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Domestic and family violence (DFV) is a serious, worldwide public health concern and the literature suggests that women who have experienced violence identify health care providers as the professio...

Author(s): Fischer, Corinne E; Ismail, Zahinoor; Youakim, James M; Creese, Byron; Kumar, Sanjeev; Nunez, Nicolas; Ryan Darby, R; Di Vita, Antonella; D'Antonio, Fabrizia; de Lena, Carlo; McGeown, William J; Ramit, Ravona; Rasmussen, Jill; Bell, Joanne; Wang, Huali; Bruneau, Marie-Andree; Panegyres, Peter K; Lanctot, Krista L; Aguera-Ortiz, Luis; Lyketsos, Constantine; Cummings, Jeffrey; Jeste, Dilip V; Sano, Mary; Devanand, DP; Sweet, Robert A; Ballard, Clive | Abstract: BackgroundPsychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice.ObjectiveTo establish research criteria for the diagnosis of psychosis in AD.MethodsThe International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria.ResultsConsensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers.ConclusionWe propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

To further fulfil their missions of promoting teaching, education and research in neurology and related clinical-academic disciplines, the Guarantors of Brain and the Brain journal family invited delegates to the first Brain Conference in Spring of this year. This event aimed to deliver excellent teaching and scientific presentations across a broad spectrum of neuroscience fields, with the key aim of making the content as accessible as possible. We hoped to capitalize on the benefits of an online format, whilst trying to capture a little of the joy of the in-person meeting. This article reports on the approach and practical choices made to achieve these goals, and we hope this will provide some guidance and advice to others organizing their own online conference., Li et al. report on what went on ‘behind the scenes’ of the first Brain Conference, which took place in March 2021. Programming, technology and organizational choices are described, as well as reflections on what went well and what should be improved for future events.

Virus-host dynamics is poorly understood in natural systems, despite known viral influences on host mortality and community structure, food web dynamics, and biogeochemical cycles. Without a universal marker gene for viruses, assessments of viral diversity and dynamics have previously relied upon models and/or low-resolution data, like viral counts or gel electrophoretic estimates of genome size. Here, de novo assemblies were created from 6.4 Gb of metagenomic sequence from eight community viral concentrate samples, collected from 12 hours to three years apart from hypersaline Lake Tyrrell (LT), Victoria, Australia. Seven complete and 133 partial, novel viral genomes were reconstructed, and new methods for assessing the diversity and dynamics of full viral assemblages were developed. This dissertation provides the first constraints on the timescales over which viral populations and assemblages tend to be stable (days) or dynamic (months-to-years). Comparisons to and reanalyses of previously reported haloviral metagenomes confirm that similar dynamics exist in other hypersaline systems and suggest that most haloviral populations have a limited or temporally variable global distribution. To place the LT viral metagenomes (viromes) in context, metagenomic data were assembled from 63 previously reported viromes from diverse environments, and genetic composition was compared across viromes. Despite spatial and temporal variation within LT, LT viral assemblages were most similar to each other and grouped with other hypersaline viromes. The 71 viromes (including eight from LT) generally clustered by ecosystem, and salinity is inferred to be a major determinant of the genetic composition of viral assemblages.To further investigate LT microbial ecology, virus-host dynamics were assessed across 17 LT samples, including the eight summer samples from which viral concentrates were sequenced, five additional summer samples, and four winter samples. Contrary to previous reports of microbial population stability in hypersaline systems, dynamics were observed in host populations on similar spatial and temporal scales as in viral populations. An analysis of clustered regularly interspaced short palindromic repeat (CRISPR) regions, which confer host immunity to viruses, indicates that both rare and highly abundant LT viruses were targeted, primarily by lower abundance host organisms. Although very few CRISPR spacers had hits to the NCBI nr database and to the 140 complete and near-complete LT viral genomes, 21% had hits to unassembled LT viral concentrate reads, indicating adaptation to the LT system and successful CRISPR maintenance of viral populations at low enough abundance to preclude metagenomic assembly. In addition to using model systems like Lake Tyrrell to understand fundamental aspects of microbial ecology, it is important to characterize understudied ecosystems, including subsurface systems, which are likely to harbor much of the carbon on Earth and have the potential to play important roles in solutions to human-induced climate change. In order to characterize the community structure and metabolic potential of a high-CO2 subsurface ecosystem, water was collected from iron-rich, CO2-driven Crystal Geyser (Green River, Utah), an established natural analog for geologic carbon sequestration (i.e., the proposed storage of anthropogenic CO2 in subsurface aquifers to mitigate climate change). Metagenomic sequences (~1.3 Gb) were generated from the 0.2 - 3.0 µm size fraction, and metagenomic assembly and binning resulted in the reconstruction of near-complete genomes of neutrophilic, iron-oxidizing Mariprofundus sp. and sulfur-oxidizing Thiomicrospira crunogena. Significant assembly was also achieved for a number of other organisms, including novel Bacterial phyla and both aerobic and anaerobic respirers predicted to oxidize iron, sulfur, and/or complex carbon. At least one-third of the microorganisms sampled were likely chemoautotrophs, demonstrating that microbial carbon fixation is an important component of the carbon cycle in this system. These results suggest that the biogeochemistry and carbon storage potential of subsurface carbon sequestration reservoirs could be significantly influenced by microorganisms of diverse phylogeny and metabolic potential.This dissertation demonstrates that next-generation sequencing, de novo metagenomic assembly, and novel analytical techniques can provide answers to important and fundamental questions in the field of microbial ecology. Specifically, this dissertation demonstrates the application of these techniques to: 1) assess viral diversity and dynamics at the highest resolution to date, 2) place those dynamics in the context of a natural ecosystem, and 3) characterize the community structure and metabolic potential of an understudied subsurface ecosystem with relevance to anthropogenic climate change.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Background The role of hydration in causing or alleviating suffering in patients with advanced cancer is poorly understood. The evidence for the efficacy of clinically assisted hydration in advanced cancer is limited, conflicting and inconclusive. Bioelectrical impedance vector analysis (BIVA) is an accurate validated method of assessing body composition. Previously we have used BIVA to demonstrate statistically significant relationships with hydration status and symptoms (dry mouth, thirst, taste and fatigue), physical signs (mouth moisture, sunken eyes and axilla dryness), oedema and survival in advanced cancer. Further work is needed to investigate how hydration status affects symptoms and quality-of-life in the dying phase. Aim The aim of this feasibility study is to develop the necessary methodology and advanced consent procedure to conduct hydration research assessments in dying cancer patients. Methodology This study will involve an observational longitudinal analysis using BIVA assessments to evaluate hydration and its relationship with clinical symptoms and quality-of-life. Family-caregivers experiences will be evaluated via questionnaire. Thirty patients with advanced cancer will be recruited initially from a hospital-based specialist palliative care inpatient unit. Following this recruitment from additional hospice sites will be facilitated. Results This study is supported by the Academy of Medical Sciences, the UKH Foundation, North West Cancer Research and the Liverpool Clinical Commissioning Group (CCG) Research Capability Funding (RCF) grant. Recruitment is planned to commence in early 2017. Proposed findings The outcomes of this study will determine the feasibility of the methodology and will inform the development of further work. The identification of variables that are associated with hydration in the dying will facilitate the development of a clinical hydration assessment tool. This will ultimately help to develop a framework to clinically assess and manage hydration states patients with cancer.

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa", La "Marató TV3" grant (20141210 to J.F.) Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Background Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. Methods This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. Results At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). Conclusions SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. Trial registration Clinicaltrials.gov, NCT01712074. Registered 19 October 2012. Electronic supplementary material The online version of this article (10.1186/s13195-018-0368-9) contains supplementary material, which is available to authorized users.

Objective To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). Methods Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14-26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. Results A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. Conclusions PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. Classification of evidence This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.

Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012.

Objective To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. Methods Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. Results Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of β-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. Conclusions Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc.

Large proportions of South Africans live in areas with inadequate sanitation and a poor infrastructure for waterborne sanitation. Service providers are looking for alternative wastewater treatment options. The anaerobic baffled reactor is being considered as a decentralised sanitation option in these areas. A 3,200 L reactor was built and is currently being evaluated at a wastewater treatment works. The reactor was built based on experiences gained from working with a laboratory reactor (10 L) and predicted flow patterns observed on a computational fluid dynamics model. The design and construction of the reactor will be discussed in this paper. The feed to the reactor consists of screen degritted sewage and the flow to the reactor is maintained by means of a programmable logic controller. The pilot-plant layout is discussed in this paper. Samples are analysed for chemical oxygen demand, pH, alkalinity, ammonia, phosphorus, solids and ash content. Reductions of between 70 and 80% are obtained for COD and the pH values for the effluent samples are within the discharge limits.

Synthetic organic colorants, the majority of which are recalcitrant in nature, are used universally in many different manufacturing processes. The dyes are released into the environment in industrial effluents and are highly visible even at low concentrations ( 20 g/L) to inhibitory (IC\D50\N = 0.2 mg/L). Batch biodegradability assays indicated that the dyes were not readily utilized by the anaerobic microorganisms as a sole substrate. Decolorization of the dye tartrazine was investigated in a laboratory-scale anaerobic baffled reactor at a concentration of 250 mg/L. Reduction in COD of 50–60% and color reduction of about 95% was achieved. Initially the tartrazine was not readily decolorized; however, decolorization improved with acclimation of the biomass. An industrial wastewater from a food dye manufacturer was fed to a second laboratory-scale anaerobic baffled reactor at a concentration of 5% (volume-to-volume ratio) and then increased to 10%. Anaerobic degradation of the wastewater was efficient. Methanogenic activity was high; the organic content of the influent was reduced by about 70%, and color was reduced by almost 90%.

BackgroundThe accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimer's disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.MethodsPart 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.ResultsPF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.ConclusionsThe adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis.

The purpose of this study was to assess the acute psychoactive and physiological properties of 5-HT 3 antagonism using ondansetron as a probe. Ondansetron is used clinically as an anti-emetic but is also under treatment consideration for a range of psychiatric disorders including drug abuse. A 15 min infusion of 40 mg ondansetron, a 1 min infusion of 25 mg of cocaine (positive control) and their respective placebos were tested intravenously in eight volunteers with histories of drug abuse in a blinded cross-over study. Ondansetron responses could not be distinguished from the placebo. Cocaine produced typical subjective and physiological effects. These findings indicate that the prototypic 5-HT 3 receptor antagonist ondansetron does not produce acute psychoactive effects when infused at doses of up to 40 mg and has no rewarding effects with this regime.

Synthetic organic colourants, the majority of which are recalcitrant in nature, are used in many different manufacturing processes. The dyes are released into the environment in industrial effluents and are highly visible even at low concentrations (< 1 mg/l). Decolorisation of the dye CI Reactive Red 141 was investigated in a laboratory-scale anaerobic baffled reactor (ABR). The results of the physical decolorisation tests suggested significant decolorisation due to adsorption to the biomass; however, it is possible that the dye chromophores were reduced due to the low redox potential environment within the test bottles. No dye breakthrough, due to adsorption saturation, was observed during operation of the reactor. COD reduction was consistently > 90 %. Colour reduction averaged 86 %. The biomass showed acclimation to the dye, with increased methanogenic activity with each increase in dye concentration. The reactor operation was stable, even with increases in the dye concentration. This investigation has shown that successful treatment of a highly coloured wastewater is possible in the ABR. Keywords: Anaerobic baffled reactor, Textile dyes, CI Red 141 (WaterSA: 2003 29(2): 129-134)

This study (PHANTASTIC) compares first-line plerixafor with granulocyte colony-stimulating factor (G-CSF) in 98 myeloma and lymphoma patients with 151 historic controls mobilised by conventional chemotherapy+G-CSF. Eleven patients developed mild transient symptoms possibly related to plerixafor. No serious adverse events were seen. Seventy (71%) plerixafor-mobilised patients achieved both ⩾ 4 × 10(6) CD34(+) cells/kg in ⩽ 2 aphereses and no neutropenia (1.0 × 10(9)/l). This is significantly48 (32%) of 151 historical chemotherapy+G-CSF-mobilised control patients achieving this end point (P0.001). Ninety-six (98%) plerixafor-mobilised patients achieved ⩾ 2 × 10(6) CD34(+) cells/kg within one harvest round compared with 114 (75%) of controls (P=0.001). Engraftment times and 12-month outcome were comparable in both groups. Prior treatment was summarised by two scoring systems. Controls mobilising either2.0 or4.0 × 10(6) CD34(+) cells/kg have significantly lower scores than mobilisation failures (P=0.002), but this relationship was not seen for plerixafor-mobilised patients. Plerixafor is a more effective and less toxic mobilising agent than conventional chemotherapy (especially in heavily pretreated patients), with comparable subsequent outcome, and merits consideration as the first-line standard of care for stem cell mobilisation.

Fluorescent in situ hybridization (FISH) using 16S and 23S rRNA-targeted probes together with construction of an archaeal 16S ribosomal DNA (rDNA) clone library was used to characterize the microbial populations of an anaerobic baffled reactor successfully treating industrial dye waste. Wastewater produced during the manufacture of food dyes containing several different azo and other dye compounds was decolorized and degraded under sulfidogenic and methanogenic conditions. Use of molecular methods to describe microbial populations showed that a diverse group of Bacteria and Archaea was involved in this treatment process. FISH enumeration showed that members of the gamma subclass of the class Proteobacteria and bacteria in the Cytophaga-Flexibacter-Bacteroides phylum, together with sulfate-reducing bacteria, were prominent members of a mixed bacterial population. A combination of FISH probing and analysis of 98 archaeal 16S rDNA clone inserts revealed that together with the bacterial population, a methanogenic population dominated by Methanosaeta species and containing species of Methanobacterium and Methanospirillum and a relatively unstudied methanogen, Methanomethylovorans hollandica , contributed to successful anaerobic treatment of the industrial waste. We suggest that sulfate reducers, or more accurately sulfidogenic bacteria, together with M. hollandica contribute considerably to the treatment process through metabolism of dye-associated sulfonate groups and subsequent conversion of sulfur compounds to carbon dioxide and methane.

Unactivated peripheral blood leukocytes show little tendency to bind to other cells or matrix components, whilst, in the presence of inflammatory mediators, adhesive interactions can rapidly increase. The Leu-CAM (beta 2 integrin) family of adhesion molecules have been shown to mediate a variety of these induced adhesion events. Here we describe a monoclonal antibody against CD18, KIM185, which stimulates JY cell homotypic aggregation by a CD11 a pathway as well as inducing the adherence of neutrophils to protein-coated plastic by a CD11b-dependent mechanism. The antibody recognizes an epitope distinct from the previously described KIM127 antibody and evidence is presented that the binding of KIM185 can cause a change in the conformation of the CD18 molecule.

Rats from dams that were well fed or underfed (50% food reduction) during lactation received either large lesions of the dorsal hippocampus or sham operations at 60 days of age. The animals then were tested for open-field behavior, spontaneous alternation, spontaneous exploration, and spatial discrimination reversal learning. Main effects of nutrition were found in the open field and on the spatial learning and reversal tasks, as well as in body weight, eye opening, and time of appearance of body hair. Significant lesion effects were found in the open field and on spontaneous alternation and reversal learning. In contrast to two earlier studies, early diet had little effect on the response to later brain damage. These data show that the finding that early diet can affect the behavioral response to focal brain damage later in life may not generalize across all experimental conditions.

Female rats immunized with mouse nerve growth factor develop an antibody (anti-NGF) which reaches offspring through the placenta and via the milk. Pups exposed to maternal anti-NGF have fewer dorsal root and sympathetic neurons. When the offspring are examined on a wide variety of behavioral tests, they exhibit severe deficits in response to stress (ulceration, corticosterone levels), and mild deficits on some sensory and cognitive tasks. Explaratory and motor functions, however, are relatively normal. The pathologic and behavioral profiles of the animals closely mimic the sensory and sympathetic aspects of familial dysautonomia.

Rats were malnourished during the first 3 weeks of life by separation from their dams for 12 hours per day. Half of these litters were exposed to a nonlactating “aunt” during this separation, while half were housed in a warm incubator. The dams whose pups underwent daily separation behaved differently from control dams, although comparably to each other. The two separation procedures produced pups with biochemical and physiological differences from control groups, and some differences from each other. When tested as adults, the malnourished and control groups performed equivalently on a number of behavioral tests (e.g. footshock sensitivity, spatial alternation), but the previously malnourished groups differed from each other and from control groups on some open field and passive avoidance measures. Thus, these procedures for producing malnutrition in offspring of adequately nourished dams can have both brain and behavioral effects. The influence of the different early environments was evident since the two experimental groups exhibited some brain and behavioral differences although their nutritional histories and contacts with lactating dams were similar.

Rats undernourished early in life did not differ from control animals in acquiring a light-dark discrimination. Posterior cortical lesions impaired retention in both nutritional groups, but the relearning scores of the undernourished animals with lesions were significantly worse than those of the lesion group that had been well fed. Amphetamine was found to enhance recovery, especially in the undernourished group. These data thus show that early nutritional history can be an important factor in accounting for differences in performance following later, focal brain damage, but that pharmacological intervention still can be of great value in these cases.

Rats received 1-stage bilateral or sequential unilateral (serial) lesions of the posterior hypothalamus and were tested for the ability to regulate body temperature after a lengthy recovery period. The groups with lesion differed from the sham-operated groups in the cold, although not under ambient or warm conditions. The fact that the serial lesion group performed the same as the 1-stage lesion groups in the cold is significant because earlier tests on these same animals revealed much better recovery after serial lesions in swimming, and a partial serial lesion effect in open field performance.

BackgroundRespiratory complications are an important cause of postoperative morbidity. We aimed to investigate whether continuous positive airway pressure (CPAP) administered immediately after major abdominal surgery could prevent postoperative morbidity.MethodsPRISM was an open-label, randomised, phase 3 trial done at 70 hospitals across six countries. Patients aged 50 years or older who were undergoing elective major open abdominal surgery were randomly assigned (1:1) to receive CPAP within 4 h of the end of surgery or usual postoperative care. Patients were randomly assigned using a computer-generated minimisation algorithm with inbuilt concealment. The primary outcome was a composite of pneumonia, endotracheal re-intubation, or death within 30 days after randomisation, assessed in the intention-to-treat population. Safety was assessed in all patients who received CPAP. The trial is registered with the ISRCTN registry, ISRCTN56012545.FindingsBetween Feb 8, 2016, and Nov 11, 2019, 4806 patients were randomly assigned (2405 to the CPAP group and 2401 to the usual care group), of whom 4793 were included in the primary analysis (2396 in the CPAP group and 2397 in the usual care group). 195 (8·1%) of 2396 patients in the CPAP group and 197 (8·2%) of 2397 patients in the usual care group met the composite primary outcome (adjusted odds ratio 1·01 [95% CI 0·81-1·24]; p=0·95). 200 (8·9%) of 2241 patients in the CPAP group had adverse events. The most common adverse events were claustrophobia (78 [3·5%] of 2241 patients), oronasal dryness (43 [1·9%]), excessive air leak (36 [1·6%]), vomiting (26 [1·2%]), and pain (24 [1·1%]). There were two serious adverse events: one patient had significant hearing loss and one patient had obstruction of their venous catheter caused by a CPAP hood, which resulted in transient haemodynamic instability.InterpretationIn this large clinical effectiveness trial, CPAP did not reduce the incidence of pneumonia, endotracheal re-intubation, or death after major abdominal surgery. Although CPAP has an important role in the treatment of respiratory failure after surgery, routine use of prophylactic post-operative CPAP is not recommended.FundingNational Institute for Health Research, Barts Charity, Intersurgical, Association of Anaesthetists, and Sapienza Università di Roma.