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Early Phase (early + phase)
Selected AbstractsREGULATION OF FIBROGENESIS DURING THE EARLY PHASE OF COMMON BILE DUCT OBSTRUCTIONANZ JOURNAL OF SURGERY, Issue 7 2006Atilla Engin Background: Both nitric oxide (NO) and prostaglandins have been proposed as inhibitor substances involved in collagen deposition in the hepatic parenchyma. The possible reciprocal connections between NO and eicosanoids in the development of liver fibrosis were investigated during the initial phase of common bile duct obstructions. Methods: A total of 30 male albino guinea pigs were randomly and equally assigned to three groups. Group 1 underwent sham laparotomy. Group 2 and group 3 were subjected to permanent common bile duct ligature for 24 and 72 h , respectively. Changes in the liver prostaglandin E2 (PGE2), leukotriene C4, malondialdehyde contents and plasma nitrite plus nitrate concentrations were measured. To evaluate the extent of hepatic fibrosis, histological assessment of liver was confirmed with the equivalent hydroxyproline contents of liver. Results: Twenty-four hours after ligature, the amount of malondialdehyde and PGE2 and plasma nitrite plus nitrate concentrations increased significantly, whereas liver hydroxyproline contents did not change. However, 72 h after ligature (Group 3), lipid peroxidation and collagen deposition were significantly higher than that of the group 2 animals. The PGE2 : leukotriene C4 ratio peaked at 24 h and later decreased, whereas PGE2 : NO ratio remained unchanged in both group 2 and group 3 animals. Conclusions: The initiation of collagen synthesis occurred in portal tract as early as within the first 72 h of bile duct obstruction. The optimum function of reactive oxygen species on the stellate cell activation might be determined by the interaction between NO and PGE2. [source] Early phase training-induced muscular adaptations are related to oestrogen statusACTA PHYSIOLOGICA, Issue 1 2006Mike McGuigan No abstract is available for this article. [source] Early phase of reperfusion of human kidney allograft does not affect an erythrocyte anti-oxidative systemNEPHROLOGY, Issue 5 2006LESZEK DOMA SUMMARY: Background: Generation of reactive oxygen specimens is the basic mechanism leading to ischaemia/reperfusion injury of the kidney graft. Oxygen burst is a trigger for sophisticated biochemical changes leading to generation of oxygenated lipids and changes in microcirculation, which recruit recipient's neutrophils and contribute to delayed graft function. It has been shown that the free radicals generation correlates with the activity of anti-oxidative system. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) are involved in protection against free radicals. Aim: To examine the activity of erythrocyte anti-oxidative system during reperfusion of the transplanted kidney allograft. Methods: The study included 40 renal transplant recipients. Blood was taken from the iliac vein before transplantation and from the graft's renal vein immediately, as well as 2 and 4 min after total reperfusion. The authors assessed the process of reperfusion using ThermaCAM SC500 termovision camera. Spectrophotometric methods were used to measure superoxide dismutase, glutathione peroxidase and catalase activity as well as glutathione concentrations in erythrocytes. Results: There were no statistically significant differences in the activities of superoxide dismutase, catalase and glutathione peroxidase as well as glutathione concentrations during the first 4 min after total graft reperfusion. Nevertheless, there was a positive correlation between the activity of superoxide dismutase and glutathione peroxidase. Conclusion: The results suggest that the erythrocyte anti-oxidative system is stable during the early phase after reperfusion. An association between some anti-oxidative enzymes was noted. [source] Quality of evidence for the present Swedish child health surveillance programmeACTA PAEDIATRICA, Issue 2000S Bremberg The present Swedish health surveillance programme includes 15 examinations by a nurse, 5 examinations by a physician, 7 assessments of development, 2 assessments of hearing and 1 assessment of visual acuity. The WHO criteria for evaluation of screening programmes can be applied to the Swedish health surveillance programme. These criteria state that the health problem must be important, that there should be an early phase during which the condition is only detectable by medical professionals and that treatment at an early phase should favourably affect the prognosis. The quality of evidence for fulfilment of these criteria has been graded I-III. Grade II-2 refers to evidence obtained from well-designed cohort or case-control analytical studies. The following disorders might be affected by health surveillance at child health centres: amblyopia, ADHD/DAMP, failure to thrive, cerebral palsy, congenital heart failure, congenital luxation of hip, hearing impairment (severe or moderate), mental retardation, retentio testis and hydrocephalus. None of these conditions fulfils the WHO criteria with quality of evidence grade II-2 or better. Thus, the evidence for the present Swedish health surveillance programme is problematic. [source] Pulsed saturation of the standard two-pool model for magnetization transfer.CONCEPTS IN MAGNETIC RESONANCE, Issue 1 2004Part I: The steady state Abstract A general framework for magnetization transfer (MT) of a two-pool system with linear exchange for arbitrary saturation by periodic radio-frequency pulses was derived. It is based on a novel parameterization adapted to the time evolution of saturation recovery. The conditions in