Prevalence of ischemic heart disease in patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is a genetic disorder manifested by recurrent attacks of peritonitis, pleuritis and arthritis, and characterized by clinical, histological and laboratory evidence for localized and systemic inflammation. Colchicine treatment usually prevents the attacks and the associated inflammation. Inflammation may play an important role in the initiation and progression of atherosclerosis and ischemic heart disease. OBJECTIVE: To study the effect of inflammation and its prevention on the occurrence of IHD, using FMF as a model. METHODS AND PATIENTS: We studied the presence of IHD and its risk factors in 290 FMF patients aged 40 years or more, and in two control groups--233 spouses of the FMF patients, and 126 patients with inflammatory diseases obtained from other outpatient clinics, FMF patients were also compared with age and gender-matched individuals from the population reference data of the Israel Ministry of Health. RESULTS: The prevalence of IHD in FMF patients was significantly lower than in the group of controls from other outpatient clinics (15.5% vs. 30.2%, P < 0.05) and comparable with their spouses (11.2%) and with the matched general population in Israel (16%). CONCLUSIONS: These findings suggest that despite the evidence of recurrent inflammation, colchicine-treated FMF patients are not more predisposed to IHD than the normal population.

Regulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and interferon-gamma.

The insulin-like growth factor-I receptor (IGF-l-R) plays a critical role in normal and pathological growth processes. The expression of the IGF-l-R gene is regulated by various stimuli, including hormones and growth factors. We have investigated the molecular mechanisms by which two inhibitory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), regulate IGF-l-R gene expression. TNF-alpha and IFN-gamma reduced the proliferation rates of the osteogenic sarcoma cell line, Saos-2, and the human salivary gland cell line, HSG, in a dose- and time-dependent fashion. This effect was associated with significant reductions in the levels of IGF-l-R mRNA and protein, and with inhibition of IGF-l-R promoter activity, suggesting that TNF-alpha and IFN-gamma affect IGF-l-R gene expression at the transcriptional level. In addition, TNF-alpha significantly decreased IGF-l-R mRNA stability. Combined cytokine treatment inhibited cellular proliferation and promoter activity in an additive manner. Taken together, these results suggest that a novel potential mechanism by which TNF-alpha and IFN-gamma affect cellular proliferation involves suppression of IGF-l-R promoter activity, as well as destabilization of IGF-l-R transcripts.

Rabies in Israel: decades of prevention and a human case.

Animal rabies is endemic in Israel, with 50-80 laboratory-confirmed cases being diagnosed annually. Despite the high incidence among animals, human rabies has not occurred in Israel for almost four decades. This is likely due to the highly effective prevention policy implemented by the Ministry of Health, based on pre-exposure vaccination of populations at risk, post-exposure treatment, and updated rules. Notwithstanding the previous success, a human case occurred in 1996 when a soldier was bitten, while asleep, by an unidentified small animal, which according to his description was a rat or a mouse. Since injuries by these rodents do not require antirabies treatment, no antirabies post-exposure prophylaxis was administered. Five weeks later the soldier complained of fever and nausea with interchanging periods of rage and calm, confusion, and water aversion. His condition deteriorated gradually, leading to deep coma and death. Immunofluorescence examination of a skin biopsy was positive for rabies, and PCR of saliva revealed Lyssavirus genotype 1. We review the changes in the epizootiology of rabies in Israel, the trends of human exposure to animals, and the pre- and post-exposure prophylaxis guidelines, and discuss possible measures that could have been undertaken to prevent the eventuality of this case. This case of rabies, the first after a long period without human disease, accentuates the importance of strict adherence to prevention guidelines. Considerations of geography, epidemiology, and the circumstances of exposure are crucial in the treatment decision-making process.

Tumor necrosis factor alpha and interferon gamma--induced cell growth arrest is mediated via insulin-like growth factor binding protein-3.

Retinoic acid (RA), and the combination of TNFalpha and Interferon (IFN-gamma) inhibit human salivary gland tumor (HSG) cell growth with the combination of all three being even more inhibitory (P<0. 05). Previous studies have demonstrated that these inhibitory effects of RA, and the combination of TNFalpha and IFN-gamma are associated with increased accumulation of IGFBP-3 in the culture medium of HSG cells. Therefore, we set out to determine if the increase in IGFBP-3 was due to increased production of IGFBP-3 by the cells and whether IGFBP-3 played a causative role in the inhibition of cellular proliferation. TNFalpha and IFN-gamma induced a rise in IGFBP-3 mRNA levels between 4 and 8 h, which returned to control levels after 24 h. IGFBP-3 was shown to inhibit HSG cell growth at concentrations of >/=75 U (P<0.05). When antibodies to IGFBP-3 were used with TNFalpha and IFN-gamma, the inhibitory effect of the cytokines on cell growth was diminished. Retinoic acid with TNFalpha and IFN-gamma had a marked inhibitory effect (P<0.05) which was similarly reversed by increasing concentrations of IGFBP-3 antibody. The present data support the hypothesis that the combination of TNFalpha and IFN-gamma with retinoic acid exert their anti-proliferative effect on HSG cells by reducing the mitogenic effect of IGF-I due to a shift in IGF-I from the free to the IGFBP-3-bound form.

Distribution of serum creatine kinase activity in young healthy persons.

The normal distribution of serum creatine kinase (CK) was determined in 428 men (mean age = 21.5) and 540 women (mean age = 20.2). The bootstrap method was employed to obtain statistical parameters of CK reference range and correlations with physical activity habits, BMI, cigarette smoking and alcohol consumption. CK distribution was non-Gaussian and skewed toward the higher values; 18.9% of the men and 4.6% of the women had values above the upper reference limits defined for the commercial assay kit. The median 97.5 percentile value was 532 u/l for men and 248 u/l for women (95% confidence interval of 384-738 u/l and 184-340 u/l, respectively). A significant correlation was found only between CK and alcohol consumption in men. Myoglobin level in a representative group of subjects correlated well with CK activity for both genders. Our findings define the range of CK values in a healthy, young, heterogeneous population. We suggest that only CK levels above the determined 97.5 percentile should warrant further clinical investigation.

[Professional assessment of senior physicians who immigrated to Israel up to 1996].

Israel has absorbed many immigrant physicians and has utilized their skills without compromising local professional standards. In accordance with this policy a special law for the assessment of the licensing of senior immigrant physicians, mainly from the former Soviet Union, who had practiced medicine for at least 14 years was implemented in 1994. Considering their considerable medical experience on the one hand and their lack of experience in speaking Hebrew or undergoing testing techniques, they were exempted from the written national licensing examination. Instead they were obliged to undergo a 6-month clinical observation period in a local hospital or clinic. At the end of this period a letter of confirmation was issued which was followed by an oral assessment of their clinical ability. In the assessment session, each candidate was presented with written presentations of 4 typical clinical cases which practitioners encounter on a daily basis, in family medicine, emergency medicine, surgery, and pediatrics or gerontology. Of 114 cases prepared, 4 were selected for each candidate by the committee of 13 trained, experienced Israeli physicians. 3 members of the committee assessed each candidate using specified criteria. The assessment, which lasted about an hour, focused on the candidates' professional knowledge involved in differential diagnosis and case management. Of 497 candidates examined between 1994 and 1996, approximately 80% passed in their first attempt. However, about 30% of the invited candidates did not appear for the exam. Characteristics of successful candidates were being young and being among the seniors with the least clinical experience. Most had specialized in internal medicine and had completed their observation period in a non-academic hospital. There they had received somewhat more attention than those who had been in academic hospitals. Significantly, the successful candidates were more proficient in Hebrew than the unsuccessful candidates, and reported no special problems during the observation period.

Seronegative spondyloarthropathy in familial Mediterranean fever.

To define a possible association between familial Mediterranean fever (FMF) and seronegative spondyloarthropathy (SNSA) and to study features of SNSA in FMF patients, we screened for the presence and manifestations of SNSA in 3,000 FMF patients attending the National Center for FMF in our institution. This population included 160 patients with chronic arthritis, most who suffered from SNSA. Patients were considered to suffer from SNSA if they had chronic arthritis, inflammatory back/neck pain, and sacroiliitis. Patients who had other diseases associated with SNSA were excluded. Eleven patients, nine men and two women, with chronic monoarthritis or oligoarthritis, grade 2 (four patients) or grades 3 to 4 (seven patients), sacroiliitis, and inflammatory back pain met the criteria for diagnosis of SNSA of FMF. These patients were rheumatoid factor (RF) and HLA-B27 negative. In seven patients, spondyloarthropathy developed while they received colchicine, and in four before colchicine. Most patients responded to treatment with nonsteroidal antiinflammatory drugs, but three required second-line agents. These findings suggest that SNSA is one of the musculoskeletal manifestations of FMF that may occur despite colchicine therapy and requires specific treatment.

[Smoking habits of young Israeli soldiers].

A random sample of 32,166 soldiers were interviewed (on their day of discharge from the Israeli Defence Forces, between 1980-1995) with regard to smoking habits. Among men, prevalence of current smoking was 46.8%, and among women 32.9%. Over the study period, prevalence in men decreased 27%. Among women, prevalence decreased from 1981 to 1991, but since then it has steadily increased. Among men, mean number of cigarettes smoked decreased from 21.6 in 1989 to 16.6 in 1995. Among women cigarettes smoked decreased from a mean of 14.3 in 1989 to 13.1 in 1995. 65.9% of the men and 49.3% of the women had started smoking by the age of 18. Among men the age distribution of smoking changed hardly at all over the years of the study. However, the proportion of women who began to smoke in the youngest age bracket (15 years of younger) doubled over the course of the study.

[ATLS course for surgery residents--should it be mandatory?].

Senior surgeons were asked about mandatory participation of general surgery residents in the advanced trauma life support (ATLS) course. Although trauma care in Israel is given by surgical residents, in the opinion of their senior mentors the course should continue to be mandatory for them.

Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response.

Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.

Blast injuries: bus versus open-air bombings--a comparative study of injuries in survivors of open-air versus confined-space explosions.

OBJECTIVES: To compare injury patterns resulting from explosions in the open air versus within confined spaces. METHODS: Medical charts of 297 victims of four bombing events were analyzed. Two explosions occurred in the open air and two inside buses. Similar explosive devices were applied in all four incidents. The incidence of primary blast injuries, significant penetrating trauma (Abbreviated Injury Scale score > or = 2), burns, Injury Severity Score, Revised Trauma Score, and mortality were compared between the two populations. RESULTS: A total of 204 casualties were involved in open-air bombings, 15 of whom died (7.8%). Ninety-three victims were involved in bus bombings, 46 of whom died (49%). The difference in mortality rate was highly significant, p < 0.00001. Primary blast injuries were observed in 25 and 31 victims (34.2% and 77.5% of admitted victims), respectively (p = 0.00003). Median Injury Severity Score was 4 versus 18, respectively (p < 0.0001). CONCLUSION: Explosions in confined spaces are associated with a higher incidence of primary blast injuries, with more severe injuries and with a higher mortality rate in comparison with explosions in the open air.

Epidemiologic characteristics of participants and nonparticipants in health-promotion programs.

There is potential for nonparticipation in health-promotion programs to impact on all overall success of these programs. The evidence on the relationship of participation of demographic and health characteristic is conflicting. The study presented here prospectively examined the relationship of personnel data and self-reported smoking, exercise, and dietary behavior to participation in the initial phase of a new health-promotion program. Compared with the total population, participants tended to be older and more educated, to be foreign-born and of Eastern ethnic origin, and to have more children. The participant population also tended to include more women, married individuals, and noncommissioned officers. A low smoking prevalence (17% of the participants), a high mean exercise rate (four times per week), and low weekly mean egg consumption (2.7) were observed among the program participants. These results indicate that this program preferentially enrolled people who already were committed to healthy lifestyles, and did not reach all segments of the work force equally.

[Findings of periodic thoracic X-ray screening of Israel Defense Forces career personnel].

Findings of routine, periodic, medical examinations of approximately 5000 Israel Defense Forces (IDF) career personnel, included a screening postero-anterior chest radiograph were reviewed. Previous studies have indicated low efficacy of routine chest X-rays in various populations. We evaluated this screening test among 4593 career military personnel. Their chest X-rays were reviewed retrospectively and in 186 (4%) there were abnormal findings. The rate of pathological findings was positively correlated with age. Additional information was found in the X-rays of 25 subjects (0.54%), but the original interpretations of 51 (1.1%) were found to be false-positive. In view of the very low yield of findings in routine chest X-rays of IDF career military personnel, we recommend X-ray screening only in high-risk populations and subjects over the age of 50.

Cytokines and growth factors modulate cell growth and insulin-like growth factor binding protein secretion by the human salivary cell line (HSG).

The human salivary cell line (HSG) was investigated for the effect of various growth factors and cytokines on cellular proliferation and on the production of insulin-like growth factor binding proteins (IGFBPs). IGF-I increased cell growth by approximately 25%, and induced the appearances of three distinct protein bands on ligand blot of the cell culture. Two bands with molecular weights of 43 and 45 Kda, respectively, proved to be IGFBP-3 using a specific antibody, and the third was a 24 Kda species (probably, IGFBP-4). Similar IGFBPs were released by the cells following stimulation by EGF and insulin as well as following incubation with the IGF-I receptor antibody alpha IR3. Retinoic acid had an inhibitory effect (50%) on IGF-I-induced cellular proliferation and an attenuative effect on the 24 Kda band when it was combined with IGF-I, and to a lesser effect EGF; however, it enhanced IGFBP-3 production when incubated with IGF-I. The IGF-I receptor antibody had an agonistic effect on IGFBPs production when applied alone or together with IGF-I. TNF-alpha and INF-gamma had minimal effects on cell growth when added alone but when applied in combination, a marked inhibition of cellular proliferation was noted. These cytokines caused increased accumulation of IGFBP-3, -4, and -5. Addition of IGF-I to these cytokines enhanced the expression of these bands. These data demonstrate that growth factors and cytokines which modulate HSG cell growth, induce specific IGFBPs which may play a role in their effects on cell growth.

Cytokines modulate interleukin-6 production by human salivary gland cell line.

The ability of HrTNF-alpha, HrIL-1 beta, and HrIFN-gamma to modulate IL-6 production by cultured human salivary cell line (HSG) was examined. IL-6 activity was measured by the hybridoma growth factor biologic activity. HrTNF-alpha had a significant dose-dependent effect, whereas HrIL-1 beta and HrIFN-gamma had moderate and minor effects, respectively. Maximal effect (920 units) was noted when cytokines were applied in combination (1000 units HrIFN-gamma and 20 units HrTNF-alpha) and incubated with human salivary gland cells for 72 hr. The same combination of cytokines had also a marked inhibitory effect (70% of control) on human salivary gland cell growth. This is the first report of these concomitant phenomena in a human cell line originating from salivary tissue.