparisons between centers are problematic.

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Background: Previous studies have demonstrated myocardial salvage by basic fibroblast growth factor administration following chronic myocardial ischemia or acute myocardial infarction.

Objectives: To study the effect of bFGF[1] on left ventricular morphometry following coronary occlusion and reperfusion episode in rats.

Methods: bFGF (0.5 mg) or placebo was continuously administered for a period of one week using an implanted osmotic pump. Animals were sacrificed 6 weeks after surgery and myocardial cross-sections were stained with Masson-trichrome and with anti-proliferating cell nuclear antigen antibody.

Results: LV[2] area, LV cavity diameter, LV cavity/wall thickness ratio, and injury size were unchanged compared with control animals. Proliferating endothelial cells were significantly more abundant in injured compared with normal myocardium, but with no differences between animals treated or not treated with bFGF.

Conclusions: One week of systemic bFGF administration following coronary occlusion and reperfusion had no additional effect on LV geometry or cellular proliferation in rats.

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[1] bFGF = basic fibroblast growth factor

[2] LV = left ventricular

Background: The importance of health promotion and disease prevention in health policy and clinical practice is widely accepted in many countries. However, a large number of medical schools do not dedicate a significant part of their curriculum to these aspects. In Israel, there are no reports on the training of the future physician towards his or her role as health promoter in general, or in the areas of cardiovascular and cancer diseases specifically.

Objectives: To examine the preparation of Israel medical students for the role of health promoter in cancer and cardiovascular diseases.

Methods: The study was carried out over 2 years in two of the four medical schools in Israel: the Sackler Faculty of Medicine at Tel Aviv University and the Faculty of Health Sciences at Ben Gurion University in Beer Sheva. The students (n=172, 70% response rate) were surveyed during 1999-2000 by means of a questionnaire, which included assessment of their training towards the role of health promoter, their clinical experiences and exposure to patients at different stages of illnesses at various medical sites, and the specific skills and relevant knowledge they acquired.

Results: Most of the students’ learning experiences occurred in hospitals with patients at the treatment stage and little time was dedicated to prevention, especially in the community. They demonstrated better knowledge, skills and satisfaction with their learning experiences in CVD than in cancer; and reported having insufficient exposure to several common cancer diseases and lacking examining skills for early detection of cancer. The students in Beer Sheva had significantly more interaction with patients at different stages of CVD and acquired more examination skills than the Tel Aviv students.

Conclusions: A change in the curriculum is urgently needed: namely training medical students in community settings and preparing them to promote the well-being of their patients, including prevention. Attention should be given to launching new learning modes in the pre-clinical and clinical curriculum. We propose that: a) pre-clinical courses include prevention techniques in CVD and cancer, problems of cancer patients, and some examining skills; and b) the clinical phase should integrate oncology concepts and total cancer and CVD care into existing clerkships in the hospitals and in the community.
 

Background: The large number of cases of West Nile fever diagnosed in Israel in 2000 once again brought into focus the confusion that frequently accompanies the use of the term “epidemic”.

Objective: To examine the different definitions of the term “epidemic” and to propose ways in which it can be used to both improve communication among professionals and provide the public with a better sense of the associated risks.

Methods: The literature wes reviewed for the various definitions of the terms “epidemic” and “outbreak”. Sources included popular and medical dictionaries, ancient documents, epidemiology texts, legal texts, and the medical literature.

Result: The term epidemic is variously defined. The broad definition given by epidemiologists - namely, more disease the is anticipated by previous experience - is less meaningful to the general public. In some ways it conflicts with the definitions found in the popular literature, which generally imply danger to the public and a very large number of victims.

Conclusions: The interpretation of the term epidemic may vary according to the context in which it is used. For risk communication, we suggest that every effort be made to add descriptive terms that characterize the epidemic.

Background: Familial Mediterranean fever is an autosomal recessive disease characterized by sporadic attacks of inflammation affecting the serosal spaces. The gene associated with FMF[1] (MEFV), mainly expressed in neutrophils, was recently found to be expressed also in primary cultures of serosal origin (peritoneal and synovial fibroblasts). A C5a inhibitor, previously detected in normal serosal fluids, was recently identified in serosal cultures as well, and was found to be deficient in serosal fluids and cultures obtained from FMF patients.

Objective: To investigate the effect of colchicine (the main therapeutic agent for FMF patients) and certain inflammatory cytokines (IL-1b, TNF-a, IFN-a, IFN-g) on MEFV expression and C5a inhibitor activity in neutrophils and primary peritoneal fibroblast cultures.

Methods: Human primary peritoneal fibroblast cultures and neutrophils were studied for MEFV expression and C5a inhibitor activity, using reverse transcription-polymerase chain reaction and C5a-induced myeloperoxidase assay, respectively, in the presence and absence of colchicine and cytokines.

Results: MEFV expression in neutrophils was high and could not be induced further. Its expression in the peritoneal fibroblasts was lower than in neutrophils and could be induced using colchicine and cytokines parallel with induction of C5a inhibitor activity. Semi-quantitative RT-PCR[2] assays enabled estimation of MEFV induction by the cytokines at 10–100-fold and could not be further increased by concomitant addition of colchicine.

Conclusion: Serosal tissues, which are afflicted in FMF, express colchicine and cytokine-inducible MEFV and contain inducible C5a inhibitor activity. The relation between colchicine ability to induce MEFV and C5a inhibitor activity, and its efficacy in FMF treatment, require further investigation.

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[1] RT-PCR = reverse transcription-polymerase chain reaction

[2] FMF = familial Mediterranean fever