Expanding Understanding of Electrocochleography in Cochlear Implantation: Auditory Neuropathy Spectrum Disorder With Normal Pure Tone Average.

Objective: Describe the preoperative decision-making, intraoperative electrocochleographic (ECoG) findings, and outcome of cochlear implantation (CI) in a patient with auditory neuropathy spectrum disorder (ANSD) and normal pure-tone thresholds.

Patients: A 19-year-old with a history of hypoxic ischemic encephalopathy and seizures was referred for hearing rehabilitation in the setting of typical hearing by pure tone audiometry but poor speech understanding. A diagnosis of ANSD was made based on acoustic brainstem response (ABR), distortion product otoacoustic emission, and acoustic reflex testing.

Understanding Patient Utilization Patterns of Cochlear Implant Processors.

Objective: To evaluate the extent of benefit the second processor provides and to better understand utilization patterns regarding cochlear implant (CI) sound processors.

Background: Institutional contracts determine the external CI sound processor hardware that a patient is eligible for. Despite the high prevalence of CI worldwide, there is a paucity in the literature regarding patient preferences and how patients utilize provided external hardware.

Rheumatoid-nodule-like cutaneous granuloma associated with recombinase activating gene 1-deficient severe combined immunodeficiency: A rare case.

Cutaneous granulomas without detectable infectious etiology rarely occur in children and adults with primary immunodeficiency disorders. These cutaneous granulomas are primarily seen in combined variable immunodeficiency, ataxia-telangiectasia, and severe combined immunodeficiency (SCID) and can emulate the reaction patterns seen in sarcoidosis and granuloma annulare. To date, the literature has described only six cases of non-infectious cutaneous granulomas in SCID.

Global changes in gene expression of Barrett's esophagus compared to normal squamous esophagus and gastric cardia tissues.

Background: Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE.

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog.

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake.

General self-efficacy influences affective task reactions during a work simulation: the temporal effects of changes in workload at different levels of control.

This study investigated the effects of workload, control, and general self-efficacy on affective task reactions (i.e., demands-ability fit, active coping, and anxiety) during a work simulation.

Endogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog.

Glucagon-like peptide-1 (GLP-1) is secreted from the L cell of the gut in response to oral nutrient delivery. To determine if endogenously released GLP-1 contributes to the incretin effect and postprandial glucose regulation, conscious dogs (n = 8) underwent an acclimation period (t = -60 to -20 min), followed by a basal sampling period (t = -20 to 0 min) and an experimental period (t = 0-320 min). At the beginning of the experimental period, t = 0 min, a peripheral infusion of either saline or GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) (Ex-9, 500 pmol/kg/min), was started.

Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus.

Dutogliptin (PHX-1149T), being developed by Phenomix Corp, Forest Laboratories Inc and Chiesi Farmaceutici SpA, is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor for the potential oral treatment of type 2 diabetes mellitus (T2DM). DPP-4 quickly degrades the insulin secretory hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1; thus inhibiting the degradation of these hormones is a viable treatment option for patients with T2DM. In preclinical studies, dutogliptin potently inhibited DPP-4 and, in a model of T2DM, treatment with dutogliptin improved glucose homeostasis.

Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo.

Objective: Insulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alterations at the cellular level.

Research Design And Methods: Conscious 60-h fasted canines were studied at three insulin levels (near basal, 4x, or 16x) during a 5-h euglycemic clamp.

Mechanistic basis for differential inhibition of the F1Fo-ATPase by aurovertin.

The mitochondrial F(1)F(o)-ATPase performs the terminal step of oxidative phosphorylation. Small molecules that modulate this enzyme have been invaluable in helping decipher F(1)F(o)-ATPase structure, function, and mechanism. Aurovertin is an antibiotic that binds to the beta subunits in the F(1) domain and inhibits F(1)F(o)-ATPase-catalyzed ATP synthesis in preference to ATP hydrolysis.

Current strategies for the inhibition of hepatic glucose production in type 2 diabetes.

Diabetes is a complex disease involving multiple organs with dysregulation in glucose and lipid metabolism. Hepatic insulin insensitivity can contribute to elevated fasting glucose levels and impaired glucose tolerance in individuals with diabetes. Several currently available therapeutics address defects at the liver.

Inhibition of dipeptidyl peptidase-4 by vildagliptin during glucagon-like Peptide 1 infusion increases liver glucose uptake in the conscious dog.

Objective: This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake.

Research Design And Methods: Fasted conscious dogs were studied in the presence (n = 6) or absence (control, n = 6) of oral vildagliptin (1 mg/kg).

Intraportally delivered GLP-1, in the presence of hyperglycemia induced via peripheral glucose infusion, does not change whole body glucose utilization.

After a meal, glucagon-like peptide-1 (GLP-1) and glucose levels are significantly greater in the hepatic portal vein than in the artery. We have previously reported that, in the presence of intraportal glucose delivery, a physiological increase of GLP-1 in the hepatic portal vein increases nonhepatic glucose uptake via a mechanism independent of changes in pancreatic hormone secretion. The aim of the present study was to determine whether intraportal glucose delivery is required to observe this effect.

Intraportal GLP-1 infusion increases nonhepatic glucose utilization without changing pancreatic hormone levels.

After a meal, glucagon-like peptide-1 (GLP-1) levels in the hepatic portal vein are elevated and are twice those in peripheral blood. The aim of this study was to determine whether any of GLP-1's acute metabolic effects are initiated within the hepatic portal vein. Experiments consisted of a 40-min basal period, followed by a 240-min experimental period, during which conscious 42-h-fasted dogs received glucose intraportally (4 mgxkg(-1)xmin(-1)) and peripherally (as needed) to maintain arterial plasma glucose levels at approximately 160 mg/dl.

Inhibition of the mitochondrial F1F0-ATPase by ligands of the peripheral benzodiazepine receptor.

Although PK11195 binds to the peripheral benzodiazepine receptor with nanomolar affinity, significant data exist which suggest that it has another cellular target distinct from the PBR. Here we demonstrate that PK11195 inhibits F(1)F(0)-ATPase activity in an OSCP-dependent manner, similar to the pro-apoptotic benzodiazepine Bz-423. Importantly, our data indicate that cellular responses observed with micromolar concentrations of PK11195, which are commonly attributed to modulation of the PBR, are likely a direct result of mitochondrial F(1)F(0)-ATPase inhibition.

Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase.

Altered cellular bioenergetics are implicated in many disease processes, and modulating the F 1 F o -ATPase, the enzyme responsible for producing the majority of ATP in eukaryotic cells, has been proposed to have therapeutic utility. Bz-423 is a 1,4-benzodiazepine that binds to the oligomycin sensitivity-conferring protein subunit of the mitochondrial F 1 F o -ATPase and inhibits the enzyme. In response to Bz-423, cells moderately decrease ATP synthesis and significantly increase superoxide, resulting in redox-regulated apoptosis.

Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423.

Bz-423 is a 1,4-benzodiazepine that suppresses disease in lupus-prone mice by selectively killing pathogenic lymphocytes, and it is less toxic compared to current lupus drugs. Cells exposed to Bz-423 rapidly generate O(2)(-) within mitochondria, and this reactive oxygen species is the signal initiating apoptosis. Phage display screening revealed that Bz-423 binds to the oligomycin sensitivity conferring protein (OSCP) component of the mitochondrial F(1)F(0)-ATPase.

Parallel synthesis of glycomimetic libraries: targeting a C-type lectin.

We have developed methods for the parallel synthesis of two libraries of non-carbohydrate-based analogues of mannose on a solid support. The natural product shikimic acid was used as a key building block. The ability of the compounds to block the binding of the C-type lectin MBP-A to a mannosylated surface was assessed in a high-throughput assay.

Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore.