Israel Medical Association Journal

Background: Epidemiological data show significant associations of vitamin D deficiency and autoimmune diseases. Vitamin D may prevent autoimmunity by stimulating naturally occurring regulatory T cells.

Objectives: To elucidate whether vitamin D supplementation increases Tregs[1] frequency (%Tregs) of circulating CD4+ T cells.

Methods: We performed an uncontrolled vitamin D supplementation trial among 50 apparently healthy subjects including supplementation of 140,000 IU at baseline and after 4 weeks (visit 1). The final follow-up visit was performed 8 weeks after the baseline examination (visit 2). Blood was drawn at each study visit to determine 25-hydroxyvitamin D levels and %Tregs. Tregs were characterized as CD4+CD25++ T cells with expression of the transcription factor forkhead box P3 and low or absent expression of CD127.

Results: Forty-six study participants (65% females, mean age ± SD 31 ± 8 years) completed the trial. 25(OH)D[2] levels increased from 23.9 ± 12.9 ng/ml at baseline to 45.9 ± 14.0 ng/ml at visit 1 and 58.0 ± 15.1 ng/ml at visit 2. %Tregs at baseline were 4.8 ± 1.4. Compared to baseline levels we noticed a significant increase of %Tregs at study visit 1 (5.9 ± 1.7, P < 0.001) and 2 (5.6 ± 1.6, P < 0.001).

Conclusions: Vitamin D supplementation was associated with significantly increased %Tregs in apparently healthy individuals. This immunomodulatory effect of vitamin D might underlie the associations of vitamin D deficiency and autoimmune diseases. Hence, our finding provides a rationale for further studies to investigate vitamin D effects on autoimmunological processes.

Background: Left atrial volume and exercise capacity are strong predictors of cardiovascular risk. Decreased exercise capacity is expected when LAV[1] is increased due to its association with abnormal left ventricular filling pressure. However, LAV enlargement is expected in chronic mitral regurgitation as well.

Objectives: To examine the linkage between LAV and exercise capacity in chronic MR[2] and to determine whether larger LAV has indeed better exercise capacity in patients with chronic severe degenerative MR and good LV systolic function.

Methods: The study included asymptomatic patients with severe chronic degenerative MR and normal LV[3] systolic function that underwent stress echocardiography. LAV was measured at rest using the biplane Simpson’s method and indexed to body surface area. The cutoff of good exercise capacity was determined at 7 METS.

Results: The patient group comprised 52 consecutive patients (age 60 ± 14 years, 36 males). Two subgroups (19 vs. 33 patients), age- and gender-matched, were formed according to LAVi[4] cutoff of 42 ml/m². Those with higher LAVi had lower exercise capacity (P = 0.004) albeit similar MR grade, baseline blood pressure, LV function and size. Receiver-operator curve analysis revealed indexed LAV value of ≤ 42 as 51% sensitive and 88% specific for predicting exercise capacity > 7 METS (AUC[5] = 0.7, P = 0.03). In multivariate analysis, age, gender and LAVi were identified as independent predictors of exercise capacity.

Conclusions: In asymptomatic patients with severe chronic degenerative MR and normal LV systolic function, mild enlargement of the left atrium (≤ 42 ml/m²) is associated with good exercise capacity.

Background: Most data on the incidence of rheumatic fever come from hospital records. We presumed that there may be cases of RF[1] that do not require hospitalization, especially in countries with high quality community health care. 

Objectives: To explore the incidence and characteristics of RF using community-based data. 

Methods: A retrospective descriptive study was conducted among the members (more than 450,000) of the Clalit Health Services, Central district, during 2000–2005. The electronic medical files of members up to 40 years old with a diagnosis of RF in hospital discharge letters or during community clinic visits were retrieved. Patients with a first episode of RF according to the modified Jones criteria were included.

Results: There were 44 patients with a first episode of RF. All patients were under the age of 29. The annual incidence among patients aged 0–30 years was 3.2:100,000; the highest incidence was among children aged 5–14 years (7.5:100,000), and in males the incidence was 2.26 times higher than in females. The incidence was higher among patients from large families, of non-Jewish ethnicity, and from rural areas. Twenty-five percent of the patients were both diagnosed and treated in an ambulatory care setting.

Conclusions: Although the incidence of RF in the western world and in Israel is low, the disease still occurs and mainly affects children. Any future estimates of disease incidence should take into account that RF is becoming an ambulatorily treated disease.  

Background: Vitamin A and its derivative retinoic acid regulate various aspects of cell behavior as growth, differentiation, and proliferation. Retinoic acid derivatives have been suggested to play a role in processes such as hepatic regeneration and fibrosis.

Objectives: To evaluate the influence of vitamin A on rat liver epithelial cell proliferation.

Methods: We performed common bile duct ligation in rats that had been subjected to differing vitamin A diets and compared their livers to control rats. Proliferation, apoptosis, and retinoic acid receptors were evaluated by histology and immunohistochemistry in bile duct cells and hepatocytes.

Results: Vitamin A deficiency was found to be associated with enhanced proliferation of bile duct epithelial cells following CBD[1] ligation. The proliferation was manifested by increased numbers of ducts, by aberrant extended ductal morphology, and by elevated numbers of nuclei expressing the proliferation marker Ki67. The amount of vitamin A in the rat diet did not affect detectably ductal cell apoptosis. We observed up-regulated expression of the retinoid X receptor-alpha in the biliary epithelium of vitamin A-deficient rats that had undergone CBD ligation, but not in vitamin A-sufficient rats.

Conclusions: We speculate that the mechanism underlying the ductal proliferation response involves differential expression of RXR[2]-alpha. Our observations suggest that deficiency of vitamin A may exacerbate cholestasis, due to excessive intrahepatic bile duct proliferation.

Background: Tuberculosis is the most common opportunistic infection among people infected with human immunodeficiency virus and its first cause of morbidity and mortality.

Objectives: To analyze the characteristics of a population in Israel with both tuberculosis disease and HIV[1] infection in order to identify factors that contribute to outcome.

Methods: The study group comprised patients hospitalized in the Pulmonary and Tuberculosis Department of Shmuel Harofeh Hospital during the period January 2000 to December 2006. They were located by a computer search in the hospital registry and the pertinent data were collected.

Results: During the study period 1059 cases of active tuberculosis disease were hospitalized; 93 of them were co-infected with HIV. Most of them came from endemic countries (61.2% from Ethiopia and 20.4% from the former Soviet Union; none of them was born in Israel). Ten percent of the cases were multiple-drug resistant and 32% showed extrapulmonary involvement. The response rate to the treatment was good, and the median hospitalization time was 70 days. The mortality rate was 3.2%.

Conclusions: Despite the high prevalence of pulmonary disease in our group, the short-term outcome was good and the Mycobacterium was highly sensitive to first-line drugs. These encouraging results can be attributed to the fact that tuberculosis patients in Israel are identified early and treated continuously and strictly, with early initiation of antiretroviral therapy, which ensures that the development of drug resistance is low.

Background: Research on synergistic effects of patient-targeted interventions combined with physician-targeted interventions has been limited.

Objectives: To compare a combined physician-patient intervention to physician feedback alone on a composite outcome of glycemic, lipid and blood pressure control.

Methods: In this cluster study 417 patients with adult-type 2 diabetes from four primary care clinics were randomized to receive either a physician-only intervention or a combined physician-plus-patient intervention. Physicians in all clinics received diabetes-related quality performance feedback during staff meetings. Patients at combined-intervention clinics also received a letter encouraging them to remind their doctors to address essential aspects of diabetes care at the next visit. At 1 year follow-up, outcome measurements included hemoglobin A1c, low density lipoprotein-cholesterol and systolic blood pressure; the proportion of patients with HbA1c[1] < 9%, LDL[2] < 130 mg/dl and SBP[3] < 140 mmHg both as separate outcomes and combined.

Results: After adjusting for patient characteristics and baseline measures, follow-up levels of HbA1c (7.5% vs. 7.8%, P = 0.09), LDL (104.7 vs. 110.7 mg/dl, P < 0.05) and SBP (135.6 vs. 139.9, P = 0.10) were marginally better for combined-intervention patients compared to physician-only intervention patients. Significantly more patients in the combined-intervention (38.8%) than physician-only intervention (24.2%) met all three targets (HbA1c < 9%, LDL < 130 mg/dl and SBP < 140 mmHg) as a single combined outcome (adjusted odds ratio 2.4, P < .01).

Conclusions: Compared to physician-feedback alone, a dual intervention combining a patient letter with physician feedback produced modest improvements in glycemic, lipid and blood pressure control individually, but substantial improvement in a combined measure of these three outcomes together. Using composite outcomes may detect meaningful improvements in the management of complex chronic disease. 

Background: Adenoviral infection in children undergoing stem cell transplantation is associated with significant morbidity and mortality. Identification of adenoviral infection by polymerase chain reaction from blood facilitates accurate and rapid diagnosis and surveillance. The incidence of adenoviral infection among children undergoing SCT[1] in Israel is not known.

Objective: To estimate the incidence of adenoviral infection in pediatric SCT patients and to characterize the morbidity associated with proven infection.

Methods: Blood samples obtained weekly from children who underwent allogeneic SCT were retrospectively tested for adenovirus using standard PCR[2]. A total of 657 samples collected from 32 patients were examined. Correlation was made between the presence of adenovirus in samples and clinical records.

Results: Of the 32 patients 4 had adenoviral infection by PCR (12.5%). Clinical disease was present in all four patients concurrent with positive PCR. Gastrointestinal complaints and abnormal hepatocellular enzymes were uniformly present. One patient died due to disseminated disease. T cell depletion was a significant risk factor for adenoviral infection (P = 0.03).

Conclusions: In the patient population studied, the incidence of adenoviral infection in children undergoing SCT was 12.5%. The combination of gastrointestinal symptoms and abnormal hepatocellular enzymes should raise the suspicion of adenoviral infection, especially when occurring during the first few months after SCT. 

Background: Hodgkin’s lymphoma is a distinct primary solid tumor of the immune system that shows wide variation in incidence among different geographic regions and among various races. It was previously suggested that susceptible people living in certain parts of Israel had a higher risk of HL[1] because of exposure to unidentified environmental factors in these regions. Compared with other parts of Israel, these regions were characterized by a higher proportion of Israeli-born Jews.

Objectives: To study time trends in the incidence rate of HL in Israeli-born Jews of all age groups during the years 1960–2005.

Results: A total of 4812 Jewish cases of HL were reported to the Israel Cancer Registry during the study period 1960–2005. There has been a persistent increase in the age-standardized incidence rate of HL, all subtypes pooled, in Israeli-born Jews in both men and women. The age distribution pattern in both genders was bimodal in all periods. The highest incidence was observed in the 20–24 year age group: for women (9.13 per 100,000 per year) during the period 1988–1996, and for men (6.60 per 100,000 per year) during the period 1997–2005.

Conclusions: The reported incidence level of HL in Israeli-born young adult Jews in Israel has increased in recent years to high levels compared with other western countries. Our findings suggest a cohort effect to unidentified factors affecting Israeli-born young adult Jews in Israel.