Neurotoxins in neurobiology: from basic research to clinical application

Recently, we reported that in rat, cyclosporine A (CsA) markedly decreases the levels of calbindin-D (CABP-D) 28 kDa in kidney. CABP-D 28 kDa is a calcium-binding protein which is highly expressed in calcium-transporting tissues such as kidney or brain. In this study, we investigated whether, in addition to the kidney, CsA also has an effect on CABP-D 28 kDa in rat brain. Three groups of male Wistar rats received 15 mg/kg/day or 50 mg/kg/day of CsA orally for 12 days, whereas controls received vehicle solution for the same period. CABP-D 28-kDa protein and CsA were quantified in homogenates of kidney, cerebral cortex and cerebellum, and the localization of CABP-D 28 kDa was assessed in the different tissue sections by immunohistochemistry. In kidney, CABP-D 28 kDa was strongly and dose dependently decreased, and was located in tubular epithelial cells. In brain, CABP-D 28 kDa was not changed and was mainly located in pyramidal cells of the cortex and in cerebellum exclusively in Purkinje cells. High CsA concentrations were measured in kidney, more than 17-fold greater than those found in cortex. In cerebellum, CsA was below the limit of detection. These data suggest that at clinically relevant doses, CsA may not affect CABP-D 28-kDa levels in brain.     

Oxygen free radicals and their clinical implications

Reactive oxygen species (ROS) have been implicated in a variety of pathological processes. The generation of highly reactive oxygen metabolites is an integral feature of normal cellular metabolism (mitochondrial respiratory chain, phagocytosis, arachidonic acid metabolism, ovulation and fertilization), however their production can multiply during pathological circumstances. Free oxygen radicals act either on the extracellular matrix or directly upon cellular membranes themselves. The fundamental defense of the organism against ROS include scavenger enzymes (superoxide dismutase, catalase, glutathione peroxidase) and lipid- and water soluble antioxidant compound (ascorbic acid, glutathione, albumin, transferrin, etc.). Their role in ischemia-reperfusion models have now been comprehensively investigated and it has become clear that ROS is to be blamed for the bulk of post-ischemic injuries, hence the basis for newly established antioxidant therapy in such cases. Also more and more studies have concluded a pivotal role of ROS in degenerative and inflammatory conditions, post-radiation processes and aging. Therefore it seems as we are continuously shedding light on the crucial part played by these molecules regarding a wide range of pathologies, we are discovering new therapeutic windows that would clinically assist us in managing such conditions.     

Knowing the self: Building a bridge from basic research to clinical practice.

The articles under discussion give promise that basic research information about the self can be translated into useful information for the clinical practitioner. Several issues were delineated that require more careful attention and research: (a) The self needs to be more clearly defined in both basic and clinical literatures; (b) the process of self-experiencing must be studied in conjunction with the study of the acquisition, functions, and developmental trajectories of self-concepts; and (c) the complexities of identity formation in multicultural societies must be factored into future research designs. Psychotherapists need to be aware that many patients have internalized self-related ideas from several different cultures and subcultures, and puzzling out these culture-based conflicts may become a significant focus of psychotherapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Endothelial dysfunction in peripheral arterial occlusive disease: from basic research to clinical use

By checking the card indexes of seven out of twelve Social Insurance Offices covering 66% of the total wage-earning population in the city of G?teborg the patients recorded for 90 days of continuous sick-listing were classified into four diagnostic categories according to the doctor's certificate: "non-specific pain" and "specific pain" of the musculoskeletal system, "other pain" and "non-pain" diagnoses. The overall yearly incidence of 90 days' sick-listing averaged 5.4%. A significant correlation was found between the incidence of 90 days' sick-listing due to "non-pain" and musculoskeletal pain diagnoses and the proportion of demographic characteristics of the areas. The hypothesis of presuming the highest association between non-specific pain diagnoses and demographic factors was rejected.     

Introduction to special section: Relapse to substance abuse: Recent findings from basic and clinical research.

A series of 6 articles concerning relapse to substance abuse and its treatment is introduced. Two articles review animal models of relapse and the potential role of drug priming effects, 2 articles present new data from experimental human research on cognitive and contextual determinants of relapse, while 2 articles describe clinical approaches and review the effectiveness of relapse prevention treatment. The series integrates clinical and basic research around a common theme and demonstrates that various types of research representing diverse perspectives are needed to understand this important feature of substance dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparing basic and clinical research: a dilemma

The authors conducted an ecological study of the distribution of malignant lymphomas in a rice-growing area in northern Italy. They considered data on concentrations of phenoxy herbicides in soil and water and found the highest incidence of non-Hodgkin's lymphoma in subjects who lived in an area where 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid existed in very high concentrations. During 1985-1988, the incidence of non-Hodgkin's lymphoma in males in the most-polluted municipalities was twice as high as was noted for the remaining less-polluted territories. During 1991-1993, non-Hodgkin's lymphoma was higher by 60%. The authors also conducted a population-based case-control study. They found an association between employment of women in rice-growing jobs (particularly as rice weeders) and risk of non-Hodgkin's lymphoma (odds ratio=1.9; 95% confidence interval=0.6, 6.0). Work in rice fields was correlated strongly with residence in polluted areas. The authors did not detect an association between area of residence or occupation and incidence of Hodgkin's disease.     

Ovarian follicular dynamics: from basic science to clinical practice

The management of low responders (LR) to ovarian stimulation in cycles of assisted reproduction (AR) is a difficult challenge. Aging of the ovary and LR are coincidental in many situations, but LR is also present in young patients undergoing AR. In fact, today it is a recognized cause of infertility. When the aged ovary is considered, there is evidence that the functioning of the granulosa cells as well as the quality of the oocytes and resulting embryos are affected. Similarly, in young LR, the production of inhibin is affected. However, there is no evidence that the quality of the oocyte and/or the resulting embryo is affected. In this study, we have retrospectively analyzed our files and observed that the quality of the oocytes and embryos was similar between younger and older LR and normal responders (NR). Studies using color Doppler vaginal ultrasound have shown that the pulsatility index (PI) and the resistance index (RI) were increased in LR as compared with NR, suggesting that there was some degree of vascular resistance to flow. Treatment of LR is also a difficult challenge. Ovum donation is a successful treatment for LR, since cumulative birth rates are > 85% with four attempts of embryo transfer. The future may be promising for LR once new technologies are introduced into clinical practice. The use of recombinant gonadotropins and genetically engineered human gonadotropin derivatives may be of considerable help for LR. Similarly, non-gonadotropin hormones, such as cytokines or growth factors, may be shown to play a role in the stimulation of the ovary in the near future, and may therefore open new frontiers for treatment of LR.     

Phospholipase A2--from basic research to clinical reality]

Phospholipase A2 (PLA2) is a group of secretory as well as intracellular enzymes that release phospholipids as an early step in inflammation and play a physiologic role in digestion. In humans, the group of secretory, low-molecular-weight PLA2 (sPLA2) is differentiated from the cytosolic, high-molecular-weight PLA2 (cPLA2). The two known cPLA2 mediate the intracellular response to inflammation by releasing arachidonic acid from membrane phospholipids. Secretory pancreatic PLA2 (sPLA2-I) is a digestive zymogen secreted from pancreatic acinar cells in its inactive form. Activated by trypsin in the duodenum, it is an important digestive enzyme. In acute pancreatitis, circulating sPLA2-I indicates pancreatic injury but is mostly inactive. Synovial-type secretory PLA2 (sPLA2-II), first isolated from synovial fluid of arthritis patients, is increased in inflammation, after surgery or trauma, and in various inflammatory diseases. Unlike sPLA2-I, its catalytic activity is held responsible for mediating the systemic inflammatory reaction and its complications by regulating the synthesis of prostaglandins, leukotrienes and platelet activating factor. Clinically, sPLA2-II offers new possibilities as an early marker for severe inflammation and predicting systemic complications in severely ill patients.     

The antisaccade: a review of basic research and clinical studies

The ability to suppress reflexive responses in favor of voluntary motor acts is crucial for everyday life. Both abilities can be tested with an oculomotor task, the antisaccade task. This task requires subjects to suppress a reflexive prosaccade to a flashed visual stimulus and instead to generate a voluntary saccade to the opposite side. This article reviews what is currently known about the neural structures and processes which are involved in the performance of this task. Current data show that a variety of brain lesions, neurological diseases and psychiatric disorders result in errors, i.e. prosaccades towards the stimulus, in this task. Brain imaging studies have shown that a widely distributed cortical and subcortical network is active during the generation of antisaccades. These findings are discussed and the potential of the antisaccade task for diagnostic purposes is evaluated.     

Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations

Over the last decade, the role of visceral sensitivity has been largely recognized in the pathophysiology of functional digestive disorders, particularly in the irritable bowel syndrome. These studies have highlighted the role of afferent pathways arising from the gut as a possible target for new treatments intended to relieve pain or modify altered reflexes present in such patients. These pharmacological targets have been identified mainly by studies on animal models of visceral hyperalgesia of various origins including local inflammation. Locally, several mediators are of paramount importance for sensitization of nerve endings: 5-hydroxytryptamine, bradykinin, tachykinins, calcitonin gene-related peptide, and neurotrophins. Selective antagonists to various subtypes of their receptors are currently available and have been shown to be active in these animal models. Other substances, such as somatostatin, opiold peptides, cholecystokinin, oxytocin, and adenosine, modulate the transmission of nociceptive inputs from the gut to the brain and are of clinical interest. This article reviews the current understanding of these mediators. Although these agents seem to be promising tools for the treatment of visceral hyperalgesia and its consequences (abdominal pain and disturbed reflexes), their clinical efficacy remains to be shown. A better understanding of the nature and the location of the defect in the sensory pathways may permit the selection of subgroups of patients for treatment according to the pharmacological properties of these new therapeutic agents.     

