Israel Medical Association Journal

Background: Leptin is a 16 kDa hormone synthesized by adipocytes and involved in body weight regulation.

Objectives: To determine serum leptin concentrations in heart, liver and kidney transplant recipients.

Methods: We investigated 57 patients: 18 male heart transplant recipients (age 25-69 years) at 1-66 months after transplantation, 6 female and 8 male liver transplant recipients (age 33-70) at 11-73 months after transplantation, and 10 female and 15 male kidney transplant recipients (age 20-61) at 3-138 months after transplantation. All recipients were receiving immunosuppressive therapy, including prednisone 0-20 mg/day, azathioprine 75-125 mg/day, cyclosporin 100-250 mg/day or tacrolimus 2-10 mg/day. The results were compared to those of 10 female and 10 male healthy controls. Morning serum concentrations of leptin were measured with a commercial radioimmunoassay (Linco Research Inc., USA), and serum insulin and cortisol levels were measured by radioimmunoassay.

Results: Patients (both men and women) after heart, liver and kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/body mass index ratios than controls. Serum leptin concentrations were significantly higher in women than in men and correlated very significantly with BMI[1] in all cases. The multivariate stepwise analyses showed that among parameters including BMI, gender, age, time after transplantation, prednisone dose, hematocrit, serum concentrations of glucose, albumin, creatinine, cortisol and insulin, only BMI, gender, cortisol and insulin were significant independent determinants of serum leptin levels in these patients.

Conclusions: This is the first report showing that, in addition to body mass index and gender, basal cortisol and insulin levels affect the hyperleptinemia in transplant patients. The clinical relevance of hyperleptinemia in these patients will require further investigation.

Background: Patients who feel involved in their treatment have better outcomes than those who do not.

Objective: To identify determinants of perceived patient involvement in obstetric care.

Methods: A retrospective study was undertaken in 1,452 (83%) of 1,750 women sampled in November 1995 from maternity wards of 14 general hospitals in Israel. A postal and telephone survey using a self-administered questionnaire included the following variables: hospital (identity number), patients' age, self-reported complications, previous deliveries, education, ethnicity, and number of obstetric interventions performed and/or considered. The main outcome measured was the reported involvement in decisions for obstetric interventions.

Results: Reported full involvement varied from 72% for epidural analgesia to 13% for forceps/vacuum extraction. Factor analysis identified two dimensions of perceived involvement: one for routine” interventions (enema, monitor­ing, IV line and episiotomy), which are performed in Israel mostly by midwives, and another for "special" interventions (forceps/vacuum extraction, epidural or other analgesia, and cesarian section) performed by physicians. Logistic regression identified hospitals, younger age, number of interventions, and Arab ethnicity as correlates of a perceived non-involvement in decisions for "special" interventions.

Conclusions: Clinical setting, age and ethnicity affected patient perception of involvement in decisions for obstetric interventions.

The hepatitis C virus is an enveloped positive-sense single-stranded RNA virus, which has been classified into 6 major genotypes and over 100 subtypes. HCV replicates mainly in the hepatocyte. Recently, infectious HCV cDNA clones have been generated. Despite evidence that innate and adaptative humoral and cellular immune responses are activated as part of an antiviral defense, HCV has a remarkable ability to establish persistent infection. The analysis of viral kinetics using mathematical modeling shows a relative steady state without treatment, while an immediate biphasic HCV decline occurs in blood during successful treatment, the latter being predictive of clearance of HCV by the end of treatment.

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.

In recent years liver transplantation was shown to be the only clinically effective method of treating acute or chronic hepatic failure due to various causes. However, this ultimate therapeutic approach is limited by the growing disparity between organ donation and the number of patient on the waiting list.

Factors such as high cost, morbidity, and the need for lifelong immunosuppression accelerated the research on alternative methods to support the failing liver. Recently, new technologies incorporating hepatocytes and extracorporal circulation devices were introduced for liver support systems and their role in the treatment of acute liver failure.

Background: Uterine rupture is a catastrophic obstetric complication, most often associated with a preexisting cesarean section scar. Although a vaginal birth after a cesarean is considered safe in modern obstetrics, it is not known whether repeated VBACs increase the risk of rupture, or whether the first VBAC proves the strength and durability of the scar, predicting further successful and less risky vaginal deliveries.

Objectives: To evaluate the effect of repeated vaginal deliveries on the risk of uterine rupture in women who have previously delivered by cesarean section.

Methods: In this retrospective study, 26 VBAC deliveries complicated by uterine rupture were matched for age, parity, and gravidity with 66 controls who achieved VBAC without rupture. The histories, demography, pregnancy, labor and delivery records, as well as neonatal outcome were compared.

Results: We found that the risk of rupture decreases dramatically in subsequent VBACs. Of the 40 cases of uterine rupture recorded during the 18 year study period, 26 occurred during VBAC deliveries. Of these, 21 were complicated first VBACs. We also found that the use of prostaglandin-estradiol, instrumental deliveries, and oxytocin had been used significantly more often during deliveries complicated with rupture than in VBAC controls.

Conclusions: Once a woman has achieved VBAC the risk of rupture falls dramatically. The use of oxytocin, PGE2 and instrumental deliveries are additional risk factors for rupture, therefore caution should be exerted regarding their application in the presence of a uterine scar, particularly in the first vaginal birth after cesarean.

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VBAC= vaginal birth after cesarean section

PGE2= prostaglandin-estradiol

Background: The beneficial effect of aprotinin, a naturally occurring protease inhibitor, on preservation of organs such as the liver, kidney and lung has been documented.

Objective: To explore the effects of hepatic ischemia and reperfusion on both liver and myocardial function, using a dual isolated perfused organ model with and without aprotinin.

Methods: Isolated rat livers were stabilized for 30 minutes with oxygenated modified Krebs-Henseleit solution at 37°C. Livers were then perfused continuously with KH or KH + aprotinin 10⁶ KIU/L for an additional 135 min. Livers of two other groups were made globally ischemic for 120 min, then perfused for 15 min with KH or with KH + aprotinin. Isolated hearts (Langendorff preparation) were stabilized for 30 min and then reperfused with KH or KH + aprotinin exiting the liver for 15 min.  The liver’s circuit was disconnected, and hearts were re-circulated with the accumulated liver + heart effluent for an additional 50 min.

Results: In the ischemia and ischemia + aprotinin groups, portal vein pressure (1 and 15 min reperfusion) was 331±99% and 339±61% vs. 308±81% and 193±35% of baseline, respectively (P<0.03 vs. ischemia). There were no other differences in the enzyme leakage  between aprotinin-treated or untreated ischemic livers. Left ventricular pressure was stable in the controls.

However, LV pressure in groups perfused with ischemic liver effluent declined within 65 min reperfusion, whether aprotinin treated or not (84±8% and 73±5% of baseline, respectively, P<0.004 only for ischemia vs. control)

Conclusion: When aprotinin was used, LV pressure was inclined to be higher while liver portal vein pressure was lower, thus providing protection against liver and heart reperfusion injury. 

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* These authors contributed equally to the article

KH = Krebs-Henseleit

LV = left ventricular

Background: The pathogenesis of neurological symptoms, the most common extraintestinal complication ofchildhood shigellosis, is unclear. To elucidate the mechanisms involved, we developed an animal model and demonstrated that TNF alpha and IL-1 beta play a role.

Objectives: To determine whether TNF alpha and IL-1 beta genes are expressed in the brain following peripheral administration of Shigella dysenteriae 60R.

Methods: Expression of mRNA for TNF alpha and IL-1 beta was examined in the brain structures (hypothalamus and hippocampus) and peripheral organs by reverse transcriptase polymerase chain reaction, at different time points after intraperitoneal injection of S. dysenteriae sonicate.

Results: In our animal model of Shigella related seizures, TNF alpha and IL-1 beta mRNA were induced in the brain, spleen and liver already 1 hour after injection of S. dysenteriae sonicate. The expression of TNF alpha and IL-1 beta mRNA in spleen, hippocampus and hypothalamus decreased after 6 h and increased again at 18 h post-injection.

Conclusions: Local production of TNF alpha and IL-1 beta in the brain may be involved in the enhanced seizure response of mice after administration of S. dysenteriae. It is possible that intracerebral production of TNF alpha and IL-1 beta plays a role in neurological disturbances of human shigellosis.
 

Objectives: To report the characteristics of liver injury induced by nimesulide.

Patients and Methods: We report retrospectively six patients, five of them females with a median age of 59 years, whose aminotransferase levels rose after they took nimesulide for joint pains. In all patients nimesulide was discontinued, laboratory tests for viral and autoimmune causes of hepatitis were performed, and sufficient follow-up was available.

Results: One patient remained asymptomatic. Four patients presented with symptoms, including fatigue, nausea and vomiting, which had developed several weeks after they began taking nimesulide (median 10 weeks, range 2–13). Hepatocellular injury was observed with median peak serum alanine aminotransferase 15 times the upper limit of normal (range 4–35), reversing to normal 2–4 months after discontinuation of the drug. The remaining patient eveloped symptoms, but continued taking the drug for another 2 weeks. She subsequently developed acute hepatic failure with encephalopathy and hepatorenal syndrome and died 6 weeks after hospitalization. In none of the cases did serological tests for hepatitis A, B and C, Epstein-Barr virus and cytomegalovirus, as well as autoimmune hepatitis reveal findings.

Conclusions: Nimesulide may cause liver damage. The clinical presentation may vary from abnormal liver enzyme levels with no symptoms, to fatal hepatic failure. Therefore, monitoring liver enzymes after initiating therapy with nimesulide seems prudent.