Ab initio and DFT conformational study on N-nitrosodiethylamine, (C2H5)2N-N=O.

Ab initio (MP2) and DFT (B3LYP) calculations, using the cc-pVTZ and aug-cc-pVTZ basis sets, have been performed to characterize some stationary points on the ground state potential energy surface of the title molecules. Several properties as, for instance, relative energies, the barriers for NO rotation around the NN bond, NBO charges on O and amino N atoms, as well as the dipole moments, have been calculated and analyzed in the light of the structures found. Both computational levels here employed yield three minima, in which the C(2)NNO frame is 'planar' or 'quasi-planar'.

Breast cancer proteomics: a review for clinicians.

Purpose: Breast cancer is one of the major health problems of the Western world. Although the survival rate has improved with progress in screening and adjuvant systemic therapies, one-third of the patients with initial breast tumor have recurrence of the disease 10 years after the diagnosis, demonstrating the presence of micrometastasis. The underlying molecular mechanism of the disease needs to be better understood.

si-RNA inhibition of brain insulin or insulin-like growth factor receptors causes developmental cerebellar abnormalities: relevance to fetal alcohol spectrum disorder.

Background: In experimental models of fetal alcohol spectrum disorder (FASD), cerebellar hypoplasia and hypofoliation are associated with insulin and insulin-like growth factor (IGF) resistance with impaired signaling through pathways that mediate growth, survival, plasticity, metabolism, and neurotransmitter function. To more directly assess the roles of impaired insulin and IGF signaling during brain development, we administered intracerebroventricular (ICV) injections of si-RNA targeting the insulin receptor, (InR), IGF-1 receptor (IGF-1R), or IGF-2R into postnatal day 2 (P2) Long Evans rat pups and examined the sustained effects on cerebellar function, structure, and neurotransmitter-related gene expression (P20).

Results: Rotarod tests on P20 demonstrated significant impairments in motor function, and histological studies revealed pronounced cerebellar hypotrophy, hypoplasia, and hypofoliation in si-InR, si-IGF-1R, and si-IGF-2R treated rats.

Peroxisome proliferator-activated receptor agonist treatment of alcohol-induced hepatic insulin resistance.

Aim:   Chronic ethanol exposure impairs insulin signaling in the liver. Peroxisome-proliferator activated receptor (PPAR) agonists function as insulin sensitizers and are used to treat type 2 diabetes mellitus. We examined the therapeutic effectiveness of PPAR agonists in reducing alcoholic hepatitis and hepatic insulin resistance in a model of chronic ethanol feeding.

Alcohol-related peripheral neuropathy: nutritional, toxic, or both?

Alcohol-related peripheral neuropathy (ALN) is a potentially debilitating complication of alcoholism that results in sensory, motor, and autonomic dysfunction. Unfortunately, ALN is rarely discussed as a specific disease entity in textbooks because it is widely assumed to primarily reflect consequences of nutritional deficiency. This hypothesis is largely based on observations first made over eight decades ago when it was demonstrated that thiamine deficiency (beriberi) neuropathy was clinically similar to ALN.

Aspartyl-(asparaginyl) beta-hydroxylase, hypoxia-inducible factor-alpha and Notch cross-talk in regulating neuronal motility.

Aspartyl-(Asparginyl)-β-Hydroxylase (AAH) promotes cell motility by hydroxylating Notch. Insulin and insulin-like growth factor, type 1 (IGF-I) stimulate AAH through Erk MAPK and phosphoinositol-3-kinase-Akt (PI3K-Akt). However, hypoxia/oxidative stress may also regulate AAH.

Plasma cytokine concentrations associated with HIV/hepatitis C coinfection are related to attention, executive and psychomotor functioning.

Cytokine disturbances have been linked to brain dysfunction among HIV-infected people. Past studies have not simultaneously examined a large set of cytokine measures and their relationships to HIV-associated neurocognitive deficits. We hypothesized that performance on measures of attention and executive and psychomotor functions would be associated with plasma cytokine concentrations in HIV-infected individuals.

Impact of pharmacist intervention on clinical outcomes in the palliative care setting.

Background: Although accepted as an integral part of the interdisciplinary team, pharmacist value in palliative care has predominantly been evaluated by subjective methods. This study was conducted to identify factors that impact physician acceptance of the pharmacist's recommendation and to determine whether acceptance is a significant predictor of clinical outcome.

Methods: As a mandated in-house quality assurance project at Niagara Hospice, Inc, 2 clinical pharmacists tracked each request for pharmacotherapeutic intervention over a 4-month period (April-July 2009).

Role of central nervous system insulin resistance in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production; and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR) level and caused by both impaired receptor binding and increased activation of phosphatases that reverse IR tyrosine kinase activity.

Expression of the zinc transporters genes and metallothionein in obese women.

Research has investigated the participation of zinc transport proteins and metallothionein in the metabolism of this mineral. However, studies about the genetic expression of these proteins in obese patients are scarce. The study determined the expression of zinc transporter protein codifying genes (ZnT-1, Zip-1 and Zip-3) and of metallothionein in 55 obese women, aged between 20 and 56 years.

Role of aspartyl-(asparaginyl)-β-hydroxylase mediated notch signaling in cerebellar development and function.

Background: Aspartyl-(Asparaginyl)-β-Hydroxylase (AAH) is a hydroxylating enzyme that promotes cell motility by enhancing Notch-Jagged-HES-1 signaling. Ethanol impaired cerebellar neuron migration during development is associated with reduced expression of AAH.

Methods: To further characterize the role of AAH in relation to cerebellar development, structure, and function, we utilized an in vivo model of early postnatal (P2) intracerebro-ventricular gene delivery to silence AAH with small interfering RNA (siAAH), or over-express it with recombinant plasmid DNA (pAAH).

Fluid dynamical niches of phytoplankton types.

The biogeochemical role of phytoplanktonic organisms strongly varies from one plankton type to another, and their relative abundance and distribution have fundamental consequences at the global and climatological scales. In situ observations find dominant types often associated to specific physical and chemical water properties. However, the mechanisms and spatiotemporal scales by which marine ecosystems are organized are largely not known.

Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease.

Background & Aims: Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of PTEN. We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but also promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function.

Rat strain differences in susceptibility to alcohol-induced chronic liver injury and hepatic insulin resistance.

The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats.

Acetaldehyde adducts in alcoholic liver disease.

Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver.

Ceramide-mediated insulin resistance and impairment of cognitive-motor functions.

Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) are associated with cognitive impairment, brain insulin resistance, and neurodegeneration. Recent studies linked these effects to increased pro-ceramide gene expression in liver and increased ceramide levels in serum. Since ceramides are neurotoxic and cause insulin resistance, we directly examined the role of ceramides as mediators of impaired signaling and central nervous system function using an in vivo model.

Emergence of variability in isogenic Escherichia coli populations infected by a filamentous virus.

The spread of epidemics not only depends on the average number of parasites produced per host, but also on the existence of highly infectious individuals. It is widely accepted that infectiousness depends on genetic and environmental determinants. However, even in clonal populations of host and viruses growing in homogeneous conditions, high variability can exist.

HCl-induced inflammatory mediators in esophageal mucosa increase migration and production of H2O2 by peripheral blood leukocytes.

Exposure of esophageal mucosa to hydrochloric acid (HCl) is a crucial factor in the pathogenesis of reflux disease. We examined supernatant of HCl-exposed rabbit mucosa for inflammatory mediators enhancing migration of leukocytes and production of H(2)O(2) as an indicator of leukocyte activation. A tubular segment of rabbit esophageal mucosa was tied at both ends to form a sac, which was filled with HCl-acidified Krebs buffer at pH 5 (or plain Krebs buffer as control) and kept oxygenated at 37 degrees C.

The p85beta regulatory subunit of PI3K serves as a substrate for PTEN protein phosphatase activity during insulin mediated signaling.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that is frequently mutated in brain, uterine, and prostate cancers. The protein phosphatase activity is poorly defined. We demonstrate that insulin stimulates phosphorylation of tyrosine and threonine/proline residues on the p85 regulatory subunit of PI3K in Huh-7, and HEK 293 cells.

An analysis of the mixing efficiency of neutral protamine Hagedorn cartridges.

In this issue of Journal of Diabetes Science and Technology, Kaiser and colleagues conducted an investigation to identify variations in the delivered dose of several different isophane insulin (neutral protamine Hagedorn, NPH) brands that use glass and metal bodies ("bullets") to facilitate mixing. Using a strategy where multiple pens from each of five different NPH insulin products (Insuman Basal, sanofi-aventis, three metal bullets; Humulin N, Lilly, one glass bullet; Berlinsulin H Basal, Berlin-Chemie, one glass bullet; Insulin B. Braun Basal, two glass bullets; and Protaphane Penfill, NovoNordisk, one glass bullet) were compared at multiple sampling points and over a range of mixing procedures (3, 6, 10, and 20 times), the authors identified deviations in the delivered dose of insulin at initial use and with repeated dosing.

Real-time PCR in clinical practice: a powerful tool for evaluating Leishmania chagasi loads in naturally infected dogs.

The performance of the less expensive SYBR-Green-based PCR assay, for quantifying Leishmania chagasi in smears of bone-marrow aspirates from naturally infected, mongrel dogs, was recently compared with that of a similar PCR based on TaqMan chemistry. Aspirates were obtained from 36 infected dogs and examined for parasites by direct examination, culture, and quantitative PCR (qPCR) using specific primers (based on the parasite's kinetoplast DNA), DNA extracted from a smear, and either the SYBR-Green or TaqMan chemistries. Every aspirate smear was found PCR-positive for L.

Characterization of cardiovascular outcomes in a type 2 diabetes glucose supply and insulin demand model.

Background: The nonsignificant reduction in macrovascular outcomes observed in Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and the Veterans Affairs Diabetes Trial have collectively created uncertainty with respect toward the proper extent of blood glucose reduction and also the optimal therapeutic choice to attain the reduction. In the article entitled "Glucose Supply and Insulin Demand Dynamics of Antidiabetic Agents" in this issue of Journal of Diabetes Science and Technology, we presented data for a pharmacokinetic/pharmacodynamic model that characterizes the effect of conventional antidiabetic therapies on the glucose supply and insulin demand dynamic. Here, it is our objective to test the hypothesis that, in conjunction with hemoglobin A1c (HbA1c), patients managed on the glucose supply side of the model would have fewer cardiovascular events versus those managed on the insulin demand side.

Glucose supply and insulin demand dynamics of antidiabetic agents.

Background: For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM.

Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration.

Background: Type 2 diabetes mellitus (T2DM) and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM.

Hypothesis: Limited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration.

Potential Role of Thymosin-alpha1 Adjuvant Therapy for Glioblastoma.

Glioblastomas are high-grade, malignant CNS neoplasms that are nearly always fatal within 12 months of diagnosis. Immunotherapy using proinflammatory cytokines such as IL-2 or IL-12 may prolong survival with glioblastoma. Thymosin-alpha1 (Talpha1) is a thymic hormone and immunemodulator that increase IL-2 production and T-cell proliferation.