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Normal Physiology (normal + physiology)
Selected AbstractsDopamine and sensory tissue development in Drosophila melanogasterDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2001Wendi Neckameyer Abstract Dopamine is an important signaling molecule in the nervous system; it also plays a vital role in the development of diverse non-neuronal tissues in the fruit fly Drosophila melanogaster. The current study demonstrates that males depleted of dopamine as third instar larvae (via inhibition of the biosynthetic enzyme tyrosine hydroxylase) demonstrated abnormalities in courtship behavior as adults. These defects were suggestive of abnormalities in sensory perception and/or processing. Electroretinograms (ERGs) of eyes from adults depleted of dopamine for 1 day as third instar larvae revealed diminished or absent on- and off-transients. These sensory defects were rescued by the addition of L -DOPA in conjunction with tyrosine hydroxylase inhibition during the larval stage. Depletion of dopamine in the first or second larval instar was lethal, but this was not due to a general inhibition of proliferative cells. To establish that dopamine was synthesized in tissues destined to become part of the adult sensory apparatus, transgenic lines were generated containing 1 or 4 kb of 5, upstream sequences from the Drosophila tyrosine hydroxylase gene (DTH) fused to the E. coli ,-galactosidase reporter. The DTH promoters directed expression of the reporter gene in discrete and consistent patterns within the imaginal discs, in addition to the expected expression in gonadal, brain, and cuticular tissues. The ,-galactosidase expression colocalized with tyrosine hydroxylase protein. These results are consistent with a developmental requirement for dopamine in the normal physiology of adult sensory tissues. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 280,294, 2001 [source] RD Lawrence Lecture 2009 Old genes, new tricks: learning about blood glucose regulation from naturally occurring genetic variation in humansDIABETIC MEDICINE, Issue 11 2009A. L. Gloyn Abstract The study of rare monogenic forms of diabetes and pancreatic B-cell dysfunction provides an unrivalled opportunity to link a specific change in gene function with precise cellular consequences and clinical phenotype in humans. Over the past 20 years there has been considerable success in determining the genetic aetiology of a number of rare monogenic forms of diabetes, which has had a significant impact on both our understanding of normal physiology and on translational medicine. The impact of these discoveries has been substantial, with insights into both developmental biology and normal physiology. There are clear examples where determining the genetic aetiology for individuals with rare monogenic subtypes of diabetes has led to improved treatment. Although formerly in the shadow of the monogenic diabetes field, over the past 3 years there has been staggering progress in our understanding of the genetic basis of Type 2 diabetes. This has been largely as a result of genome-wide association studies and has seen the list of ,diabetes susceptibility genes' increase from three to close to 20. There is now encouraging evidence to support a potential role for genetics in determining the response of individuals with Type 2 diabetes to different therapeutic options. One of the challenges that lies ahead is determining how the non-coding genetic variants exert their pathogenicity. It is possible that parallels can be drawn from functional work on rare regulatory mutations causing monogenic forms of diabetes. However, it is more likely that comprehensive approaches will be necessary. [source] What role do extracellular matrix changes contribute to the cardiovascular disease burden of diabetes mellitus?DIABETIC MEDICINE, Issue 12 2005M. H. Tayebjee Abstract Matrix metalloproteinases (MMP) and their inhibitors (TIMP) are central factors in the control of extracellular matrix turnover. They are important in normal physiology and also during a range of pathological states. In this review, we have systematically identified clinical articles relevant to cardiovascular disease in diabetes from the last 10 years. Our aim was to outline the structure, function and regulation of metalloproteinases and their key roles in cardiomyopathy and vasculopathy in diabetes. We also explore the effects of drug intervention on both human subjects with diabetes and experimental animal models. The modulation of MMP and TIMP activity using drugs that affect the expression and function of these proteins may provide us with new ways to treat this serious and disabling disease, and we explore potential mechanisms and treatments. [source] Endothelin receptor selectivity in chronic kidney disease: rationale and review of recent evidenceEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009W. Neuhofer Abstract Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ETA and ETB. In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ETB receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ETA receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ETA receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ETB receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials. [source] Concept, mechanisms and therapeutics of angiogenesis in cancer and other diseasesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2003Tayade Pralhad Angiogenesis supports normal physiology as well as contributing to the progression of various diseases including cancer. Determination of the key role of angiogenesis in cancer has led to much optimism for the development of targeted drugs without cytotoxic side-effects. Currently, research in angiogenesis therapy is robust, with the discovery of a growing number of pro- and anti-angiogenic molecules. More time, however, is required to be able to elucidate the complex interactions among these molecules, how they affect vasculature and their functions in different environments. As we learn more about the molecular mechanisms of angiogenesis, a number of effective methods to treat cancer and other diseases will be developed. [source] Co-culture in cartilage tissue engineeringJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 3 2007Jeanine Hendriks Abstract For biotechnological research in vitro in general and tissue engineering specifically, it is essential to mimic the natural conditions of the cellular environment as much as possible. In choosing a model system for in vitro experiments, the investigator always has to balance between being able to observe, measure or manipulate cell behaviour and copying the in situ environment of that cell. Most tissues in the body consist of more than one cell type. The organization of the cells in the tissue is essential for the tissue's normal development, homeostasis and repair reaction. In a co-culture system, two or more cell types brought together in the same culture environment very likely interact and communicate. Co-culture has proved to be a powerful in vitro tool in unravelling the importance of cellular interactions during normal physiology, homeostasis, repair and regeneration. The first co-culture studies focused mainly on the influence of cellular interactions on oocytes maturation to a pre-implantation blastocyst. Therefore, a brief overview of these studies is given here. Later on in the history of co-culture studies, it was applied to study cell,cell communication, after which, almost immediately as the field of tissue engineering was recognized, it was introduced in tissue engineering to study cellular interactions and their influence on tissue formation. This review discusses the introduction and applications of co-culture systems in cell biology research, with the emphasis on tissue engineering and its possible application for studying cartilage regeneration. Copyright © 2007 John Wiley & Sons, Ltd. [source] Molecular Diversity of VEGF-A as a Regulator of Its Biological ActivityMICROCIRCULATION, Issue 7 2009Jeanette Woolard ABSTRACT The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5,7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGFxxx, or antiangiogenic proteins, termed VEGFxxxb. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes. [source] Leukocyte Adhesion in Capillary-Sized, P-Selectin-Coated MicropipettesMICROCIRCULATION, Issue 2 2008Prithu Sundd ABSTRACT Objective: Leukocyte retention in lung capillaries is observed in normal physiology and following a bacterial infection. It has been hypothesized that cells either become mechanically trapped or adhere to capillary endothelial cells via adhesion molecules. We propose that retention involves both mechanical and adhesive forces and that the biochemical adhesive force is modulated by mechanical forces that alter the area of contact between leukocytes and endothelium. Methods: To probe this hypothesis, an adhesion assay has been developed in which individual HL-60 cells were aspirated into micropipettes pre-coated with P-selectin. Following aspiration, cells were exposed to physiological pressure differences. Results: Little adhesion was seen in micropipettes coated with BSA, whereas significant adhesion was observed in micropipettes coated with P-selectin. The frequency of cell arrest on P-selectin in the micropipette was much greater than on P-selectin in a parallel plate flow chamber even though the disruptive force in the micropipette assay exceeds that in the parallel plate flow chamber. These results demonstrate that receptor,ligand interactions can enhance adhesion in a capillary geometry and that differences in capillary geometry vs. venule geometry can significantly influence the adhesive phenotype. Conclusions: Taken together, these observations support the hypothesis that an interplay between mechanical and biochemical adhesive forces can play a major role in retention. [source] DNA and protein transfer from bacteria to eukaryotes, the agrobacterium storyMOLECULAR PLANT PATHOLOGY, Issue 1 2000The 18th Bateson Memorial Lecture Agrobacterium is a well-studied plant pathogen, which has the unique ability to transfer DNA and protein into a number of eukaryotes. The DNA is integrated randomly into the plant genome where it is expressed, thereby leading to the disease crown gall. This system is a paradigm for the interaction of a number of plant and animal pathogens which transfer proteins into their host cells. In Agrobacterium, the tumour inducing (Ti) plasmid codes for the functions specifically required for the transfer process. These genes, termed virulence or vir genes, are activated by plant signal molecules acting through a two component regulatory system. A key structure coded by 11 genes of the vir B operon is a pilus, synthesized at 20 °C, but poorly at 25 °C. How this pilus functions in DNA and protein transfer is unclear, but homologous genes are found in many animal pathogens. In addition to Ti plasmid-encoded vir genes, chromosomal virulence genes have also been identified. However, these mutations are often pleiotropic because they involve both the normal physiology of Agrobacterium as well as the metabolism of Agrobacterium when it is associated with plant cells. Based on 16S ribosomal RNA sequencing, Agrobacterium is closely related to the intracellular pathogen of animals, Brucella. Several chromosomal mutations of Agrobacterium required for virulence in plants are also required for invasion of animal host cells by Brucella. [source] The role of carbon monoxide in the gastrointestinal tractTHE JOURNAL OF PHYSIOLOGY, Issue 2 2004Simon J. Gibbons Carbon monoxide (CO) is a biologically active product of haem metabolism that contributes to the normal physiology of the gastrointestinal tract. In this article, we review recent data showing that CO is an integral regulator of gastrointestinal motility and an important factor in the response to gastrointestinal injury. CO is generated by haem oxygenase-2 (HO-2), which is constitutively expressed in many inhibitory neurones of the vertebrate enteric nervous system. The membrane potential gradients along and across the muscle layers of the gastrointestinal tract require the generation of CO by haem oxygenase-2. The presence of CO is also necessary for normal inhibitory neurotransmission in circular smooth muscle and appears to permit nitric oxide-mediated inhibitory neurotransmission. Genetic deletion of the haem oxygenase-2 gene in mice slows gut transit. The other major CO synthetic enzyme, haem oxygenase-1 (HO-1) is induced under conditions of stress or injury. Recent studies have demonstrated that up-regulation of haem oxygenase-1 protects the gut from several types of gastrointestinal injury, suggesting that CO or induction of HO-1 may find therapeutic use in gastrointestinal diseases and injuries. Furthermore, it is anticipated that the understanding of CO-mediated signalling in the gastrointestinal tract will inform studies in other tissues that express haem oxygenases. [source] An 11-year experience of enterocutaneous fistula,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 12 2004P. Hollington Background: Enterocutaneous fistula has traditionally been associated with substantial morbidity and mortality, related to fluid, electrolyte and metabolic disturbance, sepsis and malnutrition. Methods: A retrospective review of enterocutaneous fistula in 277 consecutive patients treated over an 11-year period in a major tertiary referral centre was undertaken to evaluate current management practice and outcome. Results: Most fistulas occurred secondary to abdominal surgery, and a high proportion (52·7 per cent) occurred in association with inflammatory bowel disease. A low rate of spontaneous healing was observed (19·9 per cent). The healing rate after definitive fistula surgery was 82·0 per cent, although more than one attempt was required to achieve surgical closure in some patients. Definitive fistula resection resulted in a mortality rate of 3·0 per cent. In addition, one patient died after laparotomy for intra-abdominal sepsis and an additional 24 patients died from complications of fistulation, giving an overall fistula-related mortality rate of 10·8 per cent. Conclusion: Early recognition and control of sepsis, management of fluid and electrolyte imbalances, meticulous wound care and nutritional support appear to reduce the mortality rate, and allow spontaneous fistula closure in some patients. Definitive surgical management is performed only after restitution of normal physiology, usually after at least 6 months. Copyright © 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Why is the management of glucocorticoid deficiency still controversial: a review of the literatureCLINICAL ENDOCRINOLOGY, Issue 5 2005Anna Crown Summary All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is ,gated' by the 11-,-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses. [source] | |||||||||||||