Association between aspirin use and cardiovascular outcomes in ALLHAT participants with and without chronic kidney disease: A post hoc analysis.

It is unclear whether aspirin is beneficial for prevention of CVD in patients with CKD. We performed a secondary analysis of the ALLHAT trial to assess the effect of baseline aspirin use on nonfatal myocardial infarction (MI) or fatal coronary heart disease (CHD), all-cause mortality, and stroke. Baseline characteristics of aspirin users and nonusers were used to generate propensity-matched cohorts. Using conditional Cox proportional hazard regression models, we examined the effect of aspirin on the outcomes in the cohort at large and across 3 levels of kidney function (eGFR ≥90, 60-89, and <60). 11 250 ALLHAT participants reported using aspirin at baseline. The propensity-matched dataset included 6894 nonusers matched with replacement to achieve a balanced analysis population (n = 22 500). Risk of fatal CHD or nonfatal MI (HR = 0.94, 95% CI 0.86-1.02) and stroke (HR = 1.01, 95% CI 0.89-1.15) was not significantly different between groups. Aspirin users were at significantly lower risk of all-cause mortality compared to nonusers (HR = 0.82, 95% CI 0.76-0.88). Aspirin use was not associated with incidence of fatal CAD or nonfatal MI in patients with CVD (HR = 0.93, CI 0.84-1.04) or without CVD at baseline (HR = 1.04, CI 0.82-1.32). Results were consistent across strata of GFR (interaction p value NS). In hypertensive patients at high cardiovascular risk, aspirin use is not associated with risk of nonfatal MI, fatal CHD, or stroke; however, aspirin use is associated with lower risk of all-cause mortality. These results are consistent across baseline eGFR.

Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis.

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

Molecular genetic analysis of Chd3 and polytene chromosome region 76B-D in Drosophila melanogaster.

The Drosophila melanogaster Chd3 gene encodes a member of the CHD group of SNF2/RAD54 ATPases. CHD proteins are conserved from yeast to man and many are subunits of chromatin-remodeling complexes that facilitate transcription. Drosophila CHD3 proteins are not found in protein complexes, but as monomers that remodel chromatin in vitro. CHD3 colocalize with elongating RNA polymerase II on salivary gland polytene chromosomes. Since the role of Chd3 in development was unknown, we isolated and characterized the essential genes within the 640-kb region of the third chromosome (polytene chromosome region 76B-D) that includes Chd3. We recovered mutations in 24 genes that are essential for zygotic viability. We found that transposon-insertion mutants for 46% of the essential genes are included in the Drosophila Gene Disruption Project collection. None of the essential genes that we identified are in a 200-kb region that includes Chd3. We generated a deletion of Chd3 by targeted gene replacement. This deletion had no effect on either viability or fertility.