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Underlying Mechanisms (underlying + mechanism)
Kinds of Underlying Mechanisms Selected Abstracts[Commentary] EARLY PUBERTAL MATURATION AND DRUG USE: UNDERLYING MECHANISMSADDICTION, Issue 1 2009RUTGER C. M. E. ENGELS No abstract is available for this article. [source] Attention Deficit Hyperactivity Disorder: Current Concepts and Underlying MechanismsJOURNAL OF CHILD AND ADOLESCENT PSYCHIATRIC NURSING, Issue 3 2000Brenda J. Wagner PhD TOPIC. Neuropsychological concentration of attention deficit hyperactivity disorder (ADHD). PURPOSE. Survey of current understanding of underlying neural systems and pathways involved in ADHD and the relationship to specific behavioral patterns. SOURCES. Literature review, author's experience in neuropsychological assessment and clinical treatment. CONCLUSIONS. Clinicians will be able to specify treat men t interventions designed to compensate for specific behavioral patterns and functional deficits. [source] Mesenteric Complications After Hypothermic Cardiopulmonary Bypass with Cardiac Arrest: Underlying MechanismsARTIFICIAL ORGANS, Issue 11 2002Terézia Bogdana Andrási Abstract: The aim of this study was to determine the pathophysiological mechanisms of postcardiopulmonary bypass (CPB) intestinal dysfunction using an in vivo canine model of extracorporeal circulation. Six dogs underwent a 90 min hypothermic CPB with continuous monitoring of mean arterial blood pressure (MAP) and mesenteric blood flow (MBF). Reactive hyperemia and vasodilator responses of the superior mesenteric artery to acetylcholine and sodium nitroprusside were determined before and after CPB. Mesenteric lactate production, glucose consumption, creatine kinase (CK) release and venous free radicals were determined. CPB induced a significant fall (p < 0.05) in MAP and MBF. After CPB, reactive hyperemia (,26 ± 15% versus ,53 ± 2%, p < 0.05) and the response to acetylcholine (,42 ± 9 versus ,55 ± 6%, p < 0.05) were significantly decreased. Reperfusion increased lactate production (0.8 ± 0.09 mmol/L versus 0.4 ± 0.18, p < 0.05) and the CK release (446 ± 98 U/L versus 5 ± 19 U/L, p < 0.01). Endothelial dysfunction, conversion from aerobic to anaerobic metabolism, and intestinal cell necrosis seem to be responsible for intestinal complications associated with CPB. [source] Underlying mechanism of portal hypertensive gastropathy in cirrhosis: A hemodynamic and morphological approachJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2009Lílian Amorim Curvęlo Abstract Background and Aim:, Portal hypertensive gastropathy (PHG) is an important cause of bleeding in patients with cirrhosis associated with portal hypertension. Histologically, the condition is characterized by dilation of the mucosal and submucosal vessels of the stomach; however, its mechanisms remain unclear. The aim of the present cross-sectional study was to evaluate the role of portal and systemic hemodynamic features, humoral factors and hepatocellular function in the development and severity of PHG in patients with cirrhosis. Methods:, Forty-six patients with cirrhosis of different etiologies underwent endoscopy. Portal hypertension was evaluated by hepatic venous pressure gradient (HVPG). The gastric mucosa was analyzed using two diagnostic methods: endoscopy according to the McCormack criteria and histological by histomorphometric analysis. Results:, The prevalence of PHG according to the endoscopic and histomorphometric methods was 93.4% and 76.1%, respectively. There were no statistically significant differences in HVPG measurements between the patients with mild (16.0 ± 5.9 mmHg) and severe PHG (16.9 ± 6.5 mmHg; P = 0.80) or between patients who did not have (15.2 ± 8.0 mmHg) and those who had PHG (16.3 ± 5.7 mmHg). No correlation was found between the presence or severity of PHG and systemic vascular resistance index (P = 0.53 and 0.34, respectively), Child,Pugh classification (P = 0.73 and 0.78, respectively) or glucagon levels (P = 0.59 and 0.62, respectively). Conclusions:, The present data show no correlation between the presence or the severity of PHG and portal pressure, Child,Pugh classification or systemic hemodynamics, suggesting that other factors may be involved in the physiopathology of PHG, such as local gastric mucosal factors or other underlying factors. [source] Increased metastatic potential of tumor cells in von Willebrand factor-deficient miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2006V. TERRAUBE Summary.,Background:,The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet,tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis.Objectives:,To investigate whether VWF is involved in metastasis development.Methods:,In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells.Results:,In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis.Conclusion:,These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated. [source] The decrease in electrically evoked force production is delayed by a previous bout of stretch,shortening cycle exerciseACTA PHYSIOLOGICA, Issue 1 2010S. Kamandulis Abstract Aim:, Unaccustomed physical exercise with a large eccentric component is accompanied by muscle damage and impaired contractile function, especially at low stimulation frequencies. A repeated bout of eccentric exercise results in less damage and improved recovery of contractile function. Here we test the hypotheses that (1) a prior stretch,shortening cycle (SSC) exercise protects against impaired muscle function during a subsequent bout of SSC exercise and (2) the protection during exercise is transient and becomes less effective as the exercise progresses. Methods:, Healthy untrained men (n = 7) performed SSC exercise consisting of 100 maximal drop jumps at 30 s intervals. The same exercise was repeated 4 weeks later. Peak quadriceps muscle force evoked by electrical stimulation at 15 (P15) and 50 (P50) Hz was measured before exercise, after 10, 25, 50 and 100 jumps as well as 1 and 24 h after exercise. Results:, P15 and P50 were higher during the initial phase of the repeated bout compared with the first exercise bout, but there was no difference between the bouts at the end of the exercise periods. P15 and P50 were again larger 24 h after the repeated bout. The P15/P50 ratio during exercise was not different between the two bouts, but it was higher after the repeated bout. Conclusion:, A prior bout of SSC exercise temporarily protects against impaired contractile function during a repeated exercise bout. The protection can again be seen after exercise, but the underlying mechanism then seems to be different. [source] Vacuolar H+ -ATPase expression is increased in acid-secreting intercalated cells in kidneys of rats with hypercalcaemia-induced alkalosisACTA PHYSIOLOGICA, Issue 4 2007W. Wang Abstract Aims:, Hypercalcaemia is known to be associated with systemic metabolic alkalosis, although the underlying mechanism is uncertain. Therefore, we aimed to examine whether hypercalcaemia was associated with changes in the expression of acid,base transporters in the kidney. Methods:, Rats were infused with human parathyroid hormone (PTH, 15 ,g kg,1 day,1), or vehicle for 48 h using osmotic minipumps. Results:, The rats treated with PTH developed hypercalcaemia and exhibited metabolic alkalosis (arterial HCO: 31.1 ± 0.8 vs. 28.1 ± 0.8 mmol L,1 in controls, P < 0.05, n = 6), whereas the urine pH of 6.85 ± 0.1 was significantly decreased compared with the pH of 7.38 ± 0.1 in controls (P < 0.05, n = 12). The observed alkalosis was associated with a significantly increased expression of the B1-subunit of the H+ -ATPase in kidney inner medulla (IM, 233 ± 45% of the control level). In contrast, electroneutral Na+ -HCO cotransporter NBCn1 and Cl,/HCO anion exchanger AE2 expression was markedly reduced in the inner stripe of the outer medulla (to 26 ± 9% and 65 ± 6%, respectively). These findings were verified by immunohistochemistry. Conclusions:, (1) hypercalcaemia-induced metabolic alkalosis was associated with increased urinary excretion of H+; (2) the increased H+ -ATPase expression in IM may partly explain the enhanced urinary acidification, which is speculated to prevent stone formation because of hypercalciuria and (3) the decreased expression of outer medullary AE2 suggests a compensatory reduction of the transepithelial bicarbonate transport. [source] Extrinsic factors derived from mouse embryonal carcinoma cell lines maintain pluripotency of mouse embryonic stem cells through a novel signal pathwayDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 2 2009Shinjirou Kawazoe Embryonic carcinoma (EC) cells, which are malignant stem cells of teratocarcinoma, have numerous morphological and biochemical properties in common with pluripotent stem cells such as embryonic stem (ES) cells. However, three EC cell lines (F9, P19 and PCC3) show different developmental potential and self-renewal capacity from those of ES cells. All three EC cell lines maintain self-renewal capacity in serum containing medium without Leukemia Inhibitory factor (LIF) or feeder layer, and show limited differentiation capacity into restricted lineage and cell types. To reveal the underlying mechanism of these characteristics, we took the approach of characterizing extrinsic factors derived from EC cells on the self-renewal capacity and pluripotency of mouse ES cells. Here we demonstrate that EC cell lines F9 and P19 produce factor(s) maintaining the undifferentiated state of mouse ES cells via an unidentified signal pathway, while P19 and PCC3 cells produce self-renewal factors of ES cells other than LIF that were able to activate the STAT3 signal; however, inhibition of STAT3 activation with Janus kinase inhibitor shows only partial impairment on the maintenance of the undifferentiated state of ES cells. Thus, these factors present in EC cells-derived conditioned medium may be responsible for the self-renewal capacity of EC and ES cells independently of LIF signaling. [source] Pigment cell distributions in different tissues of the zebrafish, with special reference to the striped pigment patternDEVELOPMENTAL DYNAMICS, Issue 2 2005Masashi Hirata Abstract The orderly pigment pattern of zebrafish (Danio rerio) is a good model system for studying how spatial patterns form in animals. Recent molecular genetic studies have shown that interactions between the pigment cells play major roles in pattern formation. In the present study, we performed comparative transmission electron microscopy of pigment cells, in order to clarify the structural interactions of pigment cells in tissues with and without a striped pattern. In patterned tissues, pigment cells were distributed as a one-cell-thick sheet. The layer order of the sheets is always kept strictly. In tissues without a striped pattern, the layer order was often disturbed or the cells were distributed in a scattered, double-sheeted, or an accumulated pile. Our observations suggest that the underlying mechanism that controls the vertical order of the pigment cells is related to that controlling the stripe pattern. Developmental Dynamics 234:293,300, 2005. © 2005 Wiley-Liss, Inc. [source] Dual mechanisms governing muscle cell death in tadpole tail during amphibian metamorphosisDEVELOPMENTAL DYNAMICS, Issue 2 2003Keisuke Nakajima Abstract The tadpole tail, which is twice as long as the body, is induced to resorb completely by thyroid hormone within several days during the anuran metamorphosis. To investigate the underlying mechanism, we undertook two approaches. First, we examined the effect of dominant-negative thyroid hormone receptor (DNTR) on muscle cell death in vitro. The overexpression of DNTR suppressed the death of a tail-derived myoblastic cell line induced by thyroid hormone. Second, tadpole tails were injected with a reporter gene and the DNTR expression construct, and the reporter gene expression in muscle cells was followed during the spontaneous metamorphosis. DNTR overexpression inhibited a decrease of the reporter gene expression that began at stage 57 in the control tadpoles but only delayed massive muscle cell death at stage 63 when tails shrink very rapidly. Some remained even a few weeks after the metamorphosis, although most DNTR-overexpressing cells died by the end of the metamorphosis. These results led us to propose that thyroid hormone induces the suicide of muscle cells (the cell-autonomous death) in the tail between stage 57 and 62 and that both the murder and suicide mechanisms execute muscle cell death in stage 62,64 to remove muscle promptly and completely. Developmental Dynamics 227:246,255, 2003. © 2003 Wiley-Liss, Inc. [source] Temporal association between food distribution and human caregiver presence and the development of affinity to humans in lambsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 2 2008Céline Tallet Abstract The presence of the caregiver around feeding favors the development of a human,animal relationship. To understand the underlying mechanism, we tested various temporal associations between food distribution and human presence: from an early age, a person was repeatedly present for 2 min just before milk distribution ("Forward"), during milk distribution ("Simultaneous"), and 20 min afterwards ("Delayed"). The "Control" group received no human contacts. During the treatments, "Forward" and "Delayed" lambs had more physical contacts with the person than "Simultaneous" lambs. When tested in unfamiliar environments, they stood longer near the person than did "Control" or "Simultaneous" lambs, which did not differ. Only "Forward" and "Delayed" lambs bleated when separated from the person. Fasting before testing had no effect. "Forward" and "Delayed" seemed to produce the same human,animal relationship, showing that this did not rely only on a conditioning process associating the caregiver with food. The caregiver may acquire properties for social support through other mechanisms (attachment and/or postingestive effects). © 2008 Wiley Periodicals, Inc. Dev Psychobiol 50: 147,159, 2008. [source] Effects of neonatal handling and maternal separation on rough-and-tumble play in the ratDEVELOPMENTAL PSYCHOBIOLOGY, Issue 3 2002Jennifer L. Arnold Abstract The extent to which brief daily handling and longer periods of separation from the mother during the first 2 weeks of life can affect play behavior in juvenile rats was assessed. Rat pups were separated from the mother for either 15 min daily (handling) or for 3 hr daily (maternal separation), and play was observed as juveniles. Overall levels of playfulness were not affected by either manipulation, although certain aspects of playful responsiveness were affected in males, but not females. In particular, the pattern of responsiveness to playful contacts was feminized in both handled and separated male rats. Activity in a novel open field at 15 days of age was increased in both males and females from the separated group, but not in the handled animals, as were the number of rears exhibited during the play bouts. These data suggest that early rearing experiences can have subtle gender-dependent effects on some aspects of play in juvenile rats and that the underlying mechanism(s) responsible for these effects may differ from those associated with other effects reported for handling and maternal separation. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 41: 205,215, 2002. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.10069 [source] A link between endoplasmic reticulum stress-induced , -cell apoptosis and the group VIA Ca2+ -independent phospholipase A2 (iPLA2,)DIABETES OBESITY & METABOLISM, Issue 2010X. Lei Endoplasmic reticulum (ER) stress is becoming recognized as an important contributing factor in various diseases, including diabetes mellitus. Prolonged ER stress can cause , -cell apoptosis; however, the underlying mechanism(s) that contribute to this process are not well understood. Early reports suggested that arachidonic acid metabolites and a Ca2+ -independent phospholipase A2 (iPLA2) activity play a role in , -cell apoptosis. The PLA2 family of enzymes catalyse the hydrolysis of the sn -2 substituent (i.e. arachidonic acid) of membrane phospholipids. In light of our findings that the pancreatic islet , -cells are enriched in arachidonate-containing phospholipids and express the group VIA iPLA2,, we considered the possibility that iPLA2, participates in ER stress-induced , -cell apoptosis. Our work revealed a novel mechanism, involving ceramide generation and triggering of mitochondrial abnormalities, by which iPLA2, participates in the , -cell apoptosis process. Here, we review our evidence linking ER stress, , -cell apoptosis and iPLA2,. Continued studies in this area will increase our understanding of the contribution of iPLA2, to the evolution of diabetes mellitus and will further our knowledge of factors that influence , -cell health in diabetes mellitus and identify potential targets for future therapeutic interventions to prevent , -cell death. [source] Cerebral cortical laminar necrosis on diffusion-weighted MRI in hypoglycaemic encephalopathyDIABETIC MEDICINE, Issue 8 2005Y. Yoneda Abstract Background Laminar necrosis of the cerebral cortex characterized neuropathologically by delayed selective neuronal necrosis occurs in hypoglycaemic encephalopathy and other brain diseases. Case report A 37-year-old male with insulin-treated Type 1 diabetes mellitus developed hypoglycaemic encephalopathy associated with respiratory failure. Brain diffusion-weighted MRI during the subacute period demonstrated high signals along the cerebral cortex. Brain single-photon emission computed tomography showed diffuse, severe cerebral hypoperfusion. The patient remained comatose and died 1 month later. Conclusions High signals along the cortical bands on diffusion-weighted MRI suggest cortical laminar necrosis, although a postmortem examination was unavailable. Sustained hypoglycaemic brain injury, possibly associated with respiratory hypoxia, may be the underlying mechanism. [source] Effects of labedipinedilol-A, third-generation dihydropyridine-type calcium blocker, on ouabain-induced arrhythmiaDRUG DEVELOPMENT RESEARCH, Issue 1 2008Jhy-Chong Liang Abstract Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist with ,/,-adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol-A on ouabain-induced tonotropy and arrhythmias in isolated whole atria, and using patch-clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol-A (10,µM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extra-systole (arrhythmia) induced by ouabain in isolate atria. In the voltage-clamp study, labedipinedilol-A (1,100,µM) reduced the peak amplitude of sodium inward current (INa) and L-type calcium current (ICa-L), and shifted the current-voltage (I-V) curve upward in a concentration-dependent manner. In contrast, the addition of labedipinedilol-A increased transient outward potassium current (Ito) and inward rectifier potassium current (IK1) significantly. Labedipinedilol-A (10,µM) also effectively depressed the isoproterenol-induced increase in the Ca2+ current. These results show that labedipinedilol-A blocks ICa-L and INa, and increases Ito and IK1. These findings indicate that labedipinedilol-A produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that labedipinedilol-A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia. Drug Dev Res 69:26,33, 2008 © 2008 Wiley-Liss, Inc. [source] Functional and molecular evidence of adenosine A2A receptor in coronary arteriolar dilation to adenosineDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Lih Kuo Abstract Adenosine is a potent vasodilator implicated in the regulation of coronary microvascular diameter during metabolic stress. However, the specific adenosine receptors and underlying mechanism responsible for the dilation of coronary microvessels to adenosine remains to be elucidated. Thus, pig subepicardial coronary arterioles (<100 ,m) were isolated, cannulated, and pressurized without flow for in vitro study. All vessels developed basal tone and dilated concentration-dependently to adenosine. Disruption of endothelium and inhibition of nitric oxide (NO) synthase by L-NAME produced identical attenuation of adenosine-induced dilation. KATP channel inhibitor glibenclamide further reduced the dilation of denuded vessels. cAMP antagonist Rp-8-Br-cAMP blocked vasodilation to forskolin, but failed to inhibit vasodilation to adenosine. Coronary dilation to adenosine was blocked by a selective adenosine A2A receptor antagonist ZM241385, but was not altered by an A1 receptor antagonist, DPCPX. Reverse transcription-polymerase chain reaction study revealed that A2A receptor mRNA was expressed in microvessels but not in cardiac myocytes; A1 receptor expression was observed only in cardiac myocytes. These results suggest that adenosine-induced dilation of coronary arterioles is mediated predominantly by A2A receptors. Activation of these receptors elicits vasodilation by endothelial release of NO and by smooth muscle opening of KATP channels in a cAMP-independent manner. Drug Dev. Res. 52:350,356, 2001. © 2001 Wiley-Liss, Inc. [source] Reference Values Describing the Normal Mitral Valve and the Position of the Papillary MusclesECHOCARDIOGRAPHY, Issue 7 2007Petrus Nordblom M.Sc. In patients with functional mitral regurgitation (MR), the principal mechanisms are insufficient coaptation due to dilatation of the mitral annulus (MA), global ventricular dysfunction with tethering of leaflets, or restricted leaflet motion with incorrect apposition due to regional ventricular dysfunction and displacement of the papillary muscles (PMs). These different entities often coexist and for this reason, knowledge of the normal reference values describing the shape and size of the MA and the position of the PMs is essential. In the present study, we describe the MA dimensions and the position of the PMs in a group of normal individuals (n = 38, 60% women, age [mean ± SD] 51 ± 9 years and BSA 1.83 ± 0.16 m2) investigated with transthoracic echocardiography. The anteroposterior dimension (AP) of the ellipse-shaped MA was measured in a parasternal long axis, while the distance from the posteromedial (PoM) to the anterolateral (AL) commissure was measured in a parasternal short axis (CC). The annular area was calculated assuming elliptic geometry. The MA shape was described by the ratios AP/CC and AP/length of the anterior leaflet. The PMs' position was described by the following distances: (a) from the MA to the tip of the PoM and AL, PMs measured in a modified two-chamber view where both PMs could be identified, (b) the interpapillary distance, and (c) the tethering distance from the tip of the PM to the contralateral MA. These data on the normal mitral valve morphology should provide useful information when assessing the underlying mechanism of functional MR. [source] Disruption effects of monophthalate exposures on inter-Sertoli tight junction in a two-compartment culture modelENVIRONMENTAL TOXICOLOGY, Issue 3 2008Yun-Hui Zhang Abstract Phthalates are suspect environmental endocrine disruptors that may affect male reproduction and development by disturbing androgen synthesis and cell,cell interactions in the seminiferous epithelium. The in vivo metabolites, monophthalates, are thought to be the active agents, and toxicant effects including testicular damage and decreased sperm motility have been described previously. In this study, the aim was to investigate the effect of monophthalates on Sertoli cells using a two-compartment cell culture model, asking whether tight junction protein structures are affected, compromising the blood-testis barrier and contributing to male-mediated toxicity. Sertoli cells were isolated from Sprague Dawley rat testes and seeded onto the filters of two-compartment wells. A Sertoli cell monolayer was allowed to form, whereupon the cultures were treated with 0, 10, 30, 150, and 600 ,mol/L monobutyl phthalate (MBP) or mono-2-ethylhexyl phthalate (MEHP) for 24 h. Effects on the tight junctions between adjacent Sertoli cells were studied by light and transmission electron microscopy, the transepithelial electrical resistance (TEER) assay, and immunofluorescence localization. Results showed that exposures to monophthalates destroyed tight junctional structure in Sertoli cell monolayers in a dose-depended manner, as evidenced by a loss of single-cell layer organization in the cultures, decline of TEER value, and decreased expression of proteins associated with tight junctions such as zonula occludens-1 (ZO-1), F-actin, and Occludin. The changes were observed at doses of 150 and 600 ,mol/L, which is 10,100 times higher relative to estimated human exposures from the environment. These results are consistent with monophthalate-induced damage to tight junctions between adjacent Sertoli cells, suggesting that damage to Sertoli cell tight junctions induced by monophthalates may be an underlying mechanism of their male-mediated reproductive toxicity. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008. [source] Response of the charophyte Nitellopsis obtusa to heavy metals at the cellular, cell membrane, and enzyme levelsENVIRONMENTAL TOXICOLOGY, Issue 3 2002Levonas Manusad, ianas Abstract The responses of the freshwater macroalga Nitellopsis obtusa to heavy metal (HM) salts of Hg, Cd, Co, Cu, Cr, and Ni were assessed at different levels: whole-cell mortality (96-h LC50), in vivo cell membrane (45-min depolarization of resting potential, EC50), and enzyme in plasma membrane preparations (K+, Mg2+ -specific H+ -ATPase inhibition, IC50). To measure ATPase activity, a novel procedure for isolation of plasma membrane,enriched vesicles from charophyte cells was developed. The short-term ATPase inhibition assay (IC50 from 6.0 × 10,7 to 4.6 × 10,4 M) was slightly more sensitive than the cell mortality test (LC50 from 1.1 × 10,6 to 2.6 × 10,3 M), and the electrophysiological test with the end point of 45-min depolarization of resting potential was characterized by less sensitivity for HMs (EC50 from 1.1 × 10,4 to 2.2 × 10,2 M). The variability of IC50 values assessed for HMs in the ATPase assays was close to that of LC50 values in the mortality tests (CVs from 33.5 to 83.5 and from 12.4% to 57.7%, respectively), whereas the EC50 values in the electrophysiological tests were characterized by CVs generally below 30%. All three end points identified two separate HM groups according to their toxicity to N. obtusa: Co, Ni, and Cr comprised a group of less toxic metals, whereas Hg, Cu, and Cd comprised a group of more toxic metals. However, the adverse effects within each group were discriminated differently. For example, the maximum difference between the highest and lowest LC50 for the group of less toxic metals in the long-term mortality test was approximately 60% of the response range, whereas the corresponding difference in IC50 values in the ATPase assay was 30%. In contrast, the LC50 values of the more toxic metals occupied only 10% of the response range, whereas the IC50 values were spread over 70%. Further investigation should be done of the underlying mechanism or mechanisms responsible for the observed differences in the dynamic range of a particular end point of the groups of toxicants of varying strength. © 2002 Wiley Periodicals, Inc. Environ Toxicol 17: 275,283, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10058 [source] Electrical and Chemical Long-term Depression Do Not Attenuate Low-Mg2+,induced Epileptiform Activity in the Entorhinal CortexEPILEPSIA, Issue 4 2005Jörg Solger Summary:,Purpose: Low-frequency electrical and magnetic stimulation of cortical brain regions has been shown to reduce cortical excitability and to decrease the susceptibility to seizures in humans and in vivo models of epilepsy. The induction of long-term depression (LTD) or depotentiation of a seizure-related long-term potentiation has been proposed to be part of the underlying mechanism. With the low-Mg2+ -model of epilepsy, this study investigated the effect of electrical LTD, chemical LTD, and depotentiation on the susceptibility of the entorhinal cortex to epileptiform activity. Methods: The experiments were performed on isolated entorhinal cortex slices obtained from adult Wistar rats and mice. With extracellular recording techniques, we studied whether LTD induced by (a) three episodes of low-frequency paired-pulse stimulation (3 × 900 paired pulses at 1 Hz), and by (b) bath-applied N -methyl- d -aspartate (NMDA, 20 ,M) changes time-to-onset, duration, and frequency of seizure-like events (SLEs) induced by omitting MgSO4 from the artificial cerebrospinal fluid. Next we investigated the consequences of depotentiation on SLEs themselves by applying low-frequency stimulation after onset of low-Mg2+,induced epileptiform activity. Results: LTD, induced either by low-frequency stimulation or by bath-applied NMDA, had no effect on time-to-onset, duration, and frequency of SLEs compared with unconditioned slices. Low-frequency stimulation after onset of SLEs did not suppress but induced SLEs that lasted for the time of stimulation and were associated with a simultaneous increase of the extracellular K+ concentration. Conclusions: Our study demonstrates that neither conditioning LTD nor brief low-frequency stimulation decreases the susceptibility of the entorhinal cortex to low-Mg2+,induced epileptiform activity. The present study does not support the hypothesis that low-frequency brain stimulation exerts its anticonvulsant effect via the induction of LTD or depotentiation. [source] Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg TypeEPILEPSIA, Issue 8 2000Brien Smith Summary: Purpose: A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. Methods: After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. Results: VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. Conclusions: VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action. [source] Increased coronary sinus blood temperature: correlation with systemic inflammationEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2006K. Toutouzas Abstract Background, Recent studies have shown that patients with single vessel coronary artery disease (CAD) suffering from acute coronary syndromes (ACS) have increased coronary sinus (CS) blood temperature compared with the right atrium (RA). The aim of this study was to investigate whether there is a correlation between systemic inflammatory indexes and CS temperature and whether there is a difference in CS temperature between patients with single vs. multivessel disease. Materials and methods, We included consecutive patients scheduled for coronary angiography for recent-onset chest pain evaluation. We measured C-reactive protein (CRP) levels in the study population. Coronary sinus and RA blood temperature measurements were performed by a 7F thermography catheter. ,, was calculated by subtracting the RA from the CS blood temperature. Results, The study population comprised 53 patients with ACS, 25 patients with stable angina (SA) and 22 subjects without CAD (control group). ,, was greater in patients with ACS and with SA compared with the control group (0·22 ± 0·10 °C, 0·18 ± 0·04 °C vs. 0·14 ± 0·07 °C, P < 0·01 for both comparisons). The ACS group had greater ,, compared with the SA group, although the difference did not reach statistical significance (P = 0·09). Eighteen (39·1%) out of 46 patients with multivessel disease had three-vessel disease and 28 (60·8%) had two-vessel disease. ,, between patients with multivessel and single vessel disease was similar (0·22 ± 0·01 °C, 0·19 ± 0·01 °C, P = 0·17). The levels of CRP were well correlated with ,, (R = 0·35b, P < 0·01). Conclusions, Systemic inflammation is well correlated with CS temperature; thus, an inflammatory process could be the underlying mechanism for increased heat production from the myocardium. [source] Nramp1 -functionality increases iNOS expression via repression of IL-10 formationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2008Gernot Fritsche Abstract In mice, resistance to certain intracellular microbes depends on the expression of a late phagosomal protein termed natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1). Nramp1- functionality is associated with alterations of cellular iron homeostasis and a sustained pro-inflammatory immune response, including the formation of the antimicrobial effector molecule NO. To investigate the underlying mechanism we used RAW-264.7 murine macrophage cells stably transfected with a functional Nramp1 allele (RAW-37) or Nramp1 non-functional controls (RAW-21). We found that the production of and signalling by the anti-inflammatory cytokine IL-10 was significantly enhanced in macrophages lacking functional Nramp1. Upon infection of macrophages with Salmonella typhimurium pathogen survival was significantly better in RAW-21 than in RAW-37, which inversely correlated to NO and TNF-, formation. Addition of a neutralising anti-IL-10 antibody to RAW-21 cells led to a significantly reduced survival of S. typhimurium within these cells and enhanced formation of NO and TNF-, reaching levels comparable to that observed in cells bearing functional Nramp1. Oppositely, supplementation of iron to RAW-21 cells further increased IL-10 formation. Thus, Nramp1 mediates effective host defence in part via suppression of excessive IL-10 production which may relate to Nramp1- mediated reduction of cellular iron pools, thus strengthening antimicrobial effector mechanisms. [source] Asymmetrical lateral ventricular enlargement in Parkinson's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2009M. M. Lewis Background:, A recent case report suggested the presence of asymmetrical lateral ventricular enlargement associated with motor asymmetry in Parkinson's disease (PD). The current study explored these associations further. Methods:, Magnetic resonance imaging (3T) scans were obtained on 17 PD and 15 healthy control subjects at baseline and 12,43 months later. Baseline and longitudinal lateral ventricular volumetric changes were compared between contralateral and ipsilateral ventricles in PD subjects relative to symptom onset side and in controls relative to their dominant hand. Correlations between changes in ventricular volume and United Parkinson's disease rating scale motor scores (UPDRS-III) whilst on medication were determined. Results:, The lateral ventricle contralateral to symptom onset side displayed a faster rate of enlargement compared to the ipsilateral (P = 0.004) in PD subjects, with no such asymmetry detected (P = 0.312) in controls. There was a positive correlation between ventricular enlargement and worsening motor function assessed by UPDRS-III scores (r = 0.96, P < 0.001). Discussion:, There is asymmetrical lateral ventricular enlargement that is associated with PD motor asymmetry and progression. Further studies are warranted to investigate the underlying mechanism(s), as well as the potential of using volumetric measurements as a marker for PD progression. [source] Attenuated human auditory middle latency response and evoked 40-Hz response to self-initiated soundsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2009Pamela Baess Abstract For several modalities, it has been shown that the processing of sensory information generated by our own actions is attenuated relative to the processing of sensory information of externally generated stimuli. It has been proposed that the underlying mechanism builds predictions about the forthcoming sensory input and forwards them to the respective sensory processing levels. The present study investigated whether early auditory processing is suppressed by the top-down influences of such an internal forward model mechanism. To this end, we compared auditory middle latency responses (MLRs) and evoked 40-Hz responses elicited by self-initiated sounds with those elicited by externally initiated but otherwise identical sounds. In the self-initiated condition, the amplitudes of the Pa (27,33 ms relative to sound onset) and Nb (40,46 ms) components of the MLRs were significantly attenuated when compared to the responses elicited by click sounds presented in the externally initiated condition. Similarly, the evoked activity in the 40-Hz and adjacent frequency bands was attenuated. Considering that previous research revealed subcortical and auditory cortex contributions to MLRs and 40-Hz responses, our results support the existence of auditory suppression effects with self-initiated sounds on temporally and structurally early auditory processing levels. This attenuation in the processing of self-initiated sounds most probably contributes to the optimal processing of concurrent external acoustic events. [source] Involvement of mitochondrial signaling pathways in the mechanism of Fas-mediated apoptosis after spinal cord injuryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Wen Ru Yu Abstract Activation of the Fas receptor has been recently linked to apoptotic cell death after spinal cord injury (SCI). Although it is generally considered that Fas activation mediates apoptosis predominantly through the extrinsic pathway, we hypothesized that intrinsic mitochondrial signaling could be involved in the underlying mechanism of Fas-induced apoptosis after SCI. In the present study, we utilized the FejotaTM clip compression model of SCI at T5,6 in C57BL/6 Fas-deficient (lpr) and wild-type mice. Complementary studies were conducted using an in vitro model of trauma or a Fas-activating antibody to induce apoptosis in primary neuronal,glial mixed spinal cord cultures. After in vivo SCI, lpr mice, in comparison with wild-type mice, exhibited reduced numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells at the lesion, reduced expression of truncation of Bid (tBid), apoptosis-inducing factor, activated caspase-9 and activated caspase-3, and increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. After in vitro neurotrauma or the induction of Fas signaling by the Jo2 activating antibody, lpr spinal cord cultures showed an increased proportion of cells retaining mitochondrial membrane integrity and a reduction of tBid expression, caspase-9 and caspase-3 activation, and TUNEL-positive cells as compared to wild-type spinal cord cultures. The neutralization of Fas ligand (FasL) protected against traumatically induced or Fas-mediated caspase-3 activation and the loss of mitochondrial membrane potential and tBid expression in wild-type spinal cord cultures. However, in lpr spinal cord cultures, FasL neutralization had no protective effects. In summary, these data provide direct evidence for the induction of intrinsic mitochondrial signaling pathways following Fas activation after SCI. [source] Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2007Sachin Patil Abstract A high-fat diet has been shown to significantly increase the risk of the development of Alzheimer's disease (AD), a neurodegenerative disease histochemically characterized by the accumulation of amyloid beta (A,) protein in senile plaques and hyperphosphorylated tau in neurofibrillary tangles. Previously, we have shown that saturated free fatty acids (FFAs), palmitic and stearic acids, caused increased amyloidogenesis and tau hyperphosphorylaion in primary rat cortical neurons. These FFA-induced effects observed in neurons were found to be mediated by astroglial FFA metabolism. Therefore, in the present study we investigated the basic mechanism relating astroglial FFA metabolism and AD-like changes observed in neurons. We found that palmitic acid significantly increased de-novo synthesis of ceramide in astroglia, which in turn was involved in inducing both increased production of the A, protein and hyperphosphorylation of the tau protein. Increased amyloidogenesis and hyperphoshorylation of tau lead to formation of the two most important pathophysiological characteristics associated with AD, A, or senile plaques and neurofibrillary tangles, respectively. In addition to these pathophysiological changes, AD is also characterized by certain metabolic changes; abnormal cerebral glucose metabolism is one of the distinct characteristics of AD. In this context, we found that palmitic acid significantly decreased the levels of astroglial glucose transporter (GLUT1) and down-regulated glucose uptake and lactate release by astroglia. Our present data establish an underlying mechanism by which saturated fatty acids induce AD-associated pathophysiological as well as metabolic changes, placing ,astroglial fatty acid metabolism' at the center of the pathogenic cascade in AD. [source] Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells: role of AktEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2007Haviryaji S. G. Kalluri Abstract Insulin-like growth factor I (IGF-I) is involved in the proliferation and differentiation of adult neural progenitor cells; however, the underlying mechanism is not clear. We analysed the involvement of the phosphatidylinositol 3-kinase/Akt and MEK/extracellular signal-regulated kinase (ERK) pathways in the IGF-I-mediated proliferation of rat neural progenitor cells. Stimulation of neural progenitor cells with IGF-I enhanced the phosphorylation of Akt but not ERK. Cell proliferation assay demonstrated that 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (phosphoinositide 3-kinase inhibitor) but not 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene (U0126) (ERK inhibitor) inhibited the IGF-I-induced survival of cells, whereas fibroblast growth factor 2 (FGF-2) enhanced the IGF-I-mediated survival of cells. Consistent with the cell proliferation assay, 5,bromo-2-deoxy-uridine incorporation studies established a negative role for IGF-I in proliferation. However, FGF-2 (ERK activator) in the presence of IGF-I (Akt activator) increased the proliferation of cells. Accordingly, stimulation of the ERK pathway by FGF-2 induced the expression of cyclin D1, which is essential for the entry of cells into cell cycle, and IGF-I in the presence of FGF-2 up-regulated the expression of cyclin D1. IGF-I in the absence or presence of FGF-2 increased the phosphorylation of glycogen synthase kinase, thus supporting its role in the survival of neural progenitor cells. To further confirm the role of ERK activation in the proliferation, we cultured cells in FGF-2 + IGF-I-containing medium in the presence and absence of U0126 (ERK inhibitor), and showed the inhibition of nestin expression in U0126-treated cells. The decrease in the cyclin D1 content in conjunction with the inhibition of nestin expression by ERK inhibitor confirms the role of ERK in the proliferation of cells. [source] Oxygen sensing in hypoxic pulmonary vasoconstriction: using new tools to answer an age-old questionEXPERIMENTAL PHYSIOLOGY, Issue 1 2008Gregory B. Waypa Hypoxic pulmonary vasoconstriction (HPV) becomes activated in response to alveolar hypoxia and, although the characteristics of HPV have been well described, the underlying mechanism of O2 sensing which initiates the HPV response has not been fully established. Mitochondria have long been considered as a putative site of oxygen sensing because they consume O2 and therefore represent the intracellular site with the lowest oxygen tension. However, two opposing theories have emerged regarding mitochondria-dependent O2 sensing during hypoxia. One model suggests that there is a decrease in mitochondrial reactive oxygen species (ROS) levels during the transition from normoxia to hypoxia, resulting in the shift in cytosolic redox to a more reduced state. An alternative model proposes that hypoxia paradoxically increases mitochondrial ROS signalling in pulmonary arterial smooth muscle. Experimental resolution of the question of whether the mitochondrial ROS levels increase or decrease during hypoxia has been problematic owing to the technical limitations of the tools used to assess oxidant stress as well as the pharmacological agents used to inhibit the mitochondrial electron transport chain. However, recent developments in genetic techniques and redox-sensitive probes may allow us eventually to reach a consensus concerning the O2 sensing mechanism underlying HPV. [source] Shuffling genes around in hot environments: the unique DNA transporter of Thermus thermophilusFEMS MICROBIOLOGY REVIEWS, Issue 3 2009Beate Averhoff Abstract Natural transformation permits the transport of DNA through bacterial membranes and represents a dominant mode for the transfer of genetic information between bacteria and between microorganisms of distant evolutionary lineages and even between members of different domains. This phenomenon, known as horizontal, or lateral, gene transfer, has been a major force for genome plasticity over evolutionary history, and is largely responsible for the spread of fitness-enhancing traits, including antibiotic resistance and virulence factors. In particular, for adaptation of prokaryotes to extreme environments, lateral gene transfer seems to have played a crucial role. Here, we present a survey of the natural transformation machinery of the thermophile Thermus thermophilus HB27. A tentative model of the transformation machinery comprising of components similar to proteins of type IV pili and type II secretion systems is presented. A comparative discussion of the subunits and the structure of the DNA translocator and the underlying mechanism of transfer of free DNA in T. thermophilus highlights conserved and unique features of the DNA translocator in T. thermophilus. We hypothesize that the extraordinary broad substrate specificity and the high efficiency of the T. thermophilus DNA uptake system is of major importance for thermoadaptation and interdomain DNA transfer in hot environments. [source] | ||||||||||||||||||||||||||||||||||||||||||||||