tissue permit a description in analogy to partial saturation of a homogeneous liquid. In this approximation, the direct saturation of bulk water is amplified by MT. Rapid transfer equilibrates the saturation of the pools in the early phase of free evolution. This kinetic "pre-equilibrium" relaxes slowly with a common relaxation rate. © 2004 Wiley Periodicals, Inc. Concepts Magn Reson Part A 21A: 37,49, 2004 [source] Experience With Implantable Loop Recorders for Recurrent Unexplained SyncopeCONGESTIVE HEART FAILURE, Issue 2008Michele Brignole MD Knowledge of what occurs during spontaneous syncope is the gold standard for evaluation. Initially, implantable loop recorders (ILRs) were used in patients with unexplained syncope at the end of unsuccessful full, conventional work-up. In pooled data regarding 247 patients, a correlation between syncope and electrocardiographic findings was found in 84 patients (34%); of these, 52% had a bradycardia or asystole at the time of the recorded event, 11% had tachycardia, and 37% had no arrhythmia. Presyncope-electrocardiography correlation was observed in another third of the patients; presyncope was much less likely to be associated with an arrhythmia than was syncope. The diagnostic yield was similar in patients with and without structural heart diseases and was higher in older than in younger patients. Recent studies showed that ILR implantation can be safely performed in an early phase of the diagnostic evaluation,provided that patients at risk for life-threatening events are carefully excluded,in the patients who have a severe presentation of syncope (because of high risk of trauma or high frequency of episodes) which can be a benefit of a mechanism-specific therapy. Congest Heart Fail. 2008;14:7,12. ©2008 Le Jacq [source] The evolution of depression and suicidality in first episode psychosisACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2010R. Upthegrove Upthegrove R, Birchwood M, Ross K, Brunett K, McCollum R, Jones L. The evolution of depression and suicidality in first episode psychosis. Objective:, To have a clearer understanding of the ebb and flow of depression and suicidal thinking in the early phase of psychosis, whether these events are predictable and how they relate to the early course of psychotic symptoms. Method:, Ninety-two patients with first episode psychosis (FEP) completed measures of depression, including prodromal depression, self-harm and duration of untreated psychosis. Follow-up took place over 12 months. Results:, Depression occurred in 80% of patients at one or more phases of FEP; a combination of depression and suicidal thinking was present in 63%. Depression in the prodromal phase was the most significant predictor of future depression and acts of self-harm. Conclusion:, Depression early in the emergence of a psychosis is fundamental to the development of future depression and suicidal thinking. Efforts to predict and reduce depression and deliberate self-harm in psychosis may need to target this early phase to reduce later risk. [source] Regional gray matter reduction and theory of mind deficit in the early phase of schizophrenia: a voxel-based morphometric studyACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2009R. Herold Objective:, We tested the association between theory of mind (ToM) performance and structural changes in the brains of patients in the early course of schizophrenia. Method:, Voxel-based morphometry (VBM) data of 18 patients with schizophrenia were compared with those of 21 controls. ToM skills were assessed by computerized faux pas (FP) tasks. Results:, Patients with schizophrenia performed significantly worse in FP tasks than healthy subjects. VBM revealed significantly reduced gray matter density in certain frontal, temporal and subcortical regions in patients with schizophrenia. Poor FP performance of schizophrenics correlated with gray matter reduction in the left orbitofrontal cortex and right temporal pole. Conclusion:, Our data indicate an association between poor ToM performance and regional gray matter reduction in the left orbitofrontal cortex and right temporal pole shortly after the onset of schizophrenia. [source] Rapid acquisition of operant conditioning in 5-day-old rat pups: A new technique articulating suckling-related motor activity and milk reinforcementDEVELOPMENTAL PSYCHOBIOLOGY, Issue 6 2007Carlos Arias Abstract Newborn rats are capable of obtaining milk by attaching to a surrogate nipple. During this procedure pups show a gradual increase in head and forelimb movements oriented towards the artificial device that are similar to those observed during nipple attachment. In the present study the probability of execution of these behaviors was analyzed as a function of their contingency with intraoral milk infusion using brief training procedures (15 min). Five-day-old pups were positioned in a smooth surface having access to a touch-sensitive sensor. Physical contact with the sensor activated an infusion pump which served to deliver intraoral milk reinforcement (Paired group). Yoked controls received the reinforcer when Paired neonates touched the sensor. Paired pups trained under a continuous reinforcement schedule emitted significantly more responses than Yoked controls following two (Experiment 1) or one training session (Experiment 2). These differences were also observed during an extinction session conducted immediately after training. The level of maternal deprivation before training (3 or 6 hr) or the volume of milk delivered (1.0 or 1.5 µl per pulse) did not affect acquisition or extinction performances. In addition, it was observed that the rate of responding of Paired pups during the early phase of the extinction session significantly predicted subsequent levels of acceptance of the reinforcer. These results indicate that the frequency of suckling-related behaviors can be rapidly modified by means of associative operant processes. The operant procedure here described represents an alternative tool for the ontogenetic analysis of self-administration or behavior processes of seeking. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 576-588, 2007. [source] Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathyDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2009Yumiko Yoshida Abstract Background Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy. Methods Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence. Results Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy. Conclusions Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy. Copyright © 2009 John Wiley & Sons, Ltd. [source] Oxidative damage of retinal pigment epithelial cells and age-related macular degenerationDRUG DEVELOPMENT RESEARCH, Issue 5 2007Suofu Qin Abstract Damage to the retinal pigment epithelial (RPE) cells is an early and crucial event in the molecular pathways leading to clinically relevant age-related macular degeneration (AMD) changes. Oxidative stress, the major environmental risk factor for atrophic AMD, causes RPE injury that results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration ultimately leads to a progressive irreversible degeneration of photoreceptors. In vitro studies show that oxidant-treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during the early phase of atrophic AMD. The main target of oxidative injury appears to be mitochondria, an organelle known to accumulate genomic damage during aging. Addition of GSH, the most abundant intracellular thiol antioxidant, protects RPE cells from oxidant-induced apoptosis. Similar protection occurs with dietary enzyme inducers that increase GSH synthesis. In addition, enhancing survival signaling preserves RPE cells under oxidative stress. These results indicate that therapeutic or nutritional intervention to enhance the antioxidant capacity and survival signaling of RPE may provide an effective way to prevent or treat AMD. This review describes major molecular and cellular events leading to RPE death, and presents currently used and new experimental, forthcoming therapeutic strategies. Drug Dev Res 68:213,225, 2007. © 2007 Wiley-Liss, Inc. [source] Prospects for therapeutic vaccination with glatiramer acetate for neurodegenerative diseases such as Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2002Michal Schwartz Abstract Neurodegenerative diseases, whatever their primary causes, are characterized by certain common features, one of which is their self-perpetuating nature. The ongoing progression of the disorder is due to the effects of destructive self-compounds, whose presence in the tissues is an outcome of the early phase of the disease and which gradually destroy remaining functional neurons. Studies in our laboratory have led to the recent formulation of a novel concept of protective autoimmunity as the body's mechanism of defense against these destructive self-compounds. This autoimmune response to central nervous system (CNS) insults is mediated by T-cells and presumably operates by activating and regulating local microglia and infiltrating macrophages (inflammatory response) to carry out their function of clearing destructive material from the tissue at risk. We suggest that a well-controlled autoimmunity counteracts and overcomes the destructive effects of the potentially harmful self-compounds, at the cost of some loss of tissue. An additional risk to the individual is the induction of an autoimmune disease, which is likely to occur if the autoimmune response is malfunctioning. An optimal balance of the various factors will lead to an outcome of maximal benefit at minimal cost to the tissue. A procedure for safely boosting the autoimmune response, by vaccination with a weak self-crossreactive antigen such as glatiramer acetate (also known as Cop-1) was found to protect rats from glutamate toxicity, a major mediator of the spread of damage and a well-known causative factor in neurodegenerative disorders. Cop-1, when administered according to a different regimen, is an FDA-approved drug for the treatment of multiple sclerosis. Different formulations of the same drug can therefore be used to treat two extreme manifestations of chronic degenerative diseases of the CNS. Drug Dev. Res. 56:143,149, 2002. © 2002 Wiley-Liss, Inc. [source] Smoking cessation during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gumADDICTION, Issue 9 2009Ned L. Cooney ABSTRACT Aims The primary aim was to compare the efficacy of smoking cessation treatment using a combination of active nicotine patch plus active nicotine gum versus therapy consisting of active nicotine patch plus placebo gum in a sample of alcohol-dependent tobacco smokers in an early phase of out-patient alcohol treatment. A secondary aim was to determine whether or not there were any carry-over effects of combination nicotine replacement on drinking outcomes. Design Small-scale randomized double-blind placebo-controlled clinical trial with 1-year smoking and drinking outcome assessment. Setting Two out-patient substance abuse clinics provided a treatment platform of behavioral alcohol and smoking treatment delivered in 3 months of weekly sessions followed by three monthly booster sessions. Participants Participants were 96 men and women with a diagnosis of alcohol abuse or dependence and smoking 15 or more cigarettes per day. Intervention All participants received open-label transdermal nicotine patches and were randomized to receive either 2 mg nicotine gum or placebo gum under double-blind conditions. Findings Analysis of 1-year follow-up data revealed that patients receiving nicotine patch plus active gum had better smoking outcomes than those receiving patch plus placebo gum on measures of time to smoking relapse and prolonged abstinence at 12 months. Alcohol outcomes were not significantly different across medication conditions. Conclusions Results of this study were consistent with results of larger trials of smokers without alcohol problems, showing that combination therapy (nicotine patch plus gum) is more effective than monotherapy (nicotine patch) for smoking cessation. [source] High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsyEPILEPSIA, Issue 1 2010Wolfgang Löscher Summary Purpose:, Progress in the management of patients with medically intractable epilepsy is impeded because we do not fully understand why pharmacoresistance happens and how it can be predicted. The presence of multiple seizures prior to medical treatment has been suggested as a potential predictor of poor outcome. In the present study, we used an animal model of temporal lobe epilepsy to investigate whether pharmacoresistant rats differ in seizure frequency from pharmacoresponsive animals. Methods:, Epilepsy with spontaneous recurrent seizures (SRS) was induced by status epilepticus. Frequency of SRS was determined by video/EEG (electroencephalography) monitoring in a total of 33 epileptic rats before onset of treatment with phenobarbital (PB). Results:, Thirteen (39%) rats did not respond to treatment with PB. Before treatment with PB, average seizure frequency in PB nonresponders was significantly higher than seizure frequency in responders, which, however, was due to six nonresponders that exhibited > 3 seizures per day. Such high seizure frequency was not observed in responders, demonstrating that high seizure frequency predicts pharmacoresistance in this model, but does not occur in all nonresponders. Discussion:, The data from this study are in line with clinical experience that the frequency of seizures in the early phase of epilepsy is a dominant risk factor that predicts refractoriness. However, resistance to treatment also occurred in rats that did not differ in seizure frequency from responders, indicating that disease severity alone is not sufficient to explain antiepileptic drug (AED) resistance. These data provide further evidence that epilepsy models are useful in the search for predictors and mechanisms of pharmacoresistance. [source] Early Death Due to Severe Organophosphate Poisoning Is a Centrally Mediated ProcessACADEMIC EMERGENCY MEDICINE, Issue 4 2003Steven B. Bird MD Objective: To distinguish whether early death from severe organophosphate (OP) poisoning with dichlorvos is mediated through peripheral or central nervous system (CNS) actions. Methods: Wistar rats (n= 72) were randomized to pretreatment with either: normal saline (controls), peripheral anticholinergics (glycopyrrolate [low, medium, or high dose] or nebulized ipratropium bromide), or CNS + peripherally acting anticholinergics (diphenhydramine, nebulized atropine, or injected atropine). All treatments were given prior to a subcutaneous injection of 25 mg/kg dichlorvos (n= 8 per group). Survival was assessed at 10 minutes (early death) and 24 hours (delayed death). Kaplan-Meier (95% confidence intervals [95% CIs]) and chi-squared analysis was then performed to determine differences between treatments. Results: Regardless of treatment, all animals exhibited profound nicotinic effects (fasciculations) without obvious seizures within 2 minutes of poisoning. In rats pretreated with peripherally acting agents, the fasciculations were rapidly followed by reduced motor activity, sedation, and death. Mortality at 10 minutes for saline controls, glycopyrrolate, and ipratropium was 88%, 96%, and 100%, respectively. The single control animal surviving beyond 10 minutes went on to develop peripheral cholinergic manifestations, including hypersalivation, urination, and defecation. Only one of 24 animals treated with injected atropine, nebulized atropine, or diphenhydramine died during the early phase of poisoning; all others survived to 24 hours (p < 0.01). Conclusions: Death in acute, severe OP poisoning is prevented by pretreatment with anticholinergic agents that cross the blood,brain barrier, but not by agents with only peripheral actions. Early death due to OP poisoning appears to be a centrally mediated process. [source] Clonal dynamics of tumor-infiltrating lymphocytesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2005Rong Yu Abstract The presence of tumor-infiltrating lymphocytes (TIL) provides important evidence of anti-tumor immunity in vivo. However, TIL are usually not sufficient for inhibiting tumor growth. We explored the spatial and temporal aspects of clonal accumulation of TIL using RT-PCR/single-strand conformation polymorphism analysis. In CMS5 fibrosarcomas in BALB/c mice, accumulated T,cell clones were specific in that dominant TIL were identical between distant tumors. Moreover, dominant TIL in the first tumor appeared consistently in the second tumor inoculated after formation of the first tumor. These results suggest that TIL show a certain level of specific tumor surveillance. When we characterized CD4+ and CD8+ TIL separately, CD8+ TIL were highly concentrated and persistently localized at the tumor site, while most CD4+ TIL clones were less concentrated and less persistent. A functional analysis showed that TIL had a certain degree of anti-tumor activity when CD4+ and CD8+ TIL were co-transferred. Co-transfer of CD4+ and CD8+ TIL exhibited equivalent anti-tumor activity, irrespective of tumor stage. However, the numbers of TIL did not increase after the early phase of tumor progression. These data suggest that TIL are specific to the tumor and potentially retain anti-tumor activity, although their accumulation in mice is impaired. [source] Expression of cell fate determinants and plastic changes after neurotoxic lesion of adult mice spinal cord by cholera toxin-B saporinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2010Rosario Gulino Abstract Recent studies have attempted to repair the damaged spinal cord (SC) by stimulating neurogenesis or neuroplasticity. Sonic hedgehog (Shh), Notch-1 and Numb are involved in the stem cell functioning. Additionally, Notch-1 has a role as modulator of synaptic plasticity. However, little is known about the role of these proteins in the adult SC after removal of motoneurons. In this study, we have injected cholera toxin-B saporin into the gastrocnemius muscle to induce a depletion of motoneurons within the lumbar SC of adult mice, and analysed the expression of choline acetyltransferase (ChAT), Synapsin-I, Shh, Notch-1 and Numb proteins. The functional outcome of the lesion was monitored by grid walk and rotarod tasks. The neurotoxin lesion determined a motoneuron depletion and a transient decrease of ChAT, Synapsin-I, Shh and Numb levels in the lumbar SC. ChAT was associated with Synapsin-I expression and motor performance at 1 week but not 1 month after lesion, suggesting that the recovery of locomotion could depend on synaptic plasticity, at least in an early phase. Shh and Notch-1 were associated with Synapsin-I levels, suggesting a role in modulating synaptic plasticity. Numb expression also appeared reduced after lesion and linked to motor performance. Moreover, unlike other lesion models, we observed glial reaction but no evidence of cell proliferation within the depleted SC. Given the mentioned roles of Shh, Notch-1 and Numb, we believe that an in vivo manipulation of their signalling after lesion could represent a suitable way to improve functional recovery by modulating synaptic plasticity and/or neurogenesis. [source] Expression of CRABP I mRNA in fastigial cells of the developing cerebellumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2002Rosalba Parenti Abstract The expression of the cellular retinoic acid binding protein type I (CRABP I) was examined in the early phase of cerebellar development in the mouse. The CRABP I was expressed from embryonic day (E) 10.5 to E15.5 in the cerebellar plate. The expression was diffused at E10.5,E11.5 and thereafter localized in a small rostrodorsal area of the cerebellar territory of both sides. By using in situ hybridization and both immunohistochemistry and carbocyanine tracing procedures, we identified the fastigial cells as the population that expresses CRABP I in the cerebellum. The results suggest that these cells play a critical role in the early development of the cerebellum. [source] APP is required during an early phase of memory formationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2000R. Mileusnic Abstract The amyloid ,/A4 protein precursor (APP) has been shown to be implicated in age-associated plastic changes at synapses that might contribute to memory loss in Alzheimer's disease. As APP has previously been reported to have multiple functions during normal development, we have employed a one-trial passive avoidance task in day-old chicks to study its role in the process of memory formation. Administration of anti-APP antibodies, injected 30 min pretraining, prevented memory for a one-trial passive avoidance task in day-old chicks without effects on general behaviour or initial acquisition. Amnesia was apparent by 30 min post-training and lasted for at least 24 h. The same result was obtained by down-regulation of APP expression by APP-antisense, injected 8,12 h pretraining. However, injections of anti-APP antibodies or APP antisense at later post-training time did not cause amnesia for the task. Unlike antibodies and antisense, injection of the APP328,332 pentapeptide, in either orientation, 30 min pretraining, rescued the memory and prevented antisense-induced amnesia. The post-training time within which the antibody- and antisense-induced amnesia, and within which the APP peptides prevent amnesia, correspond to that during which memory formation is vulnerable to disruption of the putative signal transduction functions of APP. These results suggest that: (i) APP is required during an early phase of memory formation, and (ii) the memory enhancing effect of secretory APP is localized within a 5-mer sequence of growth-promoting domain. [source] Expression of Hoxa-11 and Hoxa-13 in the pectoral fin of a basal ray-finned fish, Polyodon spathula: implications for the origin of tetrapod limbsEVOLUTION AND DEVELOPMENT, Issue 3 2005Brian D. Metscher Summary Paleontological and anatomical evidence suggests that the autopodium (hand or foot) is a novel feature that distinguishes limbs from fins, while the upper and lower limb (stylopod and zeugopod) are homologous to parts of the sarcopterygian paired fins. In tetrapod limb development Hoxa-11 plays a key role in differentiating the lower limb and Hoxa-13 plays a key role in differentiating the autopodium. It is thus important to determine the ancestral functions of these genes in order to understand the developmental genetic changes that led to the origin of the tetrapod autopodium. In particular it is important to understand which features of gene expression are derived in tetrapods and which are ancestral in bony fishes. To address these questions we cloned and sequenced the Hoxa-11 and Hoxa-13 genes from the North American paddlefish, Polyodon spathula, a basal ray-finned fish that has a pectoral fin morphology resembling that of primitive bony fishes ancestral to the tetrapod lineage. Sequence analysis of these genes shows that they are not orthologous to the duplicated zebrafish and fugu genes. This implies that the paddlefish has not duplicated its HoxA cluster, unlike zebrafish and fugu. The expression of Hoxa-11 and Hoxa-13 in the pectoral fins shows two main phases: an early phase in which Hoxa-11 is expressed proximally and Hoxa-13 is expressed distally, and a later phase in which Hoxa-11 and Hoxa-13 broadly overlap in the distal mesenchyme of the fin bud but are absent in the proximal fin bud. Hence the distal polarity of Hoxa-13 expression seen in tetrapods is likely to be an ancestral feature of paired appendage development. The main difference in HoxA gene expression between fin and limb development is that in tetrapods (with the exception of newts) Hoxa-11 expression is suppressed by Hoxa-13 in the distal limb bud mesenchyme. There is, however, a short period of limb bud development where Hoxa-11 and Hoxa-13 overlap similarly to the late expression seen in zebrafish and paddlefish. We conclude that the early expression pattern in tetrapods is similar to that seen in late fin development and that the local exclusion by Hoxa-13 of Hoxa-11 from the distal limb bud is a derived feature of limb developmental regulation. [source] mTOR as a potential therapeutic target for treatment of keloids and excessive scarsEXPERIMENTAL DERMATOLOGY, Issue 5 2007C. T. Ong Abstract:, Keloid is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix (ECM) components such as collagen, glycoproteins and fibronectin. The mammalian target of rapamycin (mTOR) is a serine/theronine kinase which plays an important role in the regulation of metabolic processes and translation rates. Published reports have shown mTOR as regulator of collagen expression and its inhibition induces a decrease in ECM deposition. Our aim was to investigate the role of mTOR in keloid pathogenesis and investigate the effect of rapamycin on proliferating cell nuclear antigen (PCNA), cyclin D1, collagen, fibronectin and alpha-smooth muscle actin (, -SMA) expression in normal fibroblasts (NF) and keloid fibroblasts (KF). Tissue extracts obtained from keloid scar demonstrated elevated expression of mTOR, p70KDa S6 kinase (p70S6K) and their activated forms, suggesting an activated state in keloid scars. Serum stimulation highlighted the heightened responsiveness of KF to mitogens and the importance of mTOR and p70S6K during early phase of wound healing. Application of rapamycin to monoculture NF and KF, dose- and time-dependently downregulates the expression of cytoplasmic PCNA, cyclin D1, fibronectin, collagen and , -SMA, demonstrating the anti-proliferative effect and therapeutic potential of rapamycin in the treatment of keloid scars. The inhibitory effect of rapamycin was found to be reversible following recovery in the expression of proteins following the removal of rapamycin from the culture media. These results demonstrate the important role of mTOR in the regulation of cell cycle and the expression of ECM proteins: fibronectin, collagen and , -SMA. [source] Implication of the glutamine synthetase/glutamate synthase pathway in conditioning the amino acid metabolism in bundle sheath and mesophyll cells of maize leavesFEBS JOURNAL, Issue 12 2008Marie-Hélène Valadier We investigated the role of glutamine synthetases (cytosolic GS1 and chloroplast GS2) and glutamate synthases (ferredoxin-GOGAT and NADH-GOGAT) in the inorganic nitrogen assimilation and reassimilation into amino acids between bundle sheath cells and mesophyll cells for the remobilization of amino acids during the early phase of grain filling in Zea mays L. The plants responded to a light/dark cycle at the level of nitrate, ammonium and amino acids in the second leaf, upward from the primary ear, which acted as the source organ. The assimilation of ammonium issued from distinct pathways and amino acid synthesis were evaluated from the diurnal rhythms of the transcripts and the encoded enzyme activities of nitrate reductase, nitrite reductase, GS1, GS2, ferredoxin-GOGAT, NADH-GOGAT, NADH-glutamate dehydrogenase and asparagine synthetase. We discerned the specific role of the isoproteins of ferredoxin and ferredoxin:NADP+ oxidoreductase in providing ferredoxin-GOGAT with photoreduced or enzymatically reduced ferredoxin as the electron donor. The spatial distribution of ferredoxin-GOGAT supported its role in the nitrogen (re)assimilation and reallocation in bundle sheath cells and mesophyll cells of the source leaf. The diurnal nitrogen recycling within the plants took place via the specific amino acids in the phloem and xylem exudates. Taken together, we conclude that the GS1/ferredoxin-GOGAT cycle is the main pathway of inorganic nitrogen assimilation and recycling into glutamine and glutamate, and preconditions amino acid interconversion and remobilization. [source] Seasonal response of nutrients to reduced phosphorus loading in 12 Danish lakesFRESHWATER BIOLOGY, Issue 10 2005MARTIN SØNDERGAARD Summary 1.,Concentrations of phosphorus, nitrogen and silica and alkalinity were monitored in eight shallow and four deep Danish lakes for 13 years following a phosphorus loading reduction. The aim was to elucidate the seasonal changes in nutrient concentrations during recovery. Samples were taken biweekly during summer and monthly during winter. 2.,Overall, the most substantive changes in lake water concentrations were seen in the early phase of recovery. However, phosphorus continued to decline during summer as long as 10 years after the loading reduction, indicating a significant, albeit slow, decline in internal loading. 3.,Shallow and deep lakes responded differently to reduced loading. In shallow lakes the internal phosphorus release declined significantly in spring, early summer and autumn, and only non-significantly so in July and August. In contrast, in deep lakes the largest reduction occurred from May to August. This difference may reflect the much stronger benthic pelagic-coupling and the lack of stratification in shallow lakes. 4.,Nitrogen only showed minor changes during the recovery period, while alkalinity increased in late summer, probably conditioned by the reduced primary production, as also indicated by the lower pH. Silica tended to decline in winter and spring during the study period, probably reflecting a reduced release of silica from the sediment because of enhanced uptake by benthic diatoms following the improved water transparency. 5.,These results clearly indicate that internal loading of phosphorus can delay lake recovery for many years after phosphorus loading reduction, and that lake morphometry (i.e. deep versus shallow basins) influences the patterns of change in nutrient concentrations on both a seasonal and interannual basis. [source] Alzheimer's disease: Mechanisms and development of therapeutic strategiesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2003Takeshi Tabira Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, , amyloid is deposited, which is composed of aggregated amyloid , protein (A,) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of A, production or a decrease of A, degradation and/or clearance of , amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP, presenilin 1 (PS1) and presenilin 2 (PS2) result in an increase of A, production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in A, production and/or its clearance. Thus, it is suggested that an inhibition of A, production and a facilitation of , amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of A, production and identified enzymes that cleave-out A, from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing , amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of A, in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important. [source] In vivo observation of the locomotion of microglial cells in the retinaGLIA, Issue 14 2010Michel Paques Abstract Microglial cells (MCs) are active sensors and reactive phagocytes of neural tissues. They are known to migrate and accumulate in areas of neuronal damage. Thus, microglial locomotion is an essential feature of the inflammatory reaction in neural tissue. Yet, to our knowledge there has been no report of direct in vivo observation of the migration of MCs. Here, we show that intravitreally injected cyanine dyes (DiO, DiI, and indocyanine green) are sequestrated in MCs during several months, and subsequently in vivo images of these fluorescent MCs can be obtained by confocal scanning laser ophthalmoscopy. This enabled noninvasive, time-lapse observation of the migrating behavior of MCs, both in the basal state and following laser damage. In the basal state, a slow, intermittent, random-like locomotion was observed. Following focal laser damage, MCs promptly (i.e., within 1 h) initiated centripetal, convergent migration. MCs up to 400 ,m away migrated into the scar at velocities up to 7 ,m/min. This early phase of centripetal migration was followed by a more prolonged phase of nontargeted locomotion around and within injured sites during at least 24 h. Cyanine-positive cells persisted within the scar during several weeks. To our knowledge, this is the first in vivo observation of the locomotion of individual MCs. Our results show that the locomotion of MCs is not limited to translocation to acutely damaged area, but may also be observed in the basal state and after completion of the recruitment of MCs into scars. © 2010 Wiley-Liss, Inc. [source] Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivoGLIA, Issue 16 2009Hyun Kyoung Lee Abstract The ubiquitin-proteasome system (UPS), lysosomes, and autophagy are essential protein degradation systems for the regulation of a variety of cellular physiological events including the cellular response to injury. It has recently been reported that the UPS and autophagy mediate the axonal degeneration caused by traumatic insults and the retrieval of nerve growth factors. In the peripheral nerves, axonal degeneration after injury is accompanied by myelin degradation, which is tightly related to the reactive changes of Schwann cells called dedifferentiation. In this study, we examined the role of the UPS, lysosomal proteases, and autophagy in the early phase of Wallerian degeneration of injured peripheral nerves. We found that nerve injury induced an increase in the ubiquitin conjugation and lysosomal-associated membrane protein-1 expression within 1 day without any biochemical evidence for autophagy activation. Using an ex vivo explant culture of the sciatic nerve, we observed that inhibiting proteasomes or lysosomal serine proteases prevented myelin degradation, whereas this was not observed when inhibiting autophagy. Interestingly, proteasome inhibition, but not leupeptin, prevented Schwann cells from inducing dedifferentiation markers such as p75 nerve growth factor receptor and glial fibrillary acidic protein in vitro and in vivo. In addition, proteasome inhibitors induced cell cycle arrest and cellular process formation in cultured Schwann cells. Taken together, these findings indicate that the UPS plays a role in the phenotype changes of Schwann cells in response to nerve injury. © 2009 Wiley-Liss, Inc. [source] G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditionsGLIA, Issue 8 2007Caroline Bouchard Abstract G protein-coupled receptor 84 (GPR84) is a recently discovered member of the seven transmembrane receptor superfamily whose function and regulation are unknown. Here, we report that in mice suffering from endotoxemia, microglia express GPR84 in a strong and sustained manner. This property is shared by subpopulations of peripheral macrophages and, to a much lesser extent, monocytes. The induction of GPR84 expression by endotoxin is mediated, at least in part, by proinflammatory cytokines, notably tumor necrosis factor (TNF) and interleukin-1 (IL-1), because mice lacking either one or both of these molecules have fewer GPR84-expressing cells in their cerebral cortex than wild-type mice during the early phase of endotoxemia. Moreover, when injected intracerebrally or added to microglial cultures, recombinant TNF stimulates GPR84 expression through a dexamethasone-insensitive mechanism. Finally, we show that microglia produce GPR84 not only during endotoxemia, but also during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In conclusion, this study reports the identification of a new sensitive marker of microglial activation, which may play an important regulatory role in neuroimmunological processes, acting downstream to the effects of proinflammatory mediators. © 2007 Wiley-Liss, Inc. [source] FDG PET studies during treatment: Prediction of therapy outcome in head and neck squamous cell carcinomaHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 2 2002Eva Brun MD Background Positron emission tomography (PET) provides metabolic information of tissues in vivo. The purpose of this study was to assess the value of PET with 2-[18 F] fluoro-2-deoxy- D -glucose (FDG) in prediction of therapy outcome (tumor response, survival, and locoregional control) in locally advanced HNSCC. Methods Between 1993 and 1999 47 patients underwent PET before (PET1) and after (PET2) 1 to 3 weeks of radical treatment with evaluation of metabolic rate (MR) and standardized uptake value (SUV) of FDG. All patients received radiotherapy, and 10 also received neoadjuvant chemotherapy. Median follow-up time was 3.3 years. Results Low and high MR FDG at PET2, with median value as cutoff, was associated with complete remission in 96% and 62% (p = .007), with 5-year overall survival in 72% and 35% (p = .0042) and with local control in 96% and 55% (p = .002), respectively. Conclusions FDG PET in the early phase of treatment of HNSCC is associated with tumor response, survival, and local control. © 2002 John Wiley & Sons, Inc. [source] Strain-dependent viral dynamics and virus-cell interactions in a novel in vitro system supporting the life cycle of blood-borne hepatitis C virus,HEPATOLOGY, Issue 3 2009Hussein Hassan Aly We developed an in vitro system that can be used for the study of the life cycle of a wide variety of blood-borne hepatitis C viruses (HCV) from various patients using a three-dimensional hollow fiber culture system and an immortalized primary human hepatocyte (HuS-E/2) cell line. Unlike the conventional two-dimensional culture, this system not only enhanced the infectivity of blood-borne HCV but also supported its long-term proliferation and the production of infectious virus particles. Both sucrose gradient fractionation and electron microscopy examination showed that the produced virus-like particles are within a similar fraction and size range to those previously reported. Infection with different HCV strains showed strain-dependent different patterns of HCV proliferation and particle production. Fluctuation of virus proliferation and particle production was found during prolonged culture and was found to be associated with change in the major replicating virus strain. Induction of cellular apoptosis was only found when strains of HCV-2a genotype were used for infection. Interferon-alpha stimulation also varied among different strains of HCV-1b genotypes tested in this study. Conclusion: These results suggest that this in vitro infection system can reproduce strain-dependent events reflecting viral dynamics and virus-cell interactions at the early phase of blood-borne HCV infection, and that this system can allow the development of new anti-HCV strategies specific to various HCV strains. (HEPATOLOGY 2009.) [source] Role of V, 14 NKT cells in the development of impaired liver regeneration in vivoHEPATOLOGY, Issue 5 2003Hiroyasu Ito Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by IL-12 or by ,-galactosylceramide (,-GalCer) on murine liver regeneration using V, 14 NKT knockout (J, 281,/,) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in J, 281+/+ but not in J, 281,/, mice by both procedures. Hepatic NKT cells expressed considerably more interferon (IFN) , and tumor necrosis factor , (TNF-,) messenger RNA (mRNA) after stimulation with both factors in J, 281+/+ mice. Either anti-IFN-, or TNF-, antibody inhibited the enhancement of liver injury. Furthermore, recombinant TNF-, injection similarly caused injury in hepatectomized livers of both J, 281+/+ and J, 281,/, mice; indeed, adoptively transferred TNF-,+/+ NKT cells enhanced liver injury after hepatectomy in TNF-, knockout mice. TNF receptor expressions on hepatocytes increased and peaked 24 hours after partial hepatectomy. In conclusion, simultaneous TNF-, synthesis and high levels of TNF receptor expression on hepatocytes cause severe liver damage by activated NKT cells during liver regeneration. [source] | |||||||||||||||||||||||||||||||||||||||||||