Israel Medical Association Journal

Background: Case-control and prospective studies indicate that an elevated plasma homocysteine level is a powerful risk factor for atherosclerotic vascular diseases. Certain medications can induce hyperhomocystinemia, such as methotrexate, trimethoprim and anti-epileptic drugs. There are few reports indicating an interaction between lipid-lowering drugs (cholestyramine and niacin) and homocysteine. Recently, an interaction was shown between fenofibrate and benzafibrates (a fibric acid derivative) and homocysteine plasma levels.

Objectives: To evaluate the effects of different fibrates on plasma homocysteine levels and to measure the reversibility of this effect.

Methods and Results: We investigated the effects of ciprofibrate and bezafibrate on homocysteine levels in patients with type IV hyperlipidemia and/or low high density lipoprotein levels. While a 57% increase in homocysteine was detected in the ciprofibrate-treated group (n=26), a 17% reduction n homocysteine was detected in the group treated with bezafibrate (n=12). The increase in homocysteine in the ciprofibrate-treated group was sustained for the 12 weeks of treatment and was partially reversible after 6 weeks of discontinuing the ciprofibrate therapy.

Conclusions: These results indicate that an increase In plasma homocysteine levels following administration of flbrates is not a class effect, at least in its magnitude. Moreover, it is reversible upon discontinuation of the treatment.
 

Background: The impact of repeated surgical resection on the survivorship of patients with malignant astrocytomas is an issue of some controversy in the medical literature.

Objectives: To clarify this issue through a retrospective analysis of treatment outcomes in a brain tumor clinic.

Methods: The patient records from the Brain Tumor Clinic at Hahnemann University Hospital for the period 1988 to 2000 were reviewed. From these, 112 cases of glioblastoma multiforme and 50 cases of anaplastic astrocytoma were chosen for analysis.

Results: The group of patients with glioblastomas showed a median survival of 415 days. When analyzed as subgroups based on the number of surgical resections, the median survival was 393 days in the group with biopsy only, 380 days in the group with one surgical resection, and 548 days in the group with two or three resections. Using the Kaplan-Meier method to generate survival plots and the log rank test to compare groups, repeat debulking was found to be a significant predictor of survival (P= 0.1 73). The group of patients with anaplastic astrocytomas showed a median survival of 1,311 days. When analyzed by subgroups, the patients with biopsy only had a median survival of 544 days, those with one debulking 1,589 days and those with two or three debulkings 1,421 days. There was a trend toward increased survival with debulking and the log rank test again showed statistical significance (P 0.1998).

Conclusions: This study indicates that repeated surgical resections offer increased survival for both glioblastomas and anaplastic astrocytomas.
 

Background: Hepatitis C virus is the major cause of acute and chronic hepatitis in patients with end-stage renal disease receiving replacement therapy.

Objectives: To define the prevalence of HCV RNA in a population of patients on dialysis in Israel, to determine the relative risk of acquiring HCV infection while treated by hemodialysis or chronic ambulatory peritoneal dialysis, and to define the HCV genotypes in this population.

Methods: During 1995 we studied 162 dialysis patients. Information was obtained regarding the mode of dialysis, years of treatment, number of blood transfusions, and results of serological testing for HCV, hepatitis B virus, and human immunodeficiency virus. Anti-HCV antibodies were tested by a third-generation microparticle enzyme immunoassay. HCV RNA was determined by polymerase chain reaction. HCV genotyping was performed by a hybridization assay.

Results: HCV RNA was detected in 18% of the HD group and 7% of the CAPD group. The number of HCV RNA-positive patients was significantly higher in the HD than the CAPD group (P < 0.05). HCV RNA-positive HD patients were treated longer than the HCV RNA-negative patients (P < 0.02).

Conclusions: Third-generation immunoassay proved to be highly sensitive (94%) and specific (91%) in identifying HCV RNA positivity. Several HCV subtypes were detected, lb being the most frequent. Identification and isolation of infected HCV patients may minimize its spread in dialysis units and prevent cross-infection.

Objectives: To compare risk behavior between subjects attending anonymous and confidential clinics for human immunodeficiency virus testing, and to assess whether anonymous testing results in a higher accrual of persons at risk for HIV.

Methods: An anonymous questionnaire that addressed sociodemographic and risk behavior aspects was administered to 140 subjects attending an anonymous clinic and 124 attending a confidential clinic in the Tel Aviv area. A logistic regression analysis was used to compare the effects of various behavioral factors on the probability of attending each clinic.

Results: Chronological age, age at first sexual intercourse and the percent of married subjects were similar in both clinics. However, there was a significant difference in the sex ratio and in educational attainment (85.0% versus 55.6% were males, P< 0.001 and 58% vs. 34% had over 12 years of education, P<0.001, in the anonymous and confidential clinics respectively).

There was a striking difference between the two clinics with regard to sexual experience characteristics: of the subjects reaching the anonymous clinic 21.4% were homosexual and 10.0% bisexual versus a total of 2.6% in the confidential clinic. A logistic regression analysis, comparing the effects of various behavioral factors on the probability of attending each clinic showed that gender (male), high education, homosexuality, number of partners and sexual encounter with sex workers were the strongest predictors for selecting anonymous HIV examination.

Conclusions: Individuals at high risk for HIV, such as homosexuals and bisexuals, prefer to attend an anonymous clinic.
 

Cancer is a multi-step disease involving a series of genetic alterations that result in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has greatly increased through the use of DNA tumor viruses and their transforming proteins as a biological tool to decipher a cascade of events that lead to deregulation of cell proliferation and subsequent tumor formation. For the past ten years our laboratory has focused on the molecular biology of the human neurotropic papovavirus, JCV. This virus causes progressive multifocal Ieukoencephalopathy, a fatal neuro­degenerative disease of the central nervous system in immunocompromised patients. JCV is a common human virus that infects more than 80% of humans but does not induce any obvious clinical symptoms. The increased incidence of acquired immune deficiency syndrome and the use of immunosuppressive chemotherapy have dramatically raised the incidence of PML. The coincidental occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-intected non­human primates, provides intriguing speculation on the association between JCV and CNS malignancies. In this report we discuss clinical data and laboratory observations pointing to the direct involvement of JCV in cancer.

Trophic factors such as nerve and fibroblast growth factors are important modulators of 13 cell physiology. These two factors induce the extension of neurite-Iike processes in primary cultures of adult rat 13 cells. Moreover, both NGF and FGF enhance glucose-induced insulin secretion. Since â cells synthesize NGF and pancreatic islet cells produce FGFs, it is possible that autocrine/paracrine interactions may be major regulators of insulin secretion, and impairment of these interactions could lead to pathological states such as diabetes mellitus.

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.

The future promises good news for the treatment of systemic lupus erythematosus, some of which can already be foreseen. Increased knowledge on genes that participate in the predis­position, pathogenesis, pharmacogenetics of, and protection against this disease may permit intervention at this level. Also, better understanding about the role of sex hormones has allowed trials of weak androgens or prolactin inhibitors. New immunomodulators or i mmunosuppresors may enable more precise treatment at the immunoregulatory level, and greater knowledge on the disturbance of circuits has already provided hints and even allowed trials of anti-interleukin-10 antibodies, an IL-10 decreasing agent, tolerance-induction strategies or intervention at the level of T cell co-stimulation, as well as immune ablation with subsequent stem cell transplantation. Autoantibodies can be removed, controlled by means of anti­idiotypes, which are blocked from reaching their target antigen or uncoupled from the tissues they have reached. All these treatment strategies will gradually become decanted in order to achieve the optimal treatment of SEE, which may turn out to be its cure.

Background: Inflammatory mediators, including cytokines and reactive oxygen species. are associated with the pathology of chronic liver disease. Hepatocytes are generally considered as targets but not producers of these important mediators.

Objectives: To investigate whether cells of hepatocellular lineage are a potential source of various cytokines we estimated the expression and secretion of tumor necrosis factor alpha, transforming growth factor beta 1 and interleukins I beta, 6 and 8 in the culture of well-differentiated human HepG2 cells treated for 24 hours with ethanol, acetaldehyde and lipopolysaccharide. Lipid peroxidation damage, glutathione content and glutathione perox­idase, catalase and superoxide dismutase activity were also determined.

Methods: HepG2 cells were treated for 24 hours with ethanol (50 mM), acetaldehyde (175 ìM) and LPS (1 ìg/ml). TNF-á, TGF­-â, L-1â, IL-6 and IL-8 mRNA were determined by reverse transcriptase polymerase chain reaction and secretion by en­zyme-linked immunoassay. Lipid peroxidation damage, glutathione content and antioxidant enzyme activities were determined spectrophotometrically.

Results: Exposure to ethanol for 24 hours induced the expression of TNF-á and TGF- â1. secretion of IL-1â and TGF-â₁ and decreased catalase activity. Acetaldehyde markedly increased TNF-á and IL-8 expression, stimulated IL-1â and IL-8 secretion, increased lipid peroxidation damage and decreased catalase activity, while LPS exposure induced the expression of TNF-á. TGF- â₁, IL-6 and IL-8, the secretion of TGF-â₁, IL-1â, IL-6 and IL-8, and a decrease in catalase activity. No change in GSH, GSHPx or SOD was found in any experimental condition.

Conclusions: The present studies confirm and extend the notion that hepatocytes respond to ethanol, acetaldehyde and LPS-producing cytokines. Oxidative stress produced by the toxic injury plays an important role in this response through up­regulation of inflammatory cytokines.

The novel neuropeptides hypocretin/orexin have recently been located on the lateral hypothalamus cells. This system has been linked to the regulation of both feeding and sleep, and recent studies have found an association between a defect in these neuropeptides and narcolepsy. We conducted a MED­LINE review of all the articles published since the discovery of hypocretin/orexin peptides, narrowing the field to the relation­ship between these neuropeptides and sleep. The finding of a deletion in the transcription of the hypocretin receptor 2 gene in narcoleptic Doberman pinschers and the development of a knockout of the hypocretin gene in mice pointed to the relevance of this system in the sleep-wake cycle. We provide further evidence of the role of the hypocretin/orexin system in narcolepsy and in sleep regulation and present an integrative model of the pathophysiology of narcolepsy. The discovery of the link between these peptides and narcolepsy opens new avenues to both the understanding of sleep mechanisms and therapeutic implications for sleep disorders.

Background: Balneotherapy has been successfully used to treat various rheumatic diseases, but has only recently been evaluated for the treatment of fibromyalgia. Since no effective treatment exists for this common rheumatic disease, comple­mentary methods of treatment have been attempted.

Objectives:To assess the effectiveness of batneotherapy at the Dead Sea area in the treatment of patients suffering from both fibromyalgia and psoriatic arthritis.

Methods: Twenty-eight patients with psoriatic arthritis and fibromyalgia were treated with various modalities of bat­neotherapy at the Dead Sea area. Clinical indices assessed were duration of morning stiffness, number of active joints, a point count of 18 fibrositic tender points, and determination of the threshold of tenderness in nine fibrositic and in four control points using a dolorimeter.

Results: The number of active joints was reduced from 18.4+10.9 to 9+8.2 (P< 0.001). The number of tender points was reduced from 12.6+2 to 7.1±5 in men (P<0.003) and from 13.1+2 to 7.5+3.7 in women (P<0.001). A significant improvement was found in dolorimetric threshold readings after the treatment period in women (P< 0.001). No correlation was observed between the reduction in the number of active joints and the reduction in the number of tender points in the same patients (r= 0.2).

Conclusions: Balneotherapy at the Dead Sea area appears to produce a statistically significant substantial improvement in the number of active joints and tender points in both male and female patients with fibromyalgia and psoriatic arthritis. Further research is needed to elucidate the distinction between the benefits of staying at the Dead Sea area without balneotherapy and the effects of balneotherapy in the study population.

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.