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עמוד בית
Sun, 14.07.24

February 2001

Special Section: Clinic and Science
Donato Alarcon-Segovia, MD and Yehuda Shoenfeld, MD
Yehuda Shoenfeld, MD, Yaniv Dhemer, MD, Yaakov George, MD and Dror Harats, MD
Bo Johanneson, BSc and Marta E. Alarcon-Riquelme, MD, PhD
Horacio Senties-Madrid, MD and Felipe Vega-Boada, MD

Paraneoplastic syndromes are disorders associated with cancer but without a direct effect of the tumor mass or its metastases on the nervous system. Small cell carcinoma of lung associated with paraneoplastic sensory neuronopathy and/or paraneoplastic encephalomyelitis with the presence of anti-Hu antibodies has been termed “anti-Hu syndrome. Anti-­Hu associated PSN-PEM is an immune disorder in which both cell-mediated and humoral mechanisms are involved. Patients are consiaered affected by Anti-Hu associated PSN-PEM when they develop clinical signs and symptoms of CNS dysfunction and/or sensory neuropathy not caused by metas­tases or other disorders, and serum or cerebrospinal fluid is positive for Hu abs. SCLC is found in more than 90% of patients with cancer and positive Hu abs. Individual patients with Hu abs associated to SCLC may suffer PSN-PEM, Iimbic encephalitis, brainstem encephalopathy, opsoclonus-myoclo­nus, paraneoplastic cerebellar degeneration or myelopathy. Hu abs have a specificity of 99% and sensitivity of 82% in detecting paraneoplastic neurological syndromes. There are two types of treatment: the first is to treat the cancer, the second is to suppress the immune reaction with the use of corticosteroids, cyclophosphamide, azathioprine, plasma ex­change, intravenous immunoglobulin and immunoadsorption however, treatment of paraneoplastic syndromes is generally unsatisfactory.

Max J. Schmulson, MD

Knowledge on the pathophysiology of irritable bowel syndrome has evolved, beginning with disturbances in motility to visceral hypersensitivity, and ultimately to alterations in brain-gut bi­directional communication, where neurotransmitters such as serotonin play a key role. Recently, a multicomponent disease model that integrates all these alterations was proposed. This model is divided into physiological, cognitive, emotional and behavioral components that explain the gastrointestinal as well as the constitutional symptoms. In recent years there has been an explosion of research together with new developments in pharmacological treatments for lBS that support each compo­nent of this model. This review presents recent data in favor of these alterations in IBS.

Marcia Hiriat, MD, PhD, Roman Vidaltamayo, PhD and M.Carmen Sanchez-Soto, MSc

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.

Zvi R. Cohen, MD, Revital Duvdevani, PhD, Dvora Nass, MD, Moshe Hadani, MD and Zvi Ram, MD

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.

Alejandro Ruiz-Arguelles, MD and Donato Alarcon-Segovia, MD, MSc

The formerly prevalent concept that intact autoantibodies could not penetrate into viable cells has been defeated by a large amount of experimental findings and clinical observations that indicate otherwise. The penetration of autoantibodies into living cells seems to participate in the pathogenesis of diverse autoimmune diseases, but it may also play a physiological role in healthy individuals. Although the fine mechanisms of the phenomenom remain to be elucidated, the potential use of penetrating autoantibodies as vectors to deliver molecules into cells, with diverse therapeutic purposes, has gained growing interest during the last few years.

Donato Alarcon-Segovoia, MD, MS, PhD

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.

Ma C. Gutierrez-Ruiz, PhD, Luis E. Gomez Quiroz, MSc, Elizabeth Hernandez, MSc, Leticia Bucio, PhD, Veronica Souza, MSc, Luis Llorente, PhD and David Kershenobich, PhD

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.

Carlos Alberto Aguilar-Salinas, MD, Onix Arita Melzer, MD, Leobardo Sauque Reyna, MD, Angelina Lopez, BSc, Ma Luisa Velasco Perez, RN, Luz E. Guillen, BSc, Francisco Javier Gomez Perez, MD and Juan A. Rull Rodrigo, MD

Background: Information is lacking on the effects of hormone replacement therapy in women with diabetes, especially during moderate chronic hyperglycemia.

Objectives: To study the effects of HRT on the lipid profile and the low density lipoprotein subclass distribution in women with type 2 diabetes under satisfactory and non-satisfactory glycemic control.

Methods: Fifty-four postmenopausal women after a 6 week run-in diet were randomized to receive either placebo(HbAlc <8%, n=13 HbAlc >8%, n=17) or HRT (HbAlc<8%, n=11 HbAlc >8%, n=13) for 12 weeks. HRT consisted of cyclical conjugated estrogens 0.625 mg/day plus medrogestone 5 mg/day. At the beginning and at the end of each treatment period the LDL subclass distribution was estimated by density gradient ultracentrifugation.

Results: At the baseline and during the study, the HbAlc level was significantly higher in hyperglycemic patients than in the near-normoglycemic controls (baseline 10.2±2.9 vs. 6.5±0.7%, P<0.01). They showed a trend for higher total and LDL cholesterol, triglycerides and lower high density lipoprotein-cholesterol compared to near-normoglycemic con­trols, as well as significantly higher triglyceride concentrations in very low density lipoprotein, intermediate density lipoprotein and LDL-1 particles and cholesterol content in LDL-1 and -2 particles. HRT decreased LDL-cholesterol in both groups. In the normoglycemic patients a small increase in HbAlc was observed (6.5±0.7 vs. 7.4+1%, P=004). In all cases, HRT did not modify the proportion of LDL represented by denser LDLs.

Conclusions: HRT did not modify the LDL subclass distribution, even in the presence of moderate chronic hyperglycemia in women with type 2 diabetes.

Rafael J. Salin-Pascual, MD, PhD

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.

Original Articles
Shaul Sukenik, MD, Ron Baradin, MD, Shlomi Codish, MD, Lily Neumann, PhD, Daniel Flusser, MD, Mahmoud Abu-Shakra, MD and Dan Buskila, MD

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.

Joram Wardi, MD, Ram Reifen, MD, Hussein Aeed, PhD, Liliana Zadel, MD, Yona Avni, MD and Rafael Bruck, MD

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.

Case Communications
Ram Silfen, MD, Jerome Keslin, MB, ChB and Haim Gutman, MD
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