Analysis of circulating insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in tobacco smokers and non-smokers

<p>Abstract</p> <p>Background</p> <p>IGF-1 and the major serum IGF-1 binding protein, IGFBP-3, are under extensive investigation as potential prognostic markers of specific malignancies and vascular diseases. However, there is conflicting evidence that tobacco smoking may influence systemic concentrations of IGF-1 and IGFBP-3.</p> <p>Subjects and methods</p> <p>Serum concentrations of IGF-1 and IGFBP-3 were measured in 20 smokers and 20 non-smokers, matched for age and gender. Serum concentrations of cotinine, the major metabolite of nicotine, and ICAM-1, known to exhibit a dose-dependent relationship with cotinine, were also assayed.</p> <p>Results</p> <p>There was no difference between the systemic concentrations of IGF-1 or IGFBP-3 found in smokers and non-smokers (IGF-1: mean [s.d]; 104 <abbrgrp><abbr bid="B29">29</abbr></abbrgrp> vs 101 <abbrgrp><abbr bid="B24">24</abbr></abbrgrp> ng ml^-1, respectively; and IGFBP-3: 2562 [522] vs 2447 [570] ng ml^-1, respectively). Similarly, there was no correlation between serum cotinine and IGF-1 or IGFBP-3 concentrations in smokers. Soluble ICAM-1 concentrations were significantly increased in smokers, compared to non-smokers (mean [s.d]; 258 [60] vs 194 [50] ng ml^-1, respectively; p = 0.002).</p> <p>Conclusion</p> <p>There was no relationship noted between tobacco smoking and either IGF-1 or IGFBP-3. These data suggest that smoking would not appear to be a major confounder of the reported clinical associations between IGF-1, IGFBP-3, or IGF-1/IGFBP-3 ratios and specific disease entities.</p

Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study.

BACKGROUND: Blood transcriptional signatures are candidates for non-sputum triage or confirmatory tests of tuberculosis. Prospective head-to-head comparisons of their diagnostic accuracy in real-world settings are necessary to assess their clinical use. We aimed to compare the diagnostic accuracy of candidate transcriptional signatures identified by systematic review, in a setting with a high burden of tuberculosis and HIV. METHODS: We did a prospective observational study nested within a diagnostic accuracy study of sputum Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) tests for pulmonary tuberculosis. We recruited consecutive symptomatic adults aged 18 years or older self-presenting to a tuberculosis clinic in Cape Town, South Africa. Participants provided blood for RNA sequencing, and sputum samples for liquid culture and molecular testing using Xpert and Ultra. We assessed the diagnostic accuracy of candidate blood transcriptional signatures for active tuberculosis (including those intended to distinguish active tuberculosis from other diseases) identified by systematic review, compared with culture or Xpert MTB/RIF positivity as the standard reference. In our primary analysis, patients with tuberculosis were defined as those with either a positive liquid culture or Xpert result. Patients with missing blood RNA or sputum results were excluded. Our primary objective was to benchmark the diagnostic accuracy of candidate transcriptional signatures against the WHO target product profile (TPP) for a tuberculosis triage test. FINDINGS: Between Feb 12, 2016, and July 18, 2017, we obtained paired sputum and RNA sequencing data from 181 participants, 54 (30%) of whom had confirmed pulmonary tuberculosis. Of 27 eligible signatures identified by systematic review, four achieved the highest diagnostic accuracy with similar area under the receiver operating characteristic curves (Sweeney3: 90·6% [95% CI 85·6-95·6]; Kaforou25: 86·9% [80·9-92·9]; Roe3: 86·9% [80·3-93·5]; and BATF2: 86·8% [80·6-93·1]), independent of age, sex, HIV status, previous tuberculosis, or sputum smear result. At test thresholds that gave 70% specificity (the minimum WHO TPP specificity for a triage test), these four signatures achieved sensitivities between 83·3% (95% CI 71·3-91·0) and 90·7% (80·1-96·0). No signature met the optimum criteria, of 95% sensitivity and 80% specificity proposed by WHO for a triage test, or the minimum criteria (of 65% sensitivity and 98% specificity) for a confirmatory test, but all four correctly identified Ultra-positive, culture-negative patients. INTERPRETATION: Selected blood transcriptional signatures met the minimum WHO benchmarks for a tuberculosis triage test but not for a confirmatory test. Further development of the signatures is warranted to investigate their possible effects on clinical and health economic outcomes as part of a triage strategy, or when used as add-on confirmatory test in conjunction with the highly sensitive Ultra test for Mycobacterium tuberculosis DNA. FUNDING: Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, and UK Medical Research Council

Phylogeny of Prokaryotes and Chloroplasts Revealed by a Simple Composition Approach on All Protein Sequences from Complete Genomes Without Sequence Alignment

The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists tree of life based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution

Operation 'Cerberus Action' and the 'Four Corners' Prosecution.

There is a generally accepted belief that a well publicised prosecution, which results in the conviction of the offenders will deter crime by sending out a ‘clear message’ to those intending to offend. Those who seek to enforce the legal protection of antiquities and archaeological sites will often decry the number of prosecutions brought, and urge a more aggressive prosecution policy against looters and traffickers in antiquities. However a prosecution may not always produce the anticipated outcome of deterrence. In this article a lawyer examines a recent high profile operation undertaken by the Federal Bureau of Investigation and the Bureau of Land Management against looters and traffickers in the south west of the United States for breaches of the Archaeological Resources Protection Act of 1979 and its outcome. It will begin with a short consideration of the context in which the prosecutions were brought: the scale of looting in the area; the difficulties facing those who have to enforce the law; the legal and historical background, and the belief of many in the area that they have a right to dig for artefacts and to collect or sell them. It will then consider ‘Operation Cerberus Action’ and its consequences in some detail, drawing on contemporaneous newspaper accounts and blog comments to illustrate that a prosecution, even where it results in conviction of all the defendants, may be counterproductive, serving only to entrench existing attitudes rather than encouraging behavioural change in intending looters and traffickers

District Health Managers' Perceptions of Supervision in Malawi and Tanzania.

Mid-level cadres are being used to address human resource shortages in many African contexts, but insufficient and ineffective human resource management is compromising their performance. Supervision plays a key role in performance and motivation, but is frequently characterised by periodic inspection and control, rather than support and feedback to improve performance. This paper explores the perceptions of district health management teams in Tanzania and Malawi on their role as supervisors and on the challenges to effective supervision at the district level. This qualitative study took place as part of a broader project, "Health Systems Strengthening for Equity: The Power and Potential of Mid-Level Providers". Semi-structured interviews were conducted with 20 district health management team personnel in Malawi and 37 council health team members in Tanzania. The interviews covered a range of human resource management issues, including supervision and performance assessment, staff job descriptions and roles, motivation and working conditions. Participants displayed varying attitudes to the nature and purpose of the supervision process. Much of the discourse in Malawi centred on inspection and control, while interviewees in Tanzania were more likely to articulate a paradigm characterised by support and improvement. In both countries, facility level performance metrics dominated. The lack of competency-based indicators or clear standards to assess individual health worker performance were considered problematic. Shortages of staff, at both district and facility level, were described as a major impediment to carrying out regular supervisory visits. Other challenges included conflicting and multiple responsibilities of district health team staff and financial constraints. Supervision is a central component of effective human resource management. Policy level attention is crucial to ensure a systematic, structured process that is based on common understandings of the role and purpose of supervision. This is particularly important in a context where the majority of staff are mid-level cadres for whom regulation and guidelines may not be as formalised or well-developed as for traditional cadres, such as registered nurses and medical doctors. Supervision needs to be adequately resourced and supported in order to improve performance and retention at the district level

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer

Evolution of a unique predatory feeding apparatus: functional anatomy, development and a genetic locus for jaw laterality in Lake Tanganyika scale-eating cichlids

Background While bilaterality is a defining characteristic of triploblastic animals, several assemblages have managed to break this symmetry in order to exploit the adaptive peaks garnered through the lateralization of behaviour or morphology. One striking example of an evolved asymmetry in vertebrates comes from a group of scale-eating cichlid fishes from Lake Tanganyika. Members of the Perissodini tribe of cichlid fishes have evolved dental and craniofacial asymmetries in order to more effectively remove scales from the left or right flanks of prey. Here we examine the evolution and development of craniofacial morphology and laterality among Lake Tanganyika scale-eating cichlids. Results Using both geometric and traditional morphometric methods we found that the craniofacial evolution in the Perissodini involved discrete shifts in skeletal anatomy that reflect differences in habitat preference and predation strategies. Further, we show that the evolutionary history of the Perissodini is characterized by an accentuation of craniofacial laterality such that certain taxa show elaborate sided differences in craniofacial shape consistent with the sub-partitioning of function between sides of the head during attacks. Craniofacial laterality in the scale-eating specialist Perissodus microlepis was found to be evident early in development and exhibited a unimodal distribution, which is contrary to the adult condition where jaw laterality has been described as a discrete, bimodal antisymmetry. Finally, using linkage and association analyses we identified a conserved locus for jaw handedness that segregates among East African cichlids. Conclusions We suggest that, during the evolution of the Perissodini, selection has accentuated a latent, genetically determined handedness of the craniofacial skeleton, enabling the evolution of jaw asymmetries in order to increase predation success. Continued work on the developmental genetic basis of laterality in the Perissodini will facilitate a better understanding of the evolution of this unique group of fishes, as well as of left-right axis determination among vertebrates in general