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

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

A numerical study of the effect of thrombus breakdown on predicted thrombus formation and growth

Thrombosis is a complex biological process which involves many biochemical reactions and is influenced by blood flow. Various computational models have been developed to simulate natural thrombosis in diseases such as aortic dissection (AD), and device-induced thrombosis in blood-contacting biomedical devices. While most hemodynamics-based models consider the role of low shear stress in the initiation and growth of thrombus, they often ignore the effect of thrombus breakdown induced by elevated shear stress. In this study, a new shear stress-induced thrombus breakdown function is proposed and implemented in our previously published thrombosis model. The performance of the refined model is assessed by quantitative comparison with experimental data on thrombus formation in a backward-facing step geometry, and qualitative comparison with in vivo data obtained from an AD patient. Our results show that incorporating thrombus breakdown improves accuracy in predicted thrombus volume and captures the same pattern of thrombus evolution as measured experimentally and in vivo. In the backward-facing step geometry, thrombus breakdown impedes growth over the step and downstream, allowing a stable thrombus to be reached more quickly. Moreover, the predicted thrombus volume, height and length are in better agreement with the experimental measurements compared to the original model which does not consider thrombus breakdown. In the patient-specific AD, the refined model outperforms the original model in predicting the extent and location of thrombosis. In conclusion, the effect of thrombus breakdown is not negligible and should be included in computational models of thrombosis

'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

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

Periodic Host Absence Can Select for Higher or Lower Parasite Transmission Rates

This paper explores the effect of discontinuous periodic host absence on the evolution of pathogen transmission rates by using Ro maximisation techniques. The physiological consequence of an increased transmission rate can be either an increased virulence, i.e. there is a transmission-virulence trade-off or ii) a reduced between season survival, i.e. there is a transmission-survival trade-off. The results reveal that the type of trade-off determines the direction of selection, with relatively longer periods of host absence selecting for higher transmission rates in the presence of a trade-off between transmission and virulence but lower transmission rates in the presence of a trade-of between transmission and between season survival. The fact that for the transmission-virulence trade-off both trade-off parameters operate during host presence whereas for the transmission-survival trade-off one operates during host presence (transmission) and the other (survival) during the period of host absence is the main cause for this difference in selection direction. Moreover, the period of host absence seems to be the key determinant of the pathogens transmission rate. Comparing plant patho-systems with contrasting biological features suggests that airborne plant pathogen respond differently to longer periods of host absence than soil-borne plant pathogens

Predicting Breast Cancer Response to Neoadjuvant Chemotherapy Using Pretreatment Diffuse Optical Spectroscopic-Texture Analysis

Purpose: Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pre-treatment DOS functional maps for predicting LABC response to NAC. Methods: LABC patients (n = 37) underwent DOS-breast imaging before starting neoadjuvant chemotherapy. Breast-tissue parametric maps were constructed and texture analyses were performed based on grey level co-occurrence matrices (GLCM) for feature extraction. Ground-truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS-textural features computed on volumetric tumour data before the start of treatment (i.e. “pre-treatment”) to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naïve Bayes, and k-nearest neighbour (k-NN) classifiers. Results: Data indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate between treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) were 86.5 and 89.0%, respectively and accuracy was 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn/%Sp = 78.0/81.0% and an accuracy of 79.5%. Conclusions: This study demonstrated that pre-treatment tumour DOS-texture features can predict breast cancer response to NAC and potentially guide treatments

An approach to the control of disease transmission in pig-to-human xenotransplantation.

Abstract: Although several major immunologic hurdles need to be overcome, the pig is currently considered the most likely source animal of cells, tissues and organs for transplantation into humans. Concerns have been raised with regard to the potential for the transfer of infectious agents with the transplanted organ to the human recipient. This risk is perceived to be increased as it is likely that the patient will be iatrogenically immunocompromised and the organ-source pig may be genetically engineered in such a way to render its organs particularly susceptible to infection with human viruses. Furthermore, the risk may not be restricted to the recipient, but may have consequences for the health of others in the community. The identification of porcine endogenous retroviruses and of hitherto unknown viruses have given rise to the most concern. We document here the agents we believe should be excluded from the organ-source pigs. We discuss the likelihood of achieving this aim and outline the potential means by which it may best be achieved

Extrinsic primary afferent signalling in the gut

Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular–mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders.Australian National Health and Medical Research Counci

A review of source tracking techniques for fine sediment within a catchment

Excessive transport of fine sediment, and its associated pollutants, can cause detrimental impacts in aquatic environments. It is therefore important to perform accurate sediment source apportionment to identify hot spots of soil erosion. Various tracers have been adopted, often in combination, to identify sediment source type and its spatial origin; these include fallout radionuclides, geochemical tracers, mineral magnetic properties and bulk and compound-specific stable isotopes. In this review, the applicability of these techniques to particular settings and their advantages and limitations are reviewed. By synthesizing existing approaches, that make use of multiple tracers in combination with measured changes of channel geomorphological attributes, an integrated analysis of tracer profiles in deposited sediments in lakes and reservoirs can be made. Through a multi-scale approach for fine sediment tracking, temporal changes in soil erosion and sediment load can be reconstructed and the consequences of changing catchment practices evaluated. We recommend that long-term, as well as short-term, monitoring of riverine fine sediment and corresponding surface and subsurface sources at nested sites within a catchment are essential. Such monitoring will inform the development and validation of models for predicting dynamics of fine sediment transport as a function of hydro-climatic and geomorphological controls. We highlight that the need for monitoring is particularly important for hilly catchments with complex and changing land use. We recommend that research should be prioritized for sloping farmland-dominated catchments