The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694
patients with other B-cell precursor ALL (P = 0.63; 84.2 +/- 7.1% (s.e.) vs 84.0 +/- 1.8% at 5 years). However, patients with the t(1; 19) had a lower cumulative incidence of any hematological relapse (P = 0.06; 0 vs 8.3 +/- 1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P < 0.001; 9.0 +/- 5.1% vs 1.0 +/- 0.4% at 5 years). In a multivariate analysis, the t(1; 19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1; 19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse. Leukemia (2009) 23, 1406-1409; doi:10.1038/leu.2009.42; published online 12 March 2009″
“Anxiety disorders, depression and animal models of selleck chemicals vulnerability to a depression-like syndrome have been associated with dysregulation of brain serotonergic systems. These effects could result from genetic influences, adverse early life experiences (ELE), or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to neuropsychiatric disorders. Selleckchem Alvocidib To evaluate the effects of ELE, adverse experiences during adulthood, and potential interactions
between these factors on neuronal tryptophan hydroxylase 2 (tph2) mRNA expression, we
investigated in rats the effects of maternal separation (MS)(separation from the dam for 180 min/day from postnatal day 2-14; MS180, a model of vulnerability to a depression-like syndrome), neonatal handling (separation from the dam for 15 min/day from postnatal day 2-14; MS15, a model of decreased stress sensitivity), or normal animal facility rearing (AFR) control conditions, with or without subsequent exposure to adult social defeat, on tph2 mRNA expression in the dorsal raphe nucleus (DR). Among rats exposed to social defeat, MS180 rats had increased tph2 mRNA expression in the DR, while MS15 rats had decreased tph2 mRNA expression see more compared to AFR rats. Social defeat increased tph2 mRNA expression, but only in MS180 rats and only in the “”lateral wings”" of the DR, a subdivision of the DR that is part of a sympathomotor command center. Overall, these data demonstrate that ELE and stressful experience during adulthood interact to determine tph2 mRNA expression. These changes in tph2 mRNA expression represent a potential mechanism through which adverse ELEs and stressful life experiences during adulthood may interact to increase vulnerability to stress-related psychiatric disease. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.
(C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The alpha 7 subunit of the nicotinic acetylcholine receptor (alpha 7nAChR) is expressed in the prefrontal cortex (PFC), a brain region where these receptors are implicated in cognitive function and in the pathophysiology of schizophrenia. Activation of this receptor is dependent on release of acetylcholine (ACh) from axon terminals that contain the vesicular acetylcholine transporter (VAChT). Since rat and mouse models are widely used for studies of specific DMXAA manufacturer abnormalities in schizophrenia,
we sought to determine the subcellular location of the alpha 7nAChR with respect to VAChT storage vesicles in axon terminals in the PFC in both species. For this, we used dual electron microscopic immunogold and immunoperoxidase
labeling of antisera raised against the alpha 7nAChR and VAChT. In both species, the alpha 7nAChR-immunoreactivity ((-)ir) was principally identified selleck products within dendrites and dendritic spines, receptive to axon terminals forming asymmetric excitatory-type synapses, but lacking detectable alpha 7nAChR or VAChT-ir. Quantitative analysis of the rat PFC revealed that of alpha 7nAChR-labeled neuronal profiles, 65% (2991463) were postsynaptic structures (dendrites and dendritic spine) and only 22% (104/463) were axon terminals or small unmyelinated axons. In contrast, VAChT was principally localized to varicose vesicle-filled axonal profiles, without recognized synaptic specializations (n=240). Of the alpha 7nAChR-labeled axons, 47% (37/79) Inositol monophosphatase 1 also contained VAChT, suggesting that ACh release is autoregulated through the presynaptic alpha 7nAChR. The VAChT-labeled terminals rarely formed synapses, but frequently
apposed alpha 7nAChR-containing neuronal profiles. These results suggest that in rodent PFC, the alpha 7nAChR plays a major role in modulation of the postsynaptic excitation in spiny dendrites in contact with VAChT containing axons. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Fatigue could be induced following forced exercise, sickness, heat stroke or sleep disturbance and impaired brain-related functions such as concentration, attention and memory. Here we investigated whether fatigue altered the dendrites of central neurons. Central fatigue was induced by housing rats in cage with 1.5-cm deep water for 1-5 days. Three days of sleep deprivation seriously compromised rats’ performance in weight-loaded forced swimming and spatial learning tests, and 5 days of treatment worsened it further.
Here, we present a novel general purpose tool called MPA (multiple peak alignment) able to perform multiple comparisons of proteomic
profiles both in a pairwise guided fashion and in a fully automatic mode using a strategy based on dynamic programing and progressive alignment of time series. The tool is available at http://grup.cribi.unipd.it/people/stefano/mpa/.”
“Studies with animal models showed that cellular, structural, and behavioral changes induced by environmental enrichment are related to increased levels of brain-derived neurotrophic factor (BDNF) in the brain. These evidence suggest that BDNF could be an interesting biomarker of the effects of lifestyle on cognition and other behavioral parameters in humans, mainly selleck chemical if the BDNF alterations in brain are accompanied by correspondent peripheral modifications, since human studies depend basically on the evaluation of this neurotrophin in Bucladesine ic50 serum or plasma. To test this hypothesis, we analyzed the effects of environmental enrichment on long-term memory for object recognition and on BDNF levels of hippocampus, frontal cortex, and serum of rats exposed to an experimental protocol that could be more easily translated to human intervention studies. Animals were maintained for 10 weeks in a social (standard laboratory conditions) or enriched (increased opportunity for physical exercise and learning
experiences) condition. In the 7th week, they were submitted to behavioral testing (open field and novel object memory task), and at the end of the 10th week, they were killed and BDNF levels were analyzed. Animals maintained in the enriched condition showed enhanced performance on the
memory task in the absence of any significant alteration in central or peripheral BDNF levels. The results of this study are important to highlight the need to develop experimental protocols using animal models that more closely resemble the characteristics of studies with humans and motivate more investigations to determine the conditions under which BDNF could be a biomarker of the effects of environment enrichment. (C) 2011 Published by Elsevier Evodiamine Ltd on behalf of IBRO.”
“Although postoperative pain remains incompletely controlled in some settings, increased understanding of its mechanisms and the development of several therapeutic approaches have substantially improved pain control in past years. Advances in our understanding of the process of nociception have led to insight into gene-based pain therapy, the development of acute opioid-induced hyperalgesia, and persistent postsurgical pain. Use of specific analgesic techniques such as regional analgesia could improve patient outcomes. We also examine the development of new analgesic agents and treatment modalities and regimens for acute postoperative pain.”
“Human butyrylcholinesterase (hBChE) is a highly glycosylated protein present in human plasma.
“In vitro and in vivo experiments were carried out to investigate the consequences on brain cells of a chronic treatment with hyperforin, a plant extract known to dissipate the mitochondrial membrane potential and to release Zn(2+) and Ca(2+) from these organelles. Dissociated cortical neurons were grown in a culture medium supplemented with 1 mu M hyperforin. Live-cell imaging experiments with the fluorescent probes FluoZin-3 and Fluo-4 show that a 3 day-hyperforin treatment diminishes the size of the hyperforin-sensitive pools of Ca(2+) and Zn(2+) whereas it increases the size of the DTDP-sensitive pool of Zn(2+) without affecting the
ionomycin-sensitive pool of Ca(2+). When assayed selleckchem by quantitative PCR the levels of mRNA coding for metallothioneins (MTs) I, II and III were increased in cortical neurons after a 3 day-hyperforin treatment. This was prevented by the zinc chelator TPEN, indicating that the plant extract controls the expression of MTs in a zinc-dependent manner. Brains of adult mice who received a daily injection (i.p.) of hyperforin (4 mg/kg/day) for 4 weeks had a higher sulphur content than control animals. They also exhibited an enhanced expression of https://www.selleckchem.com/products/i-bet151-gsk1210151a.html the genes coding for MTs. However, the long-term treatment did not affect the brain levels of calcium and
zinc. Based on these results showing that hyperforin influences the size of the internal pools of Zn(2+), the expression of MTs and the brain cellular sulphur content, it is proposed that hyperforin changes
the Zn-storage capacity of brain cells and interferes with their thiol status. (C) 2011 Elsevier Ltd. All rights reserved.”
“Lactate dehydrogenase-elevating Tangeritin virus (LDV) can infect transplantable mouse tumors or xenograft tumors in mice through [DV-contaminated mouse biological materials, such as Matrigel, or through mice infected with LDV. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. The traditional approaches to remove LDV from tumor cells, by transplanting tumors into rats or culturing tumor cells in vitro, are inefficient, labor-intensive and time-consuming. Furthermore, these approaches are not feasible for primary tumor cells that cannot survive tissue culture conditions or that may change phenotype in rats. This study reports that fluorescence-activated cell sorting (FACS) is a simple and efficient approach for purifying living primary human breast tumor cells from LDV(+) mouse stromal cells, which can be completed in a few hours. When purified from Matrigel contaminated LDV(+) tumors, sorted human breast tumor cells, as well as tumors grown from sorted cells, were shown to be LDV-free, as tested by PCR. The results demonstrate that cell sorting is effective, much faster and less likely to alter tumor cell phenotype than traditional methods for removing LDV from xenograft models.
Notably, ORF19 behaves as a true late gene, indicating that RTA regulates all three phases of the lytic program. For each new promoter, the response to RTA was dependent on CSL, and 5 of the 10 candidate sites were shown to bind CSL in vitro. Analysis of individual sites highlighted the importance of a cytosine residue flanking Apoptosis inhibitor the core CSL binding sequence. These findings broaden the role for CSL in coordinating the KSHV lytic gene expression program and help to define a signature
motif for functional CSL sites within the viral genome.”
“Astrocytes play an important role in protecting neurons during ischemia and reperfusion in the central nervous system. Although many studies have shown that oxygen-glucose deprivation (OGD) can induce astrocyte apoptosis, the role of PERK/eIF2 alpha/ATF4 integrated stress response (ISR) in astrocyte apoptosis mediated by oxygen-glucose-serum deprivation (OGSD)/restoration remains uncertain. Astrocytes were subjected to a combination of oxygen, glucose, and serum deprivation for 8 h followed by restoration. Hoechst 33342 staining was performed to quantify apoptotic astrocytes and cell viability
was assessed with Cell Counting Kit-8 (CCK8). Immunocytochemical analysis and Western blotting for some related molecules, including pancreatic ER stress kinase (PERK), p-PERK, eukaryotic initiation factor 2 SB431542 alpha (eIF2 alpha), p-eIF2 alpha, activating transcription FER factor 4 (ATF4), caspase-12, were examined. Caspase activation and apoptosis were detected in neonatal rat astrocytes from spinal cord subjected to OGSD/restoration. We also observed an increase
in cytoplasmic staining of p-eIF2 alpha in astrocytes (8 h OGSD/15 min restoration) compared with that of non-treated cells. In addition, we found the sequential activation of PERK, eIF2 alpha, and ATF4 during OGSD/restoration by Western blotting. These results indicate that both the PERK/eIF2 alpha/ATF4 ISR and activation of caspase-12 may be involved in apoptosis of spinal cord astrocytes induced by OGSD/restoration. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“The DA strain and other members of the TO subgroup of Theiler’s murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection associated with an inflammatory white matter demyelinating disease. TO subgroup strains synthesize an 18-kDa protein, L*, out of frame with the polyprotein from an initiation codon 13 nucleotides downstream from the polyprotein’s AUG codon. We previously generated a mutant virus from our infectious DA full-length clone that has a change of the L* AUG codon to ACG (with no change in the polyprotein’s amino acid sequence). Studies of this mutant virus showed that L* was key to the TO subgroup phenotype because the mutant had a decreased ability to persist and demyelinate.
Comparison was made with control data of our laboratory. Dysarthria was the presenting symptom in 5 patients (38.5%) and chorea, tremors,
dystonia and abnormal gait in 2 patients each (15.4%). RMT was recordable in 10 patients and not recordable in 3. Compared to controls, patients in whom RMT was recordable, had significantly higher mean RMT (80.9 Selumetinib +/- 14.8 vs. 41.1 +/- 7, p < 0.0001) and CMCT (6.7 +/- 0.5 ms vs. 4.8 +/- 0.6 ms; p < 0.0001). In 2 of the 3 patients with non-recordable RMT, MEP could be obtained with active contraction. CMCT in these 2 patients was also prolonged. Patients with WD have reduced cortical excitability and prolonged CMCT which may be due to the intracortical presynaptic LY294002 molecular weight motor dysfunction. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Scaffold proteins regulate intracellular MAP kinase signaling by providing critical spatial and temporal specificities. We have shown previously that the scaffold protein MEK1 partner (MP1) is localized to late endosomes by the adaptor protein p14. Using conditional gene disruption of p14 in livers of mice (p14(Delta heP)) we analyzed protein and transcript signatures in tissue samples. Further biological network analysis predicted that the differentially expressed transcripts and proteins are involved in cell cycle progression and regulation of cellular proliferation. Although some of the here identified signatures were previously linked
to phospho-ERK activity, most of them were novel targets of the late endosomal p14/MP1/MEK/ERK signaling module. Finally, the proliferation defect was confirmed in a chemically induced liver regeneration model in p14(Delta hep) knockout mice.”
address the prognostic value of minimal residual disease (MRD) before unrelated cord blood transplantation (UCBT) in children with acute lymphoblastic leukemia (ALL), we analyzed 170 ALL children transplanted in complete clonidine remission (CR) after myeloablative conditioning regimen. In all, 72 (43%) were in first CR (CR1), 77 (45%) in second CR (CR2) and 21 (12%) in third CR (CR3). The median interval from MRD quantification to UCBT was 18 days. All patients received single-unit UCBT. Median follow-up was 4 years. Cumulative incidence (CI) of day-60 neutrophil engraftment was 85%. CI of 4 years relapse was 30%, incidence being lower in patients with negative MRD before UCBT (hazard ratio (HR) = 0.4, P = 0.01) and for those transplanted in CR1 and CR2 (HR = 0.3, P = 0.002). Probability of 4 years leukemia-free survival (LFS) was 44%, (56, 44 and 14% for patients transplanted in CR1, CR2 and CR3, respectively (P = 0.0001)). Patients with negative MRD before UCBT had better LFS after UCBT compared with those with positive MRD (54% vs 29%; HR = 2, P = 0.003). MRD assessment before UCBT for children with ALL in remission allows identifying patients at higher risk of relapse after transplantation.
Materials and Methods: We searched ClinicalTrials.gov to identify novel agents for advanced renal cell carcinoma in ongoing phase
II/III clinical trials. Using the relevant agents as search terms we reviewed the medical literature for mechanisms of action and efficacy, and safety results to date, including data from recent major oncology meetings.
Results: A total of 11 novel targeted TSA HDAC chemical structure agents, including next generation tyrosine kinase inhibitors, and inhibitors of vascular endothelial growth factor ligand binding, Akt and endothelial cell proliferation, and 3 novel immunomodulatory agents, are under evaluation for renal cell carcinoma. In addition to ongoing phase II/III trials of emerging agents, head-to-head, crossover and combination trials of approved targeted agents are under way.
