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.