Invariant Natural Killer T cell dynamics in HIV-associated tuberculosis.

RATIONALE: Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with HIV infection. HIV-infected patients with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence anti-retroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. OBJECTIVES: We investigated the hypothesis that invariant Natural Killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. METHODS: In a cross-sectional study of 101 HIV-infected and -uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterised by flow cytometry. In a second study of 49 HIV-1-infected TB patients commencing anti-retroviral therapy, iNKT cells in TB-IRIS patients with non-IRIS controls were compared longitudinally. MEASUREMENTS AND MAIN RESULTS: Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in HIV-infected patients with active TB was associated with development of TB-IRIS following anti-retroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset deplete and degranulated around the time of TB-IRIS onset. CONCLUSIONS: Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality towards cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS

Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related)

Comparison of MRI and DXA to measure muscle size and age-related atrophy in thigh muscles

Objectives: Magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) were used to examine the thigh lean mass in young and old men and women. Methods: A whole-body DXA scan was used to estimate thigh lean mass in young (20 men; 22.4±3.1y; 18 women; 22.1±2.0y) and older adults (25 men; 72.3±4.9y; 28 women; 72.0±4.5y). Thigh lean mass deter-mined with a thigh scan on the DXA or full thigh MRI scans were compared. Results: Although the thigh lean mass quantified by DXA and MRI in young and older participants were correlated (R2=0.88; p<0.001) the magnitude of the differences in thigh lean mass between young and old was smaller with DXA than MRI (old vs. young men 79.5±13.1% and 73.4±11.2%; old vs. young women 88.6±11.8% and 79.4±12.3%, respectively). Detailed analysis of MRI revealed 30% smaller quadriceps muscles in the older than young individuals, while the other thigh muscles were only 18% smaller. Conclusions: DXA underestimates the age-related loss of thigh muscle mass in comparison to MRI. The quadriceps muscles were more susceptible to age-related atrophy compared with other thigh muscles

Standards and Practices for Forecasting

One hundred and thirty-nine principles are used to summarize knowledge about forecasting. They cover formulating a problem, obtaining information about it, selecting and applying methods, evaluating methods, and using forecasts. Each principle is described along with its purpose, the conditions under which it is relevant, and the strength and sources of evidence. A checklist of principles is provided to assist in auditing the forecasting process. An audit can help one to find ways to improve the forecasting process and to avoid legal liability for poor forecasting

Dynamical tunneling in molecules: Quantum routes to energy flow

Dynamical tunneling, introduced in the molecular context, is more than two decades old and refers to phenomena that are classically forbidden but allowed by quantum mechanics. On the other hand the phenomenon of intramolecular vibrational energy redistribution (IVR) has occupied a central place in the field of chemical physics for a much longer period of time. Although the two phenomena seem to be unrelated several studies indicate that dynamical tunneling, in terms of its mechanism and timescales, can have important implications for IVR. Examples include the observation of local mode doublets, clustering of rotational energy levels, and extremely narrow vibrational features in high resolution molecular spectra. Both the phenomena are strongly influenced by the nature of the underlying classical phase space. This work reviews the current state of understanding of dynamical tunneling from the phase space perspective and the consequences for intramolecular vibrational energy flow in polyatomic molecules.Comment: 37 pages and 23 figures (low resolution); Int. Rev. Phys. Chem. (Review to appear in Oct. 2007

Child mortality and poverty in three world regions (the West, Asia and Sub-Saharan Africa) 1988-2010: Evidence of relative intra-regional neglect?

Aims: Poverty kills children. This study assesses the relationship between poverty and child mortality rates (CMRs) in 71 societies from three world regions to determine whether some countries, relative to their region, neglect their children. Methods: Spearman rank order correlations were calculated to determine any association between the CMR and poverty data, including income inequality and gross national income. A current CMR one standard deviation (SD) above or below the regional average and a percentage change between 1988 and 2010 were used as the measures to assess the progress of nations. Results: There were positive significant correlations between higher CMRs and relative poverty measures in all three regions. In Western countries, the current CMRs in the USA, New Zealand and Canada were 1 SD below the Western mean. The narrowest income inequalities, apart from Japan, were seen in the Scandinavian nations alongside low CMRs. In Asia, the current CMRs in Pakistan, Myanmar and India were the highest in their region and were 1 SD below the regional mean. Alongside South Korea, these nations had the lowest percentage reductions in CMRs. In Sub-Saharan Africa, the current CMRs in Somalia, Burkina Faso, Sierra Leone, Chad, Democratic Republic of Congo and Angola were the highest in their region and were 1 SD below the regional mean. Conclusions: Those concerned with the pursuit of social justice need to alert their societies to the corrosive impact of poverty on child mortality. Progress in reducing CMRs provides an indication of how well nations are meeting the needs of their children. Further country-specific research is required to explain regional differences