Conclusions: Although many agents are approved or in development for renal cell carcinoma, comparative effectiveness data are lacking. Ongoing and future head-to-head trials using appropriate comparators are essential to update renal cell carcinoma treatment guidelines. Future research should be aimed at identifying agents that improve patient outcomes and have decreased toxicity compared
with currently approved agents with the goal of complete remission.”
“Insight impairment is common early in the course of psychosis. Most studies have focused on the relationship between insight and depression, although manic symptoms are also frequent in psychoses. The main aim of this study was to examine the relationship GNS-1480 clinical trial between insight dimensions and manic and depressive symptoms in first-episode psychosis. A group of inpatients in their first psychotic episodes (n=124) were evaluated using the Scale to Assess Unawareness of Mental
Disorder. GBA3 Young Mania Rating Scale and Hamilton Depression Rating Scale. To study the effect of clinical, manic and depressive symptoms on insight, awareness of mental disorder, awareness of the achieved effects of medication, and awareness of the social consequences of having a mental disorder were modelled using ordinal logistic regression techniques. Results showed that greater awareness of mental disorder was significantly related to higher age at first episode together with higher scores for negative and depressive symptoms. The opposite was found to be true in presentations with a higher severity of disease and manic symptoms. The model fitting unawareness of the achieved effects of medication identified the same significant variables, except in the case of negative symptoms. Finally, the model assessing the social consequences of having a mental disorder showed unawareness to be greater when manic symptoms and disease severity were high. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Purpose: We describe the outcomes of undescended testes and sex development disorders in adolescence and young adulthood.
(c) 2007 Elsevier Ireland Ltd. All rights reserved.”
“Aims: Acid and heat tolerance of 17 persistent and 23 nonpersistent Listeria monocytogenes strains, recovered from three meat-processing plants, were investigated.
Methods and Results: The isolates were genotyped by pulsed-field gel electrophoresis and categorized into persistent strains according to the frequency of the strain and duration of the contamination. The persistent and nonpersistent strains
were challenged to acidic conditions (pH 2.4 for 2 h, 1 mol l(-1) HCl were used to acidify the suspension) and to heat (55 degrees C for 40 min) to receive a reduction in cell count. Listeria monocytogenes strains showed large variation in acid tolerance (over 6 log units) Histone Methyltransferase inhibitor and in heat tolerance (3 log units). The persistent strains showed higher tolerance to acidic conditions than the nonpersistent strains (Student’s t-test, P = 0.02), but significant differences in heat tolerance between persistent and nonpersistent strains were not observed.
Conclusions: The results indicate that acid tolerance may have an effect on the persistence of L. monocytogenes contamination.
Significance and Impact of the Study: This study highlights the fact that there are great differences in acid and heat tolerances between L. monocytogenes strains, and the preventive measures should be designed to be effective against the most
“It was discovered fifty years ago that a minced skeletal muscle replaced in its bed is able to regenerate. This regeneration is due to the presence of quiescent muscle precursor cells so-called satellite EPZ5676 solubility dmso cells in the adult muscle which proliferate and fuse to regenerate new centronucleated fibres when the muscle is damaged. These observations open therapeutic perspectives
and, in this study, we attempted to test in the mouse whether fragments of minced muscle regenerate new fibres to fill the gap resulting from the trans-section and retraction of the extensor digitorum longus muscle (EDL). When untreated this gap never regenerates. In agreement with Studitsky, we observed that a minced EDL replaced in its bed regenerates fibres that are spatially disorganised. Minced fragments of abdominus rectus muscle placed in the gap resulting of the trans-section of the EDL regenerate muscle fibres in the gap with a Chorioepithelioma better organisation that in the whole minced muscle. These results could have putative clinical applications, for instance in the prevention of incontinence following prostatectomy which implies removal excision of a large part of the striated urethral sphincter. (c) 2007 Elsevier Ireland Ltd. All rights reserved.”
“Children with Developmental Coordination Disorder (DCD) are reported to have high temporal variability in tasks requiring precise timing. The current study examined whether this timing deficit was due to the cerebellar ‘explicit timing’ process in the discontinuous, but not the continuous movement.
Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm
civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, Lenvatinib chemical structure apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals check details experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways
by which SARS-CoV infection induces changes in the host response, leading to death.”
“Conflict between sensory modalities can be resolved by one modality overwriting another. For example, movement of a limb that is visible in a stationary Demeclocycline visual afterimage results in selective fading of that limb in the afterimage. We investigated the interaction of these two sensory modalities by inducing a mismatch between visual and proprioceptive hand location. Whereas this discrepancy did not affect the initial appearance of the hand in the afterimage, it did prevent subsequent
motion with the hand from affecting the hand’s appearance. Location mismatch disconnected the visual and proprioceptive experiences of the hand, “”protecting”" the visual afterimage from interaction with proprioception. Investigation of subjective higher order bodily experiences showed a strong negative correlation between afterimage disruption and the subjective feeling of ownership, suggesting that the brain can resolve multimodal location mismatch by ‘disowning’ a visible limb, and that the interaction between proprioception and vision is mediated by higher order bodily experiences. (C) 2009 Elsevier Ltd. All rights reserved.”
“Avian H7 influenza viruses have been responsible for poultry outbreaks worldwide and have resulted in numerous cases of human infection in recent years.
Results: There were no significant differences between groups at baseline. Three patients in group A experienced either cerebrovascular or cardiac ischemic attacks, while two patients in group B underwent coronary angioplasty during follow-up. Group B showed a more pronounced improvement in total cholesterol and LDL-cholesterol compared with group A (P < .05). Moreover, atorvastatin treatment suppressed serum hsCRP, OPN, and OPG ATM inhibitor levels from baseline in both groups (P < .001). Notably,
aggressive treatment decreased OPN (P = .012) and OPG (P = .025) levels to a greater degree compared with moderate treatment. Similarly, GSM score was remarkably increased in both groups, but that augmentation was greater in group B (from 66.39 +/- 23.66 to 100.4 +/- 25.31) than in group A (from 64.4 +/- 23.62 to 85.39 +/- 20.21) (P = .024). No change in the degree of carotid stenosis was noted in both treatment arms. Importantly, the aforementioned GSK461364 mouse reduction in OPN (r = -0.517, P = .024) and OPG (r = -0.312, P = .008) levels was inversely associated with GSM score changes in univariate and standard multiple regression analysis (R(2) = 0.411, P = .021).
Conclusions: Among patients with moderate carotid stenosis, an aggressive atorvastatin regimen enhanced carotid plaque echogenicity and reduced serum
OPN and OPG levels to a greater extent than respective moderate atorvastatin therapy. Most importantly, those atorvastatin-induced effects were associated with Methane monooxygenase OPN and OPG suppression in a dose-dependent manner. (J Vase Surg 2010;51:114-21.)”
“Bupivacaine is one of the amide type local anesthetics and is widely used for epidural anesthesia and blockade of nerves. Bupivacaine administration locally could result in neuron injury showing transient neurologic symptoms. Dexamethasone is a synthetic glucocorticoid and may exert cytoprotective properties against damage induced by some stimuli. In the present study,
we evaluated the effects of dexamethasone on bupivacaine-induced toxicity in mouse neuroblastoma N2a cells. N2a cells were exposed to bupivacaine in the presence or absence of dexamethasone. After treatment, the cell viability, nuclear condensation, and lactate dehydrogenase levels were evaluated. Mitochondrial potential and Akt (threonine serine protein kinase B) activation were also examined. In a separate experiment, we examined the effect of Akt inhibition by triciribine on cell viability following dexamethasone treatment. We also investigated whether dexamethasone could prevent lidocaine-induced neurotoxicity. Treatment of N2a cells with bupivacaine resulted in significant cell injury as evidenced by morphological changes, LDH leakage, and nuclear condensation. Pretreatment of the cells with dexamethasone significantly attenuated bupivacaine- and lidocaine-induced cell injury.