A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis

Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 - 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB

The open solution methodology approach to problem solving

The Open Solution Methodology is a generic problem solving methodology which is used to solve system related problems through the application of problem solving techniques. The focus of the application of this methodology is aimed at modelling organisations, or areas within organisations. The application ofthe Open Solution Methodology provides the benefit of having the ability to comprehend and integrate all aspects of the system, while having a formal and structured approach for problem solving. Together with the reduction in system analysis time, problem solving techniques such as simulation modelling are focused through the Open Solution Methodology models to enhance the quality Ofsolutions.Die "Open Solution Methodology" is 'n generiese probleemoplossingsmetodologie wat gebruik word om stelselverwante probleme op te los deur die toepassing van problemoplossingstegnieke. Die fokus van hierdie metodologie toepassing is gernik op die modellering van organisasies, of gedeeltes van organisasies. Die "Open Solution Methodology" toepassing verskaf die voordeel om aile aspekte van die stelsel te verstaan en te integreer, terwyl daarvan 'n formele en gestruktureerde benadering tot probleemoplossing gebruik gemaak word. Tesame met die gepaardgaande verkorting van stelselanalisetyd, word die "Open Solution Methodology" modelle gebruik om die toepassing van probleemoplossingstegnieke te fokus omsodoende kwaliteit van die oplossings te verhoog

The quantum state vector in phase space and Gabor's windowed Fourier transform

Representations of quantum state vectors by complex phase space amplitudes, complementing the description of the density operator by the Wigner function, have been defined by applying the Weyl-Wigner transform to dyadic operators, linear in the state vector and anti-linear in a fixed `window state vector'. Here aspects of this construction are explored, with emphasis on the connection with Gabor's `windowed Fourier transform'. The amplitudes that arise for simple quantum states from various choices of window are presented as illustrations. Generalized Bargmann representations of the state vector appear as special cases, associated with Gaussian windows. For every choice of window, amplitudes lie in a corresponding linear subspace of square-integrable functions on phase space. A generalized Born interpretation of amplitudes is described, with both the Wigner function and a generalized Husimi function appearing as quantities linear in an amplitude and anti-linear in its complex conjugate. Schr\"odinger's time-dependent and time-independent equations are represented on phase space amplitudes, and their solutions described in simple cases.Comment: 36 pages, 6 figures. Revised in light of referees' comments, and further references adde

Positivity properties of phase‐plane distribution functions

The aim of this paper is to compare the members of Cohen's class of phase-plane distributions with respect to positivity properties. It is known that certain averages (which are in a sense compatible with Heisenberg's uncertainty principle) of the Wigner distribution over the phase-plane yield non-negative values for all states. It is shown in this paper that the Wigner distribution is unique in this respect among the members of Cohen's class that have correct marginals or that satisfy Moyal's formula for all states. The subset of members of Cohen's class (not necessarily satisfying one of these two conditions) with positivity properties comparable with those for the Wigner distribution is shown to be rather small

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder

Macrophages Homing to Metastatic Lymph Nodes Can Be Monitored with Ultrasensitive Ferromagnetic Iron-Oxide Nanocubes and a 1.5T Clinical MR Scanner

Background: Due to the ability of macrophages to specifically home to tumors, their potential use as a delivery vehicle for cancer therapeutics has been suggested. Tracking the delivery and engraftment of macrophages into human tumors with a 1.5T clinical MR scanner requires the development of sensitive contrast agents for cell labeling. Therefore, this study aimed to determine whether intravenously injected macrophages could target a primary tumor as well as metastatic LNs, and whether these cells could be detected in vivo by MRI. Methodology: Peritoneal macrophages were obtained from BALB/c nude mice. The viability, phagocytotic capacity and migratory activity of the macrophages were assessed. MR imaging was performed using a clinical 1.5 T MR scanner and we estimated the T2 * of the labeled macrophages. Metastatic lymph nodes were produced in BALB/c nude mice. We administrated 2610 6 macrophages labeled with 50 mg Fe/mL FIONs intravenously into the mice. In the 3D T2 * GRE MR images obtained one day after the injection of the labeled macrophages or FION solution, the percentages of pixels in the tumors or LNs below the minimum normalized SI (signal intensity) threshold were summated and reported as the black pixel count (%) for the FION hypointensity. Tumors in the main tumor model as well as the brachial, axillary and inguinal lymph nodes in the metastatic LN models were removed and stained. For all statistical analyses, single-group data were assessed using t test or the Mann-Whitney test. Repeated measurements analysis of variance (ANOVA) with Tukey–Krame

Cellular mechanisms of bone resorption in breast carcinoma

The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Osteoclasts are marrow-derived cells which form by fusion of mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have determined whether circulating osteoclast precursors are increased in number or have an increased sensitivity to humoral factors for osteoclastogenesis in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to patients with primary breast cancer and age-matched normal controls. Monocytes were isolated and cocultured with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D3[1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slices. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to controls. Osteoclast precursors in these patients also did not exhibit increased sensitivity to 1,25(OH)2D3 or M-CSF in terms of osteoclast formation. The addition of parathyroid hormone-related protein and interleukin-6 did not increase osteoclast formation. The addition of the supernatant of cultured breast cancer cell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte-osteoclast formation in a dose-dependent fashion. These results indicate that the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteoclast precursors. They also suggest that tumour cells promote osteoclast formation in the bone microenvironment by secreting soluble osteoclastogenic factor(s). © 2001 Cancer Research Campaign http://www.bjcancer.co

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies