H2O2-mediated modulation of cytosolic signaling and organelle function in rat hippocampus

Reactive oxygen species (ROS) released from (dys-)functioning mitochondria contribute to normal and pathophysiological cellular signaling by modulating cytosolic redox state and redox-sensitive proteins. To identify putative redox targets involved in such signaling, we exposed hippocampal neurons to hydrogen peroxide (H2O2). Redox-sensitive dyes indicated that externally applied H2O2 may oxidize intracellular targets in cell cultures and acute tissue slices. In cultured neurons, H2O2 (EC50 118 µM) induced an intracellular Ca2+ rise which could still be evoked upon Ca2+ withdrawal and mitochondrial uncoupling. It was, however, antagonized by thapsigargin, dantrolene, 2-aminoethoxydiphenyl borate, and high levels of ryanodine, which identifies the endoplasmic reticulum (ER) as the intracellular Ca2+ store involved. Intracellular accumulation of endogenously generated H2O2—provoked by inhibiting glutathione peroxidase—also released Ca2+ from the ER, as did extracellular generation of superoxide. Phospholipase C (PLC)-mediated metabotropic signaling was depressed in the presence of H2O2, but cytosolic cyclic adenosine-5′-monophosphate (cAMP) levels were not affected. H2O2 (0.2–5 mM) moderately depolarized mitochondria, halted their intracellular trafficking in a Ca2+- and cAMP-independent manner, and directly oxidized cellular nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2). In part, the mitochondrial depolarization reflects uptake of Ca2+ previously released from the ER. We conclude that H2O2 releases Ca2+ from the ER via both ryanodine and inositol trisphosphate receptors. Mitochondrial function is not markedly impaired even by millimolar concentrations of H2O2. Such modulation of Ca2+ signaling and organelle interaction by ROS affects the efficacy of PLC-mediated metabotropic signaling and may contribute to the adjustment of neuronal function to redox conditions and metabolic supply

Too Much Glucagon, Too Little Insulin: Time course of pancreatic islet dysfunction in new-onset type 1 diabetes

OBJECTIVE—To determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes

Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide

OBJECTIVE—Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVETo determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes.RESEARCH DESIGN AND METHODSThis 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2.RESULTSMean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient.CONCLUSIONSLiraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control

The portal of Neviaser: a valid option for antegrade nailing of humerus fractures

Introduction: The objective of this retrospective non-randomized study was to evaluate the portal of Neviaser (PN) as an alternative approach in antegrade humeral nailing. Methods: The surgical approach for the straight antegrade intramedullary nail (SAIN) was either the anterolateral delta-split (group 2, n = 79) or the portal of Neviaser (group 3, n = 27). Length of surgery and time of radiation were extracted from charts. Patients stabilized using the PN were followed for a clinical and radiological exam. At follow-up we evaluated the DASH (Disability of the Arm, Shoulder and Hand) and CMS (Constant-Murley Score). Results: Between 10.2015 and 12.2018 191 proximal and diaphyseal humeral fractures were operated using either an angular stable extramedullary device (group 1, PHILOS®, n = 85) or a straight humeral nail (MultiLoc®, n = 106). Time of radiation and intervention followed a normal distribution. The mean length of surgery was 172.9 min (SD 91.5) in group 1, 121.5 min (SD 54.1) in group 2 and 96.4 min (SD 33.7) in group 3 (p < 0.01). Time of radiation was significantly different with 1.1 min (SD 0.6: group 1), 3.1 min (SD 1.6: group 2) and 2.9 min (SD 1.7: group 3) (p < 0.01). After a mean interval of 21.5 months (range 6–43 months) 14 / 27 patients of group 3 were available for a clinical and radiological follow-up. The mean DASH in group 3 was 25, the CMS reached 70. The age and sex weighted CMS mean value was 96%. Forward flexion was 131°, abduction 125°. The ratio of strength affected versus non-affected side was 4.4: 6.2 kg. Conclusions: The portal of Neviaser is a feasible and safe approach and is an alternative to the anterolateral delta-split. Length of surgery and time of radiation were significantly shorter. Level of evidence: IV

DURAbility of Basal Versus Lispro Mix 75/25 Insulin Efficacy (DURABLE) Trial 24-Week Results: Safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes

OBJECTIVE - To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes. RESEARCH DESIGN AND METHODS - During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs. RESULTS - Baseline A1C was similar (LM75/25: 9.1 +/- 1.3%; GL: 9.0 +/- 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had tower A1C than GL patients (7.2 +/- 1.1. vs. 7.3 +/- 1.1%, P = 0.005), greater A1C reduction (-1.8 +/- 1.3 vs. -1.7 +/- 1.3%, P = 0.005), and higher percentage reaching A1C target CONCLUSIONS - Compared With GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C targe

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy

Self-Control and Adverse “Drinking” Consequences

Most research on adverse alcohol consequences such as problems with health, work, and relationships focuses only on alcohol use itself as a cause of these outcomes. However, Gottfredson and Hirschi’s (1990) self-control theory holds that alcohol use and these negative outcomes are likely to have a common cause–low self-control. Tests of hypotheses derived from self-control theory show that self-control predicts negative drinking consequences better than combined measures of alcohol dependence and frequency and quantity of drinking. This suggests that various forms of risk–taking behavior and negative outcomes can be conceptualized as indicators of underlying levels of self-control

Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

OBJECTIVE—Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes