Israel Medical Association Journal

Background: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC[1] in the same population has not been assessed.

Objectives: To assess the contribution of the DNA-MMR[2] system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients.

Methods: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI[3] determination was carried out using the five Bethesda markers and for determining LOH[4] two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared.

Results: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 l. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers.

Conclusions: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.

Background: Metastatic melanoma is an aggressive and highly malignant cancer. The 5 year survival rate of patients with metastatic disease is less than 5% with a median survival of only 6–10 months. Drugs like dacarbazin (DTIC) as a single agent or in combination with other chemotherapy agents have a response rate of 15–30%, but the duration of response is usually short with no impact on survival. Interleukin-2-based immunotherapy has shown more promising results. The National Institutes of Health recently reported that lymphodepleting chemotherapy, followed by an adoptive transfer of large numbers of anti-tumor specific tumor-infiltrating lymphocytes, resulted in an objective regression in 51% of patients.

Objectives: To introduce the TIL[1] technology to advanced metastatic melanoma patients in Israel.

Methods: We generated TIL cultures from tumor tissue, choosing those with specific activity against melanoma and expanding them to large numbers.

Results: TIL cultures from nine patients were established and examined for their specific activity against the patients' autologous tumor cells. Twelve TIL cultures derived from 5 different patients showed the desired anti-tumor activity, making those 5 patients potential candidates for the therapy.

Conclusions: Pre-clinical studies of the TIL technology in a clinical laboratory set-up were performed successfully and this modality is ready for treating metastatic melanoma patients at the Sheba Medical Center's Ella Institute.

Background: The contribution of drugs and alcohol to current trauma‑related morbidity and mortality in Israel is not known. Identification of these factors in the fast-changing demographics of the Israeli population might lead to better care and, no less importantly, to targeted prevention measures.

Objectives: To determine the incidence of alcohol‑related trauma, and to specify the time of day, the cause of trauma, and the morbidity and mortality rates as compared to non-alcohol‑associated trauma in the tertiary trauma unit of a large medical center in Tel Aviv.

Methods: Data were obtained from the Israel National Trauma Registry, based on patient records in our institution (Tel Aviv Sourasky Medical Center) from January 2001 to December 2003.

Results: Of the 5,529 patients who were enrolled in the study, 170 had high alcohol blood levels (> 50 mg/dl). Patients intoxicated with alcohol had higher rates of road accident injuries (35% versus 24% non‑intoxicated) and stab wounds (29% vs. 7%). The Injury Severity Score of the alcohol‑intoxicated patients was higher (32% ³ 16 vs. 12% ³ 16). The alcohol‑intoxicated patients were more likely to be non-Jewish (34% vs. 9%), young (82% aged 15–44 years) and males (91%). Most of the alcohol‑related injuries occurred during the weekend (47%) and during evening‑late night hours (from 7 a.m. to 11 p.m.; 55%).

Conclusions: Alcohol‑associated trauma differs from non-alcohol‑associated trauma in many ways. Since the population at risk can be identified, it is important that legislative, social, enforcement and educational measures be adopted to reduce the extent of alcohol abuse and thereby improve the level of public safety.
 

Background: Cardiovascular disease is now well established as a multifactorial disease. In a given individual, the level of cardiovascular risk is due to the interaction between genetic and environmental components. The BIP cohort comprised 3000 patients with cardiovascular disease who were tested for the benefits of bezafibrate treatment. This cohort has the data for the lipid profile of each individual, fibrinogen, Insulin, as well as clinical, demographic and lifestyle parameters

Objectives: To genotype up to 64 variable sites in 36 genes in the BIP cohort. The genes tested in this assay are involved in pathways implicated in the development and progression of atherosclerotic plaques, lipid and homocystein metabolism, blood pressure regulation, thrombosis, rennin-angiotensin system, platelet aggregation, and leukocyte adhesion.

Methods:  DNA was extracted from 1000 Israeli patients from the BIP cohort. A multilocus assay, developed by the Roche Molecular System, was used for genotyping. Allele frequencies for some of the markers were compared to the published frequencies in a healthy population (the French Stanislas cohort, n=1480).

Results: Among the 26 comparable alleles checked in the two cohorts, 16 allele frequencies were significantly different from the healthy French population: ApoE (E3, E2, E4), ApoB (71ile), ApoC (3482T, 455C, 1100T, 3175G, 3206G), CETP (405val), ACE (Del), AGT (235thr), ELAM (128arg); p<0001 and LPL (93G, 291Ser, 447ter); p < 005.

Conclusions: Although a comparable healthy Israeli population study is needed for more precise interpretation of these results, frequency differences in these polymorphic alleles, associated with lipid metabolism, renin-angiotensin system and leukocyte adhesion mechanism, between CVD patients and healthy individuals nevertheless implicate these candidate genes as predisposing for CVD.lic safety.
 

Tumor necrosis factor-associated fever syndrome is an autosomal dominant disorder caused by mutations of the TNFRSF 1A gene encoding the 55 kD TNF receptor (p55 TNF-RI).

A 32 year old man presented with a huge tumor in the right chest wall that had increased dramatically in size over the previous 6 months.

Background: The prevalence of morbid obesity is increasing rapidly. Weight reduction is very difficult using diet restriction and physical activity alone. Sibutramine has been shown to be effective and safe as an adjuvant therapy to diet restrictions.

Objectives: To describe our experience using sibutramine in weight reduction treatment of adolescents suffering from morbid obesity.

Methods: The study group comprised 20 young persons (13 females, mean age 15 years 4 months, range 13–18 years) with morbid obesity (body mass index over the 95th percentile for age and/or ≥ 30 kg/m²) were treated with sibutramine 10 mg once a day for 1 year.

Results: Mean BMI[1] was 40 ± 5.6 kg/m² (range 30.1–49.5 kg/m²) at the beginning of treatment. Most patients showed an early weight reduction to mean BMI 39.3 ± 4.9 and 35.9 ± 5.7 at 3 and 6 months respectively, but stopped losing weight over the next 6 months. During the follow-up period 17 patients discontinued the treatment. The main reason for dropout was the slow rate of weight reduction after 6 months. Patients suffering from concomitant disorders (severe asthma, hypertension, sleep obstructive apnea) showed improvement after weight reduction. Adverse reactions from the treatment were transient, mild and well tolerated.

Conclusions: Sibutramine may help in achieving weight reduction for a short period and in improving concomitant health problems, however its long-term effect is limited.

Background: Advanced glycation end products, formed by the non-enzymatic glycation of proteins with reducing sugars, are thought to play a pathogenetic role in the vascular complications of diabetes, uremia and atherosclerosis. β2-microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis. AGE[1]-modified β2m[2] has been found in amyloid deposits of long-term hemodialysis patients. AGE-modified β2m has also been shown to enhance chemotaxis and increase tumor necrosis factor-alpha and interleukin-1 beta secretion by circulating and tissue monocytes/macrophages.

Objectives: To investigate the effect of AGE-modified β2m and AGE-human serum albumin on TNF-α[3] and IL-1β[4] secretion by human peritoneal macrophages derived from patients on continuous ambulatory peritoneal dialysis.

Methods: Human PMØ[5] were isolated from peritoneal dialysis effluent of stable CAPD[6] patients and were incubated for 24 hours with AGE-modified β2m, β2m, AGE-HSA[7], HSA or lipopolysaccharide. TNF-α or IL-1β secretion was measured by enzyme-linked immunosorbent assay in cell-free culture supernatants.

Results: Both AGE-modified β2m and AGE-HSA significantly increased TNF-α and IL-1β secretion by human PMØ in a dose-dependent manner (50–200 μg/ml). In contrast, β2m or HSA had no such stimulatory effect on TNF-α secretion but had a small significant increase in IL-1β secretion.

Conclusions: AGE-modified β2m promotes in vitro TNF-α and IL-1β secretion by human PMØ of CAPD patients. Activation of these macrophages by AGE-modified β2m may be a contributory factor to the morphologic changes and altered permeability of the peritoneal membrane in long-term CAPD. 

Background: There are no national data on the burden and management of acute cerebrovascular disease in Israel.

Objectives: To delineate the burden, characteristics, management and outcomes of hospitalized patients with acute cerebrovascular disease in Israel, and to examine adherence to current guidelines.

Methods: We prospectively performed a national survey in all 28 hospitals in Israel admitting patients with acute cerebrovascular events (stroke or transient ischemic attacks) during February and March 2004.

Results: During the survey period 2,174 patients were admitted with acute cerebrovascular disease (mean age 71 ± 13 years, 47% women; 89% ischemic stroke or TIA[1], 7% intracerebral hemorrhage and 4% undetermined stroke). Sixty-two percent of patients were admitted to departments of Medicine and a third to Neurology, of which only 7% were admitted to departments with a designated stroke unit. Head computed tomography was performed during hospitalization in 93% of patients. The overall rate of urgent thrombolytic therapy for acute ischemic stroke was 0.5%. Among patients with ischemic stroke or TIA, 94% were prescribed an antithrombotic medication at hospital discharge, and among those with atrial fibrillation about half were prescribed warfarin. Carotid duplex was performed in 30% and any vascular imaging study in 36% of patients with ischemic events. The mean length of hospital stay was 12 ± 27 days for ICH[2] and 8 ± 11 days for ischemic stroke. Among patients with ICH, 28% died and 66% died or had severe disability at hospital discharge, and for ischemic stroke the corresponding rates were 7% and 41% respectively. Mortality rates within 3 months were 34% for ICH and 14% for ischemic stroke.

Conclusions: This national survey demonstrates the high burden of acute stroke in Israel and reveals discordance between existing guidelines and current practice. The findings highlight important areas for which reorganization is imperative for patients afflicted with acute stroke.

Intravenous immunoglobulins have been used as therapeutic proteins since the early 1980s.

Background: In the last decade there has been an increase in asthma morbidity. Hospital admission rates for childhood asthma are influenced by the prevalence of asthma and the quality of asthma care.

Objective: To assess trends in hospital admission and readmission rates for childhood asthma in the Jezreel Valley in Israel in the last decade, and to evaluate the possible effect of changes in asthma treatment upon hospitalization for acute asthma during this period.

Methods: All records from pediatric patients from the central hospital in the Jezreel Valley in northeastern Israel over a 10 year period from 1990 through 1999 who were diagnosed as having asthma were thoroughly reviewed and analyzed for admissions, re-admissions, and treatment before and during admissions

Results: There were 1584 admissions, 1208 were first-time admissions and 374 were re-admissions. The number of first-time admissions increased significantly over time (P < 0.0001), with a significant decrease of re-admissions (P < 0.005); this finding was more significant in children under the age of 8 years (P < 0.005). The length of hospital stay decreased significantly from 3.3 days to 2.7 days (P < 0.002). Significant changes in the use of medications included an increase in inhalant glucocorticoids and a decrease in the use of sodium cromoglycate and theophylline. Controller medication use was concomitant with a significant decrease in the re-admission rates.

Conclusions: The increase in the admission rate and the decrease in the rate of re-admissions and the length of hospital stay probably reflect the increase in the prevalence of asthma and changes in its treatment, respectively. It is essential that asthma be recognized as a significant cause of morbidity and that controller medications be administered to decrease the asthma's severity, morbidity, and resultant hospital admissions.
 

In the last few decades there has been a tendency towards reinstitutionalization.

Objectives: To examine whether hostility, anxiety and autobiographical memory (a correlate of depression) are associated with IIH[1].

Methods: Using a case-control cross sectional design, 20 patients with IIH were compared with 9 healthy controls of similar age, weight and height, and 11 headache controls. Patients were assessed for hostility and anxiety. The Autobiographical Memory Test was used to assess episodic memories.

Results: The IIH group reported significantly more anxiety and more general episodic memories than the healthy controls, but not the headache control group. The headache control patients reported more general memories than did the healthy controls.

Conclusions: Patients with headaches, whether of general origin or related to IIH, have a poor psychosocial profile. While the study design does not permit any conclusions regarding causality, our results support the need to consider psychological factors in evaluating and treating IIH and headache patients. 

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[1] IIH = idiopathic intracranial hypertension

Objectives: To describe the sociodemographic, medical and functional characteristics of people aged 80–90 and 90+ who were admitted to a sub-acute geriatric hospital and to compare the hospitalization outcomes between these subgroups.

Methods: We compared the demographic and clinical data (extracted by means of chart review) of two groups of elderly who were admitted to the Reuth Medical Center during 2001–2002: those aged 90+ and those 80–89. Among survivors, the main outcome measures at discharge were mortality rate, functional ability, and place of residence.

Results: The study included 108 patients who were admitted to different divisions of Reuth: 55 patients aged 90+ and 53 aged 80–90. The mortality rate was significantly elevated in the older age group (49.1% vs. 28.1% in the younger age group) on multivariate analysis. The most important prognostic factors for mortality were incontinence (odds ratio 3.45) and being dependent before admission (OR[1] 4.76). Among survivors an association was found between being incontinent and dependent before hospitalization, and being dependent on discharge.

Conclusions: The main prognostic factors for mortality and functional outcome in patients admitted to a non-acute geriatric hospital are incontinence and functional state prior to admission, and not age per se.

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[1] OR = odds ratio