Functional Role of the Polymorphic 647 T/C Variant of ENT1 (SLC29A1) and Its Association with Alcohol Withdrawal Seizures

Adenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1. Our functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild-type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level. Together with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans

Microstructural Abnormalities in Subcortical Reward Circuitry of Subjects with Major Depressive Disorder

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression

The Vascular-Renal Connection in Patients Hospitalized With Hypertensive Crisis: A Population-Based Study

Objective: To determine the risks of acute kidney injury development and long-term clinical outcomes of patients with hypertensive crisis. Patients and Methods: This was a population study of Olmsted County residents with hypertensive crisis between January 1, 2000, and December 31, 2008, with follow-up until June 30, 2016. Results: The results demonstrated that those with underlying chronic kidney disease upon admission for hypertensive crisis, defined as a systolic blood pressure above 180 mm Hg or diastolic blood pressure above 120 mm Hg, were more likely to develop acute kidney injury during hospitalization (odds ratio, 6.04; 95% CI, 1-26; P=.02). Hospitalization length of stay was increased when patients developed acute kidney injury during hypertensive crisis hospitalization (7.6±9 vs 3.4±4 days; P=.04). Furthermore, those who developed acute kidney injury had increased cardiac rehospitalization frequency over 10 years (87% vs 46%; P=.009). These results suggest that those with poor renal reserve are more likely to have further acute kidney damage in the setting of hypertensive crisis, likely due to decreased renal perfusion and neurohormonal dysregulation. Conclusion: In patients hospitalized for hypertensive crisis, chronic renal insufficiency was a risk factor associated with acute kidney injury development during hospitalization. Those who developed acute kidney injury had longer hospitalizations with increased rehospitalization frequency. Future studies are warranted to further investigate whether the preservation of renal function will improve clinical outcomes in hospitalized patients with hypertensive crisis

Variability of Consecutive Lumbar Puncture Opening Pressures

Lumbar puncture (LP) opening pressures (OPs) are known to fluctuate based on diurnal, environmental, and pathologic conditions. Despite their dynamic nature, single OPs are often deemed sufficient for diagnosis of elevated intracranial pressures (ICPs) in nonspecialists' hands. The purpose of this study was to determine the variability of consecutive LP OPs at a large referral center to determine the potential range of variability for a given LP O

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Altered RNA processing and export lead to retention of mRNAs near transcription sites and nuclear pore complexes or within the nucleolus

Many protein factors are required for mRNA biogenesis and nuclear export, which are central to the eukaryotic gene expression program. It is unclear, however, whether all factors have been identified. Here we report on a screen of >1000 essential gene mutants in Saccharomyces cerevisiae for defects in mRNA processing and export, identifying 26 mutants with defects in this process. Single-molecule FISH data showed that the majority of these mutants accumulated mRNA within specific regions of the nucleus, which included 1) mRNAs within the nucleolus when nucleocytoplasmic transport, rRNA biogenesis, or RNA processing and surveillance was disrupted, 2) the buildup of mRNAs near transcription sites in 3′-end processing and chromosome segregation mutants, and 3) transcripts being enriched near nuclear pore complexes when components of the mRNA export machinery were mutated. These data show that alterations to various nuclear processes lead to the retention of mRNAs at discrete locations within the nucleus