The pS2/TFF1 trefoil factor, from basic research to clinical applications

pS2/TFF1 trefoil factor is normally expressed in the stomach, and is found ectopically in gastrointestinal inflammatory disorders and in various carcinomas. It is involved in stomach ontogenesis and in the maintenance of the integrity of the mucosa, and may represent a pharmacological tool for prevention and healing of gastrointestinal ulcerations. In breast cancer, it can be used to select patients suitable for hormone therapy. pS2/TFF1 is a pleiotropic factor involved in mucin polymerization, cell motility, cell proliferation and/or differentiation, and possibly in the nervous system.     

Cerebral vasospasm and free radicals

The literature implicating free radical reactions in the genesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage is reviewed. While this condition has features of a prototypical free radical-mediated disease and a plausible theory can be outlined, data to support the theory are limited. An association of lipid peroxidation with vasospasm has been observed, but more sophisticated techniques for detection of free radicals and for detection of free radical damage to arterial wall proteins and nucleic acids have not been used. There are conflicting reports about efficacy of various antioxidant treatments for vasospasm. In these studies, concomitant experiments have usually not confirmed that the treatments have decreased free radicals or lipid peroxides in cerebrospinal fluid. Because smooth muscle contraction is involved in vasospasm, it would be interesting to investigate the actions of free radicals on smooth muscle cells using, for example, isometric tension recordings and patch clamp techniques. Studies of cardiac myocytes indicate that free radicals alter conductances through potassium and calcium channels and through the sodium-calcium exchanger and may result in elevations in intracellular calcium. Few studies have been performed on cerebral smooth muscle cells. In one study, exposure of cerebrovascular smooth muscle cells to free radicals resulted in increased outward currents, decreased membrane resistance, cell contraction, appearance of membrane blebs, and cell death. In summary, more investigations using better experimental techniques are required before free radicals and reactions induced by them can be said with certainty to be the primary cause of vasospasm.     

Alcohol and free radicals. Various consequences: protein synthesis, endocrine disorders, immunity. Role of stress

Ethanol is a powerful generator of oxygen free radicals, when metabolized in the liver or in other organs. Isoenzyme 2E1 of cytochrome P450 and aldehyde oxidase are the main mechanisms for the generation of these radicals. A consequence of free radical generation is a decrease in protein synthesis. As a result we have endocrine and immunity alterations. The paper ords with a brief discussion of stress associated to alcoholism.     

Pre-eclampsia and oxygenated free radicals

Preeclampsia, clinically defined by arterial hypertension, oedema and proteinuria is a frequently occurred complication of pregnancy. This disease seems to be linked to oxidative stress within placenta. The local accumulation of lipid peroxides, resulting from free radicals production increase altered prostacyclin/thromboxane synthesis. Increased production of lipid peroxides, thromboxane and/or cytokines triggered vascular and organic dysfunctions observed in preeclampsia. Changes in lipoprotein metabolism, namely increase in plasma very low density lipoproteins concentrations (VLDL) and oxidized low density lipoproteins (LDL) concentrations could participate to endothelial dysfunctions observed during preeclampsia.     

Cancer gene therapy: connecting basic research with clinical inquiry

Molecular genetics has spawned an impressive outpouring of insights into the biology of neoplastic transformation and the host-tumor relationship. This deeper understanding of cancer pathogenesis presents a rich opportunity to develop novel therapeutic agents with improved selectivity for cancer cells. One promising approach involves gene therapy, which is the introduction of genetic material into a patient's tissues with the intent to achieve therapeutic benefit. A number of gene transfer systems have been designed that enable the genetic modification of relevant target cells, albeit with varying strengths and limitations. Several strategies to exploit gene transfer as a tool to target specific molecular defects intrinsic to cancer cells, enhance tumor chemosensitivity, and augment tumor immunogenicity are under intensive investigation. A number of these approaches have entered initial clinical testing and already provide intriguing new information about the biology of cancer in patients. In this review, I will highlight the critical issues and controversies that underscore preclinical experiments in cancer gene therapy, discuss some of the preliminary findings from the first wave of clinical trials, and speculate about the prospects that cancer gene therapy will change the way that cancer medicine is practiced.     

Making progress: does clinical research lead to breakthroughs in basic biomedical sciences?

Beta-catenin is a pivotal player in the signaling pathway initiated by Wnt proteins, mediators of several developmental processes. beta-catenin activity is controlled by a large number of binding partners that affect the stability and the localization of beta-catenin and is thereby able to participate in such varying processes as gene expression and cell adhesion. Activating mutations in beta-catenin and in components regulating its stability can contribute to the formation of certain tumors.     

国内外易切削钢的研究现状和前景

易切削钢与普通碳素钢相比,具有优良的切削性能和表面光洁度,介绍了国内外易切削钢的分类、成分控制,并介绍了国内外易切削钢的研究现状,对其研究前景进行了展望.