No abstract

There has been a significant increase in obesity rates worldwide with the corresponding surge in diabetes. Diabetes causes various microvascular and macrovascular changes often culminating in major clinical complications, 1 of which, is stroke. Although gains have been made over the last 2 decades in reducing the burden of stroke, the recent rise in rates of diabetes threatens to reverse these advances. Of the several mechanistic stroke subtypes, individuals with diabetes are especially susceptible to the consequences of cerebral small vessel diseases. Hyperglycemia confers greater risk of stroke occurrence. This increased risk is often seen in individuals with diabetes and is associated with poorer clinical outcomes (including higher mortality), especially following ischemic stroke. Improving stroke outcomes in individuals with diabetes requires prompt and persistent implementation of evidence-based medical therapies as well as adoption of beneficial lifestyle practices.

Purpose The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction. Methods Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. Results All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. Conclusions NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.

Recent studies have indicated that obesity is associated with hypertension, sodium retention, and increased sympathetic nervous system activity. The purpose of this study was to determine the role of renal nerves in mediating the sodium retention and hypertension associated with obesity. We determined the hemodynamic and renal excretory responses to a high-fat diet in control (n=6) and bilaterally renal-denervated (n=7) chronically instrumented dogs. After a control period of 8 days, dogs were placed on a high-fat diet for 5 weeks. In response to a high-fat diet, body weight increased from 19.9±2.2 to 29.9±2.4 kg in the control group and from 21.1±2.0 to 32.4±1.9 kg in the bilaterally renal-denervated group. Heart rate increased from 81±8 to 113±7 beats per minute in the control group and from 79±7 to 103±8 beats per minute in the bilaterally renal-denervated group. Arterial pressure increased significantly from 95±2 to 109±4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the bilaterally renal-denervated group did not significantly increase arterial pressure (which went from 87±3 to 90±4 mm Hg). Furthermore, the decrease in sodium excretion in response to the high-fat diet was significantly greater in the control group than in the bilaterally renal-denervated group. After 5 weeks of a high-fat diet, cumulative sodium retention was 455±85 mmol in the control group and only 252±47 mmol in the bilaterally renal-denervated group. Similar increases in glomerular filtration rate and renal plasma flow occurred in both groups in response to the high-fat diet. The results of this study indicate that the renal nerves play an important role in mediating the sodium retention and hypertension associated with obesity in dogs.