When Did HIV Incidence Peak in Harare, Zimbabwe? Back-Calculation from Mortality Statistics

HIV prevalence has recently begun to decline in Zimbabwe, a result of both high levels of AIDS mortality and a reduction in incident infections. An important component in understanding the dynamics in HIV prevalence is knowledge of past trends in incidence, such as when incidence peaked and at what level. However, empirical measurements of incidence over an extended time period are not available from Zimbabwe or elsewhere in sub-Saharan Africa. Using mortality data, we use a back-calculation technique to reconstruct historic trends in incidence. From AIDS mortality data, extracted from death registration in Harare, together with an estimate of survival post-infection, HIV incidence trends were reconstructed that would give rise to the observed patterns of AIDS mortality. Models were fitted assuming three parametric forms of the incidence curve and under nine different assumptions regarding combinations of trends in non-AIDS mortality and patterns of survival post-infection with HIV. HIV prevalence was forward-projected from the fitted incidence and mortality curves. Models that constrained the incidence pattern to a cubic spline function were flexible and produced well-fitting, realistic patterns of incidence. In models assuming constant levels of non-AIDS mortality, annual incidence peaked between 4 and 5% between 1988 and 1990. Under other assumptions the peak level ranged from 3 to 8% per annum. However, scenarios assuming increasing levels of non-AIDS mortality resulted in implausibly low estimates of peak prevalence (11%), whereas models with decreasing underlying crude mortality could be consistent with the prevalence and mortality data. HIV incidence is most likely to have peaked in Harare between 1988 and 1990, which may have preceded the peak elsewhere in Zimbabwe. This finding, considered alongside the timing and location of HIV prevention activities, will give insight into the decline of HIV prevalence in Zimbabwe

The simplest supramolecular helix

Diethylamine is the smallest and simplest molecule that features a supramolecular helix as its lowest energy aggregate.</p

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

© 2016 The Author(s) Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies

Variation in the use of chemotherapy in lung cancer

Factors influencing the use of chemotherapy for the initial (6 months) treatment of lung cancer in South East England were investigated. The variables explored as possibly influencing the use of chemotherapy were sex, age, the year of diagnosis, the type of lung cancer, the stage, the index of multiple deprivation and the cancer network of residence. χ2 analysis and multivariate logistic regression models were used to examine the effect of each of the variables on the use of chemotherapy. The results showed a highly significant trend in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 13.6% in 1994 to 29.3% in 2003. However, age, cancer network and type of lung cancer had the strongest influence on the use of chemotherapy. This finding is important when we consider that the NHS Cancer Plan aims at improving inequalities in cancer care in the UK

Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer is a disease that continues to plague females during their entire lifetime. IL-6 and CRP are found to be elevated in various inflammatory and malignant diseases and their levels are found to correlate with the extent of the disease. The primary objective of this study was to determine the preoperative serum levels of IL-6 and CRP in breast carcinoma, and to correlate them with the staging of the disease and the prognosis.</p> <p>Methods</p> <p>59 female patients admitted for breast cancer were identified for the study and were subjected to thorough evaluation. Serum levels of IL-6 were assessed via Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumour size, lymph node (LN) metastasis, and tumour staging. Relevant investigations were made to find out the presence of distant metastasis. Statistical analysis of the data was then processed.</p> <p>Results</p> <p>Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels correlated with LN metastasis (P < 0.001, P < 0.001) and TNM stage (P < 0.001, P < 0.001). Tumour invasion and the presence of distant metastasis is associated with higher IL-6 levels (P = 0.001, P = 0.009). When we established the cutoff value for IL-6 level (20.55 pg/dl) by ROC curve, we noted a significant difference in overall survival (OS; P = 0.008). However, CRP evidenced no significance with regard to patient's OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.579, P < 0.01)</p> <p>Conclusion</p> <p>Serum levels of IL-6 correlates well with the extent of tumor invasion, LN metastasis, distant metastasis and TNM staging thus enveloping all aspects of breast cancer.</p

Knowledge about safe motherhood and HIV/AIDS among school pupils in a rural area in Tanzania

\ud The majority of adolescents in Africa experience pregnancy, childbirth and enter motherhood without adequate information about maternal health issues. Information about these issues could help them reduce their pregnancy related health risks. Existing studies have concentrated on adolescents' knowledge of other areas of reproductive health, but little is known about their awareness and knowledge of safe motherhood issues. We sought to bridge this gap by assessing the knowledge of school pupils regarding safe motherhood in Mtwara Region, Tanzania. We used qualitative and quantitative descriptive methods to assess school pupils' knowledge of safe motherhood and HIV/AIDS in pregnancy. An anonymous questionnaire was used to assess the knowledge of 135 pupils ranging in age from 9 to 17 years. The pupils were randomly selected from 3 primary schools. Underlying beliefs and attitudes were assessed through focus group interviews with 35 school children. Key informant interviews were conducted with six school teachers, two community leaders, and two health staffs. Knowledge about safe motherhood and other related aspects was generally low. While 67% of pupils could not mention the age at which a girl may be able to conceive, 80% reported it is safe for a girl to be married before she reaches 18 years. Strikingly, many school pupils believed that complications during pregnancy and childbirth are due to non-observance of traditions and taboos during pregnancy. Birth preparedness, important risk factors, danger signs, postpartum care and vertical transmission of HIV/AIDS and its prevention measures were almost unknown to the pupils. Poor knowledge of safe motherhood issues among school pupils in rural Tanzania is related to lack of effective and coordinated interventions to address reproductive health and motherhood. For long-term and sustained impact, school children must be provided with appropriate safe motherhood information as early as possible through innovative school-based interventions.\u

Population Response to Habitat Fragmentation in a Stream-Dwelling Brook Trout Population

Fragmentation can strongly influence population persistence and expression of life-history strategies in spatially-structured populations. In this study, we directly estimated size-specific dispersal, growth, and survival of stream-dwelling brook trout in a stream network with connected and naturally-isolated tributaries. We used multiple-generation, individual-based data to develop and parameterize a size-class and location-based population projection model, allowing us to test effects of fragmentation on population dynamics at local (i.e., subpopulation) and system-wide (i.e., metapopulation) scales, and to identify demographic rates which influence the persistence of isolated and fragmented populations. In the naturally-isolated tributary, persistence was associated with higher early juvenile survival (∼45% greater), shorter generation time (one-half) and strong selection against large body size compared to the open system, resulting in a stage-distribution skewed towards younger, smaller fish. Simulating barriers to upstream migration into two currently-connected tributary populations caused rapid (2–6 generations) local extinction. These local extinctions in turn increased the likelihood of system-wide extinction, as tributaries could no longer function as population sources. Extinction could be prevented in the open system if sufficient immigrants from downstream areas were available, but the influx of individuals necessary to counteract fragmentation effects was high (7–46% of the total population annually). In the absence of sufficient immigration, a demographic change (higher early survival characteristic of the isolated tributary) was also sufficient to rescue the population from fragmentation, suggesting that the observed differences in size distributions between the naturally-isolated and open system may reflect an evolutionary response to isolation. Combined with strong genetic divergence between the isolated tributary and open system, these results suggest that local adaptation can ‘rescue’ isolated populations, particularly in one-dimensional stream networks where both natural and anthropogenically-mediated isolation is common. However, whether rescue will occur before extinction depends critically on the race between adaptation and reduced survival in response to fragmentation

Characterization of BTBD1 and BTBD2, two similar BTB-domain-containing Kelch-like proteins that interact with Topoisomerase I

BACKGROUND: Two-hybrid screening for proteins that interact with the core domain of human topoisomerase I identified two novel proteins, BTBD1 and BTBD2, which share 80% amino acid identities. RESULTS: The interactions were confirmed by co-precipitation assays demonstrating the physical interaction of BTBD1 and BTBD2 with 100 kDa topoisomerase I from HeLa cells. Deletion mapping using two-hybrid and GST-pulldown assays demonstrated that less than the C-terminal half of BTBD1 is sufficient for binding topoisomerase I. The topoisomerase I sequences sufficient to bind BTBD2 were mapped to residues 215 to 329. BTBD2 with an epitope tag localized to cytoplasmic bodies. Using truncated versions that direct BTBD2 and TOP1 to the same cellular compartment, either the nucleus or the cytoplasm, co-localization was demonstrated in co-transfected Hela cells. The supercoil relaxation and DNA cleavage activities of topoisomerase I in vitro were affected little or none by co-incubation with BTBD2. Northern analysis revealed only a single sized mRNA for each BTBD1 and BTBD2 in all human tissues tested. Characterization of BTBD2 mRNA revealed a 255 nucleotide 90% GC-rich region predicted to encode the N-terminus. BTBD1 and BTBD2 are widely if not ubiquitously expressed in human tissues, and have two paralogs as well as putative orthologs in C. elegans and D. melanogaster. CONCLUSIONS: BTBD1 and BTBD2 belong to a small family of uncharacterized proteins that appear to be specific to animals. Epitope-tagged BTBD2 localized to cytoplasmic bodies. The characterization of BTBD1 and BTBD2 and their interaction with TOP1 is underway

Improved change detection with nearby hands

Recent studies have suggested altered visual processing for objects that are near the hands. We present three experiments that test whether an observer’s hands near the display facilitate change detection. While performing the task, observers placed both hands either near or away from the display. When their hands were near the display, change detection performance was more accurate and they held more items in visual short-term memory (experiment 1). Performance was equally improved for all regions across the entire display, suggesting a stronger attentional engagement over all visual stimuli regardless of their relative distances from the hands (experiment 2). Interestingly, when only one hand was placed near the display, we found no facilitation from the left hand and a weak facilitation from the right hand (experiment 3). Together, these data suggest that the right hand is the main source of facilitation, and both hands together produce a nonlinear boost in performance (superadditivity) that cannot be explained by either hand alone. In addition, the presence of the right hand biased observers to attend to the right hemifield first, resulting in a right-bias in change detection performance (experiments 2 and 3)

Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome