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At least 541 records · Page 30Linked to original sources
PubMed2005

Future alternative therapies in a quest to halt aberrations in diabetes mellitus.

Under normal physiological conditions, euglycaemia is maintained principally by the homeostatic balance of insulin and glucagon which are secreted from the pancreas. In both type 1 and type 2 diabetes mellitus there is a substantial and chronic increase in the circulating glucose concentration. This elevation in glucose levels is accompanied by a plethora of other biochemical disturbances, including disruption of carbohydrate, fat and protein metabolism. Clinical manifestations of diabetes, which arise from the metabolic disturbances vary between individuals but are often a serious threat to quality and length of life. Pancreas transplantation (Tx) and islet modifications are methods used to restore endogenous insulin secretion in insulin-dependent diabetic patients. In order for this to be achieved successfully, however, some of the problems such as hyperglycemia states (> 150 mg/dl), which may harm pancreatic graft beta cells, immunorejection, the effects of immunosuppression, for example, must be overcome. Considering these problems, therefore, it seems logical that the replacement of the islet tissue itself, either by transplanting a vascularised pancreatic allograft or by transplanting modified pancreatic islet cells, provides a better alternative therapeutic approach than simply replacing insulin that has been lost. This review will show the recent development in the use of pancreatic islets and their modification in a quest to halt the aberrations seen in diabetes mellitus.

Diabetes Mellitus↗
PubMed2006

On the use of multi-objective evolutionary algorithms for survival analysis.

This paper proposes and evaluates a multi-objective evolutionary algorithm for survival analysis. One aim of survival analysis is the extraction of models from data that approximate lifetime/failure time distributions. These models can be used to estimate the time that an event takes to happen to an object. To use of multi-objective evolutionary algorithms for survival analysis has several advantages. They can cope with feature interactions, noisy data, and are capable of optimising several objectives. This is important, as model extraction is a multi-objective problem. It has at least two objectives, which are the extraction of accurate and simple models. Accurate models are required to achieve good predictions. Simple models are important to prevent overfitting, improve the transparency of the models, and to save computational resources. Although there is a plethora of evolutionary approaches to extract models for classification and regression, the presented approach is one of the first applied to survival analysis. The approach is evaluated on several artificial datasets and one medical dataset. It is shown that the approach is capable of producing accurate models, even for problems that violate some of the assumptions made by classical approaches.

Algorithms↗
PubMed2006

Design, synthesis, and anti-integrase activity of catechol-DKA hybrids.

Following the discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors, a plethora of new molecules have been published leading to four drugs under clinical trial. In an attempt to rationally design new dimeric diketoacids (DKAs) targeting two divalent metal ions on the active site of IN, potent inhibitors against purified IN were found with varied selectivity for strand transfer. In this context, we designed and synthesized a new series of catechol-DKA hybrids. These compounds presented micromolar anti-integrase activities with moderate antiviral properties.

Acids↗
PubMed2004

Management of infertility and prevention of ovarian hyperstimulation in women with polycystic ovary syndrome.

Anovulatory infertility is a prevalent presenting feature of polycystic ovary syndrome (PCOS). Restoration of ovulation might be achieved by ovarian stimulation or by reducing insulin and LH concentrations. Clomiphene citrate is the first-line ovulation-inducing agent, usually followed by direct stimulation with follicle stimulating hormone (FSH), if unsuccessful. The prevalent complications of ovarian hyperstimulation syndrome and multiple pregnancies can largely be avoided by administering FSH in a low dose and individualized regimen. Hyperinsulinaemia can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Advice about weight loss is critical in modern management of PCOS and infertility. Laparoscopic ovarian drilling produces similar results to FSH stimulation, and in vitro fertilization/embryo transfer (IVF/ET)-if all else fails-produces excellent results. The possible use of aromatase inhibitors, novel insulin sensitizers and in vitro maturation of oocytes is still being evaluated. The plethora of treatment options available today ensures that the great majority of women who are subfertile due to PCOS can be treated successfully.

Clomiphene↗
PubMed2004

Involvement of spinal neurokinins, excitatory amino acids, proinflammatory cytokines, nitric oxide and prostanoids in pain facilitation induced by Phoneutria nigriventer spider venom.

The major local symptom of Phoneutria nigriventer envenomation is an intense pain, which can be controlled by infiltration with local anesthetics or by systemic treatment with opioid analgesics. Previous work showed that intraplantar (i.pl) injection of Phoneutria nigriventer venom in rats induces hyperalgesia, mediated peripherally by tachykinin and glutamate receptors. The present study examined the spinal mechanisms involved in pain-enhancing effect of this venom. Intraplantar injection of venom into rat hind paw induced hyperalgesia. This phenomenon was inhibited by intrathecal (i.t.) injection of tachykinin NK1 (GR 82334) or NK2 (GR 94800) receptor antagonists, a calcitonin gene-related peptide (CGRP) receptor antagonist (CGRP8-37) and N-methyl-D-aspartate (NMDA; MK 801 and AP-5), non-NMDA ionotropic (CNQX), or metabotropic (AIDA and MPEP) glutamate receptor antagonists, suggesting the involvement of spinal neurokinins and excitatory amino acids. The role of proinflammatory cytokines, nitric oxide (NO), and prostanoids in spinally mediated pain facilitation was also investigated. Pharmacological blockade of tumour necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL-1beta) reduced the hyperalgesic response to venom. Intrathecal injection of L-N6-(1-iminoethyl)lysine (L-NIL), but not of 7-nitroindazole (7-NI), inhibited hyperalgesia induced by the venom, indicating that NO, generated by the activity of the inducible form of nitric oxide synthase, also mediates this phenomenon. Furthermore, indomethacin, an inhibitor of cyclooxigenases (COX), or celecoxib, a selective inhibitor of COX-2, abolished venom-induced hyperalgesia, suggesting the involvement of spinal prostanoids in this effect. These data indicate that the spinal mechanisms of pain facilitation induced by Phoneutria nigriventer venom involves a plethora of mediators that may cooperate in the genesis of venom-induced central sensitization.

Animals↗
PubMed2005

Autoantibodies in breast cancer sera: candidate biomarkers and reporters of tumorigenesis.

A plethora of promising breast cancer-associated autoantigens have been cloned by immunoscreening cDNA expression libraries with breast cancer sera or identified using proteomics, yet no biomarkers, whether individual autoantigens or panels of antigens developed using antibody-based methods have been validated and incorporated to routine oncologic practice for the early diagnosis of breast cancer. Recently, the addition of genomics, proteomics and high throughput technology to traditional immunological techniques has revived the interest in this field, and some of the most promising breast cancer autoantigens are in the process of being validated prospectively in large cohorts of patients with breast cancer. In addition, some of the identified breast cancer-associated autoantigens are recognized by T-cells and may prove to have a role in the treatment of breast cancer in the future. Autoantibodies found in breast cancer patient sera provide important clues about their significance. The discovery of breast cancer-associated antigens has provocative implications beyond the quest for novel diagnostic biomarkers, because autoantibodies target molecules involved in signal transduction, cell cycle regulation, cell proliferation and apoptosis, all of them key processes in carcinogenesis. Molecular components of the DNA double-strand break repair machinery as well as several members of the rapamycin-sensitive pathway elicit an autoantibody response in breast cancer. Data obtained by screening cDNA expression libraries of breast cancer antigens with autoantibodies present in breast cancer sera suggest that autoantibodies in cancer sera may be linked to the process of apoptosis. The studies reviewed here, clearly demonstrate the participation of autoimmunity in breast cancer to an extent previously unsuspected, which may have broad implications for the discovery of molecular targets for drug therapy and cancer biomarkers in general.

Autoantibodies↗
PubMed2005

Vascular NADPH oxidases: molecular mechanisms of activation.

Oxygen-derived free radicals are thought to contribute to the initiation and progression of cardiovascular disease via several different mechanisms, such as consumption of nitric oxide, oxidation of proteins and lipids, and activation of redox-sensitive signalling cascades. Vascular NADPH oxidases are important sources of vascular radical formation. The activities of these enzymes, which in some aspects are similar to the leukocyte NADPH oxidase, are controlled on the expression level and complex activation mechanisms. As a plethora of vascular stimuli, such as growth factors, cytokines, physical stimuli, and lipids elicits radical formation by these enzymes, a careful analysis is required for the understanding of the activation of the NADPH oxidases. This article reviews the components of the NADPH oxidases in leukocytes and vascular tissue. Emphasis is put on the activation of the oxidases, including upstream signalling events and molecular modes of interaction between the subunits.

Animals↗
PubMed2006

Statins in the treatment of chronic heart failure: biological and clinical considerations.

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.

Animals↗
PubMed2006

Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease.

It is only some forty years since the discovery of the heat shock or cell stress response and just over twenty years since the heat shock/cell stress response was linked to protein misfolding. The plethora of intracellular proteins which promote correct protein folding in the cell, variously termed molecular chaperones, heat shock proteins, or cell stress proteins, have only been identified in the last fifteen years. During this period it has also been discovered that: (i) molecular chaperones are potent immunogens with immunomodulatory activity and (ii) they can be secreted by cells and exhibit intercellular signaling actions. These various functions of molecular chaperones are increasingly being linked to the pathology of the cardiovascular system. Molecular chaperones within cells can exhibit cardioprotection if their levels are artificially elevated, suggesting that these proteins may have therapeutic activity. In contrast, there is evidence that atherogenesis may be linked to immunity to one specific molecular chaperone, Hsp60. This may offer the possibility of treating atherosclerosis by vaccination. However, there is also growing evidence that secreted molecular chaperones have pro- or anti-inflammatory actions that are relevant to cardiovascular pathology. This review brings these various strands of research together to provide an overview of the role of molecular chaperones in cardiovascular disease.

Animals↗
PubMed2006

Role of bone morphogenetic proteins in cardiac differentiation.

Bone morphogenetic proteins (BMP) are involved in the regulation of a plethora of processes underlying cardiovascular development. This review summarizes the effects of BMP and the signaling pathways that regulate the differentiation of cardiomyocytes from mesoderm in the heart-forming region and at the distal borders of the heart tube from the second heart field. Subsequently, the role of BMPs in the formation of the ventricular chambers and septovalvulogenesis in the atrioventricular canal and outflow tract is described. Finally, the effects of BMPs in stem cell biology and cardiac regeneration are discussed.

Animals↗
PubMed2005

Riboswitches and the role of noncoding RNAs in bacterial metabolic control.

Microorganisms use a plethora of genetic strategies to regulate expression of their genes. In recent years there has been an increase in the discovery and characterization of riboswitches, cis-acting regulatory RNAs that function as direct receptors for intracellular metabolites. Nine classes have been uncovered that together regulate many essential biochemical pathways. Two classes, responding to either glucosamine-6-phosphate (GlcN6P) or glycine, have been found to employ novel mechanisms of genetic control. Additionally, progress has been achieved in elucidating molecular details for regulation by the other riboswitches, via X-ray crystallography and biochemical analyses of riboswitch-metabolite interactions. The complete repertoire of metabolite-sensing RNAs and extent of their usage in modern organisms remains to be determined; however, these current data assist in establishing a foundation from which to build future expectations.

Bacteria↗
PubMed2006

Predictive value of in vitro safety studies.

The predictive value of in vitro safety studies is discussed for three important areas of pharmaceutical safety evaluations. In genetic toxicology, currently assays are sensitive for the prediction of cancer, but their overall predictive value is strongly diminished because of their low specificity. In the area of safety pharmacology blockage of hERG channel in vitro has recently been introduced to predict cardiac repolarization delay (QT interval prolongation) in patients. There is a plethora of in vitro methods to predict and characterize liver toxicity. However, little data is available that demonstrate a reliable prediction for hepatotoxicity in vivo over a wide range of chemical structures. In all three areas, further improvements are needed. 'Omics' technologies and new cell lines derived from stem cells are expected to strongly contribute to establish new and more predictive in vitro assays.

Animals↗
PubMed2006

Proteomic discovery of protease substrates.

Elucidation of in vivo substrate degradomes of a protease is a daunting endeavor because of the large number of proteins in a proteome and often minute and transient amounts of key substrates. Proteomic substrate screens for proteases are currently experiencing impressive progress. Mass spectrometry-based global proteome analysis, interfaced with liquid-chromatography and together with stable isotope labeling strategies, has provided increased coverage and sensitivity for quantitative proteomics. ICAT and iTRAQ labeling have been used to identify a plethora of new matrix metalloproteinase substrates. Emerging techniques focus on the quantitative analysis of proteolytically generated neo amino-termini, which we call terminopes, on a system-wide basis. In vivo SILAC pulse-chase experiments have also enabled the study of individual protein turnover and global proteome dynamics in cells and whole organisms. Together with activity-based probes for the profiling of functional proteases, there is now in place an array of complementary technologies to dissect the 'protease web' and its distortion in pathology.

Chromatography, Liquid↗
PubMed2006

Marine invertebrate cytochrome P450: emerging insights from vertebrate and insects analogies.

Cytochrome P450 enzymes (P450s) are responsible for the oxidative metabolism of a plethora of endogenous and exogenous substrates. P450s and associated activities have been demonstrated in numerous marine invertebrates belonging to the phyla Cnidaria, Annelida (Polychaeta), Mollusca, Arthropoda (Crustacea) and Echinodermata. P450s of marine invertebrates and vertebrates show considerable sequence divergence and the few orthologs reveal the selective constraint on physiologically significant enzymes. P450s are present in virtually all tissues of marine invertebrates, although high levels usually are found in hepatic-like organs and steroidogenic tissues. High-throughput technologies result in the rapid acquisition of new marine invertebrate P450 sequences; however, the understanding of their function is poor. Based on analogy to vertebrates and insects, it is likely that P450s play a pivotal role in the physiology of marine invertebrates by catalyzing the biosynthesis of signal molecules including steroids such as 20-hydroxyecdysone (the molting hormone of crustaceans). The metabolism of many exogenous compounds including benzo(a)pyrene (BaP), pyrene, ethoxyresorufin, ethoxycoumarin and aniline is mediated by P450 enzymes in tissues of marine invertebrates. P450 gene expression, protein levels and P450 mediated metabolism of xenobiotics are induced by PAHs in some marine invertebrate species. Thus, regulation of P450 enzyme activity may play a central role in the adaptation of animals to environmental pollutants. Emphasis should be put on the elucidation of the function and regulation of the ever-increasing number of marine invertebrate P450s.

Animals↗
PubMed2006

Critical care in Africa.

This article identifies the key challenges facing critical care practitioners in Africa. As a continent with a large proportion of the poorest countries and a plethora of unique diseases that place large demands for critical resources, the provision of care is largely in the context of severely constrained human and material resources. Diverse cultures and social norms predicate sensitivity to community values in the provision of care. Such realities demand novel approaches to the provision of critical care.

Africa↗
PubMed2004

Role of the ubiquitin-proteasome pathway in the diagnosis of human diseases.

The ubiquitin-proteasome pathway constitutes the major system for nuclear and extralysosomal cytosolic protein degradation in eukaryotic cells. A plethora of cell proteins implicated in the maintenance and regulation of essential cellular processes undergoes processing and functional modification by proteolytic degradation via the ubiquitin-proteasome pathway. Deregulations of the pathway have been shown to contribute to the pathogenesis of several human diseases, such as cancer, neurodegenerative, autoimmune, genetic and metabolic disorders, most of them exhibiting abnormal accumulation and altered composition of components of the pathway that is suitable for diagnostic proceedings. While the ubiquitin-proteasome pathway is currently exploited to develop novel therapeutic strategies, it is less regarded as a diagnostic area. Future research should lead to an improved understanding of the pathophysiology of the ubiquitin-proteasome pathway with the aim of allowing the development of subtle diagnostic strategies.

Autoimmune Diseases↗
PubMed2004

Test result variation and the quality of evidence-based clinical guidelines.

BACKGROUND: There is a plethora of supposedly evidence-based published clinical guidelines, most often prepared under the auspices of professional bodies. Many guidelines contain numerical laboratory test results as criteria for clinical action, very often simply quoted as single numbers. Every test result is subject to a number of sources of variation. Analytical imprecision and within-subject biological variation are particularly important. The influence of both of these on the dispersion of a single test result and on the number of samples required to make clinical decisions can be easily calculated using simple formulae. The effect of performing replicate analyses of one sample and of taking multiple samples can also be easily investigated. Authors of scientific statements, clinical guidelines, and practice recommendations should undertake such calculations before promulgating their efforts in the public domain. Guidelines on cholesterol and high sensitivity C-reactive protein have been examined using these approaches and these investigations allow the following conclusions. CONCLUSIONS: Analytical imprecision should be made low. If analytical imprecision is generally greater than biological variation, then reduction in analytical imprecision is valuable. If biological variation is greater than imprecision, then collection of more than one sample from an individual prior to decision-making is useful.

C-Reactive Protein↗
PubMed2005

Recent advances in the protein kinase B signaling pathway.

The phosphoinositide 3' kinase signaling pathway is activated in response to a plethora of growth factors and cytokines, and initiates a cascade of signaling events primarily via the induction of specific protein-serine/threonine kinases. Interest in the pathway has been driven by its frequent aberrant activation in disease and its impact on cell fate decisions owing to roles in survival signaling and metabolic control. There have been recent advances in our understanding of the primary components of this pathway, namely phosphoinositide-dependent kinase-1, protein kinase B and glycogen synthase kinase-3, including insights into their mechanisms of regulation, substrate proteins and cellular functions.

3-Phosphoinositide-Dependent Protein Kinases↗