Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

Development and validation of A quasi-dimensional model for (M)Ethanol-Fuelled SI engines

RESEARCH OBJECTIVE - The use of methanol and ethanol in spark-ignition engines forms an interesting approach to decarbonizing transport and securing domestic energy supply. Experimental work has produced promising results, however, the full potential of light alcohols in modern engine technology remains to be explored. Today, this can be addressed at low cost using system simulations of the whole engine, provided that the employed models account for the effect of the fuel on engine operation. The goal of current work is to develop an engine cycle model that can accurately predict performance, efficiency, pollutant emissions and knock onset in state-of-the-art neat alcohol engines. METHODOLOGY - Two-zone thermodynamic engine modeling, in combination with 1D gas dynamics, is put forward as a useful tool for cheap and fast optimization of engines. Typically, this model class derives the mass burning rate of fuel from turbulent combustion models. A fundamental building block of turbulent combustion models is an expression for the laminar burning velocity of the fuel-air-residuals mixture at instantaneous cylinder pressure and temperature. This physicochemical property basically groups the contribution of the chemical reactions (of the fuel) to combustion. Consequently, an important part of our study consisted of calculating (using chemical kinetics) and measuring the laminar burning velocity of methanol and ethanol at engine-like conditions. In order to validate the developed engine model, its predictions were compared against a database of experimental results obtained on three different flex-fuel and dedicated alcohol engines. RESULTS - Comparison of the experimental and simulated cylinder, intake and exhaust pressure traces confirmed the predictive power of our engine model for methanol-fuelled engines. A wide variety of engine operating points were accurately reproduced thanks to a new laminar burning velocity correlation, which correctly accounts for changes in pressure, temperature, mixture richness and residual ratio. The Flame Closure Model of Zimont-Lipatnikov emerged as the most widely applicable model from a comparison of several turbulent combustion models. With regard to the gas dynamics it proved necessary to include a fuel puddling submodel to take the cooling effect due to alcohol injection into consideration. LIMITATIONS - The developed model was successfully validated for normal combustion in port-injected neat methanol engines. The validation of the routines for ethanol combustion and engines with direct injection is part of ongoing work. Now that normal combustion can be accurately simulated, further work will look at the prediction of pollutant emissions and knock onset in these engines. NOVELTY - This paper presents the first recent attempt to model the application of neat alcohols in modern and anticipated future engine technologies. Compared to previous work the effects of in-cylinder and mixture conditions on the combustion are more accurately predicted thanks to the inclusion of a new and widely validated laminar burning velocity correlation. In contrast to other studies, the current experimental database also includes measurements on turbocharged, high compression ratio engines with elevated amounts of EGR, which is representative of future dedicated alcohol engines. CONCLUSIONS - The current work focused on adapting the various submodels of quasi-dimensional engine codes to the properties of light alcohols. The developed simulation tools can be used with confidence to optimize current and future engines running on neat methanol and ethanol. This work also forms the starting point for an extension of the modelling concepts to alcohol-gasoline blends, which hold more industrial relevance

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

Ecological Release and Venom Evolution of a Predatory Marine Snail at Easter Island

BACKGROUND:Ecological release is coupled with adaptive radiation and ecological diversification yet little is known about the molecular basis of phenotypic changes associated with this phenomenon. The venomous, predatory marine gastropod Conus miliaris has undergone ecological release and exhibits increased dietary breadth at Easter Island. METHODOLOGY/PRINCIPAL FINDINGS:We examined the extent of genetic differentiation of two genes expressed in the venom of C. miliaris among samples from Easter Island, American Samoa and Guam. The population from Easter Island exhibits unique frequencies of alleles that encode distinct peptides at both loci. Levels of divergence at these loci exceed observed levels of divergence observed at a mitochondrial gene region at Easter Island. CONCLUSIONS/SIGNIFICANCE:Patterns of genetic variation at two genes expressed in the venom of this C. miliaris suggest that selection has operated at these genes and contributed to the divergence of venom composition at Easter Island. These results show that ecological release is associated with strong selection pressures that promote the evolution of new phenotypes

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4–based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism

'Riots engulfed the city':an experimental study investigating the legitimating effects of fire metaphors in discourses of disorder

In Cognitive Linguistic Critical Discourse Studies (CL-CDS), metaphor is identified as a key index of ideology and an important device in the legitimation of social action. From this perspective, metaphor is a cognitive-semiotic operation, invoked by metaphorical expressions in discourse, in which a source frame is mobilised to provide a template for sense-making inside a target frame, leading to particular framing effects. However, the extent to which metaphors in discourse genuinely activate an alternative frame and thereby achieve framing effects has recently been subject to question. Amid calls for more empirical forms of analysis in Critical Discourse Studies, the paper reports two experiments testing the legitimating framing effects of fire metaphors in discourses of disorder. Results show that images of fire and fire metaphors in the absence of competing images facilitate support for police use of water cannon in response to social unrest. The study not only justifies attention to metaphor in CL-CDS but similar effects across semiotic modalities are interpreted as evidence in support of simulation-based theories of metaphor

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml−1 min and paclitaxel 175 mg m−2 (CP, n=36) or standard therapy plus ASA404 1200 mg m−2 (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial

Maternal Near Miss and Mortality in a Rural Referral Hospital in Northern Tanzania: A Cross-Sectional Study.

Maternal morbidity and mortality in sub-Saharan Africa remains high despite global efforts to reduce it. In order to lower maternal morbidity and mortality in the immediate term, reduction of delay in the provision of quality obstetric care is of prime importance. The aim of this study is to assess the occurrence of severe maternal morbidity and mortality in a rural referral hospital in Tanzania as proposed by the WHO near miss approach and to assess implementation levels of key evidence-based interventions in women experiencing severe maternal morbidity and mortality. A prospective cross-sectional study was performed from November 2009 until November 2011 in a rural referral hospital in Tanzania. All maternal near misses and maternal deaths were included. As not all WHO near miss criteria were applicable, a modification was used to identify cases. Data were collected from medical records using a structured data abstraction form. Descriptive frequencies were calculated for demographic and clinical variables, outcome indicators, underlying causes, and process indicators. In the two-year period there were 216 maternal near misses and 32 maternal deaths. The hospital-based maternal mortality ratio was 350 maternal deaths per 100,000 live births (95% CI 243-488). The maternal near miss incidence ratio was 23.6 per 1,000 live births, with an overall case fatality rate of 12.9%. Oxytocin for prevention of postpartum haemorrhage was used in 96 of 201 women and oxytocin for treatment of postpartum haemorrhage was used in 38 of 66 women. Furthermore, eclampsia was treated with magnesium sulphate in 87% of all cases. Seventy-four women underwent caesarean section, of which 25 women did not receive prophylactic antibiotics. Twenty-eight of 30 women who were admitted with sepsis received parenteral antibiotics. The majority of the cases with uterine rupture (62%) occurred in the hospital. Maternal morbidity and mortality remain challenging problems in a rural referral hospital in Tanzania. Key evidence-based interventions are not implemented in women with severe maternal morbidity and mortality. Progress can be made through up scaling the use of evidence-based interventions, such as the use of oxytocin for prevention and treatment of postpartum haemorrhage

Development of mandibular, hyoid and hypobranchial muscles in the zebrafish: homologies and evolution of these muscles within bony fishes and tetrapods

<p>Abstract</p> <p>Background</p> <p>During vertebrate head evolution, muscle changes accompanied radical modification of the skeleton. Recent studies have suggested that muscles and their innervation evolve less rapidly than cartilage. The freshwater teleostean zebrafish (<it>Danio rerio</it>) is the most studied actinopterygian model organism, and is sometimes taken to represent osteichthyans as a whole, which include bony fishes and tetrapods. Most work concerning zebrafish cranial muscles has focused on larval stages. We set out to describe the later development of zebrafish head muscles and compare muscle homologies across the Osteichthyes.</p> <p>Results</p> <p>We describe one new muscle and show that the number of mandibular, hyoid and hypobranchial muscles found in four day-old zebrafish larvae is similar to that found in the adult. However, the overall configuration and/or the number of divisions of these muscles change during development. For example, the undivided adductor mandibulae of early larvae gives rise to the adductor mandibulae sections A0, A1-OST, A2 and Aω, and the protractor hyoideus becomes divided into dorsal and ventral portions in adults. There is not always a correspondence between the ontogeny of these muscles in the zebrafish and their evolution within the Osteichthyes. All of the 13 mandibular, hyoid and hypobranchial muscles present in the adult zebrafish are found in at least some other living teleosts, and all except the protractor hyoideus are found in at least some extant non-teleost actinopterygians. Of these muscles, about a quarter (intermandibularis anterior, adductor mandibulae, sternohyoideus) are found in at least some living tetrapods, and a further quarter (levator arcus palatini, adductor arcus palatini, adductor operculi) in at least some extant sarcopterygian fish.</p> <p>Conclusion</p> <p>Although the zebrafish occupies a rather derived phylogenetic position within actinopterygians and even within teleosts, with respect to the mandibular, hyoid and hypobranchial muscles it seems justified to consider it an appropriate representative of these two groups. Among these muscles, the three with clear homologues in tetrapods and the further three identified in sarcopterygian fish are particularly appropriate for comparisons of results between the actinopterygian zebrafish and the sarcopterygians.</p