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Find video protocols related to scientific articles indexed in Pubmed.
Cerebellar secretin modulates eyeblink classical conditioning.
Learn. Mem.
PUBLISHED: 12-01-2014
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We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1-3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1-2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1-2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel ?-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell-Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites.
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Fitting a distribution to censored contamination data using markov chain monte carlo methods and samples selected with unequal probabilities.
Environ. Sci. Technol.
PUBLISHED: 10-31-2014
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The fitting of statistical distributions to chemical and microbial contamination data is a common application in risk assessment. These distributions are used to make inferences regarding even the most pedestrian of statistics, such as the population mean. The reason for the heavy reliance on a fitted distribution is the presence of left-, right-, and interval-censored observations in the data sets, with censored observations being the result of nondetects in an assay, the use of screening tests, and other practical limitations. Considerable effort has been expended to develop statistical distributions and fitting techniques for a wide variety of applications. Of the various fitting methods, Markov Chain Monte Carlo methods are common. An underlying assumption for many of the proposed Markov Chain Monte Carlo methods is that the data represent independent and identically distributed (iid) observations from an assumed distribution. This condition is satisfied when samples are collected using a simple random sampling design. Unfortunately, samples of food commodities are generally not collected in accordance with a strict probability design. Nevertheless, pseudosystematic sampling efforts (e.g., collection of a sample hourly or weekly) from a single location in the farm-to-table continuum are reasonable approximations of a simple random sample. The assumption that the data represent an iid sample from a single distribution is more difficult to defend if samples are collected at multiple locations in the farm-to-table continuum or risk-based sampling methods are employed to preferentially select samples that are more likely to be contaminated. This paper develops a weighted bootstrap estimation framework that is appropriate for fitting a distribution to microbiological samples that are collected with unequal probabilities of selection. An example based on microbial data, derived by the Most Probable Number technique, demonstrates the method and highlights the magnitude of biases in an estimator that ignores the effects of an unequal probability sample design.
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Re Jamie (no 2): A positive development for transgender young people.
J Law Med
PUBLISHED: 10-25-2014
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Re Jamie (No 2) is an important decision of the Full Family Court that significantly clarifies the law concerning "special medical procedures". The court has held that so-called stage one treatment for gender dysphoria, designed to suppress pubertal development, no longer requires judicial approval. The decision contains an important endorsement of the view that the phenomenon of gender dysphoria could be de-pathologised. Crucially, the decision also confirms that if a young person is found to be Gillick competent, the court has no power to override their treatment decisions. However, given the consequences of such treatment, and consistently with the authority in Marion's Case, the court will continue to have a "safeguard" role in determining whether Gillick competence exists. The article outlines some cautionary notes about the removal of court oversight at stage one, but argues that the decision is a positive one for enabling access to treatment and ameliorating the financial burden of legal proceedings on the families of transgender adolescents.
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Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe haemophilia A, 2000-2011.
Blood
PUBLISHED: 10-24-2014
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The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe haemophilia A previously untreated patients born in the UK between 1/January/2000 and 31/December/2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Since exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titre, after a median (interquartile range) 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate Nexgen 45 (35.2%, 95% CI 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95%CI 18.6-31.4%) with Advate (P=0.04). The adjusted hazard ratio (95% CI) for Kogenate Bayer/Helixate Nexgen compared to Advate was 2.14 (1.12-4.10), P=0.02 for high titre and 1.75 (1.11-2.76), P=0.02 for all inhibitors. When excluding UK-RODIN patients the adjusted HR (95% CI) for high titre inhibitors was 2.00 (0.93-4.34), P=0.08. ReFacto AF was associated with a higher incidence of all, but not high titre, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands.
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Development and characterization of a mantle cell lymphoma cell bank in the American Type Culture Collection.
Leuk. Lymphoma
PUBLISHED: 10-16-2014
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ABSTRACT Mantle cell lymphoma (MCL) is a rare B-cell malignancy that carries a relatively poor prognosis compared to other forms of non-Hodgkin's lymphoma. Standardized preclinical tools are desperately required to hasten the discovery and translation of promising new treatments for MCL. Through an initiative organized through the Mantle Cell Lymphoma Consortium and the Lymphoma Research Foundation, we gathered MCL cell lines from laboratories around the world to create a characterized MCL cell bank at the American Type Culture Collection (ATCC). Initiated in 2006, this collection now contains 8 cell lines, all of which have been rigorously characterized and are now stored and available for distribution to the general scientific community. We believe the awareness and use of these standardized cell lines will decrease variability between investigators, harmonize international research efforts, improve our understanding of the pathogenesis of the disease, and hasten the development of novel treatment strategies.
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Assessing spatial learning and memory in rodents.
ILAR J
PUBLISHED: 09-17-2014
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Maneuvering safely through the environment is central to survival of almost all species. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and nearby proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures; in humans this system encodes allocentric, semantic, and episodic memory. This form of memory is assessed in laboratory animals in many ways, but the dominant form of assessment is the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and, when overlearned, becomes procedural memory. In this article, several allocentric assessment methods for rodents are reviewed and compared with the MWM. MWM advantages (little training required, no food deprivation, ease of testing, rapid and reliable learning, insensitivity to differences in body weight and appetite, absence of nonperformers, control methods for proximal cue learning, and performance effects) and disadvantages (concern about stress, perhaps not as sensitive for working memory) are discussed. Evidence-based design improvements and testing methods are reviewed for both rats and mice. Experimental factors that apply generally to spatial navigation and to MWM specifically are considered. It is concluded that, on balance, the MWM has more advantages than disadvantages and compares favorably with other allocentric navigation tasks.
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Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster.
PLoS Genet.
PUBLISHED: 09-04-2014
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In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2? and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2? and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2? and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2? may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.
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Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.
J. Clin. Oncol.
PUBLISHED: 08-25-2014
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In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR.
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Toll-Like Receptor 3 Activation Is Required for Normal Skin Barrier Repair Following UV Damage.
J. Invest. Dermatol.
PUBLISHED: 08-12-2014
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UV damage to the skin leads to the release of noncoding RNA (ncRNA) from necrotic keratinocytes that activates Toll-like receptor 3 (TLR3). This release of ncRNA triggers inflammation in the skin following UV damage. Recently, TLR3 activation was also shown to aid wound repair and increase the expression of genes associated with permeability barrier repair. Here, we sought to test whether skin barrier repair after UVB damage is dependent on the activation of TLR3. We observed that multiple ncRNAs induced expression of skin barrier repair genes, that the TLR3 ligand Poly (I:C) also induced expression and function of tight junctions, and that the ncRNA U1 acts in a TLR3-dependent manner to induce expression of skin barrier repair genes. These observations were shown to have functional relevance as Tlr3(-/-) mice displayed a delay in skin barrier repair following UVB damage. Combined, these data further validate the conclusion that recognition of endogenous RNA by TLR3 is an important step in the program of skin barrier repair.Journal of Investigative Dermatology advance online publication, 18 September 2014; doi:10.1038/jid.2014.354.
