Antiplasmodial and larvicidal flavonoids from Derris trifoliata

From the dichloromethane-methanol (1:1) extract of the seed pods of Derris trifoliata, a new flavanone derivative (S)-lupinifolin 4´-methyl ether was isolated. In addition, the known flavonoids lupinifolin and rotenone were identified. The structures were determined on the basis of spectroscopic evidence. Lupinfolin showed moderate in vitro antiplasmodial activity against the D6 (chloroquine-sensitive) and W2 (chloroquineresistant)strains of Plasmodium falciparum. The different parts of this plant showed larvicidal activities against Aedes aegypti and rotenoids were identified as the active principles

Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK): a prospective observational study

BACKGROUND: Evidence is conflicting about how HIV modulates COVID-19. We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the ISARIC WHO CCP study. METHODS: We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, ten individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy). RESULTS: Among 47,592 patients, 122 (0.26%) had confirmed HIV infection and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 versus 74 years; p<0.001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive vs. HIV-negative groups (26.7% vs. 32.1%; p=0.16), but in those under 60 years of age HIV-positive status was associated with increased mortality (21.3% vs. 9.6%; p<0.001 [log-rank test]). Mortality was higher among people with HIV after adjusting for age (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.01-2.14; p=0.05), and the association persisted after adjusting for the other variables (aHR 1.69; 95% CI 1.15-2.48; p=0.008) and when restricting the analysis to people aged <60 years (aHR 2.87; 95% CI 1.70-4.84; p<0.001). CONCLUSIONS: HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19

A Plasmodium Whole-Genome Synteny Map: Indels and Synteny Breakpoints as Foci for Species-Specific Genes

Whole-genome comparisons are highly informative regarding genome evolution and can reveal the conservation of genome organization and gene content, gene regulatory elements, and presence of species-specific genes. Initial comparative genome analyses of the human malaria parasite Plasmodium falciparum and rodent malaria parasites (RMPs) revealed a core set of 4,500 Plasmodium orthologs located in the highly syntenic central regions of the chromosomes that sharply defined the boundaries of the variable subtelomeric regions. We used composite RMP contigs, based on partial DNA sequences of three RMPs, to generate a whole-genome synteny map of P. falciparum and the RMPs. The core regions of the 14 chromosomes of P. falciparum and the RMPs are organized in 36 synteny blocks, representing groups of genes that have been stably inherited since these malaria species diverged, but whose relative organization has altered as a result of a predicted minimum of 15 recombination events. P. falciparum-specific genes and gene families are found in the variable subtelomeric regions (575 genes), at synteny breakpoints (42 genes), and as intrasyntenic indels (126 genes). Of the 168 non-subtelomeric P. falciparum genes, including two newly discovered gene families, 68% are predicted to be exported to the surface of the blood stage parasite or infected erythrocyte. Chromosomal rearrangements are implicated in the generation and dispersal of P. falciparum-specific gene families, including one encoding receptor-associated protein kinases. The data show that both synteny breakpoints and intrasyntenic indels can be foci for species-specific genes with a predicted role in host-parasite interactions and suggest that, besides rearrangements in the subtelomeric regions, chromosomal rearrangements may also be involved in the generation of species-specific gene families. A majority of these genes are expressed in blood stages, suggesting that the vertebrate host exerts a greater selective pressure than the mosquito vector, resulting in the acquisition of diversity

Physiological Properties of Cholinergic and Non-Cholinergic Magnocellular Neurons in Acute Slices from Adult Mouse Nucleus Basalis

The basal forebrain is a series of nuclei that provides cholinergic input to much of the forebrain. The most posterior of these nuclei, nucleus basalis, provides cholinergic drive to neocortex and is involved in arousal and attention. The physiological properties of neurons in anterior basal forebrain nuclei, including medial septum, the diagonal band of Broca and substantia innominata, have been described previously. In contrast the physiological properties of neurons in nucleus basalis, the most posterior nucleus of the basal forebrain, are unknown.Here we investigate the physiological properties of neurons in adult mouse nucleus basalis. We obtained cell-attached and whole-cell recordings from magnocellular neurons in slices from P42-54 mice and compared cholinergic and non-cholinergic neurons, distinguished retrospectively by anti-choline acetyltransferase immunocytochemistry. The majority (70-80%) of cholinergic and non-cholinergic neurons were silent at rest. Spontaneously active cholinergic and non-cholinergic neurons exhibited irregular spiking at 3 Hz and at 0.3 to 13.4 Hz, respectively. Cholinergic neurons had smaller, broader action potentials than non-cholinergic neurons (amplitudes 64+/-3.4 and 75+/-2 mV; half widths 0.52+/-0.04 and 0.33+/-0.02 ms). Cholinergic neurons displayed a more pronounced slow after-hyperpolarization than non-cholinergic neurons (13.3+/-2.2 and 3.6+/-0.5 mV) and were unable to spike at high frequencies during tonic current injection (maximum frequencies of approximately 20 Hz and >120 Hz).Our results indicate that neurons in nucleus basalis share similar physiological properties with neurons in anterior regions of the basal forebrain. Furthermore, cholinergic and non-cholinergic neurons in nucleus basalis can be distinguished by their responses to injected current. To our knowledge, this is the first description of the physiological properties of cholinergic and non-cholinergic neurons in the posterior aspects of the basal forebrain complex and the first study of basal forebrain neurons from the mouse

Interpretation of ambiguous situations: evidence for a dissociation between social and physical threat in Williams syndrome

There is increasing evidence that Williams syndrome (WS) is associated with elevated anxiety that is non-social in nature, including generalised anxiety and fears. To date very little research has examined the cognitive processes associated with this anxiety. In the present research, attentional bias for non-social threatening images in WS was examined using a dot-probe paradigm. Participants were 16 individuals with WS aged between 13 and 34 years and two groups of typically developing controls matched to the WS group on chronological age and attentional control ability respectively. The WS group exhibited a significant attention bias towards threatening images. In contrast, no bias was found for group matched on attentional control and a slight bias away from threat was found in the chronological age matched group. The results are contrasted with recent findings suggesting that individuals with WS do not show an attention bias for threatening faces and discussed in relation to neuroimaging research showing elevated amygdala activation in response to threatening non-social scenes in WS

Multidisciplinary teams, and parents, negotiating common ground in shared-care of children with long-term conditions: A mixed methods study

Background: Limited negotiation around care decisions is believed to undermine collaborative working between parents of children with long-term conditions and professionals, but there is little evidence of how they actually negotiate their respective roles. Using chronic kidney disease as an exemplar this paper reports on a multi-method study of social interaction between multidisciplinary teams and parents as they shared clinical care. Methods. Phases 1 and 2: a telephone survey mapping multidisciplinary teams' parent-educative activities, and qualitative interviews with 112 professionals (Clinical-psychologists, Dietitians, Doctors, Nurses, Play-specialists, Pharmacists, Therapists and Social-workers) exploring their accounts of parent-teaching in the 12 British children's kidney units. Phase 3: six ethnographic case studies in two units involving observations of professional/parent interactions during shared-care, and individual interviews. We used an analytical framework based on concepts drawn from Communities of Practice and Activity Theory. Results: Professionals spoke of the challenge of explaining to each other how they are aware of parents' understanding of clinical knowledge, and described three patterns of parent-educative activity that were common across MDTs: Engaging parents in shared practice; Knowledge exchange and role negotiation, and Promoting common ground. Over time, professionals had developed a shared repertoire of tools to support their negotiations with parents that helped them accomplish common ground during the practice of shared-care. We observed mutual engagement between professionals and parents where a common understanding of the joint enterprise of clinical caring was negotiated. Conclusions: For professionals, making implicit knowledge explicit is important as it can provide them with a language through which to articulate more clearly to each other what is the basis of their intuition-based hunches about parents' support needs, and may help them to negotiate with parents and accelerate parents' learning about shared caring. Our methodology and results are potentially transferrable to shared management of other conditions. © 2013 Swallow et al.; licensee BioMed Central Ltd

Serratia marcescens Is Able to Survive and Proliferate in Autophagic-Like Vacuoles inside Non-Phagocytic Cells

Serratia marcescens is an opportunistic human pathogen that represents a growing problem for public health, particularly in hospitalized or immunocompromised patients. However, little is known about factors and mechanisms that contribute to S. marcescens pathogenesis within its host. In this work, we explore the invasion process of this opportunistic pathogen to epithelial cells. We demonstrate that once internalized, Serratia is able not only to persist but also to multiply inside a large membrane-bound compartment. This structure displays autophagic-like features, acquiring LC3 and Rab7, markers described to be recruited throughout the progression of antibacterial autophagy. The majority of the autophagic-like vacuoles in which Serratia resides and proliferates are non-acidic and have no degradative properties, indicating that the bacteria are capable to either delay or prevent fusion with lysosomal compartments, altering the expected progression of autophagosome maturation. In addition, our results demonstrate that Serratia triggers a non-canonical autophagic process before internalization. These findings reveal that S. marcescens is able to manipulate the autophagic traffic, generating a suitable niche for survival and proliferation inside the host cell

The VicGeneration study - a birth cohort to examine the environmental, behavioural and biological predictors of early childhood caries: background, aims and methods

Background Dental caries (decay) during childhood is largely preventable however it remains a significant and costly public health concern, identified as the most prevalent chronic disease of childhood. Caries in children aged less than five years (early childhood caries) is a rapid and progressive disease that can be painful and debilitating, and significantly increases the likelihood of poor child growth, development and social outcomes. Early childhood caries may also result in a substantial social burden on families and significant costs to the public health system. A disproportionate burden of disease is also experienced by disadvantaged populations. Methods/Design This study involves the establishment of a birth cohort in disadvantaged communities in Victoria, Australia. Children will be followed for at least 18 months and the data gathered will explore longitudinal relationships and generate new evidence on the natural history of early childhood caries, the prevalence of the disease and relative contributions of risk and protective biological, environmental and behavioural factors. Specifically, the study aims to: 1. Describe the natural history of early childhood caries (at ages 1, 6, 12 and 18 months), tracking pathways from early bacterial colonisation, through non-cavitated enamel white spot lesions to cavitated lesions extending into dentine. 2. Enumerate oral bacterial species in the saliva of infants and their primary care giver. 3. Identify the strength of concurrent associations between early childhood caries and putative risk and protective factors, including biological (eg microbiota, saliva), environmental (fluoride exposure) and socio-behavioural factors (proximal factors such as: feeding practices and oral hygiene; and distal factors such as parental health behaviours, physical health, coping and broader socio-economic conditions). 4. Quantify the longitudinal relationships between these factors and the development and progression of early childhood caries from age 1-18 months. Discussion There is currently a lack of research describing the natural history of early childhood caries in very young children, or exploring the interactions between risk and protective factors that extend to include contemporary measures of socio-behavioural factors. This study will generate knowledge about pathways, prevalence and preventive opportunities for early childhood caries, the most prevalent child health inequality

Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

&lt;p&gt;Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.&lt;/p&gt; &lt;p&gt;Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.&lt;/p&gt; &lt;p&gt;Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.&lt;/p&gt; &lt;p&gt;Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.&lt;/p&gt

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression