Israel Medical Association Journal

Background: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense pre­clinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothetial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer.

Objective: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature.

Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir). was evaluated.

Results: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.

Conclusion: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.

Objective: To study whether retinolpalmitate, beta-car­otene or lycopene could prevent liver cirrhosis induced by thioacetamide in rats.

Methods: In the control group liver cirrhosis was induced in male Wistar rats by intraperitoneal injections of TAA 200 mg/ kg for 12 weeks. The three study groups received in addition to TM either beta-carotene, lycopene or retinolpalmitate by gavage through an orogastric tube. Histopathological analysis and determination of the hydroxyproline contents of the livers were performed at the end of the protocol.

Results: Rats treated with beta-carotene and TAA had lower histopathologic scores and reduced levels of hepatic hydroxyproline (P= 0.02) than those treated by TAA alone. A trend of decreased fibrosis was observed in the rats treated with lycopene and TAA although this lacked statistical significance.

Conclusions: Beta-carotene attenuated liver cirrhosis induced by TAA in rats. The mechanism may be related to effects on hepatic stellate cells or to scavenging of free radicals by beta-carotene. Retinolpalmitate and lycopen had no significant beneficial effect.

Objective: To identify correlates for under-utilization of influenza immunization among the elderly.

Methods: A telephone survey was conducted among a random sample of patients aged 65 and over registered at a Jerusalem primary care community clinic. The 626 questionnaires were analyzed for associations of immunization receipt for the latest influenza season. Multivariate logistic regression was performed to identify independent correlates. Respondents were also asked what factors had influenced their decision about immunization.

Results: The most frequently reported influence on getting immunized was a physician's recommendation. Immunization was independently associated with the identity of the primary care physician (P0.0001) and with having visited the physician during the previous 3 months (P=0.0006). Immunization was more likely among persons who believed that it provides complete protection from influenza (P0.0001) and less likely among those who believed immunization can cause influenza (P0.0001). Higher immunization rates were also associated with being married (P=0.0031).

Conclusion: Through their influence on patient knowledge and the effect of their recommendation, primary care physicians play a pivotal role in determining immunization rates. Physicians should routinely discuss the effects of immunization and recommend it to the elderly.

The screening program in Israel for Tay-Sachs disease has proven very successful, giving Jewish couples a choice not to have affected children. The technology of carrier detection is now possible in several other severe genetic diseases that are relatively frequent among Jews. Due to the current confusion, a policy is needed to determine how the TSD screening program should be continued in the Israeli Jewish population. We propose that such a screening program include only mutations agreed by consensus as causing a disease severe enough to warrant the possibility of therapeutic abortion. We also propose that general screening include only mutations that are relatively frequent, taking into account the carrier frequencies in the Israeli Jewish population.

Background: About one-third of patients with severe ulcerative colitis do not respond to conventional therapy and require urgent colectomy. It was recently shown that cyclosporin is effective in some of these patients.

Objectives: To review the current experience of six hospitals in central Israel that used cyc-losporin in patients with severe ulcerative colitis.

Methods: The files of all 32 patients treated with cyclosporin for corticosteroid-resistant ulcerative colitis were reviewed. Activity of disease was measured by a clinical activity, index colonoscopy and laboratory tests.

Results: The average duration of treatment with intravenous cyclosporin was 12.7 days (range 9–28) after which the disease activity index dropped from an average of 14.22 to 4.74. The mean time for response was 7.5 days (4–14). Twelve patients (40%) required surgery within 6 months and another 6 patients (18.8%) were operated on after more than 6 months. Twelve patients (37%) maintained remission for at least 6 months and did not require surgery. In one patient treatment was stopped because of non-compliance and one was lost to follow-up. There were numerous side effects, but in only one case with neurotoxicity was treatment withdrawn.

Conclusions: Cyclosporin is a relatively safe and effective treatment for severe ulcerative colitis. It induced long-term remission in 37% of the patients, and in those who required surgery the treatment resulted in an improved clinical condition before the operation.

Background: General pediatricians in Israel are actively involved in the initial evaluation, resuscitation and management of traumatized children. However, pediatric trauma care is not a part of pediatric specialty training in Israel, and the few Advanced Trauma Life Support^R courses per year are insufficient for most pediatricians working in accident and emergency care.

Objective: To examine the value of the course in relation to the limited resources available for such training.

Methods: A telephone survey of 115 pediatricians who had taken the course between 1990 and 1994 was conducted. The responding physicians (67%) were asked to complete a specially designed questionnaire on life-saving procedures that were taught in the course. In addition, they were asked to subjectively assess the practical utility of the course.

Results: Forty-three (56%) pediatricians reported that they routinely treated both adult and pediatric trauma cases. Of these, 81% performed 27 life-saving ATLS^R procedures. Pediatric trauma was treated by only 22 (28%), of whom 72.3% performed 18 life-saving ATLS^R procedures. These pediatricians ranked the courses as being "very high" to "high" in impact.

Conclusions: These figures indicate that an ATLS^R course designed specifically for pediatricians can markedly improve pediatric trauma care. To ensure standard education and patient care, such a course should be developed and made a mandatory component of residency training. Further studies to examine the objective impact of the courses on pediatric trauma care should be carried out.

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ATLS= Advanced Trauma Life Support