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Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies.
Neurotoxicol Teratol
PUBLISHED: 08-10-2014
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Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed.
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Prevalence of masked hypertension in african americans.
J Clin Hypertens (Greenwich)
PUBLISHED: 07-28-2014
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Masked hypertension (MH), the presence of normal office blood pressure (BP) with elevated ambulatory pressure, has been shown to correlate with organ damage. Population-based studies from Europe and Asia estimate a prevalence of 8.5% to 15.8%. Two small studies in African Americans estimate a prevalence >40%. Therefore, the authors utilized ambulatory BP monitoring (ABPM) to identify the prevalence of MH in our African American population. Pressure was recorded every 30 minutes while awake and every 60 minutes while asleep. Patients with 24-hour average BP ?135/85 mm Hg, awake average BP ?140/90 mm Hg, or asleep average BP ?125/75 mm Hg had MH. Seventy-three participates had valid data. The mean age of the patients was 49.8 years, mean body mass index was 31.1, and 39 patients (53%) were women. Thirty-three patients (45.2%) had MH. Patients with MH had higher clinic systolic BP and trended toward higher BMI values. The authors corroborated the high prevalence of MH in African Americans. ABPM is critical to diagnose hypertension in African Americans, particularly in those with high-normal clinic pressure and obesity.
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Pdx1 (GFP/w) mice for isolation, characterization, and differentiation of pancreatic progenitor cells.
Methods Mol. Biol.
PUBLISHED: 07-28-2014
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It is well known that human cells are diverse with respect to their epigenome, transcriptome, and proteome. In the context of regenerative medicine, it is important for the transplanted cells or tissues to faithfully recapitulate their intended tissue type in each of these respects. Whether the cells chosen for such an application are embryonic, postnatal, or induced pluripotent stem cells, the transplanted product must behave in a predictable and reliable manner to be a safe and effective treatment option. Irrespective of the choice of cells used in such an application, the characterization and understanding of the developmental cues responsible for establishing and maintaining the desired cell phenotype are essential.Animal models are extremely important in understanding the development of a specific tissue, which can then be subsequently extrapolated to human studies. Generation of transgenic animal models with whole-body gene knockout, conditional knockout, constitutive fluorescent gene reporters, and Cre-Lox-based conditional and lineage reporters has revolutionized the field of developmental biology. An intrinsically complex network of the actions and interactions of the multitude of different signalling cascades is required for development. A thorough understanding of such networks, gained through studies on transgenic animal models, is essential for the development of the techniques necessary to reliably differentiate a given stem or progenitor cell population into a specific cell type, such as an islet-like, insulin-producing cell aggregate.In this chapter, we describe the use of GFP (green fluorescent protein)-based reporter mice for isolation of cells of choice, analyzing gene expression in those cells as well as their use for screening signalling molecules to understand their effect on differentiation.
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Automated synthesis of 18F-fluoropropoxytryptophan for amino acid transporter system imaging.
Biomed Res Int
PUBLISHED: 07-20-2014
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This study was to develop a cGMP grade of [(18)F]fluoropropoxytryptophan ((18)F-FTP) to assess tryptophan transporters using an automated synthesizer.
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The prevalence of age-related macular degeneration in Alzheimer's disease.
J. Alzheimers Dis.
PUBLISHED: 07-16-2014
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Age-related macular degeneration (AMD) and Alzheimer's disease (AD) share several features, including the presence of extracellular abnormal deposits associated with neuronal degeneration, drusen, and plaques, respectively. Investigation of any association of AMD and specifically AD is worthwhile but has rarely been done.
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Elevated expression of IL-23/IL-17 pathway-related mediators correlates with exacerbation of pulmonary inflammation during polymicrobial sepsis.
Shock
PUBLISHED: 07-01-2014
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Sepsis is a leading cause of death in the United States, claiming more than 215,000 lives every year. A primary condition observed in septic patients is the incidence of acute respiratory distress syndrome, which is characterized by the infiltration of neutrophils into the lung. Prior studies have shown differences in pulmonary neutrophil accumulation in C57BL/6J (B6) and A/J mice after endotoxic and septic shock. However, the mechanism by which neutrophils accumulate in the lung after polymicrobial sepsis induced by cecal ligation and puncture still remains to be fully elucidated. We show in this study that lung inflammation, characterized by neutrophil infiltration and expression of inflammatory cytokines, was aggravated in B6 as compared with A/J mice and correlated with a high expression of p19, the interleukin 23 (IL-23)-specific subunit. Furthermore, lipopolysaccharide stimulation of B6- and A/J-derived macrophages, one of the main producers of IL-23 and IL-12, revealed that B6 mice favored the production of IL-23, whereas A/J-derived macrophages expressed higher levels of IL-12. In addition, expression of IL-17, known to be upregulated by IL-23, was also more elevated in the lung of B6 mice when compared with that in the lung of A/J mice. In contrast, pulmonary expression of interferon-? was much more pronounced in A/J than that in B6 mice, which was most likely a result of a higher production of IL-12. The expression of the IL-17-dependent neutrophil recruitment factors chemokine (CXC motif) ligand 2 and granulocyte colony-stimulating factor was also higher in B6 mice. Altogether, these results suggest that increased activation of the IL-23/IL-17 pathway has detrimental effects on sepsis-induced lung inflammation, whereas activation of the IL-12/interferon-? pathway may lead, in contrast, to less pronounced inflammatory events. These two pathways may become possible therapeutic targets for the treatment of sepsis-induced acute respiratory distress syndrome.
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Evaluating big deal journal bundles.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 06-16-2014
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Large commercial publishers sell bundled online subscriptions to their entire list of academic journals at prices significantly lower than the sum of their á la carte prices. Bundle prices differ drastically between institutions, but they are not publicly posted. The data that we have collected enable us to compare the bundle prices charged by commercial publishers with those of nonprofit societies and to examine the types of price discrimination practiced by commercial and nonprofit journal publishers. This information is of interest to economists who study monopolist pricing, librarians interested in making efficient use of library budgets, and scholars who are interested in the availability of the work that they publish.
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Consent versus scrutiny: restricting liberties in post-Bournewood Victoria.
J Law Med
PUBLISHED: 05-09-2014
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The article considers the problem of people with impaired capacity who face restrictions on their liberty but who are compliant with such practices. The issue has bedevilled courts and law reform commissions throughout the common law world since HL v United Kingdom [2004] ECHR 471 exposed the legal "gap" in which such people were languishing. Proposals to address it have either been excessively complex, or largely concerned with the mechanism for lawful consent to restrictive practices rather than scrutinising the practices themselves. The article critically discusses these proposals and argues that a suitable, if not ideal, regime for regulating the problem already exists in the Victorian Disability Act 2006.
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Comment: the trouble with "n" in normal-pressure hydrocephalus.
Neurology
PUBLISHED: 03-14-2014
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Idiopathic normal-pressure hydrocephalus (iNPH) is a reversible syndrome of gait impairment, dementia, and incontinence that affects persons over 65 years of age.(1) Currently, the only effective treatment is surgical implantation of a shunt(2); however, the need for pharmacologic adjunctive treatments was noted at the 2005 NIH workshop on hydrocephalus.(3.)
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Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury.
Hepatology
PUBLISHED: 02-25-2014
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In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2(+/) (-) 4(+/) (-) , and St8sia2(-) (/) (-) 4(-) (/) (-) ). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2(+/) (-) 4(+/) (-) and St8sia2(-) (/) (-) 4(-) (/) (-) mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM(+) cells. Subsequent to injury, NCAM(+) cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma.
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The Drosophila Kctd-family homologue Kctd12-like modulates male aggression and mating behaviour.
Eur. J. Neurosci.
PUBLISHED: 02-14-2014
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In Drosophila, serotonin (5-HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor (GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5-HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like (Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5-HT receptor 5-HT7, and we observed that both Ktl and the 5-HT1A receptor are required in insulin-producing cells (IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5-HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5-HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5-HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour.
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Absolute quantification of apolipoproteins and associated proteins on human plasma lipoproteins.
J Proteomics
PUBLISHED: 01-20-2014
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Lipoprotein-associated proteins form an intrinsic part of the major plasma lipoprotein classes. There is increasing evidence that the quantity of these proteins per lipoprotein particle determines lipoprotein function including redox, inflammatory and thrombotic properties and may impact on lipoprotein-related risks for developing heart disease. However, only limited information on the relative quantity of these proteins has been published and no comprehensive absolute quantitative data providing the stoichiometry of proteins associated with lipoproteins is available to date. To address this, we performed extensive absolute quantification by mass spectrometry of 17 lipoprotein-associated proteins on VLDL, LDL, Lp(a) and HDL from healthy subjects. For the first time we show the exact stoichiometry of apolipoproteins on different lipoprotein classes. The most distinct differences were seen in the abundance of all apoCs, apoE and apoF. We further revealed strong variations between individual samples, which indicates the complexity of the protein complement of lipoproteins and can provide additional insights into lipoprotein-related risk factors. This approach has the potential to determine alterations in the protein profiles of lipoproteins in disease states such as CVD or diabetes and, if performed on large cohorts, to translate into a tool for identifying new candidate biomarkers for risk of disease.
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The Drosophila small GTPase Rac2 is required for normal feeding and mating behaviour.
Behav. Genet.
PUBLISHED: 01-17-2014
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All multicellular organisms require the ability to regulate bodily processes in order to maintain a stable condition, which necessitates fluctuations in internal metabolics, as well as modifications of outward behaviour. Understanding the genetics behind this modulation is important as a general model for the metabolic modification of behaviour. This study demonstrates that the activity of the small GTPase Rac2 is required in Drosophila for the proper regulation of lipid storage and feeding behaviour, as well as aggression and mating behaviours. Rac2 mutant males and females are susceptible to starvation and contain considerably less lipids than controls. Furthermore, Rac2 mutants also have disrupted feeding behaviour, eating fewer but larger meals than controls. Intriguingly, Rac2 mutant males rarely initiate aggressive behaviour and display significantly increased levels of courtship behaviour towards other males and mated females. From these results we conclude that Rac2 has a central role in regulating the Drosophila homeostatic system.
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Complement inhibitors for age-related macular degeneration.
Cochrane Database Syst Rev
PUBLISHED: 01-17-2014
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Given the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD.
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Kaolin-induced ventriculomegaly at weaning produces long-term learning, memory, and motor deficits in rats.
Int. J. Dev. Neurosci.
PUBLISHED: 01-03-2014
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Ventriculomegaly occurs when there is imbalance between creation and absorption of cerebrospinal fluid (CSF); even when treated, long-term behavioral changes occur. Kaolin injection in the cisterna magna of rats produces an obstruction of CSF outflow and models one type of hydrocephalus. Previous research with this model shows that neonatal onset has mixed effects on Morris water maze (MWM) and motoric performance; we hypothesized that this might be because the severity of ventricular enlargement was not taken into consideration. In the present experiment, rats were injected with kaolin or saline on postnatal day (P)21 and analyzed in subgroups based on Evan's ratios (ERs) of the severity of ventricular enlargement at the end of testing to create 4 subgroups from least to most severe: ER0.4-0.5, ER0.51-0.6, ER0.61-0.7, and ER0.71-0.82, respectively. Locomotor activity (dry land and swimming), acoustic startle with prepulse inhibition (PPI), and MWM performance were tested starting on P28 (122cm maze) and again on P42 (244cm maze). Kaolin-treated animals weighed significantly less than controls at all times. Differences in locomotor activity were seen at P42 but not P28. On P28 there was an increase in PPI for all but the least severe kaolin-treated group, but no difference at P42 compared with controls. In the MWM at P28, all kaolin-treated groups had longer path lengths than controls, but comparable swim speeds. With the exception of the least severe group, probe trial performance was worse in the kaolin-treated animals. On P42, only the most severely affected kaolin-treated group showed deficits compared with control animals. This group showed no MWM learning and no memory for the platform position during probe trial testing. Swim speed was unaffected, indicating motor deficits were not responsible for impaired learning and memory. These findings indicate that kaolin-induced ventriculomegaly in rats interferes with cognition regardless of the final enlargement of the cerebral ventricles, but final size critically determines whether lasting locomotor, learning, and memory impairments occur.
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Estimating the correlation between concentrations of two species of bacteria with censored microbial testing data.
Int. J. Food Microbiol.
PUBLISHED: 01-02-2014
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Indicator organisms, such as generic Escherichia coli (GEC) and coliforms, can be used to measure changes in microbial contamination during the production of food products. Large and consistent reductions in the concentration of these organisms demonstrates an effective and well-controlled production process. Nevertheless, it is unclear to what degree concentrations of indicator organisms are related to pathogenic organisms such as Campylobacter and Salmonella on a sample-by-sample basis. If a strong correlation exists between the concentrations of different organisms, then the monitoring of indicator organisms would be a cost-effective surrogate for the measurement of pathogenic organisms. Calculating the correlation between the concentrations of an indicator and pathogenic organism is complicated because microbial testing datasets typically contain a large proportion of censored observations (i.e., samples where the true concentration is not observable, with nondetects and samples that are only screen-test positive being examples). This study proposes a maximum likelihood estimator that can be used to estimate the correlation between the concentrations of indicator and pathogenic organisms. An example based on broiler chicken rinse samples demonstrates modest, but significant positive correlations between the concentration of the indicator organism GEC when compared to the concentration of both Campylobacter and Salmonella. A weak positive correlation was also observed between concentrations of Campylobacter and Salmonella, but it was not statistically significant.
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Plasma heat shock protein 27 is associated with coronary artery disease, abdominal aortic aneurysm and peripheral artery disease.
Springerplus
PUBLISHED: 01-01-2014
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Low protein levels of Hsp27 have been reported in atherosclerotic plaques. In addition, human studies have indicated that circulating Hsp27 levels are lower in coronary artery disease patients compared with controls. It remains, however, unclear whether this applies to other forms of atherosclerotic disease. Plasma Hsp27 from 280 subjects was examined by ELISA. The cohort included 80 coronary artery disease (CAD), 40 peripheral artery disease (PAD) and 80 abdominal aortic aneurysm (AAA) patients. Eighty elderly subjects, without any clinical history of vascular diseases, were used as a control group. Receiver operating curve (ROC) and logistic regression model analysis were performed to evaluate the potential value of Hsp27 as a circulating biomarker. Patients with atherosclerotic vascular diseases had significantly lower levels of Hsp27 than control subjects (p?
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A computerized neuropsychological test battery designed for idiopathic normal pressure hydrocephalus.
Fluids Barriers CNS
PUBLISHED: 01-01-2014
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A tool for standardized and repeated neuropsychological assessments in patients with idiopathic normal pressure hydrocephalus (INPH) is needed. The objective of this study was to develop a computerized neuropsychological test battery designed for INPH and to evaluate its reliability, validity and patient's ability to complete the tests.
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Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.
PLoS ONE
PUBLISHED: 01-01-2014
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A set of 14 insulin-producing cells (IPCs) in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5). Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.
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The management of acute coronary syndrome patients across New Zealand in 2012: results of a third comprehensive nationwide audit and observations of current interventional care.
N. Z. Med. J.
PUBLISHED: 12-24-2013
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To audit all patients admitted to a New Zealand (NZ) Hospital with a suspected or definite acute coronary syndrome (ACS) over a 14-day period, to assess their presentation type and management in hospital and at discharge, with emphasis on time delays for invasive management and revascularisation treatments.
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Transplantation for mantle cell lymphoma: is it the right thing to do?
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-10-2013
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Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab + a high-dose cytarabine-containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab + bendamustine, or R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.
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Diagnosis and management of idiopathic normal-pressure hydrocephalus.
Neurol Clin Pract
PUBLISHED: 11-01-2013
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The diagnosis and management of idiopathic normal-pressure hydrocephalus (iNPH), a disorder of gait impairment, incontinence, and dementia that affects elderly patients, incorporates an organized approach using familiar principles for neurologists. The starting point is a comprehensive history and neurologic examination, review of neuroimaging, and evaluation of the differential diagnosis. Coexisting disorders should be treated before specific iNPH testing is performed. Specific iNPH testing includes assessing patient response to temporary CSF removal and testing CSF hydrodynamics. In properly selected patients, all iNPH symptoms, including dementia, can improve after shunt surgery. The longitudinal care of iNPH patients with shunts includes evaluation of the differential diagnosis of worsening iNPH symptoms and treatment of coexisting disorders. Evaluation of shunt obstruction is often indicated, and if it is found, surgical correction is likely to result in symptomatic improvement.
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Replicated, replicable and relevant-target engagement and pharmacological experimentation in the 21st century.
Biochem. Pharmacol.
PUBLISHED: 10-29-2013
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A pharmacological experiment is typically conducted to: i) test or expand a hypothesis regarding the potential role of a target in the mechanism(s) underlying a disease state using an existing drug or tool compound in normal and/or diseased tissue or animals; or ii) characterize and optimize a new chemical entity (NCE) targeted to modulate a specific disease-associated target to restore homeostasis as a potential drug candidate. Hypothesis testing necessitates an intellectually rigorous, null hypothesis approach that is distinct from a high throughput fishing expedition in search of a hypothesis. In conducting an experiment, the protocol should be transparently defined along with its powering, design, appropriate statistical analysis and consideration of the anticipated outcome (s) before it is initiated. Compound-target interactions often involve the direct study of phenotype(s) unique to the target at the cell, tissue or animal/human level. However, in vivo studies are often compromised by a lack of sufficient information on the compound pharmacokinetics necessary to ensure target engagement and also by the context-free analysis of ubiquitous cellular signaling pathways downstream from the target. The use of single tool compounds/drugs at one concentration in engineered cell lines frequently results in reductionistic data that have no physiologically relevance. This overview, focused on trends in the peer-reviewed literature, discusses the execution and reporting of experiments and the criteria recommended for the physiologically-relevant assessment of target engagement to identify viable new drug targets and facilitate the advancement of translational studies.
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Regulation of Aggression by Obesity-Linked Genes TfAP-2 and Twz Through Octopamine Signaling in Drosophila.
Genetics
PUBLISHED: 10-18-2013
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In Drosophila the monoamine octopamine, through mechanisms that are not completely resolved, regulates both aggression and mating behavior. Interestingly, our study demonstrates that the Drosophila obesity-linked homologues Transcription factor AP-2 (TfAP-2, TFAP2B in humans) and Tiwaz (Twz, KCTD15 in humans) interact to modify male behavior by controlling the expression of Tyramine ?-hydroxylase (Tbh) and Vesicular monanime transporter (Vmat), genes necessary for octopamine production and secretion. Furthermore, we reveal that octopamine in turn regulates aggression through the Drosophila cholecystokinin (CCK) satiation hormone homologue Drosulfakinin (Dsk). Finally, we establish that TfAP-2 is expressed in octopaminergic neurons known to control aggressive behaviour and that TfAP-2 requires functional Twz for its activity. We conclude that genetically manipulating the obesity-linked homologues TfAP-2 and Twz is sufficient to affect octopamine signalling, which in turn modulates Drosophila male behavior through the regulation of the satiation hormone Dsk.
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Translational paradigms in pharmacology and drug discovery.
Biochem. Pharmacol.
PUBLISHED: 10-16-2013
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The translational sciences represent the core element in enabling and utilizing the output from the biomedical sciences and to improving drug discovery metrics by reducing the attrition rate as compounds move from preclinical research to clinical proof of concept. Key to understanding the basis of disease causality and to developing therapeutics is an ability to accurately diagnose the disease and to identify and develop safe and effective therapeutics for its treatment. The former requires validated biomarkers and the latter, qualified targets. Progress has been hampered by semantic issues, specifically those that define the end product, and by scientific issues that include data reliability, an overt reductionistic cultural focus and a lack of hierarchically integrated data gathering and systematic analysis. A necessary framework for these activities is represented by the discipline of pharmacology, efforts and training in which require recognition and revitalization.
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Exposure to Bisphenol A Affects Lipid Metabolism in Drosophila melanogaster.
Basic Clin. Pharmacol. Toxicol.
PUBLISHED: 09-26-2013
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Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin-like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.
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MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia.
Sci Transl Med
PUBLISHED: 09-20-2013
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Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.
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The fall and rise of pharmacology - (Re-)defining the discipline?
Biochem. Pharmacol.
PUBLISHED: 09-07-2013
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Pharmacology is an integrative discipline that originated from activities, now nearly 7000 years old, to identify therapeutics from natural product sources. Research in the 19th Century that focused on the Law of Mass Action (LMA) demonstrated that compound effects were dose-/concentration-dependent eventually leading to the receptor concept, now a century old, that remains the key to understanding disease causality and drug action. As pharmacology evolved in the 20th Century through successive biochemical, molecular and genomic eras, the precision in understanding receptor function at the molecular level increased and while providing important insights, led to an overtly reductionistic emphasis. This resulted in the generation of data lacking physiological context that ignored the LMA and was not integrated at the tissue/whole organism level. As reductionism became a primary focus in biomedical research, it led to the fall of pharmacology. However, concerns regarding the disconnect between basic research efforts and the approval of new drugs to treat 21st Century disease tsunamis, e.g., neurodegeneration, metabolic syndrome, etc. has led to the reemergence of pharmacology, its rise, often in the semantic guise of systems biology. Against a background of limited training in pharmacology, this has resulted in issues in experimental replication with a bioinformatics emphasis that often has a limited relationship to reality. The integration of newer technologies within a pharmacological context where research is driven by testable hypotheses rather than technology, together with renewed efforts in teaching pharmacology, is anticipated to improve the focus and relevance of biomedical research and lead to novel therapeutics that will contain health care costs.
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Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.
J. Clin. Oncol.
PUBLISHED: 09-03-2013
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Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib.
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Low back pain following a fall.
J Orthop Sports Phys Ther
PUBLISHED: 07-31-2013
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The patient was a 29-year-old man who presented to an emergency department with a chief complaint of low back pain. Symptom onset occurred 3 weeks earlier, following a fall off a roof. The physician ordered radiographs of the thoracic and lumbar spines, which were interpreted as normal. After receiving the results of the radiographs, the physician referred the patient to a physical therapist working in the emergency department. Because of the strong suspicion for a fracture and because radiographs are not considered to be sensitive to some of the bony changes associated with fractures,1 computed tomography imaging of the thoracic and lumbar spines was ordered. The computed tomography imaging revealed multilevel, small end-plate compression defects, most marked at T12-L1, with mild anterior wedging and retropulsion of a small bone fragment at L1.
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Defining and characterizing drug/compound function.
Biochem. Pharmacol.
PUBLISHED: 07-22-2013
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The receptor concept, now more than century old, remains the core concept in understanding the mechanisms of disease causality and drug action. Originally formulated in the early 1900s, receptor theory has evolved in both detail and complexity as the tools of molecular biology and increasingly sophisticated research technologies have facilitated the study of drug/ligand receptor interactions at the molecular level. The result has been a more detailed and nuanced understanding of the parameters of drug action that together with knowledge of the pleotropic nature of cellular targets and associated signaling pathways has reshaped the receptor concept. Added to the basic agonist/antagonist view of drug/ligand function, concepts like allosterism, inverse agonism, biased signaling and compound residence time have provided a broader understanding of compound-target interactions to better inform drug discovery efforts. The iteration of descriptive data from pharmacological experiments to provide generic indices of affinity and efficacy can now be used to predict expected drug/compound effects in other cell/organ systems where the sensitivity of the latter to drug effects (either via expression levels of cell surface receptors or variances in the efficiency with which those receptors are coupled to cytosolic metabolic processes) can be accommodated.
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Links Between Hepatic Fibrosis, Ductular Reaction, and Progenitor Cell Expansion.
Gastroenterology
PUBLISHED: 07-16-2013
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Interactions between cells and their extracellular matrix have been shown to be crucial in a wide range of biological processes, including the proliferation and differentiation of stem cells. Ductular reactions containing both hepatic progenitor cells and extracellular matrix are seen in response to acute severe and chronic liver injury. Understanding the molecular mechanisms whereby cell-matrix interactions regulate liver regeneration may allow novel strategies to enhance this process. Both the ductular reaction in humans and hepatic progenitor cells in rodent models are closely associated with collagen and laminin, although there is still debate about cause and effect. Recent studies have shown a requirement for matrix remodeling by matrix metalloproteinases for the proliferation of hepatic progenitor cells and suggested defined roles for specific matrix components. Understanding the interactions between progenitor cells and matrix is critical for the development of novel regenerative and antifibrotic therapies.
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Animal models of asthma: Reprise or reboot?
Biochem. Pharmacol.
PUBLISHED: 06-21-2013
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Animal models of disease represent the pinnacle of hierarchical research efforts to validate targets and compounds for therapeutic intervention. Yet models of asthma, particularly in the mouse, which, for practical reasons, has become the sine qua non of asthma research, have been a bone of contention for decades. With barely a nod to their limitations and an extensive history of translational failures, they continue to be used for target identification and to justify the clinical evaluation of new compounds. Recent improvements - including sensitization directly to the airways; use of more relevant allergens; development of a chronic rather than short-term condition; utilization of techniques to measure lung function beyond uninterpretable measures of airway hyperresponsiveness - are laudable but cannot bridge the chasm between the models and the myriad complexities of the human disorder and multiple asthma endophenotypes. While further model developments are necessary, including recognition of key environmental factors beyond allergens, the judicious integration with newer ex vivo and in vitro techniques, including human precision-cut lung slices, reprograming of patient-derived induced pluripotent stem cells and fibroblasts to epithelial and smooth muscle cells, and use of other clinical samples to create a more holistic depiction of activities, might improve their translational success.
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Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.
N. Engl. J. Med.
PUBLISHED: 06-19-2013
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Brutons tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkins lymphoma, including mantle-cell lymphoma.
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Antioxidants and diabetic retinopathy.
Curr. Diab. Rep.
PUBLISHED: 05-08-2013
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The biochemical perturbations in diabetes mellitus (DM) create the conditions for the production of free radicals, the consequence of which is increased oxidative stress. Evidence has accrued over the past 2 decades that suggests that oxidative stress is an important pathogenetic factor in the development of diabetic retinopathy (DR). Experimental data show that the use of strategies that ameliorate oxidative stress can prevent and retard the development of DR in the animal model. Clinical observations also suggest that reducing oxidative stress may help to reverse pathological manifestations of DR. The present article constitutes an examination of the role of antioxidants in the management of DR and the current state of clinically relevant knowledge.
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Wernickes Encephalopathy: An Unusual Consequence of the Acquired Immune Deficiency Syndrome-Case Report and Literature Review.
Case Rep Med
PUBLISHED: 04-24-2013
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Introduction. Wernickes encephalopathy is a well-described syndrome characterized by the classic triad of confusion, ataxia, and ophthalmoplegia. Wernickes encephalopathy results from thiamine (vitamin B1) deficiency. Common causes include alcoholism and gastric disorders. Wernickes has been described in patients with acquired immune deficiency syndrome (AIDS); however, given these patients immunosuppressed state, the diagnosis of Wernickes encephalopathy is not apparent. Case Presentation. A 31-year-old previously healthy male presented to the ER complaining of progressive dyspnea. Workup revealed HIV/AIDS and PCP pneumonia. He was treated and improved. On day 14 he became confused and developed nystagmus and ataxia. Considering his immunocompromised state, infectious and neoplastic etiologies topped the differential diagnosis. CT head was negative. Lumbar puncture was unremarkable. Brain MRI revealed increased T2 signal in the medial thalamus bilaterally. Intravenous thiamine was administered resulting in resolution of symptoms. Discussion. The classic triad of Wernickes encephalopathy occurs in 10% of cases. When immunosuppressed patients develop acute neurologic symptoms infectious or neoplastic etiologies must be excluded. However, given the relative safety of thiamine supplementation, there should be a low threshold for initiating therapy in order to reverse the symptoms and prevent progression to Korsakoff dementia, which is permanent.
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Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care. A report of the ISHCSF task force on comorbidities in INPH.
Fluids Barriers CNS
PUBLISHED: 04-22-2013
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Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.
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Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-01-2013
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Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury. We therefore examined a model without injury; a single i.v. injection of unfractionated BMCs in healthy mice. This induced ductular reactions (DRs) in healthy mice. We demonstrate that macrophages within the unfractionated BMCs are responsible for the production of DRs, engrafting in the recipient liver and localizing to the DRs. Engrafted macrophages produce the cytokine TWEAK (TNF-like weak inducer of apoptosis) in situ. We go on to show that recombinant TWEAK activates DRs and that BMC mediated DRs are TWEAK dependent. DRs are accompanied by liver growth, occur in the absence of liver tissue injury and hepatic progenitor cells can be isolated from the livers of mice with DRs. Overall these results reveal a hitherto undescribed mechanism linking macrophage infiltration to DRs in the liver and highlight a rationale for macrophage derived cell therapy in regenerative medicine.
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Current and emerging therapies in mantle cell lymphoma.
Curr Treat Options Oncol
PUBLISHED: 03-21-2013
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Mantle Cell Lymphoma, characterized by the t(11;14)(q13; q32) chromosomal translocation and cyclin D1 expression, remains one of the most challenging lymphoma subtypes to treat. Therapy can be divided into treatment modalities for younger, stem cell transplant (SCT)-eligible patients vs older, SCT-ineligible patients. For clinically fit patients younger than 60-65 years of age we recommend cytarabine-containing induction and conditioning regimens such as Rituximab (R)-CHOP alternating with R-DHAP followed by autologous SCT consolidation. Elderly patients benefit from R-bendamustine or R-CHOP with maintenance rituximab following induction therapy, especially after R-CHOP. While standard chemoimmunotherapy provides high overall response rates, the responses are not durable and sequential therapies are thus necessary. MCL is proving to be sensitive to novel therapies that may in the near future become useful adjuncts to standard regimens. For example, bortezomib, lenalidomide, and temsirolimus each have single-agent efficacy in relapsed and refractory disease. Several targeted agents are emerging that likewise may transform management of MCL. The B-cell receptor pathway appears to be critical in the pathogenesis of MCL, and novel agents such as ibrutinib and idelalisib that target this signaling pathway are highly active in relapsed and refractory MCL. Similarly, cell cycle inhibitors targeting cyclin dependent kinases as well as HDAC inhibitors have shown promise in early studies.
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Recent advances in mantle cell lymphoma: report of the 2012 Mantle Cell Lymphoma Consortium Workshop.
Leuk. Lymphoma
PUBLISHED: 03-04-2013
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Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 and the t(11;14)(q13;q32) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. While a subset of patients have an indolent clinical course, the overall outcome for patients with MCL remains poor. There is no proven curative therapy, and no standard of care has been established for initial or subsequent lines of therapy. Several regimens are highly active in previously untreated patients, and recent research has led to improvements in currently available therapy. Moreover, investigational agents have recently demonstrated promising activity in clinical trials. A workshop was held to review recent data on MCL pathogenesis, novel molecular targets and alternative approaches to immunotherapy, and to discuss recent and ongoing clinical trials in MCL. The presentations are summarized in this article, which is intended to highlight areas of active investigation and identify important avenues for future research.
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Sample size guidelines for fitting a lognormal probability distribution to censored most probable number data with a Markov chain Monte Carlo method.
Int. J. Food Microbiol.
PUBLISHED: 03-01-2013
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Levels of pathogenic organisms in food and water have steadily declined in many parts of the world. A consequence of this reduction is that the proportion of samples that test positive for the most contaminated product-pathogen pairings has fallen to less than 0.1. While this is unequivocally beneficial to public health, datasets with very few enumerated samples present an analytical challenge because a large proportion of the observations are censored values. One application of particular interest to risk assessors is the fitting of a statistical distribution function to datasets collected at some point in the farm-to-table continuum. The fitted distribution forms an important component of an exposure assessment. A number of studies have compared different fitting methods and proposed lower limits on the proportion of samples where the organisms of interest are identified and enumerated, with the recommended lower limit of enumerated samples being 0.2. This recommendation may not be applicable to food safety risk assessments for a number of reasons, which include the development of new Bayesian fitting methods, the use of highly sensitive screening tests, and the generally larger sample sizes found in surveys of food commodities. This study evaluates the performance of a Markov chain Monte Carlo fitting method when used in conjunction with a screening test and enumeration of positive samples by the Most Probable Number technique. The results suggest that levels of contamination for common product-pathogen pairs, such as Salmonella on poultry carcasses, can be reliably estimated with the proposed fitting method and samples sizes in excess of 500 observations. The results do, however, demonstrate that simple guidelines for this application, such as the proportion of positive samples, cannot be provided.
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Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice.
Hum. Mol. Genet.
PUBLISHED: 02-27-2013
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Individual saposin A (A-/-) and saposin B (B-/-)-deficient mice show unique phenotypes caused by insufficient degradation of myelin-related glycosphingolipids (GSLs): galactosylceramide and galactosylsphingosine and sulfatide, respectively. To gain insight into the interrelated functions of saposins A and B, combined saposin AB-deficient mice (AB-/-) were created by knock-in point mutations into the saposins A and B domains on the prosaposin locus. Saposin A and B proteins were undetectable in AB-/- mice, whereas prosaposin, saposin C and saposin D were expressed near wild-type (WT) levels. AB-/- mice developed neuromotor deterioration at >61 days and exhibited abnormal locomotor activity and enhanced tremor. AB-/- mice (~96 days) lived longer than A-/- mice (~85 days), but shorter than B-/- mice (~644 days). Storage materials were observed in Schwann cells and neuronal processes by electron microscopy. Accumulation of p62 and increased levels of LC3-II were detected in the brainstem suggesting altered autophagy. GSL analyses by (liquid chromatography) LC/MS identified substantial increases in lactosylceramide in AB-/- mouse livers. Sulfatide accumulated, but galactosylceramide remained at WT levels, in the AB-/- mouse brains and kidneys. Brain galactosylsphingosine in AB-/- mice was ~68% of that in A-/- mice. These findings indicate that combined saposins A and B deficiencies attenuated GalCer-?-galactosylceramidase and GM1-?-galactosidase functions in the degradation of lactosylceramide preferentially in the liver. Blocking sulfatide degradation from the saposin B deficiency diminished galactosylceramide accumulation in the brain and kidney and galctosylsphingosine in the brain. These analyses of AB-/- mice continue to delineate the tissue differential interactions of saposins in GSL metabolism.
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Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits.
J. Inherit. Metab. Dis.
PUBLISHED: 02-22-2013
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Creatine transporter (CrT) deficiency (CTD) is an X-linked disorder characterized by intellectual disability and speech delay. There have been reports that show female carriers have clinical symptoms. We have created CrT knockout (CrT(-/y)) mice in which males show severe cognitive deficits as a model of this disorder. The purpose of this study was to examine if the female carrier mice show cognitive deficits. Reductions in Cr levels as well as CrT transcript were observed in the brains of the female CrT(+/-) mice. CrT(+/-) mice show hyperactivity and increased latency to find the cued platform in the Morris water maze (MWM). CrT(+/-) female mice showed deficits in MWM hidden platform acquisition but not during reversal testing. Memory deficits on probe trials were observed during both phases. Novel object recognition memory and contextual fear memory were not affected in female CrT(+/-) mice. Female CrT(+/-) mice show moderate cognitive deficits, which is consistent with some of the human data. Female CrT(+/-) mice could prove to be beneficial in further understanding CTD and testing therapeutic approaches.
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Characterizing uncertainty when evaluating risk management metrics: risk assessment modeling of Listeria monocytogenes contamination in ready-to-eat deli meats.
Int. J. Food Microbiol.
PUBLISHED: 01-13-2013
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This report illustrates how the uncertainty about food safety metrics may influence the selection of a performance objective (PO). To accomplish this goal, we developed a model concerning Listeria monocytogenes in ready-to-eat (RTE) deli meats. This application used a second order Monte Carlo model that simulates L. monocytogenes concentrations through a series of steps: the food-processing establishment, transport, retail, the consumers home and consumption. The model accounted for growth inhibitor use, retail cross contamination, and applied an FAO/WHO dose response model for evaluating the probability of illness. An appropriate level of protection (ALOP) risk metric was selected as the average risk of illness per serving across all consumed servings-per-annum and the model was used to solve for the corresponding performance objective (PO) risk metric as the maximum allowable L. monocytogenes concentration (cfu/g) at the processing establishment where regulatory monitoring would occur. Given uncertainty about model inputs, an uncertainty distribution of the PO was estimated. Additionally, we considered how RTE deli meats contaminated at levels above the PO would be handled by the industry using three alternative approaches. Points on the PO distribution represent the probability that - if the industry complies with a particular PO - the resulting risk-per-serving is less than or equal to the target ALOP. For example, assuming (1) a target ALOP of -6.41 log10 risk of illness per serving, (2) industry concentrations above the PO that are re-distributed throughout the remaining concentration distribution and (3) no dose response uncertainty, establishment POs of -4.98 and -4.39 log10 cfu/g would be required for 90% and 75% confidence that the target ALOP is met, respectively. The PO concentrations from this example scenario are more stringent than the current typical monitoring level of an absence in 25 g (i.e., -1.40 log10 cfu/g) or a stricter criteria of absence in 125 g (i.e., -2.1 log10 cfu/g). This example, and others, demonstrates that a PO for L. monocytogenes would be far below any current monitoring capabilities. Furthermore, this work highlights the demands placed on risk managers and risk assessors when applying uncertain risk models to the current risk metric framework.
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Cognitive impairments from developmental exposure to serotonergic drugs: citalopram and MDMA.
Int. J. Neuropsychopharmacol.
PUBLISHED: 01-11-2013
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We previously showed that developmental 3,4-methylenedioxymethamphetamine (MDMA) treatment induces long-term spatial and egocentric learning and memory deficits and serotonin (5-HT) reductions. During brain development, 5-HT is a neurotrophic factor influencing neurogenesis, synaptogenesis, migration, and target field organization. MDMA (10 mg/kg × 4/d at 2 h intervals) given on post-natal day (PD) 11-20 in rats (a period of limbic system development that approximates human third trimester brain development) induces 50% reductions in 5-HT during treatment and 20% reductions when assessed as adults. To determine whether the 5-HT reduction is responsible for the cognitive deficits, we used citalopram (Cit) pretreatment to inhibit the effects of MDMA on 5-HT reuptake in a companion study. Cit attenuated MDMA-induced 5-HT reductions by 50% (Schaefer et al., 2012). Here we tested whether Cit (5 or 7.5 mg/kg × 2/d) pretreatment attenuates the cognitive effects of MDMA. Within each litter, different offspring were treated on PD11-20 with saline (Sal) + MDMA, Cit + MDMA, Cit + Sal or Sal + Sal. Neither spatial nor egocentric learning/memory was improved by Cit pretreatment. Unexpectedly, Cit + Sal (at both doses) produced spatial and egocentric learning deficits as severe as those caused by Sal + MDMA. These are the first data showing cognitive deficits resulting from developmental exposure to a selective serotonin reuptake inhibitor. These data indicate the need for further research on the long-term safety of antidepressants during pregnancy.
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Neurobehavioral phenotype of C57BL/6J mice prenatally and neonatally exposed to cigarette smoke.
Neurotoxicol Teratol
PUBLISHED: 01-02-2013
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Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of active maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light-dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function.
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Biogeography and body size shuffling of aquatic salamander communities on a shifting refuge.
Proc. Biol. Sci.
PUBLISHED: 01-01-2013
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Freshwater habitats of coastal plains are refugia for many divergent vertebrate lineages, yet these environments are highly vulnerable to sea-level fluctuations, which suggest that resident communities have endured dynamic histories. Using the fossil record and a multi-locus nuclear phylogeny, we examine divergence times, biogeography, body size evolution and patterns of community assembly of aquatic salamanders from North American coastal plains since the Late Cretaceous. At least five salamander families occurred on the extensive Western Interior Coastal Plain (WICP), which existed from the Late Cretaceous through the Eocene. Four of these families subsequently colonized the emergent Southeastern Coastal Plain (SECP) by the Early Oligocene to Late Miocene. Three families ultimately survived and underwent extensive body size evolution in situ on the SECP. This included at least two major size reversals in recent taxa that are convergent with confamilial WICP ancestors. Dynamics of the coastal plain, major lineage extinctions and frequent extreme changes in body size have resulted in significant shuffling of the size structure of aquatic salamander communities on this shifting refuge since the Cretaceous.
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Young adults with complex communication needs: research and development in AAC for a "diverse" population.
Assist Technol
PUBLISHED: 12-02-2011
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A successful transition to adult society requires attention to four major goals: (a) have a safe and supportive place to live; (b) participate in meaningful activities; (c) maintain access to needed services; and (d) develop friendships and intimate relationships. For young adults with complex communication needs (CCN), access to augmentative and alternative communication (AAC) plays a critical role in the achievement of these valued outcomes. This article discusses what is known about the use of AAC to support communication by young adults with CCN, and identifies areas for future research and development in AAC technology.
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Using AAC technology to access the world.
Assist Technol
PUBLISHED: 12-02-2011
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This paper describes the monumental shift in the nature of augmentative and alternative communication (AAC) access that has occurred over the past three decades. In its earliest days AAC technology was directed at enabling interpersonal face-to-face interactions mainly for persons with physical impairment. Contemporary AAC access attempts to mirror the access needs of a broader population. Accordingly AAC access to todays mainstream technologies expands the focus from interpersonal communication to access of information and services over the expanding World Wide Web. With this expanded view comes a new range of challenges and opportunities. At the same time AAC has expanded its reach to include more people with a wider range of complex communication needs.
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Estimating changes in public health following implementation of hazard analysis and critical control point in the United States broiler slaughter industry.
Foodborne Pathog. Dis.
PUBLISHED: 11-17-2011
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A common approach to reducing microbial contamination has been the implementation of a Hazard Analysis and Critical Control Point (HACCP) program to prevent or reduce contamination during production. One example is the Pathogen Reduction HACCP program implemented by the U.S. Department of Agricultures Food Safety and Inspection Service (FSIS). This program consisted of a staged implementation between 1996 and 2000 to reduce microbial contamination on meat and poultry products. Of the commodities regulated by FSIS, one of the largest observed reductions was for Salmonella contamination on broiler chicken carcasses. Nevertheless, how this reduction might have influenced the total number of salmonellosis cases in the United States has not been assessed. This study incorporates information from public health surveillance and surveys of the poultry slaughter industry into a model that estimates the number of broiler-related salmonellosis cases through time. The model estimates that-following the 56% reduction in the proportion of contaminated broiler carcasses observed between 1995 and 2000-approximately 190,000 fewer annual salmonellosis cases (attributed to broilers) occurred in 2000 compared with 1995. The uncertainty bounds for this estimate range from approximately 37,000 to 500,000 illnesses. Estimated illnesses prevented, due to the more modest reduction in contamination of 13% between 2000 and 2007, were not statistically significant. An analysis relating the necessary magnitude of change in contamination required for detection via human surveillance also is provided.
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Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats.
ACS Chem Neurosci
PUBLISHED: 10-21-2011
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Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drugs cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
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Conflict of interest guidelines for clinical guidelines.
Med. J. Aust.
PUBLISHED: 10-19-2011
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• Clinical guidelines are being increasingly produced to improve quality of care, but are vulnerable to bias. • Only 15% of guidelines on the National Health and Medical Research Council portal from the most prolific developers have published conflict of interest statements, and fewer detail the processes used to manage conflicts. • Comprehensive disclosure of conflicts is needed to safeguard the integrity of clinical guidelines and the medical profession. • Peak bodies and clinicians should seek to promote an improvement to current poor practice.
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CEP-26401 (irdabisant), a potent and selective histamine H? receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities.
J. Pharmacol. Exp. Ther.
PUBLISHED: 10-14-2011
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CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H? receptor (H?R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H?R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H?R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³?S]guanosine 5-O-(?-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H?R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC?? = 0.1 ± 0.003 mg/kg), and antagonism of the H?R agonist R-?-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED?? = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H?R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
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Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03.
Br. J. Haematol.
PUBLISHED: 09-09-2011
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Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0·004) corresponded to a hazard ratio of 3·48 [95% confidence interval: (1·42-8·53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0·026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2·0 [0·7-5·6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction.
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Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial.
Stroke
PUBLISHED: 08-25-2011
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Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis.
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Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats.
Neurotoxicol Teratol
PUBLISHED: 08-03-2011
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In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.
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Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study.
J. Clin. Oncol.
PUBLISHED: 08-01-2011
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The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with follicular lymphoma whose disease was relapsed or refractory to prior treatment.
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Location, location, location: Beneficial effects of autologous fat transplantation.
Sci Rep
PUBLISHED: 07-01-2011
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Visceral adiposity is a risk factor for cardiovascular disorders, type 2 diabetes mellitus (T2D) and associated metabolic diseases. Sub-cutaneous fat is believed to be intrinsically different from visceral fat. To understand molecular mechanisms involved in metabolic advantages of fat transplantation, we studied a rat model of diet-induced adiposity. Adipokine genes (Adiponectin, Leptin, Resistin and Visfatin) were expressed at 10,000 to a million-fold lower in visceral fat depot as compared to peripheral (thigh/chest) fat depots. Interestingly, autologous transplantation of visceral fat to subcutaneous sites resulted in increased gene transcript abundance in the grafts by 3 weeks post-transplantation, indicating the impact of local (residence) factors influencing epigenetic memory. We show here that active transcriptional state of adipokine genes is linked with glucose mediated recruitment of enzymes that regulate histone methylation. Adipose depots have "residence memory" and autologous transplantation of visceral fat to sub-cutaneous sites offers metabolic advantage.
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Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats.
Int. J. Neuropsychopharmacol.
PUBLISHED: 06-28-2011
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Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.