Biochemical Determinants of Tissue Regeneration Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy

Abstract Metaplasia is the irreversible conversion of one differentiated cell or tissue type into another. Metaplasia usually occurs in tissues that undergo regeneration, and may, in a pathological context, predispose to an increased risk of disease. Studying the conditions leading to the development of metaplasia is therefore of significant clinical interest. In contrast, transdifferentiation (or cellular reprogramming) is a subset of metaplasia that describes the permanent conversion of one differentiated cell type into another, and generally occurs between cells that arise from neighbouring regions of the same germ layer. Transdifferentiation, although rare, has been shown to occur in Nature. New insights into the signalling pathways involved in normal tissue development may be obtained by investigating the cellular and molecular mechanisms in metaplasia and transdifferentiation, and additional identification of key molecular regulators in transdifferentiation and metaplasia could provide new targets for therapeutic treatment of diseases such as cancer, as well as generating cells for transplantation into patients with degenerative disorders. In the present review, we focus on the transdifferentiation of pancreatic cells into hepatocytelike cells, the development of Barrett's metaplasia in the oesophagus, and the cellular and molecular mechanisms underlying both processes

A New Experimental Infection Model in Ferrets Based on Aerosolised Mycobacterium bovis

There is significant interest in developing vaccines to control bovine tuberculosis, especially in wildlife species where this disease continues to persist in reservoir species such as the European Badger (Meles meles). However, gaining access to populations of badgers (protected under UK law) is problematic and not always possible. In this study, a new infection model has been developed in ferrets (Mustela furo), a species which is closely related to the badger. Groups of ferrets were infected using a Madison infection chamber and were examined postmortem for the presence of tuberculous lesions and to provide tissue samples for confirmation of Mycobacterium bovis by culture. An infectious dose was defined, that establishes infection within the lungs and associated lymph nodes with subsequent spread to the mesentery lymph nodes. This model, which emphasises respiratory tract infection, will be used to evaluate vaccines for the control of bovine tuberculosis in wildlife species

Cost and quality of life analysis of HIV self-testing and facility-based HIV testing and counselling in Blantyre, Malawi.

BACKGROUND: HIV self-testing (HIVST) has been found to be highly effective, but no cost analysis has been undertaken to guide the design of affordable and scalable implementation strategies. METHODS: Consecutive HIV self-testers and facility-based testers were recruited from participants in a community cluster-randomised trial ( ISRCTN02004005 ) investigating the impact of offering HIVST in addition to facility-based HIV testing and counselling (HTC). Primary costing studies were undertaken of the HIVST service and of health facilities providing HTC to the trial population. Costs were adjusted to 2014 US$and INT$. Recruited participants were asked about direct non-medical and indirect costs associated with accessing either modality of HIV testing, and additionally their health-related quality of life was measured using the EuroQol EQ-5D. RESULTS: A total of 1,241 participants underwent either HIVST (n = 775) or facility-based HTC (n = 446). The mean societal cost per participant tested through HIVST (US$9.23; 95$9.14-US$9.32) was lower than through facility-based HTC (US$11.84; 95 % CI: US$10.81-12.86). Although the mean health provider cost per participant tested through HIVST (US$8.78) was comparable to facility-based HTC (range: US$7.53-US$10.57), the associated mean direct non-medical and indirect cost was lower (US$2.93; 95$1.90-US$3.96). The mean health provider cost per HIV positive participant identified through HIVST was higher (US$97.50) than for health facilities (range: US$25.18-US$76.14), as was the mean cost per HIV positive individual assessed for anti-retroviral treatment (ART) eligibility and the mean cost per HIV positive individual initiated onto ART. In comparison to the facility-testing group, the adjusted mean EQ-5D utility score was 0.046 (95 % CI: 0.022-0.070) higher in the HIVST group. CONCLUSIONS: HIVST reduces the economic burden on clients, but is a costlier strategy for the health provider aiming to identify HIV positive individuals for treatment. The provider cost of HIVST could be substantially lower under less restrictive distribution models, or if costs of oral fluid HIV test kits become comparable to finger-prick kits used in health facilities

Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study)

Background: Adults seeking diagnosis and treatment for tuberculosis (TB) and HIV in low-resource settings face considerable barriers and have high pre-treatment mortality. Efforts to improve access to prompt TB treatment have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can best be implemented. Design and methods: The PROSPECT Study is an open, three-arm pragmatic randomised study that will investigate the effectiveness and cost-effectiveness of optimised HIV and TB diagnosis and linkage to care interventions in reducing time to TB diagnosis and prevalence of undiagnosed TB and HIV in primary care in Blantyre, Malawi. Participants (≥ 18 years) attending a primary care clinic with TB symptoms (cough of any duration) will be randomly allocated to one of three groups: (i) standard of care; (ii) optimised HIV diagnosis and linkage; or (iii) optimised HIV and TB diagnosis and linkage. We will test two hypotheses: firstly, whether prompt linkage to HIV care should be prioritised for adults with TB symptoms; and secondly, whether an optimised TB triage testing algorithm comprised of digital chest x-ray evaluated by computer-aided diagnosis software and sputum GeneXpert MTB/Rif can outperform clinician-directed TB screening. The primary trial outcome will be time to TB treatment initiation by day 56, and secondary outcomes will include prevalence of undiagnosed TB and HIV, mortality, quality of life, and cost-effectiveness. Conclusions: The PROSPECT Study will provide urgently-needed evidence under “real-life” conditions to inform clinicians and policy makers on how best to improve TB/HIV diagnosis and treatment in Africa

Orientation Dependence of the Anomalous Hall Resistivity in Single Crystals of Yb14MnSb11

The Hall resistivity, electrical resistivity and magnetization of single crystals of the tetragonal ferromagnet Yb14MnSb11 are reported as a function of the direction of the current, I, and magnetic field, H with respect to the principal crystallographic axes. With I along the unique c direction and H in the a-b plane, the anomalous Hall resistivity in the limit of zero applied field is negative for all temperatures T less than Tc= 53 K. In this direction, the anomalous Hall effect behaves in a manner similar to that observed in other ferromagnets such as Fe, Co, Mn5Ge3, and EuFe4Sb12. However, with I in the a-b plane and H along the c direction, the anomalous Hall behavior is completely different. The anomalous Hall resistivity data are positive for all T less than Tc and a similar analysis of these data fails. In this direction, the anomalous response is not a simple linear function of the magnetization order parameter, and for a fixed temperature (T less than Tc) does not depend on the magnitude of the magnetization perpendicular to the current in the a-b plane. That is, when the magnetization and applied field are rotated away from the c direction, the anomalous Hall resistivity does not change. In all other soft ferromagnets that we have examined (including La doped crystals of Yb14MnSb11, i.e. Yb13.3La0.7MnSb11) rotation of the magnetization and magnetic field by an angle theta away from a direction perpendicular to I results in a decrease in both the anomalous and normal portions of the Hall resistivity that approximately scales as cos(theta). We suggest that the unique response exhibited by Yb14MnSb11 is a direct reflection of the delicate balance between ferromagnetism and Kondo screening.Comment: 20 pages, 12 Figures, Submitted to Physical Review B, July 18, 200

Access to Research Veterinary Medicine International Volume

There is significant interest in developing vaccines to control bovine tuberculosis, especially in wildlife species where this disease continues to persist in reservoir species such as the European Badger (Meles meles). However, gaining access to populations of badgers (protected under UK law) is problematic and not always possible. In this study, a new infection model has been developed in ferrets (Mustela furo), a species which is closely related to the badger. Groups of ferrets were infected using a Madison infection chamber and were examined postmortem for the presence of tuberculous lesions and to provide tissue samples for confirmation of Mycobacterium bovis by culture. An infectious dose was defined, that establishes infection within the lungs and associated lymph nodes with subsequent spread to the mesentery lymph nodes. This model, which emphasises respiratory tract infection, will be used to evaluate vaccines for the control of bovine tuberculosis in wildlife species

Sun, Moon, Stars, Rain, Vol. 7 No. 11

Official publication of the Sigma Tau Delta English Honor Society, Alpha Zet Chapter, Stephen F. Austin State University. Published one a year in the Fall Semester, in cooperation with the English Department of Stephen F. Austin State University.https://scholarworks.sfasu.edu/smsr/1000/thumbnail.jp

Economic Costs and Health-Related Quality of Life Outcomes of HIV Treatment After Self-and Facility-Based HIV Testing in a Cluster Randomized Trial

Background: The scale-up of HIV self-testing (HIVST) in Africa is recommended, but little is known about how this novel approach influences economic outcomes following subsequent antiretroviral treatment (ART) compared with established facility-based HIV testing and counseling (HTC) approaches. Setting: HIV clinics in Blantyre, Malawi. Methods: Consecutive HIV-positive participants, diagnosed by HIVST or facility-based HTC as part of a community cluster-randomized trial (ISRCTN02004005), were followed from initial assessment for ART until 1-year postinitiation. Healthcare resource use was prospectively measured, and primary costing studies undertaken to estimate total health provider costs. Participants were interviewed to establish direct nonmedical and indirect costs over the first year of ART. Costs were adjusted to 2014 US$and INT$. Health-related quality of life was measured using the EuroQol EQ-5D at each clinic visit. Multivariable analyses estimated predictors of economic outcomes. Results: Of 325 participants attending HIV clinics for assessment for ART, 265 were identified through facility-based HTC, and 60 through HIVST; 168/265 (69.2%) and 36/60 (60.0%), respectively, met national ART eligibility criteria and initiated treatment. The mean total health provider assessment costs for ART initiation were US$22.79 (SE: 0.56) and US$19.92 (SE: 0.77) for facility-based HTC and HIVST participants, respectively, and was US$2.87 (bootstrap 95$1.01 to US$4.73) lower for the HIVST group. The mean total health provider costs for the first year of ART were US$168.65 (SE: 2.02) and US$164.66 (SE: 4.21) for facility-based HTC and HIVST participants, respectively, and comparable between the 2 groups (bootstrap 95$12.38 to US$4.39). EQ-5D utility scores immediately before and one year after ART initiation were comparable between the 2 groups. EQ-5D utility scores 1 year after ART initiation had increased by 0.129 (SE: 0.011) and 0.139 (SE: 0.027) for facility-based HTC and HIVST participants, respectively

Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?

BACKGROUND: Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss. METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB. RESULTS: Overall, 147/1,545 (9.5%) subjects had culture-positive TB, of which 32 (21.8%) had DR-TB (MDR, 13.6%; isoniazid mono-resistant, 7.5%; rifampicin mono-resistant, 0.7%). A total of 553 subjects (35.8%) reported one or more MDR-TB risk factors; of these, 506 (91.5%; 95% CI, 88.9-93.7%) did not have TB, 32/553 (5.8%; 95% CI, 3.4-8.1%) had drug-susceptible TB, and only 15/553 (2.7%; 95% CI, 1.5-4.4%) had DR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2%; 95% CI, 34.7-70.9). CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority