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Pathological Situations (pathological + situation)
Selected AbstractsOcclusion of the Middle Cerebral Artery: a New Method of Focal Cerebral Ischemia in RatsANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2005E. Cam The study in Wistar rats attempted to improve the occlusion technique of the middle cerebral artery (MCA) as a precise method for initiating stroke. In a first part it was necessary to study the exact anatomy of blood vessels of the brain in seven rats of 170-410 g body weight by corrosion cast. The lengths and diameters of defined locations of the blood vessels were measured. The temporary as well as the permanent methods were refined or replaced. The first one was completed in main training the physiological blood flow after temporary occlusion, while the permanent occlusion was performed by positioning a silicone cap in the MCA. A filament guide was introduced from the common carotid artery (CCA) via internal carotid artery (ICA) to guide the silicon cap at the branch of the MCA. Histological sections of the brain of rats showed 24 h after the permanent occlusion a reproducible infarct in the brain. This area corresponded very well with the supply of the MCA. The new occlusion method with a silicon cap was compared with the occlusion methods of CCA route and external carotid artery (ECA) route. The total infarct volume was significantly larger in the CCA route and ECA route groups than in the silicon cap group (means: CCA route 261 mm3; ECA route 191 mm3 vs. 128 mm3 silicon cap group; P < 0,05). It could be demonstrated that the new silicon cap occlusion technique imitates the pathological situation of a cerebral infarct in man. Moreover it is less invasive for the animals and more precise and reproducible regarding the infarcted area in comparison to the other occlusion methods. Based on anatomical measurements of the blood vessels the described silicon cap method can be recommended for rats of a body weight between 340,370 g. [source] Cardiac basal metabolism: energetic cost of calcium withdrawal in the adult rat heartACTA PHYSIOLOGICA, Issue 3 2010P. Bonazzola Abstract Aim:, Cardiac basal metabolism upon extracellular calcium removal and its relationship with intracellular sodium and calcium homeostasis was evaluated. Methods:, A mechano-calorimetric technique was used that allowed the simultaneous and continuous measurement of both heat rate and resting pressure in arterially perfused quiescent adult rat hearts. Using pharmacological tools, the possible underlying mechanisms related to sodium and calcium movements were investigated. Results:, Resting heat rate (expressed in mW g,1dry wt) increased upon calcium withdrawal (+4.4 ± 0.2). This response was: (1) unaffected by the presence of tetrodotoxin (+4.3 ± 0.6), (2) fully blocked by both, the decrease in extracellular sodium concentration and the increase in extracellular magnesium concentration, (3) partially blocked by the presence of either nifedipine (+2.8 ± 0.4), KB-R7943 (KBR; +2.5 ± 0.2), clonazepam (CLO; +3.1 ± 0.3) or EGTA (+1.9 ± 0.3). The steady heat rate under Ca2+ -free conditions was partially reduced by the addition of Ru360 (,1.1 ± 0.2) but not CLO in the presence of EGTA, KBR or Ru360. Conclusion:, Energy expenditure for resting state maintenance upon calcium withdrawal depends on the intracellular rise in both sodium and calcium. Our data are consistent with a mitochondrial Ca2+ cycling, not detectable under normal calcium diastolic levels. The experimental condition here analysed, partially simulates findings reported under certain pathological situations including heart failure in which mildly increased levels of both diastolic sodium and calcium have also been found. Therefore, under such pathological conditions, hearts should distract chemical energy to fuel processes associated with sodium and calcium handling, making more expensive the maintenance of their functions. [source] Development of an inhibitory antibody fragment to human tissue factor using phage display technologyDRUG DEVELOPMENT RESEARCH, Issue 3 2009S.M. Meiring Abstract Tissue factor is involved in the etiology of thrombotic diseases initiating the thrombosis associated with the inflammation that occurs during infection. The prevention of blood coagulation and inflammation is of primary importance in a number of pathological situations. A single-chain variable antibody fragment of molecular weight of 26,kD that inhibits the action of human tissue factor was selected by phage display technology, purified and tested for its tissue factor inhibitory effect, purified on a protein A column, and its purity evaluated on SDS-PAGE. The effects of the antibody fragment on prothrombin times, Factor Xa production, and thrombin generation were assessed with increasing fragment concentrations, using chromogenic and fluorometric substrates. The antibody fragment dose-dependently prolonged the prothrombin time (IC50=0.5,,M) and delayed the lag phase before the thrombin generation burst and the peak thrombin concentration in the thrombin generation assay. The effect on thrombin generation was more pronounced in thrombophilic plasma than in normal plasma. Antibody-based tissue factor inhibitors therefore may provide an effective treatment for thrombotic disease without serious bleeding complications. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc. [source] Myeloid-derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Vincenzo Bronte Abstract Although originally described in tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) have been detected under numerous pathological situations that cause enhanced demand of myeloid cells. Thus, MDSC might be part of a conserved response to different endogenous and exogenous stress signals, including inflammation. Two processes are fundamental for MDSC biology: differentiation from myeloid progenitors and full activation of their immune regulatory program by factors released from activated T cells or present in the microenvironment conditioned by either tumor growth or inflammation. How these two processes are controlled and linked is still an open question. In this issue of the European Journal of Immunology, a paper demonstrates that a combination of the known inflammatory molecules, IFN-, and LPS, sustains MDSC expansion and activation while suppressing differentiation of DC from bone marrow precursors. Moreover, this paper contributes to defining the cell subsets that possess immunoregulatory properties within the broad population of CD11b+Gr-1+ cells, often altogether referred to as MDSC. [source] Are Nonresorbing Osteoclasts Sources of Bone Anabolic Activity?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2007Morten A Karsdal PhD Abstract Some osteopetrotic mutations lead to low resorption, increased numbers of osteoclasts, and increased bone formation, whereas other osteopetrotic mutations lead to low resorption, low numbers of osteoclasts, and decreased bone formation. Elaborating on these findings, we discuss the possibility that osteoclasts are the source of anabolic signals for osteoblasts. In normal healthy individuals, bone formation is coupled to bone resorption in a tight equilibrium. When this delicate balance is disturbed, the net result is pathological situations, such as osteopetrosis or osteoporosis. Human osteopetrosis, caused by mutations in proteins involved in the acidification of the resorption lacuna (ClC-7 or the a3-V-ATPase), is characterized by decreased resorption in face of normal or even increased bone formation. Mouse mutations leading to ablation of osteoclasts (e.g., loss of macrophage-colony stimulating factor [M-CSF] or c- fos) lead to secondary negative effects on bone formation, in contrast to mutations where bone resorption is abrogated with sustained osteoclast numbers, such as the c-src mice. These data indicate a central role for osteoclasts, and not necessarily their resorptive activity, in the control of bone formation. In this review, we consider the balance between bone resorption and bone formation, reviewing novel data that have shown that this principle is more complex than originally thought. We highlight the distinct possibility that osteoclast function can be divided into two more or less separate functions, namely bone resorption and stimulation of bone formation. Finally, we describe the likely possibility that bone resorption can be attenuated pharmacologically without the undesirable reduction in bone formation. [source] Acidosis Impairs the Protective Role of hERG K+ Channels Against Premature StimulationJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2010B.Sc., CHUN YUN DU M.B. Acidosis and the hERG K+ Channel.,Introduction: Potassium channels encoded by human ether-à-go-go-related gene (hERG) underlie the cardiac rapid delayed rectifier K+ channel current (IKr). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including IKr. The aim of this study was to characterize effects of extracellular acidosis on hERG current (IhERG), with particular reference to quantifying effects on IhERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli. Methods and Results: IhERG recordings were made from hERG-expressing Chinese Hamster Ovary cells using whole-cell patch-clamp at 37°C. IhERG during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state IhERG activation were shifted by ,+6 mV; maximal IhERG conductance was reduced. The voltage-dependence of IhERG inactivation was little-altered. Fast and slow time-constants of IhERG deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time-course of recovery of IhERG from inactivation was observed, but time-course of activation was unaffected. The amplitude of outward IhERG transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3. Conclusion: During acidosis the contribution of IhERG to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1160-1169) [source] Glucose metabolism and proliferation in glia: role of astrocytic gap junctionsJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Arantxa Tabernero Abstract Astrocytes play a well-established role in brain metabolism, being a key element in the capture of energetic compounds from the circulation and in their delivery to active neurons. Their metabolic status is affected in many pathological situations, such as gliomas, which are the most common brain tumors. This proliferative dysfunction is associated with changes in gap junctional communication, a property strongly developed in normal astrocytes studied both in vitro and in vivo. Here, we summarize and discuss the findings that have lead to the identification of a link between gap junctions, glucose uptake, and proliferation. Indeed, the inhibition of gap junctional communication is associated with an increase in glucose uptake due to a rapid change in the localization of both GLUT-1 and type I hexokinase. This effect persists due to the up-regulation of GLUT-1 and type I hexokinase and to the induction of GLUT-3 and type II hexokinase. In addition, cyclins D1 and D3 have been found to act as sensors of the inhibition of gap junctions and have been proposed to play the role of mediators in the mitogenic effect observed. Conversely, in C6 glioma cells, characterized by a low level of intercellular communication, an increase in gap junctional communication reduces glucose uptake by releasing type I and type II hexokinases from the mitochondria and decreases the exacerbated rate of proliferation due to the up-regulation of the Cdk inhibitors p21 and p27. Identification of the molecular actors involved in these pathways should allow the determination of potential therapeutic targets that could lead to the testing of alternative strategies to prevent, or at least slow down, the proliferation of glioma cells. [source] Antiplatelet Effect of Marchantinquinone, Isolated from Reboulia hemisphaerica, in Rabbit Washed PlateletsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2000CHANG-HUI LIAO Platelet activation is involved in serious pathological situations, including atherosclerosis and restenosis. It is important to find efficient antiplatelet medicines to prevent fatal thrombous formation during the course of these diseases. Marchantinquinone, a natural compound isolated from Reboulia hemisphaerica, inhibited platelet aggregation and ATP release stimulated by thrombin (0.1 units mL,1), platelet-activating factor (PAF; 2 ng mL,1), collagen (10 ,g mL,1), arachidonic acid (100 ,m), or U46619 (1 ,m) in rabbit washed platelets. The IC50 values of marchantinquinone on the inhibition of platelet aggregation induced by these five agonists were 62.0 ± 9.0, 86.0 ± 7.8, 13.6 ± 4.7, 20.9 ± 3.1 and 13.4 ± 5.3 ,m, respectively. Marchantinquinone inhibited thromboxane B2 (TxB2) formation induced by thrombin, PAF or collagen. However, marchantinquinone did not inhibit TxB2 formation induced by arachidonic acid, indicating that marchantinquinone did not affect the activity of cyclooxygenase and thromboxane synthase. Marchantinquinone did inhibit the rising intracellular Ca2+ concentration stimulated by the five platelet-aggregation inducers. The formation of inositol monophosphate induced by thrombin was inhibited by marchantinquinone. Platelet cAMP and cGMP levels were unchanged by marchantinquinone. The results indicate that marchantinquinone exerts antiplatelet effects by inhibiting phosphoinositide turnover. [source] Bicuculline-induced brain activation in mice detected by functional magnetic resonance imagingMAGNETIC RESONANCE IN MEDICINE, Issue 2 2001Thomas Mueggler Abstract Dynamic measurements of local changes in relative cerebral blood volume (CBVrel) during a pharmacological stimulation paradigm were performed in mice. Using magnetite nanoparticles as an intravascular contrast agent, high-resolution CBVrel maps were obtained. Intravenous administration of the GABAA antagonist bicuculline prompted increases in local CBVrel as assessed by MRI with a high spatial resolution of 0.2 × 0.2 mm2 and a temporal resolution of 21 s. Signal changes occurred 20,30 s after the onset of drug infusion in the somatosensory and motor cortex, followed by other cortical and subcortical structures. The magnitudes of the CBVrel increases were 18% ± 4%, 46% ± 14%, and 67% ± 7%, as compared to prestimulation values for the cortex, and 9% ± 3%, 25% ± 4%, and 36% ± 7% for the caudate putamen for bicuculline doses of 0.6, 1.25, and 1.5 mg/kg, respectively. On-line monitoring of transcutaneous carbon dioxide tension PtcCO2 reflecting arterial PaCO2 did not show any alteration during the stimulation paradigm. One of five of the mice receiving the highest bicuculline dose, and three of seven receiving the intermediate dose displayed a different cortical response pattern. After a CBVrel increase of 40% lasting for approximately 1 min, significant CBVrelreductions by 80% have been observed. Subcortical structures did not display this behavior. The present study suggests that this noninvasive approach of functional MRI (fMRI) can be applied to study drug-induced brain activation by central nervous system (CNS) drugs in mice under normal and pathological situations. Magn Reson Med 46:292,298, 2001. © 2001 Wiley-Liss, Inc. [source] Review: Autophagy in neurodegeneration: firefighter and/or incendiarist?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2009A. Rami Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membrane autophagosomes, which subsequently fuse with lysosomes where their contents are degraded. This system has been implicated in various physiological processes including protein and organelle turnover, stress response, cellular differentiation, programmed cell death and pathological conditions. Defects in the autophagy machinery might have several consequences, as they have been associated with neurodegenerative disease and different forms of cancer. Thus, autophagy occupies a crucial position within the cell's metabolism, and its modulation may represent an alternative therapeutic strategy in several pathological settings including stroke, Alzheimer's, Huntington's, Parkinson's diseases and cancer. Recently, research has begun to identify some characteristics of neuronal autophagy. The results suggest that autophagy may provide a neuroprotective mechanism. However, there is evidence showing that dysfunction of autophagy in certain pathological situations can trigger and mediate programmed cell death. Autophagy has also been defined as prime suspect cause of non-apoptotic cellular demise. However, there is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell death and cell survival. It will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death programme and thus contribute to cell death. Many questions are open. Is autophagy a direct death execution pathway? Is autophagy an innocent bystander? Is autophagy a defence mechanism or just a scavenger or self-clearance tool in the cell? A profound understanding of the biological effects and the mechanisms underlying autophagy in neurones might be helpful in seeking effective new treatments for neurodegenerative diseases. Here, we review the defining characteristics of autophagy with special attention to its role in neurodegenerative disorders, and recent efforts to delineate the pathway of autophagic protein degradation in neurone. [source] The case for a central nervous system (CNS) origin for the Schwann cells that remyelinate CNS axons following concurrent loss of oligodendrocytes and astrocytesNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2005W. F. Blakemore In certain experimental and naturally occurring pathological situations in the central nervous system (CNS), demyelinated axons are remyelinated by Schwann cells. It has always been assumed that these Schwann cells are derived from Schwann cells associated with peripheral nerves. However, it has become apparent that CNS precursors can give rise to Schwann cells in vitro and following transplantation into astrocyte-free areas of demyelination in vivo. This paper compares the behaviour of remyelinating Schwann cells following transplantation of peripheral nerve derived Schwann cells over, and into, astrocyte-depleted areas of demyelination to that which follows transplantation of CNS cells and that seen in normally remyelinating ethidium bromide induced demyelinating lesions. It concludes that while the examination of normally remyelinating lesions can not resolve the origin of the remyelinating Schwann cells, the results from transplantation studies provide strong evidence that the Schwann cells that remyelinate CNS axons are most likely generated from CNS precursors. In addition these studies also indicate that the precursors that give rise to these Schwann cells are the same cells that give rise to remyelinating oligodendrocytes. [source] Proteomic profiling of exosomes: Current perspectivesPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 19 2008Richard J. Simpson Professor Abstract Exosomes are 40,100,nm membrane vesicles of endocytic origin secreted by most cell types in vitro. Recent studies have shown that exosomes are also found in vivo in body fluids such as blood, urine, amniotic fluid, malignant ascites, bronchoalveolar lavage fluid, synovial fluid, and breast milk. While the biological function of exosomes is still unclear, they can mediate communication between cells, facilitating processes such as antigen presentation and in trans signaling to neighboring cells. Exosome-like vesicles identified in Drosophila (referred to as argosomes) may be potential vehicles for the spread of morphogens in epithelia. The advent of current MS-based proteomic technologies has contributed significantly to our understanding of the molecular composition of exosomes. In addition to a common set of membrane and cytosolic proteins, it is becoming increasingly apparent that exosomes harbor distinct subsets of proteins that may be linked to cell-type associated functions. The secretion of exosomes by tumor cells and their implication in the transport and propagation of infectious cargo such as prions and retroviruses such as HIV suggest their participation in pathological situations. Interestingly, the recent observation that exosomes contain both mRNA and microRNA, which can be transferred to another cell, and be functional in that new environment, is an exciting new development in the unraveling exosome saga. The present review aims to summarize the physical properties that define exosomes as specific cell-type secreted membrane vesicles. [source] Pregnancy as a Model of Controlled Invasion Might Be Attributed to the Ratio of CD3/CD8 to CD56AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2000P.C. ARCK PROBLEM: Pregnancy can be considered as a model of successfully controlled tissue invasion. Cellular mediated immunity appears to regulate the controlled invasion of fetal trophoblast cells. In endometrium cancer, a dysregulation of invasive malignant cells can be observed. Since immuncompetent cells are known to be involved in recognition and rejection of ,non-self' antigens, we investigated the presence and distribution pattern of CD3, CD8, CD56, and CD68 positive cells in decidua from normal and failing pregancies, compared with malignant and benign endometrium. METHOD OF STUDY: Decidual tissue from first trimester normal pregancies (NP; n=15) and abortion (AB; n=12), endometrial samples from premenopausal women (NE; n=8), and endometrioid adenocarcinoma (EA; n=8) were examined by immunohistochemistry using monoclonal antibody against large spectrum cytokeratin, and against the receptors CD3, CD8, CD56 and CD68, respectively. RESULTS: In NP, we observed 32.5% CD3, 44.7% CD56, and 22.9% CD68+ cells. In AB, we found 36.9% CD3, 45.3% CD56, and 17.8% CD68+ cells. The differences in ratio between normal pregnancy and abortion were not statistically significant. In NE, we counted 39.5% CD3, 30.2% CD56 and 30.2% CD68+ cells. In EA, we observed 47.9% CD3, 12.4% CD56 and 39.7% CD68+ cells. The decrease of CD56 positive cells in endometrioid adenocarcinoma was statistically significant. Interestingly, we found 4.1% of cells positive for CD8 in NP, 4.9% in AB, 22.7% in NE, and 48.2% in EA. CONCLUSIONS: The increase of CD8 cells in NE, and particularely in EA, and decrease of CD56 cells, compared with NP or AB, suggests an interaction between CD8 cells and CD56 cells. Studying different pathological situations in the uterus, such as malignancies or ectopic pregnancies, might help us to understand the mechanisms involved in the maintenance of pregnancy. [source] Intermittent hypobaric hypoxia-induced oxidative stress in rat erythrocytes: protective effects of vitamin E, vitamin C, and carnitineCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2007S. Asha Devi Abstract This study was aimed at determining the effect of vitamin E, vitamin C, and carnitine on intermittent hypobaric-hypoxia-induced oxidative stress (OS) in erythrocytes. For this purpose, male Wistar rats of 4 months of age were orally supplemented with one of the antioxidants prior to exposure to altitudes of 5700,m or 6300,m. Hemoglobin (Hb) and OS indices such as osmotic fragility and hemolysis were measured together with lipid peroxidation (LPO) and protein oxidation. The increase in Hb was accompanied by increase in activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) during exposure to both the altitudes without any further elevation by supplements. The extent of reduction in osmotic fragility and hemolysis by vitamin E and carnitine was greater at 6300,m than at 5700,m. Increase in LPO products, for example, malondialdehyde (MDA) and lipofuscin-like autofluorescent substances (AFS) was noticeable at both the altitudes, and vitamin E and carnitine were effective in reducing LPO. While protein oxidation products such as carbonyl content (PrC) and advanced oxidation protein products (AOPP) increased at 6300,m, protein sulphydryl (P-SH) content decreased. P-SH levels were restored on supplementation of antioxidants. Hence, our results indicate that vitamin E, vitamin C, and carnitine may be beneficial in overcoming OS and hemolysis under situations such as intermittent hypobaric hypoxia (IHH) and hypobarotherapy wherein hypoxia is used to correct many pathological situations in humans. Further, this study suggests that supplementation of vitamin E, vitamin C, and L -carnitine alone and not in combination can be beneficial in attenuating the OS associated with IHH compared to the unsupplemented rats exposed to two different altitudes. Copyright © 2006 John Wiley & Sons, Ltd. [source] | |||||||||||||