Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

OBJECTIVES: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. RESULTS: DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.     

Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders

Neural abnormalities commonly associated with autism spectrum disorders include prefrontal cortex (PFC) dysfunction and cerebellar pathology in the form of Purkinje cell loss and cerebellar hypoplasia. It has been reported that loss of cerebellar Purkinje cells results in aberrant dopamine neurotransmission in the PFC which occurs via dysregulation of multisynaptic efferents from the cerebellum to the PFC. Using a mouse model, we investigated the possibility that developmental cerebellar Purkinje cell loss could disrupt glutamatergic cerebellar projections to the PFC that ultimately modulate DA release. We measured glutamate release evoked by local electrical stimulation using fixed-potential amperometry in combination with glutamate selective enzyme-based recording probes in urethane-anesthetized Lurcher mutant and wildtype mice. Target sites included the mediodorsal and ventrolateral thalamic nuclei, reticulotegmental nuclei, pedunculopontine nuclei, and ventral tegmental area. With the exception of the ventral tegmental area, the results indicated that in comparison to wildtype mice, evoked glutamate release was reduced in Lurcher mutants by between 9 and 72 % at all stimulated sites. These results are consistent with the notion that developmental loss of cerebellar Purkinje cells drives reductions in evoked glutamate release in cerebellar efferent pathways that ultimately influence PFC dopamine release. Possible mechanisms whereby reductions in glutamate release could occur are discussed.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

Predominant endothelial vasomotor activity during human sleep: a near‐infrared spectroscopy study

Vasomotion is important in the study of vascular disorders, including stroke. Spontaneous low and very low hemodynamic oscillations (3–150 mHz) measured with near‐infrared spectroscopy (NIRS) reflect the endothelial (3–20 mHz), neurogenic (20–40 mHz) and myogenic (40–150 mHz) components of vasomotion. We investigated sleep‐specific patterns of vasomotion by characterizing hemodynamic oscillations with NIRS in healthy subjects, and tested the feasibility of NIRS as a bedside tool for monitoring vasomotion during whole‐night sleep. To characterize local cerebral vasomotion, we compared cerebral NIRS measurements with muscular NIRS measurements and peripheral arterial oxygen saturation (SpO₂) during different sleep stages in 14 healthy volunteers. Spectral powers of hemodynamic oscillations in the frequency range of endothelial vasomotion were systemically predominant in every sleep stage, and the powers of endothelial and neurogenic vasomotion decreased in deep sleep as compared with light sleep and rapid eye movement (REM) sleep in brain, muscle, and SpO₂. The decrease in the powers of myogenic vasomotion in deep sleep only occurred in brain, and not in muscle. These results point to a predominant role of endothelial function in regulating vasomotion during sleep. The decline in cerebral endothelial and neurogenic vasomotion during progression to deeper non‐REM sleep suggests that deep sleep may play a protective role for vascular function. NIRS can be used to monitor endothelial control of vasomotion during nocturnal sleep, thus providing a promising non‐invasive bedside tool with which to study the sleep‐relevant pathological mechanisms in vascular diseases and stroke.     

Differential vulnerability of white matter structures to experimental infantile hydrocephalus detected by diffusion tensor imaging

Purpose

The differential vulnerability of white matter (WM) to acute and chronic infantile hydrocephalus and the related effects of early and late reservoir treatment are unknown, but diffusion tensor imaging (DTI) could provide this information. Thus, we characterized WM integrity using DTI in a clinically relevant model.

Methods

Obstructive hydrocephalus was induced in 2-week-old felines by intracisternal kaolin injection. Ventricular reservoirs were placed 1 (early) or 2 (late) weeks post-kaolin and tapped frequently based solely on neurological deficit. Hydrocephalic and age-matched control animals were sacrificed 12 weeks postreservoir. WM integrity was evaluated in the optic system, corpus callosum, and internal capsule prereservoir and every 3 weeks using DTI. Analyses were grouped as acute (<6 weeks) or chronic (≥6 weeks).

Results

In the corpus callosum during acute stages, fractional anisotropy (FA) decreased significantly with early and late reservoir placement (p?=?0.0008 and 0.0008, respectively), and diffusivity increased significantly in early (axial, radial, and mean diffusivity, p?=?0.0026, 0.0012, and 0.0002, respectively) and late (radial and mean diffusivity, p?=?0.01 and 0.0038, respectively) groups. Chronically, the corpus callosum was thinned and not detectable by DTI. FA was significantly lower in the optic chiasm and tracts (p?=?0.0496 and 0.0052, respectively) with late but not early reservoir placement. In the internal capsule, FA in both reservoir groups increased significantly with age (p?Conclusions All hydrocephalic animals treated with intermittent ventricular reservoir tapping demonstrated progressive ventriculomegaly. Both reservoir groups demonstrated WM integrity loss, with the CC the most vulnerable and the optic system the most resilient.     

Alternatives to Warfarin for Thromboembolism Prophylaxis in Nonrheumatic Atrial Fibrillation

A 45-year-old male with a preexcited QRS consistent with WPW syndrome was hospitalized for syncope. ECG monitoring revealed episodes of advanced atrioventricular block. An electrophysiologic study demonstrated right anteroseptal preexcitation and revealed an intermittent block in the accessory pathway and AV complete block causing long periods of spontaneous asystole. A DDD pacemaker was implanted without ablation of the accessory pathway.     

Trial of vaginal breech delivery: current role

Breech presentation occurs at term in approximately 3% to 4% of singleton gestations. This presentation is associated with a variety of maternal and fetal conditions including preterm labor, abnormal amniotic fluid volume, hydrocephaly, anencephaly, mullerian anomalies, abnormal placentation, and multifetal gestation. Cesarean delivery has been associated with increased risk of subsequent accreta, placenta previa, hemorrhage, and hysterectomy. The Term Breech Trial initially suggested that planned vaginal breech delivery is associated with increased neonatal morbidity and mortality compared with planned cesarean delivery. Long-term follow-up of these vaginally delivered infants contradict the initial findings. Current debate surrounds the dilemma of whether the untoward complications of cesarean delivery are warranted given uncertain minimal increases in neonatal survival and improvement in neurologic outcome with planned cesarean.     

Ready-to-use binder-free Co(OH)2 plates@porous rGO layers/Ni foam electrode for high-performance supercapacitors

In this work, an outstanding nano-structured composite electrode is fabricated through the co-deposition of Co(OH)₂ nanoplates and porous reduced GO (p-rGO) nanosheets onto Ni foam (NF). Through field emission scanning electron microscopy and transmission electron microscopy observations, it was confirmed that porous reduced graphene oxide sheets are completely wrapped by uniform hexagonal Co(OH)₂ plates. Due to the unique architecture of both components of the prepared composite, a high surface area of 234.7 m² g⁻¹ and mean pore size of 3.65 nm were observed for the Co(OH)₂@p-rGO composite. The constructed Co(OH)₂@p-rGO/NF composite electrode shows higher energy storage capability compared to that of Co(OH)₂/NF and p-rGO/NF electrodes. The Co(OH)₂/NF electrode shows specific capacitances of 902 and 311 F g^–1 at 5 and 30 A g^–1, while the Co(OH)₂@p-rGO/NF electrode delivers 1688 and 1355 F g^–1 under the same current loads, respectively. Furthermore, when the current load was increased from 1 to 30 A g^–1, 74.5% capacitance retention was observed for the Co(OH)₂@p-rGO/NF electrode, indicating its outstanding high-power capability, while the Co(OH)₂/NF electrode retained only 38.5% of its initial capacitance. The fabricated Co(OH)₂@p-rGO/NF//rGO/NF ASC device shows an areal capacitance of 3.29 F cm⁻², cycling retention of 91.2% after 4500 cycles at 5 A g⁻¹ and energy density of 68.7 W h kg⁻¹ at a power density of 895 W kg⁻¹. The results of electrochemical tests prove that Co(OH)₂@p-rGO/NF exhibits good performance as a positive electrode for use in an asymmetric supercapacitor device. The prepared porous composite electrode is thus a promising candidate for use in supercapacitor applications.

Fabrication mechanism of a ready-to-use Co(OH)2@p-rGO/NF electrode: (a) base generation step, (b) electrophoretic deposition of rGO onto NF and (c) chemical formation of Co(OH)2 on rGO.