Introduction and scaling up of new drugs for drug-resistant TB: experiences from the Americas.

The number of multidrug-resistant tuberculosis (MDR-TB) cases reported in the Americas has increased by 21.2%, from 3737 in 2016 to 4791 in 2018. The WHO has been recommending changes on the treatment of DR-TB, moving from long-duration treatment with injectables to a short oral regimen with new drugs such as bedaquiline (BDQ) and delamanid (DLM), in selected cases and only under programmatic conditions. Injectables are no longer recommended by the WHO due to lower efficacy and the increasing seriousness of adverse events. The introduction of new oral drugs for DR-TB received a boost with a global donation of BDQ to some eligible countries, which continues with the countries purchasing drugs through the Pan American Health Organization Strategic Fund. The main challenges in the scaling up of new drugs for DR-TB include low DR-TB detection rate, the slow pace in transitioning to molecular testing and delays in the introduction of new oral short regimens for MDR-TB. The Americas need to accelerate the scale up of new oral treatments, improve detection rates, increase molecular diagnosis of resistance, and ensure the registration and introduction of the shorter treatment regimen in national MDR-TB guidelines.

Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination.

Cell-cell interactions promote juxtacrine signals in specific subcellular domains, which are difficult to capture in the complexity of the nervous system. For example, contact between axons and Schwann cells triggers signals required for radial sorting and myelination. Failure in this interaction causes dysmyelination and axonal degeneration. Despite its importance, few molecules at the axo-glial surface are known. To identify novel molecules in axo-glial interactions, we modified the 'pseudopodia' sub-fractionation system and isolated the projections that glia extend when they receive juxtacrine signals from axons. By proteomics we identified the signalling networks present at the glial-leading edge, and novel proteins, including members of the Prohibitin family. Glial-specific deletion of Prohibitin-2 in mice impairs axo-glial interactions and myelination. We thus validate a novel method to model morphogenesis and juxtacrine signalling, provide insights into the molecular organization of the axo-glial contact, and identify a novel class of molecules in myelination.

PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways.

Myogenic differentiation is a highly orchestrated multistep process controlled by extracellular growth factors that modulate largely unknown signals into the cell affecting the muscle-transcription program. P38MAPK-dependent signalling, as well as PI3K/Akt pathway, has a key role in the control of muscle gene expression at different stages during the myogenic process. P38MAPK affects the activities of transcription factors, such as MyoD and myogenin, and contributes, together with PI3K/Akt pathway, to control the early and late steps of myogenic differentiation. The aim of our work was to better define the role of PKR, a dsRNA-activated protein kinase, as potential component in the differentiation program of C2C12 murine myogenic cells and to correlate its activity with p38MAPK and PI3K/Akt myogenic regulatory pathways. Here, we demonstrate that PKR is an essential component of the muscle development machinery and forms a functional complex with p38MAPK and/or Akt, contributing to muscle differentiation of committed myogenic cells in vitro. Inhibition of endogenous PKR activity by a specific (si)RNA and a PKR dominant-negative interferes with the myogenic program of C2C12 cells, causing a delay in activation of myogenic specific genes and inducing the formation of thinner myofibers. In addition, the construction of three PKR mutants allowed us to demonstrate that both N and C-terminal regions of PKR are critical for the interaction with p38MAPK and Akt. The novel discovered complex permits PKR to timely regulate the inhibition/activation of p38MAPK and Akt, controlling in this way the different steps characterizing skeletal muscle differentiation.

Passive sentinel surveillance system for sexually transmitted diseases in primary healthcare sites in Ethiopia, 1991-3.

BACKGROUND: In 1989 the ministry of health of Ethiopia launched an STD control programme to strengthen the STD case management capabilities at public health centres and hospitals. The programme included the introduction of a syndrome based system for notification of STD cases. We here report the data originated by the syndromic case reporting system under programme conditions. METHODS: 35 (17%) of the total 225 hospitals and public health centres of Ethiopia were included in the programme. Information relevant to the years 1991 to 1993 was analysed at mid 1994. RESULTS: 32 clinical sites (91% of the total) provided at least one monthly report. The proportion of monthly reports received was 65% of those due, ranging from 51% in 1991 to 73% in 1992 and 42% in 1993. A total of 77,294 consultations for STD related symptoms were recorded, including 70,200 new cases, 6588 repeated consultations, and 506 partners of STD patients. Among first attendant patients 38,459 (52.7%) were males with a male to female ratio of 1:1. Urethral discharge and vaginal discharge were the leading cause of consultation among males (58%) and females (64%) respectively. The frequency of genital ulcer diseases was 26% among males and 15% among females. Inguinal adenopathy in the absence of genital ulcers was also frequent, accounting for 10% of consulting males and 5% of females. Based on Gram stain, gonorrhoea was identified in 64% of the cases of urethral discharge, while trichomoniasis and candidiasis were identified by wet mount in 28% and 16% of the cases of vaginal discharge respectively. CONCLUSIONS: STDs are a common cause of consultation at public health centre sites in Ethiopia. A syndromic case reporting system proved to be efficient and produced valuable information to initiate assessment of the problem and to set up bases for monitoring trends of STD morbidity.