Israel Medical Association Journal

Background: Despite the controversy regarding the risks and benefits of hormone replacement therapy, studies in various countries indicate a two- to threefold increase in the use of HRT[1] during the last decade.

Objectives: To estimate the prevalence of HRT use among post-menopausal Jewish women in Israel and to determine the variables predicting current HRT use.

Methods: A cross-sectional telephone survey was conducted in 1998 on a random sample of Jewish women aged 45–74. Of 935 women who were located and eligible, 704 (75%) were interviewed by means of a structured questionnaire.

Results: A total of 589 women (85%) were peri-menopausal or post-menopausal.  Ninety-nine of them (16.8%) were currently using HRT and 78 (13.2%) were past users. Higher rates of current use were found among women who had undergone hysterectomy and/or oophorectomy (38%) than among all other women (13.5%).  Among naturally menopausal women the highest rate of current use (25.6%) was found in those aged 55–59.  A multiple logistic regression showed that the variables associated with current HRT use among naturally menopausal women  were: having a regular gynecologist (odds ratio 3.6, 95% confidence interval 1.7–7.5), visiting a gynecologist during the past year (OR[2] 2.9, 95% CI[3] 1.4–6.0), experiencing symptoms of menopause (OR 2.0, 95% CI 1.01–3.8), having more than a high-school education (OR 1.9, 95% CI 1.04–3.6), and a lower body mass index (OR 0.91, 95% CI 0.85–0.99).

Conclusions: The factors associated with HRT use may be markers for other socioeconomic or psychological characteristics. The disparities noted between population subgroups may be indicative of differences in awareness or in the delivery of preventive healthcare services to women in Israel, and as such need to be addressed by the health system.

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Background: Low density lipoprotein apheresis is used as a complementary method for treating hypercholesterolemic patients who cannot reach target LDL[1]-cholesterol levels on conventional dietary and drug treatment. The DALI system (direct absorption of lipoproteins) is the only extracorporeal LDL-removing system compatible with whole blood.

Objective: To describe our one year experience using the DALI[2] system.

Methods: LDL apheresis was used in 13 patients due to inability to reach target LDL-C levels on conventional treatment. They included seven patients with familial hypercholesterolemia, three who had adverse reactions to statins, and three patients with ischemic heart disease who did not reach LDL-C target level on medical treatment.

Results: The average triglyceride, total cholesterol, high density lipoprotein-C and LDL-C levels before and after treatment in all patients were: 170 ± 113 vs. 124 ± 91, 269 ± 74 vs. 132 ± 48, 42 ± 8 vs. 37 ± 7.9, and 196 ± 77 vs. 80 ± 52 mg/dl, respectively. Comparing the results of a subgroup of seven patients who had previously been treated with plasma exchange, it is noteworthy that while the reduction in triglyceride, total cholesterol and LDL-C are comparable, the effect on HDL[3]-C concentration was less apparent: from an average of 39.7 ± 8.7 and 23 ± 5.7 mg/dl before and after plasma exchange to an average of 43.9 ± 8.1 and 38.4 ± 7 mg/dl before and after LDL apheresis, respectively. Five patients developed treatment-related adverse events: three experienced allergic reactions manifested as shortness of breath, urticaria and facial flushing; one patient developed rhabdomyolysis, an adverse reaction that was not reported previously as a result of LDL apheresis; and one patient had myopathy with back pain. All untoward effects occurred during the first few treatment sessions.

Conclusions: LDL apheresis using the DALI system is highly efficacious for the treatment of hypercholesterolemia. It is associated with a significant number of side effects occurring during the first treatment sessions. In patients not experiencing adverse effects in the early treatment period, it is well tolerated, and can provide remarkable clinical benefit even after short-term therapy.

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Background: While most allelic pairs of DNA replicate synchronously during the S phase of the cell cycle, some genes normally replicate asynchronously, i.e., genes on the X chromosome and imprinted genes. The replication control mechanism is unknown but was shown to be impaired in malignancies and chromosomal trisomies where replication pattern becomes asynchronous.

Objectives: To determine the level of asynchronization in replication timing of cells from patients with microdeleted genomes.

Methods: We applied monocolor fluorescent in situ hybridization with different probes on leukocytes from microdeleted genomes.

Results: All samples derived from the microdeleted genomes showed significantly higher levels of an asynchronized pattern compared to normal individuals.

Conclusions: Even a “small” genetic imbalance (microdeletion) can interfere with gene replication and cell cycle progression, as previously shown in full trisomies.
 

Background: Celiac disease is common in both children and adults. Small intestinal biopsy is mandatory for establishing a diagnosis. Anti-endomysial antibodies, detected by immunofluorescence, have a sensitivity and specificity close to 100% in the diagnosis of CD[1]. Recently, tissue transglutaminase has been identified as the target autoantigen of antibodies against endomysium, and TTG[2] antibodies are comparable to EMA-IMF[3] in the diagnosis of CD.

Objective: To evaluate a new enzyme-linked immunosorbent assay kit for EMA, compared to EMA-IMF and TTG antibodies in the diagnosis of CD.

Methods: Our study population included all subjects with positive EMA-IMF who underwent intestinal biopsy (n=21). From the same sera, TTG antibodies and EMA-ELISA[4] were determined, and all antibody results were compared to the biopsy findings.

Results: EMA-IMF was able to predict biopsy findings of CD in 19 of 21 cases (90.5%). When patients with biopsy findings compatible with CD and positive EMA-IMF (n=19) were tested for EMA-ELISA and TTG antibodies, 18 of the 19 were positive for both EMA-ELISA and TTG antibodies. A significant correlation was found between EMA-ELISA and TTG antibody titers (r = 0.74, P < 0.001).

Conclusions: Our study demonstrates that EMA-ELISA is comparable to TTG antibodies in the diagnosis of CD, and supports the use of EMA-ELISA as a serologic marker for this disease.

The appearance of “new” infectious diseases, the reemergence of “old” infectious diseases, and the deliberate introduction of infectious diseases through bioterrorism has highlighted the need for improved and innovative infectious disease surveillance systems. A review of publications reveals that traditional current surveillance systems are generally based on the recognition of a clear increase in diagnosed cases before an outbreak can be identified. For early detection of bioterrorist-initiated outbreaks, the sensitivity and timeliness of the systems need to be improved. Systems based on syndromic surveillance are being developed using technologies such as electronic reporting and the internet. The reporting sources include community physicians, public health laboratories, emergency rooms, intensive care units, district health offices, and hospital admission and discharge systems. The acid test of any system will be the ability to provide analyses and interpretations of the data that will serve the goals of the system. Such analytical methods are still in the early stages of development.

Background: Platelet adhesion and aggregation are mediated by specific platelet membrane glycoproteins GPIa/IIa, GPIba, and GPIIb/IIIa, and are essential steps in thrombus formation and development of acute myocardial infarction.

Objective: To evaluate the risks exerted by each of the following polymorphisms: HPA-1a/b in GPIIIa; 807C/T in GPIa; and HPA-2a/b, VNTR and Kozak C/T in GPIba in young males with AMI[1]..

Methods: We conducted a case-control study of 100 young males with first AMI before the age of 53 and 119 healthy controls of similar age. All subjects were tested for the above polymorphisms.

Results: The allele frequencies of each of the platelet polymorphism were not significantly different between the young men with AMI and the controls. Smoking alone was associated with a 9.97-fold risk, and the presence of at least one metabolic risk factor resulted in a 2.57-fold risk of AMI.

Conclusion: These results indicate that platelet glycoproteins polymorphisms are not an independent risk factor for AMI.

Background: Multiple factors are involved in the pathogenesis of hypertension in the obese individual.

Objective: To evaluate the role of a decrease in sympathetically mediated thermogenesis and the effect of the correlation between the plasma leptin and daily urinary nitric oxide levels on obesity-related hypertension.

Methods: We evaluated three groups: 25 obese hypertensive patients (age 45.7±1.37 years, body mass index 34.2±1.35 kg/m², systolic/diastolic blood pressure 155±2.9/105±1.3, mean arterial pressure 122±1.50 mmHg); 21 obese normotensive patients (age 39.6±1.72, BMI[1] 31.3±0.76, SBP/DBP[2] 124±2.1/85.4±1.8, MAP[3] 98.2±1.80); and 17 lean normotensive subjects (age 38.1±2.16, BMI 22.1±0.28, SBP/DBP 117±1.7/76.8±1.5, MAP 90.1±1.50). We determined basal resting metabolic rates, plasma insulin (radioimmunoassay), norepinephrine (high performance liquid chromatography) in all subjects. Thereafter, 14 obese hypertensives underwent a weight reduction diet. At weeks 6 (n=14) and 14 (n=10) of the diet the above determinations were repeated. Plasma leptin (enzyme-linked immunosorbent assay) and UNOx[4] (spectrophotometry) were assayed in 17 obese hypertensives and 17 obese normotensives, and in 19 obese hypertensives versus 11 obese normotensives, respectively.

Results: Obese hypertensive patients had significantly higher basal RMR[5] and plasma NE[6] levels. Insulin levels were lower in the lean group, with no difference between the hypertensive and normotensive obese groups. At weeks 6 and 14, BMI was significantly lower, as were insulin and NE levels. RMR decreased to values of normotensive subjects. MAP normalized but remained significantly higher than that of obese normotensives. Leptin blood levels and the leptin/UNOx ratio were significantly higher in the obese hypertensive compared to the obese normotensive patients. Both these parameters were strongly correlated to BMI, MAP⁵, RMR, and plasma NE and insulin .Obese hypertensive patients excreted less urinary NO metabolites. A strong correlation was found between MAP and the leptin/UNOx ratio.  

Conclusions: A reduction of sympathetically mediated thermogenesis, as reflected by RMR, results in normalization of obesity-related hypertension. In contrast, insulin does not seem to play a major role in the pathogenesis of hypertension associated with obesity. Increased leptin levels in conjunction with decreased NO production in the presence of enhanced sympathetic activity may contribute to blood pressure elevation in the obese.

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[1] BMI = body mass index

[2] SBP/DBP = systolic blood pressure/diastolic blood pressure

[3] MAP = mean arterial pressure

[4] UNOx = urinary nitric oxide

[5] RMR – resting metabolic rate

[6] NE = norepinephrine

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. In this review we discuss the elements that contribute to the complexity of polygenic diseases and describe an experimental strategy for disease-related gene discovery that attempts to overcome these factors. This strategy involves a population-based case-control paradigm and makes use of a highly informative, homogeneous founder population, many of whose members presently reside in Israel. The properties of single nucleotide polymorphisms, which are presently the markers of choice, are discussed, and the technologies that are currently available for SNP[1] genotyping are briefly presented.

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[1] SNP = single nucleotide polymorphism

Background: Clinical studies showing an association between immigration and increased prevalence of coronary risk factors or mortality rate in patients immigration is associated with greater risk among immigrants from the Soviet with coronary artery disease are scarce.

Objectives: To compare the risk profile and mortality of coronary patients born in Israel with those who immigrated to Israel, and to determine whether recent Union.

Methods: Demographic, clinical, and laboratory data were collected on chronic coronary artery disease patients from 18 Israeli medical centers during the screening period of the Bezafibrate Infarction Prevention Study in the early 1990s. Data on mortality after a mean 7.7 year follow-up were obtained from the Israel Population Registry.

Results: While significant differences in mortality (14.7% vs. 18.5%, P < 0.001) were observed between Israeli-born patients and immigrants respectively, the mortality in these groups was similar when compared within specific age groups. Immigrants suffered more from hypertension and angina pectoris, and their New York Heart Association functional limitation class was higher, as compared to their Israeli-born counterparts. A multivariate analysis of mortality comparing patients from the Soviet Union who immigrated after 1970 with those who immigrated before 1970 showed an increased risk for newer immigrants, with a hazard ratio of 1.69 (95% confidence interval 1.19-2.40) for those immigrating between 1970 and 1984, and 1.68 (95% CI[1] 1.01-2.28) for those immigrating between 1985 and 1991.

Conclusion: The worse profile and prognosis observed among patients who recently emigrated from the Soviet Union cannot be explained by traditional risk factors for CAD[2] such as smoking, diabetes, hypertension, and lipid disorders. Further investigation, including variables such as psychological stress to which immigrants are more exposed than others, is needed.

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Background: Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes were proposed to be involved in osteoporosis, but the precise genes and their relative contribution remain unknown.

Objectives: To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986s in the calcium-sensing receptor gene.

Methods: We analyzed 86 Jewish Israeli patients with LBMD[1]: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR[2] gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986s polymorphism in the CaSR[3] gene was performed using the denaturing gradient gel electrophoresis technique.  

Reaults: In LBMD women the distributions of VDR alleres in Apal polymorphism were AA=7/28, Aa=16/28 and aa=5/28; in TaqI polymorphism TT=10/31, Tt=16/31 and tt=5/31; and in BsmI polymorphism BB=7/32, Bb=14/32 and 11/32. In LBMD men the distributions were AA=17/39, Aa=21/39 and aa=1/39; in TaqI polymorphism TT=12/42, Tt=23/42 and tt=7/42; and in BsmI polymorphism BB=12/41 Bb=18/41 and bb=11/41. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986s polymorphism, compared with 40 of 203 controls (19.7%) (P=0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD[4] between homozygotes and heterozygotes (P=0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.

Conclusions: In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.

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Background: Matrix metalloproteinases are proteolytic enzymes that degrade extracellular matrix components. Numerous studies have demonstrated that individual MMPs[1] play a crucial role in tumor invasion and metastasis.

Objective: To examine the expression of MMPs and their inhibitor TIMP-2 in neoplastic and normal thyroid tissues.

Methods: We examined 33 cases of thyroid tumor (papillary, follicular and medullary carcinoma, follicular adenoma and multinodular goiter). MMP protein content and activity were measured by enzyme-linked immunosorbent assay and gel zymography. Immunohistochemistry was also performed.

Results: The thyroid tissues examined secreted MMP-2 and 9 as well as TIMP-2, but only MMP-2 was significantly higher in papillary carcinoma cases compared to the adjacent normal tissue or to the other tumor entities. Increased MMP-2 immunohistochemical staining was demonstrated in the neoplastic papillary epithelial component. No significant difference was seen between papillary carcinomas with lymph node metastases and those without.

Conclusions: Increased MMP-2 expression may be useful as a diagnostic marker to differentiate papillary carcinoma from other thyroid neoplasms, but it cannot serve as a useful prognostic marker.

Background: The emergency department is one of the hospital’s busiest facilities and is frequently described as a bottleneck. Management by constraint is a managerial methodology that helps to focus on the most critical issues by identifying such bottlenecks. Based on this theory, the benefit of adding medical staff may depend on whether or not physician availability is the bottleneck in the system.

Objective: To formulate a dynamic statistical model to forecast the need for allocating additional medical staff to improve the efficacy of work in the emergency department, taking into account patient volume.

Methods: The daily number of non-trauma admissions to the general ED[1] was assessed for the period 1 January 1992 to 1 December 1995 using the hospital computerized database. The marginal benefit to shortening patient length of stay in the ED by adding a physician during the evening shift was examined for different patient volumes. Data were analyzed with the SAS software package using a Gross Linear Model.

Results: The addition of a physician to the ED staff from noon to midnight significantly shortened patient LOS[2]: an average decrease of 6.61 minutes for 80–119 admissions (P<0.001). However, for less than 80 or more than 120 admissions, adding a physician did not have a significant effect on LOS in the ED.

Conclusions: The dynamic model formulated in this study shows that patient volume determines the effectiveness of investing manpower in the ED. Identifying bottleneck critical factors, as suggested by the theory of constraints, may be useful for planning and coordinating emergency services that operate under stressful and unpredictable conditions. Consideration of patient volume may also provide ED managers with a logical basis for staffing and resource allocation.

Background: Acute appendicitis is one of the most common conditions requiring surgical intervention. Open appendectomy has been a safe and effective operation for acute appendicitis for more than a century. Recently, several authors proposed that the new technique of laparoscopic appendectomy should be the preferred treatment for acute appendicitis. However, unlike laparoscopic cholecystectomy, LA[1] has not yet gained popularity.

Objectives: To compare open with laparoscopic appendectomy for length of operation, complications, postoperative pain control, length of hospitalization, and hospital costs.

Methods: A sample of 194 patients who underwent OA[2] and LA during 1995 was randomly selected for the study. Patients' demographic data, preoperative laboratory and physical values, histopathologic diagnosis of removed appendix, mean operating time, length of hospitalization, and postoperative pain control and complications were reviewed.

Results: Acute appendicitis was confirmed in 66% of patients. The groups were similar demographically (gender and mean age). We could not find any statistical differences in intraoperative and postoperative complications and use of antibiotics. The operative time was longer in the OA group (62.4 vs. 57.3 minutes), but the difference was not statistically significant (P=0.075). The hospital stay was 2.5 days in the LA group and 2.7 days in the OA group. Higher operative costs were observed in the LA group.

Conclusion: Laparoscopic appendectomy is comparable to open appendectomy with regard to complications, length of operation, hospital stay, but it is more costly. Laparoscopic appendectomy does not offer any significant benefit over the open approach.

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