Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes mellitus, diabetes insipidus, optic atrophy and a number of neurological symptoms including deafness, ataxia and peripheral neuropathy. Mitochondrial DNA deletions have been described in a few patients and a locus has been mapped to 4p16 by linkage analysis. Susceptibility to psychiatric illness is reported to be high in affected individuals and increased in heterozygous carriers in Wolfram syndrome families. We screened four candidate genes in a refined critical linkage interval covered by an unfinished genomic sequence of 600 kb. One of these genes, subsequently named wolframin, codes for a predicted transmembrane protein which was expressed in various tissues, including brain and pancreas, and carried loss-of- function mutations in both alleles in Wolfram syndrome patients.      

Suppression of peroxisomal membrane protein defects by peroxisomal ATP binding cassette (ABC) proteins

X-Linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by reduced peroxisomal very long chain fatty acid (VLCFA) beta-oxidation. The X - ALD gene product (ALDP) is a peroxisomal transmembrane protein with an ATP binding cassette (ABC). ALDP and three other ABC proteins (PMP70, ALDR, P70R) localize to the peroxisomal membrane. The function of this family of peroxisomal membrane proteins is unknown. We used complementation studies to begin analysis of their role in VLCFA beta-oxidation and on the peroxisomal membrane. Expression of either ALDP or PMP70 restores VLCFA beta- oxidation in X-ALD fibroblasts, indicating overlapping functions. Their expression also restores peroxisome biogenesis in cells that are deficient in the peroxisomal membrane protein Pex2p. Thus it is likely that complex protein interactions are involved in the function and biogenesis of peroxisomal membranes that may contribute to disease heterogeneity.      

Methylprednisolone exacerbates axonal loss following optic nerve trauma in rats

The excitability of human axons can be studied reliably using the technique of threshold tracking, which allows the strength of a test stimulus to be adjusted by computer to activate a defined fraction of the maximal nerve or muscle action potential. The stimulus current that just evokes the target response is considered the 'threshold' for that response. More useful than the resting threshold are other indices of axonal excitability derived from pairs of threshold measurements, such as refractoriness, supernormality, strength-duration time constant and 'threshold electrotonus' (i.e. the changes in threshold produced by long-lasting depolarizing or hyperpolarizing current pulses). Each of these measurements depends on membrane potential and on other biophysical properties of the axons. Together they can provide new information about the pathophysiology underlying abnormalities in excitability in neuropathy.     

Global infant mortality trends and attributable determinants – an ecological study using data from 192 countries for the period 1990–2011

Background

Infant mortality rate (IMR) is regarded as an important indicator of population health. IMR rates vary substantially with the highest found in sub-Saharan Africa (SSA) compared to the lowest in Europe. Identifying spatial disparities in IMR and quantifying attributable risk factors is essential for policymakers when tailoring time-appropriate interventions at a global, regional, and country level.

Methods

Data for 192 countries were extracted from the World Bank Development Indicator database for the period 1990–2011. Spatial clustering was used to identify significant higher-risk IMR countries. A robust ecological generalized linear negative binomial regression model was used to quantify risk factors and associated decomposition values (Shapley).

Results

Significant reductions were observed in IMR for all of the World Health Organization regions for the period 1990–2011 except for SSA, which indicated a reversal of this trend in the 1990s due to HIV. Significant high-risk clustering of IMR is also indicated in SSA countries and parts of Asia. Maternal mortality (survival), lack of water and sanitation and female education were confirmed as prominent and high attributable risk factors for IMR. Distinct temporal changes in the attributability of these factors were observed, as well as significant heterogeneity with regards to the most attributable factor by region and country.

Conclusions

Our study suggests that maternal mortality is the most prominent attributable risk factor for infant mortality, followed by lack of access to sanitation, lack of access to water, and lower female education. Variation exists across regions and countries with regards to the most attributable factor. Our study also suggests significant underestimation of IMR in regions known for poorer data quality. The results will aid policymakers in re-tailoring time-appropriate interventions to more effectively reduce IMR in line with Millennium Development Goal 4.