An exploration of complex longitudinal relationships between care factors and post-care outcomes in South Africa

Abstract: Research on young people transitioning out of the child care system and into young adulthood is inevitably reductionist, in that it is unable to take into account the many complex forces that play a role in the development of a child from birth, into and through the care system and on to adulthood. Consequently, studies on the outcomes of care-leaves need to be interpreted with care and thought. This paper serves to illustrate these challenges in research and the various ways that research results can be interpreted, by drawing on data from a study being conducted in a residential care programme in South Africa. Demographic, pre-care and in-care variables of a sample of care-leavers are compared with a set of independent living outcome variables a year after aging out of care. Unanticipated results are contrasted with those that were anticipated, and multiple interpretations of the same results are provided. Through this, the author calls for judicious and humble use of research results when making judgements about the outcomes of care-leavers and the effectiveness of child welfare interventions

The two most common histological subtypes of malignant germ cell tumour are distinguished by global microRNA profiles, associated with differential transcription factor expression.

BACKGROUND: We hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas. RESULTS: By direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs. CONCLUSIONS: Differential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Estimating taxon-specific population dynamics in diverse microbial communities

Understanding how population-level dynamics contribute to ecosystem-level processes is a primary focus of ecological research and has led to important breakthroughs in the ecology of macroscopic organisms. However, the inability to measure population-specific rates, such as growth, for microbial taxa within natural assemblages has limited ecologists’ understanding of how microbial populations interact to regulate ecosystem processes. Here, we use isotope incorporation within DNA molecules to model taxon- specific population growth in the presence of 18O-labeled water. By applying this model to phylogenetic marker sequencing data collected from stable-isotope probing studies, we estimate rates of growth, mortal- ity, and turnover for individual microbial populations within soil assemblages. When summed across the entire bacterial community, our taxon-specific estimates are within the range of other whole-assemblage measurements of bacterial turnover. Because it can be applied to environmental samples, the approach we present is broadly applicable to measuring population growth, mortality, and associated biogeochemical process rates of microbial taxa for a wide range of ecosystems and can help reveal how individual microbial populations drive biogeochemical fluxes

Lack of correlation between predicted and actual off-target effects of short-interfering RNAs targeting the human papillomavirus type 16 E7 oncogene.

BACKGROUND: When designing therapeutic short-interfering RNAs (siRNAs), off-target effects (OTEs) are usually predicted by computational quantification of messenger RNAs (mRNAs) that contain matches to the siRNA seed sequence in their 3' UTRs. It is assumed that the higher the number of predicted transcriptional OTEs, the greater the size of the actual OTE signature and the more detrimental the phenotypic consequences in target-negative cells. METHODS: We tested this general assumption by investigating the OTEs of potential therapeutic siRNAs targeting the human papillomavirus (HPV) type-16 E7 oncogene. We studied HPV-negative squamous epithelial cells, from normal cervix (NCx) and skin (HaCaT), which would be vulnerable to 'bystander' OTEs following transfection in vivo. RESULTS: We observed no correlation between the number of computationally predicted OTEs and the actual number of seed-dependent OTEs (P=0.76). On average only 20.5% of actual transcriptional OTEs were seed-dependent (i.e., predicted). The unpredicted OTEs included stimulation of innate immune pathways, as well as indirect (downstream) effects of other OTEs, which affected important cancer-associated pathways. Although most significant OTEs observed were seen in both NCx and HaCaT cells, only 0-5.9% of differentially expressed genes overlapped between the two cell types. CONCLUSION: These data do not support the assumption that actual OTEs correlate well with predicted OTEs

A Method for Distinctly Marking Honey Bees, Apis mellifera, Originating from Multiple Apiary Locations

Inexpensive and non-intrusive marking methods are essential to track natural behavior of insects for biological experiments. An inexpensive, easy to construct, and easy to install bee marking device is described in this paper. The device is mounted at the entrance of a standard honey bee Apis mellifera L. (Hymenoptera: Apidae) hive and is fitted with a removable tube that dispenses a powdered marker. Marking devices were installed on 80 honey bee colonies distributed in nine separate apiaries. Each device held a tube containing one of five colored fluorescent powders, or a combination of a fluorescent powder (either green or magenta) plus one of two protein powders, resulting in nine unique marks. The powdered protein markers included egg albumin from dry chicken egg whites and casein from dry powdered milk. The efficacy of the marking procedure for each of the unique markers was assessed on honey bees exiting each apiary. Each bee was examined, first by visual inspection for the presence of colored fluorescent powder and then by egg albumin and milk casein specific enzyme-linked immunosorbent assays (ELISA). Data indicated that all five of the colored fluorescent powders and both of the protein powders were effective honey bee markers. However, the fluorescent powders consistently yielded more reliable marks than the protein powders. In general, there was less than a 1% chance of obtaining a false positive colored or protein-marked bee, but the chance of obtaining a false negative marked bee was higher for “protein-marked” bees

Neurobiological Mechanisms That Contribute to Stress-related Cocaine Use

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress-induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake-dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a “stage setter” for drug use – increasing sensitivity to cocaine and drug-associated cues – under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven

Mucins and Pathogenic Mucin-Like Molecules Are Immunomodulators During Infection and Targets for Diagnostics and Vaccines

Mucins and mucin-like molecules are highly O-glycosylated proteins present on the cell surface of mammals and other organisms. These glycoproteins are highly diverse in the apoprotein and glycan cores and play a central role in many biological processes and diseases. Mucins are the most abundant macromolecules in mucus and are responsible for its biochemical and biophysical properties. Mucin-like molecules cover various protozoan parasites, fungi and viruses. In humans, modifications in mucin glycosylation are associated with tumors in epithelial tissue. These modifications allow the distinction between normal and abnormal cell conditions and represent important targets for vaccine development against some cancers. Mucins and mucin-like molecules derived from pathogens are potential diagnostic markers and targets for therapeutic agents. In this review, we summarize the distribution, structure, role as immunomodulators, and the correlation of human mucins with diseases and perform a comparative analysis of mucins with mucin-like molecules present in human pathogens. Furthermore, we review the methods to produce pathogenic and human mucins using chemical synthesis and expression systems. Finally, we present applications of mucin-like molecules in diagnosis and prevention of relevant human diseases

HIV/AIDS, Food Supplementation and Livelihood Programs in Uganda: A Way Forward?

BACKGROUND: Over the last decade, health, nutrition and policy experts have become increasingly aware of the many ways in which food insecurity and HIV infection negatively impact and reinforce one another. In response, many organizations providing HIV care began supplying food aid to clients in need. Food supplementation, however, was quickly recognized as an unsustainable and incomplete intervention. Many HIV care organizations therefore developed integrated HIV and livelihood programs (IHLPs) to target the root causes of food insecurity. METHODS AND FINDINGS: We conducted a qualitative study using in-depth interviews with 21 key informants who worked at seven organizations providing HIV care, food aid, or IHLPs in Kampala, Uganda in 2007-2008 to better understand the impact of IHLPs on the well-being of people living with HIV and AIDS (PLWHAs) and the challenges in transitioning clients from food aid to IHLPs. There was strong consensus among those interviewed that IHLPs are an important intervention in addressing food insecurity and its adverse health consequences among PLWHAs. Key informants identified three main challenges in transitioning PLWHAs from food supplementation programs to IHLPs: (1) lack of resources (2) timing of the transition and (3) logistical considerations including geography and weather. Factors seen as contributing to the success of programs included: (1) close involvement of community leaders (2) close ties with local and national government (3) diversification of IHLP activities and (4) close integration with food supplementation programs, all linked through a central program of HIV care. CONCLUSION: Health, policy and development experts should continue to strengthen IHLPs for participants in need. Further research is needed to determine when and how participants should be transitioned from food supplementation to IHLPs, and to determine how to better correlate measures of food insecurity with objective clinical outcomes so as to better evaluate program results

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Evaluating the reactivation of herpesviruses and inflammation as cardiovascular and cerebrovascular risk factors in antiretroviral therapy initiators in an African HIV-infected population (RHICCA): a protocol for a longitudinal cohort study.

INTRODUCTION In Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years. METHODS AND ANALYSIS We will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study's primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints. ETHICS AND DISSEMINATION The University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER ISRCTN42862937