Serum CA 125 concentrations in women with endometriosis or uterine fibroids treated with gonadotrophin-releasing hormone agonist analogues

We assessed the possible role of CA 125 in the monitoring of gonadotrophin-releasing hormone (GnRH) agonist analogue therapy in women with endometriosis and uterine fibroids. Serum concentrations of this cell surface antigen did not correlate with uterine volume and appeared to have no value in the assessment of shrinkage of uterine fibroids during GnRH agonist treatment. While CA 125 levels were not always elevated in subjects with endometriosis, they fell during treatment in all patients. The change accurately reflected therapeutic progress in these women and was of particular value in those patients who had commenced therapy with elevated levels. It is suggested that CA 125 may be useful in the monitoring of therapeutic progress in selected patients with endometriosis treated with GnRH agonists; the need for surgical follow-up may be obviated

Economic appraisal of dabigatran as first-line therapy for stroke prevention in atrial fibrillation

Background. Dabigatran is an oral anticoagulant direct thrombin inhibitor recently registered in South Africa (SA) to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). Owing to the price disparity between warfarin (the current gold standard for treatment of patients with AF) and dabigatran, we conducted an economic appraisal of the use of dabigatran compared with warfarin from a payer perspective in the South African private healthcare setting.Objectives. To estimate the cost-effectiveness (CE) and budget impact of dabigatran compared with warfarin for the prevention of strokein AF patients.Methods. A previously published Markov model was populated with SA cost and mortality data to estimate the CE and budget impact analysis of dabigatran over a lifetime horizon. The model population consisted of a cohort of patients of whom those aged younger than 80 years used dabigatran 150 mg twice daily and those older than 80 years 110 mg twice daily. Modelled outcomes included total cost, qualityadjusted life years (QALYs) and incremental CE ratio (ICER), with the effectiveness measured by QALYs gained.Results. Dabigatran compared with warfarin as first-line treatment was estimated to have an ICER of R93 290 and an average incrementalcost per beneficiary per month of R0.39 over a 5-year period. Conservative assumptions were made regarding the number of international normalised ratio monitoring tests for patients on warfarin, and the ICER is estimated to decrease by as much as 15.7% under less stringent assumptions. A robust sensitivity analysis was also performed.Conclusion. Dabigatran as first-line treatment compared with warfarin for the use of stroke prevention in patients with AF is deemed costeffectivewhen used in accordance with its registered indication in the SA private sector

A Panel of Ancestry Informative Markers for the Complex Five-Way Admixed South African Coloured Population

Admixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce false-positive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al's -statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.Department of HE and Training approved lis

T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10

Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies

Revival of the magnetar PSR J1622-4950: observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR

New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100x larger than during its dormant state. The X-ray flux one month after reactivation was at least 800x larger than during quiescence, and has been decaying exponentially on a 111+/-19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.Comment: Published in ApJ (2018 April 5); 13 pages, 4 figure

Growth hormone secretion is correlated with neuromuscular innervation rather than motor neuron number in early-symptomatic male amyotrophic lateral sclerosis mice

GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1(G93A) mice throughout the course of ALS disease. Male wild-type and hSOD1(G93A) mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1(G93A) mice; compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1(G93A) mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs

Antibacterial and dermal toxicological profiles of ethyl acetate extract from Crassocephalum bauchiense (Hutch.) Milne-Redh (Asteraceae)

<p>Abstract</p> <p>Background</p> <p>The emergence in recent years of numerous resistant strains of pathogenic bacteria to a range of formerly efficient antibiotics constitutes a serious threat to public health. <it>Crassocephalum bauchiense</it>, a medicinal herb found in the West Region of Cameroon is used to treat gastrointestinal infections as well as liver disorders. The ethyl acetate extract from the leaves of <it>C. bauchiense </it>was evaluated for its antibacterial activity as well as acute and sub-acute toxicities.</p> <p>Methods</p> <p>The plant extract was prepared by maceration in ethyl acetate. Its phytochemical screening was done by standard methods. The broth microdilution method was used to evaluate the <it>in vitro </it>antibacterial activity. The <it>in vivo </it>antibacterial activity of a gel formulation (0.05, 1 and 2% w/v) of this extract was evaluated using a <it>Staphylococcus aureus</it>-induced dermatitis in a murine model. Selected haematological and biochemical parameters were used to evaluate the dermal sub-acute toxicity of the extract in rats.</p> <p>Results</p> <p>Phytochemical screening of the <it>C. bauchiense </it>extract revealed the presence of alkaloids, phenols, tannins and sterols. <it>In vitro </it>antibacterial activities were observed against all the tested microorganisms (MIC = 0.04-6.25 mg/ml). Formulated extract-gel (2% w/v) and gentamycin (reference drug) eradicated the microbial infection after five days of treatment. A single dermal dose of this extract up to 32 g/kg body weight (bw) did not produce any visible sign of toxicity. Also, daily dermal application of the <it>C. bauchiense </it>extract gel formulation for 28 days did not show any negative effect, instead some biochemical parameters such as alanine aminotransferase (ALT and AST), low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides were significantly (p < 0.05) affected positively.</p> <p>Conclusion</p> <p>These results indicate that the <it>C. bauchiense </it>ethyl acetate extract can be used safely for the treatment of some bacterial infections.</p

Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors

HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an E-box motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression