Human resources for control of tuberculosis and HIV-associated tuberculosis.

The global targets for tuberculosis (TB) control were postponed from 2000 to 2005, but on current evidence a further postponement may be necessary. Of the constraints preventing these targets being met, the primary one appears to be the lack of adequately trained and qualified staff. This paper outlines: 1) the human resources and skills for global TB and human immunodeficiency virus (HIV) TB control, including the human resources for implementing the DOTS strategy, the additional human resources for implementing joint HIV-TB control strategies and what is known about human resource gaps at global level; 2) the attempts to quantify human resource gaps by focusing on a small country in sub-Saharan Africa, Malawi; and 3) the main constraints to human resources and their possible solutions, under six main headings: human resource planning; production of human resources; distribution of the work-force; motivation and staff retention; quality of existing staff; and the effect of HIV/AIDS. We recommend an urgent shift in thinking about the human resource paradigm, and exhort international policy makers and the donor community to make a concerted effort to bridge the current gaps by investing for real change

The biology of ageing and the omics revolution

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this recor

What can the SEDs of first hydrostatic core candidates reveal about their nature?

The first hydrostatic core (FHSC) is the first stable object to form in simulations of star formation. This stage has yet to be observed definitively, although several candidate FHSCs have been reported. We have produced synthetic spectral energy distributions (SEDs) from 3D hydrodynamical simulations of pre-stellar cores undergoing gravitational collapse for a variety of initial conditions. Variations in the initial rotation rate, radius and mass lead to differences in the location of the SED peak and far-infrared flux. Secondly, we attempt to fit the SEDs of five FHSC candidates from the literature and five newly identified FHSC candidates located in the Serpens South molecular cloud with simulated SEDs. The most promising FHSC candidates are fitted by a limited number of model SEDs with consistent properties, which suggests the SED can be useful for placing constraints on the age and rotation rate of the source. The sources we consider most likely to be in FHSC phase are B1-bN, CB17-MMS, Aqu-MM1 and Serpens South candidate K242. We were unable to fit SerpS-MM22, Per-Bolo 58 and Chamaeleon-MMS1 with reasonable parameters, which indicates that they are likely to be more evolved.Comment: 26 pages, 28 figures. Accepted for publication in MNRA

Growing syntax: The development of a DP in North Germanic

Grammaticalization as standardly conceived is a change whereby an item develops from a lexical to a grammatical or functional meaning, or from being less to more grammatical. In this article we show that this can only be part of the story; for a full account we need to understand the syntactic structures into which grammaticalizing elements fit and how they too develop. To achieve this end we consider in detail the history of definiteness marking within the noun phrase in North Germanic, and in particular in Faroese. We show how this change requires us to distinguish between projecting and nonprojecting categories, and how a category can emerge over time and only subsequently develop into a head with its own associated functional projection. The necessary structure, rather than being intrinsic to an aprioristic universal grammar, grows over time as part of the grammaticalization process. We suggest that this in turn argues for a parallel correspondence theory of grammar such as the one adopted here, lexical-functional grammar, in which dif-ferent dimensions of linguistic structure can change at different rates

Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL).

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © 2009 Hanlon et al.BACKGROUND: MicroRNAs (miRNAs) are short, noncoding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. The miRNAs, MIR-15a/16-1, at chromosome band 13q14 are down-regulated in the majority of patients with chronic lymphocytic leukaemia (CLL). METHODOLOGY/PRINCIPAL FINDINGS: We have measured the expression of MIR-15a/16-1, and 92 computationally-predicted MIR-15a/16-1 target genes in CLL patients and in normal controls. We identified 35 genes that are deregulated in CLL patients, 5 of which appear to be specific targets of the MIR-15a/16-1 cluster. These targets included 2 genes (BAZ2A and RNF41) that were significantly up-regulated (p<0.05) and 3 genes (RASSF5, MKK3 and LRIG1) that were significantly down-regulated (p<0.05) in CLL patients with down-regulated MIR-15a/16-1 expression. SIGNIFICANCE: The genes identified here as being subject to MIR-15a/16-1 regulation could represent direct or indirect targets of these miRNAs. Many of these are good biological candidates for involvement in tumorigenesis and as such, may be important in the aetiology of CLL.Exeter Leukaemia Fun

The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India

Background: India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TBrelated deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with “early” death, occurring in the initial 8 weeks of treatment. Methods: This was a retrospective study in 16 selected Designated Microscopy Centres (DMCs) in Hyderabad, Krishna and Adilabad districts of Andhra Pradesh, South India. A review was performed of treatment cards and medical records of all TB patients (adults and children) registered and placed on standardized anti-tuberculosis treatment from January 2005 to September 2009. Results: There were 8,240 TB patients (5183 males) of whom 492 (6%) were known to have died during treatment. Case-fatality was higher in those previously treated (12%) and lower in those with extra-pulmonary TB (2%). There was an even distribution of deaths during anti-tuberculosis treatment, with 28% of all patients dying in the first 8 weeks of treatment. Increasing age and new as compared to recurrent TB disease were significantly associated with “early death”. Conclusion: In this large cohort of TB patients, deaths occurred with an even frequency throughout anti-TB treatment. Reasons may relate to i) the treatment of the disease itself, raising concerns about drug adherence, quality of anti-tuberculosis drugs or the presence of undetected drug resistance and ii) co-morbidities, such as HIV/ AIDS and diabetes mellitus, which are known to influence mortality. More research in this area from prospective and retrospective studies is needed

Building leadership capacity and future leaders in operational research in low-income countries: why and how?

Very limited operational research (OR) emerges from programme settings in low-income countries where the greatest burden of disease lies. The price paid for this void includes a lack of understanding of how health systems are actually functioning, not knowing what works and what does not, and an inability to propose adapted and innovative solutions to programme problems. We use the National Tuberculosis Control Programme as an example to advocate for strong programme-level leadership to steer OR and build viable relationships between programme managers, researchers and policy makers. We highlight the need to create a stimulating environment for conducting OR and identify some of the main practical challenges and enabling factors at programme level. We focus on the important role of an OR focal point within programmes and practical approaches to training that can deliver timely and quantifiable outputs. Finally, we emphasise the need to measure successful OR leadership development at programme level and we propose parameters by which this can be assessed. This paper 1) provides reasons why programmes should take the lead in coordinating and directing OR, 2) identifies the practical challenges and enabling factors for implementing, managing and sustaining OR and 3) proposes parameters for measuring successful leadership capacity development in OR

Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.AIMS/HYPOTHESIS: Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction. METHODS: The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by microarray. The functional impact of age-associated differences in miRNA expression was investigated by mimicking the observed changes in primary beta cells from young animals. RESULTS: Beta cells from 12-month-old rats retained normal insulin content and secretion, but failed to proliferate in response to mitotic stimuli. The islets of these animals displayed modifications at the level of several miRNAs, including upregulation of miR-34a, miR-124a and miR-383, and downregulation of miR-130b and miR-181a. Computational analysis of the transcriptomic modifications observed in the islets of 12-month-old rats revealed that the differentially expressed genes were enriched for miR-34a and miR-181a targets. Indeed, the induction of miR-34a and reduction of miR-181a in the islets of young animals mimicked the impaired beta cell proliferation observed in old animals. mRNA coding for alpha-type platelet-derived growth factor receptor, which is critical for compensatory beta cell mass expansion, is directly inhibited by miR34a and is likely to be at least partly responsible for the effects of this miRNA. CONCLUSIONS/INTERPRETATION: Changes in the level of specific miRNAs that occur during ageing affect the proliferative capacity of beta cells. This might reduce their ability to expand under conditions of increased insulin demand, favouring the development of type 2 diabetes.Swiss National Science FoundationFondation Francophone pour la Recherche sur le DiabèteWellcome Trust Senior Investigator AwardMRC Programme GrantRoyal Society Wolfson Research Merit AwardWellcome Trust project gran