Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques.

The incidence of alcohol use disorder (AUD) is higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapy (ART) has significantly reduced mortality, shifting the course of HIV infection to a chronic illness. However, this is associated with an increased incidence of comorbid conditions, including type 2 diabetes mellitus, insulin resistance, and cardiovascular complications. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, previous studies have demonstrated that chronic binge alcohol (CBA) administration decreases whole body insulin responsiveness, irrespective of ART administration. The objective of the current study was to determine the effects of CBA and ART on insulin-sensitive peripheral tissues before the development of overt clinical symptoms of SIV disease. Our results show that CBA reduced omental adipocyte cell size, increased collagen expression, and decreased the in vitro differentiation potential of adipose-derived stem cells. In contrast, it did not alter skeletal muscle or omental or hepatic expression of insulin signaling proteins. However, ART significantly decreased skeletal muscle expression of phosphatase and tensin homolog, total mechanistic target of rapamycin, and ribosomal protein S6. In addition, ART increased hepatic phosphorylation of AMP-activated protein kinase α and increased gene expression of key enzymes required for gluconeogenesis and fatty acid synthesis. These findings suggest that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that may underlie insulin resistance associated with alcohol, SIV, and ART. Whether this is translated in PLWH with AUD remains to be determined.

Repeated Binge-Like Alcohol Intoxication: Depot-Specific Adipose Tissue Immuno-Metabolic Dysregulation.

Repeated binge-like alcohol intoxication (RBAI) induces whole-body insulin resistance, which is predicted to increase the risk for metabolic syndrome and type 2 diabetes. Previously, we showed that acute alcohol intoxication increases mesenteric lymphatic permeability, perilymphatic adipose tissue (PLAT) inflammation, and circulating lipopolysaccharide levels in rats. We hypothesize that mesenteric lymphatic hyperpermeability, adipose tissue inflammation and associated dysregulated adipokine expression, and insulin signaling are central mechanisms underlying whole-body metabolic dysregulation resulting from RBAI. To test this hypothesis, male Sprague-Dawley rats surgically fitted with an intragastric catheter received a bolus of 2.5 g/kg/day of alcohol (12.5% alcohol w/v) or isocaloric dextrose in Vanilla Ensure (116 kcal/kg/day) for 3 days. Mesenteric lymphatic permeability, mesenteric (MFAT = PLAT) and subcutaneous (SFAT) adipose tissue inflammatory milieu, circulating adipokines, and markers of insulin responsiveness (pAKT and PTP1B protein expression) were determined following the last alcohol/dextrose administration. RBAI resulted in increased lymphatic permeability, MFAT-specific expression of inflammatory cytokines and markers of inflammatory cells (macrophages, dendritic, and T cells), decreased circulating adiponectin and visfatin levels, and MFAT-specific attenuation of insulin-stimulated protein kinase B phosphorylation (Ser) compared with dextrose-treated control animals. These results suggest that RBAI-induced mesenteric lymphatic hyperpermeability promotes inflammatory milieu, decreased insulin-sensitizing adipokines, and impaired insulin signaling in MFAT, which we propose may be an early event preceding systemic metabolic dysregulation. We speculate that RBAI-induced increase in gut-derived toxins, promoting lymphatic leak, and MFAT inflammatory milieu are mechanisms deserving further investigation to elucidate lymphatic-MFAT crosstalk events that precede and predispose for alcohol-induced insulin resistance.

Chronic binge alcohol administration impairs glucose-insulin dynamics and decreases adiponectin in asymptomatic simian immunodeficiency virus-infected macaques.

Alcohol use disorders (AUDs) frequently exist among persons living with HIV/AIDS. Chronic alcohol consumption, HIV infection, and antiretroviral therapy (ART) are independently associated with impairments in glucose-insulin dynamics. Previous studies from our laboratory have shown that chronic binge alcohol (CBA) administration decreases body mass index, attenuates weight gain, and accentuates skeletal muscle wasting at end-stage disease in non-ART-treated simian immunodeficiency virus (SIV)-infected male rhesus macaques. The aim of this study was to investigate whether CBA and ART alone or in combination alter body composition or glucose-insulin dynamics in SIV-infected male rhesus macaques during the asymptomatic phase of SIV infection. Daily CBA or sucrose (SUC) administration was initiated 3 mo before intrarectal SIV inoculation and continued until the study end point at 11 mo post-SIV infection. ART or placebo was initiated 2.5 mo after SIV infection and continued until study end point. Four treatment groups (SUC/SIV ± ART and CBA/SIV ± ART) were studied. CBA/SIV macaques had significantly decreased circulating adiponectin and resistin levels relative to SUC/SIV macaques and reduced disposition index and acute insulin response to glucose, insulin, and C-peptide release during frequently sampled intravenous glucose tolerance test, irrespective of ART status. No statistically significant differences were observed in homeostatic model assessment-insulin resistance values, body weight, total body fat, abdominal fat, or total lean mass or bone health among the four groups. These findings demonstrate CBA-mediated impairments in glucose-insulin dynamics and adipokine profile in asymptomatic SIV-infected macaques, irrespective of ART.

Alcohol's Burden on Immunity Following Burn, Hemorrhagic Shock, or Traumatic Brain Injury.

Alcohol consumption contributes to increased incidence and severity of traumatic injury. Compared with patients who do not consume alcohol, alcohol-consuming patients have higher rates of long-term morbidity and mortality during recovery from injury. This can be attributed in part to an impaired immune response in individuals who consume alcohol. Acute and chronic alcohol use can affect both the innate and adaptive immune defense responses within multiple organ systems; the combination of alcohol use and injury results in increased susceptibility to bacterial and viral pathogens. This review examines the major deleterious effects of alcohol on immunity following tissue damage or traumatic injury, with a focus on alcohol's influence on the ability of the immune and major organ systems to fight disease and to repair damaged tissues following injury.

Direct evidence for intrarenal chymase-dependent angiotensin II formation on the diabetic renal microvasculature.

Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type 2 diabetes mellitus. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes mellitus. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro(10)]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared with control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro(11), D-Ala(12)]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared with control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3, and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro(11), D-Ala(12)]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro(11), D-Ala(12)]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mouse mast cell protease-4 or chymase/ß-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/ß-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared with control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute to the progression of diabetic kidney disease.

Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members.

Limited effectiveness data are available comparing live attenuated influenza vaccine (LAIV) to inactivated influenza vaccine (TIV) among adults. To compare the incidence of influenza-like illness following immunization of adults with LAIV vs. TIV, we conducted a retrospective cohort analysis of active component U.S. military personnel for the 2005-2006 and 2006-2007 influenza seasons. Recruits experienced a much higher burden of disease compared to non-recruits, with crude incidence rates of influenza-like illness 2-16 times higher than non-recruits depending on the season and cohort. For both seasons, a slightly greater protection from influenza-like illness was found for non-recruits who received TIV compared to LAIV (adjusted incidence rate ratio, 1.17 (95% CI, 1.14-1.20) and 1.33 (95% CI, 1.30-1.36), 2005-2006 and 2006-2007 influenza seasons, respectively). However, for Army and Air Force recruits, LAIV was found to provide significantly greater protection from influenza-like illnesses compared to TIV, with adjusted incidence rates of influenza-like illness 22-51% and 18-47% lower among LAIV compared to TIV recipients for the 2005-2006 and 2006-2007 influenza seasons, respectively. Possible reasons for differences in recruit and non-recruit findings include differences in pre-existing influenza antibody levels, differing respiratory disease burden, and/or unmeasured confounding. Consideration of these findings should be made when developing influenza immunization policies.

Stability of oseltamivir in various extemporaneous liquid preparations.

The purpose of this study was to determine the stability of oseltamivir, the active ingredient in Tamiflu, in contemporaneously compounded suspensions for a period of not less than 90 days. The suspension vehicles provided for the study were chosen because of ease of preparation, commercial availability, and palatability. Stability of the active ingredient was demonstrated for suspensions prepared in PCCA-Plus, PCCA Acacia, and 1% methylcellulose and was independent of storage temperature (tested temperatures were 2 deg C to 8 deg C and 25 deg C). A control sample of the commercial liquid form of Tamiflu was prepared, stored and analyzed along with the samples prepared from the contents of capsules. There was no difference in the apparent stability of the two forms of the drug preparation.

Pandemics, avian influenza A (H5N1), and a strategy for pharmacists.

Epidemics of influenza occur annually and account for more morbidity in the developed world than all other respiratory diseases combined. On average, 36,000 Americans die from influenza or its complications each year. Pandemics occur when influenza viruses undergo either antigenic drift or antigenic shift that results in a new viral strain that infects humans, when they are capable of sustained transmission from person-to-person, and when they are introduced in populations with little or no preexisting immunity. The influenza pandemic of 1918 caused an estimated 20-40 million deaths worldwide. An avian influenza A (H5N1) virus, currently circulating in Asia, has pandemic potential. However, no evidence currently exists that a pandemic is occurring. Pharmacists are uniquely positioned to initiate nearterm practice changes that may positively impact both seasonal and potential pandemic morbidity and mortality. Pharmacists must be immunization advocates and provide pharmaceutical care that includes evaluation of immunization status. Increasing immunization to prevent invasive pneumococcal disease, as well as seasonal influenza immunization, is encouraged. A pandemic vaccine represents the most effective strategy to mitigate the effects of a pandemic. Antiviral agents represent a treatment bridge until a pandemic-specific vaccine is available. The neuraminidase inhibitors oseltamivir and zanamivir are active against H5N1, although oseltamivir resistance has been reported. Advances in vaccine research, development, and production through the use of reverse-genetics systems represent the most effective technology to rapidly produce a pandemic influenza vaccine.

Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia.

Intravenous immunoglobulin (IVIG) therapy is associated with rare reports of thromboembolic events and severe hyponatremia. We hypothesized that IVIG therapy may result in hyperproteinemia, increased serum viscosity, and pseudohyponatremia. We conducted a prospective observational study to evaluate the incidence of hyperproteinemia occurring after IVIG therapy and its relationship to serum sodium, viscosity, osmolality, and the serum osmolar gap. Eighteen IVIG infusions at a standard dose of 2 g/kg administered over 2-5 days were evaluated. Serum glucose, sodium, protein, viscosity, osmolality, and a calculated osmolar gap were obtained prior to therapy, 6 hr after the initiation of therapy, 24 hr after the conclusion of therapy, and on post-treatment day 10. Paired t-testing revealed a statistically significant increase in serum protein and viscosity and decrease in serum sodium and calculated osmolality 24 hr after the completion of IVIG therapy. The calculated serum osmolar gap increased insignificantly. In multivariate analysis, hyperproteinemia at the 6-hr time point predicted hyponatremia (P < 0.000), and hyperproteinemia at the 24-hr time point predicted both hyponatremia and increased serum viscosity (P = 0.024). These data demonstrate that increased serum viscosity occurs following IVIG therapy due to hyperproteinemia, and the rare hyponatremia reported is a pseudohyponatremia also due to hyperproteinemia.

Depressive Disorder in Older Medical Inpatients on General Medicine and Cardiology Services at a University Teaching Hospital.

The authors examined the prevalence, characteristics, and correlates of depressive disorder among medical inpatients age 60 or over at a private teaching hospital. Seventy-six of 129 patients admitted to the general medicine and cardiology services at Duke University Hospital were screened for depressive disorder using DSM-III-R criteria. Depressive disorders were diagnosed in 34.2% of patients: major depression in 13.2%, adjustment disorder in 11.8%, depression not otherwise specified in 5.3%, organic mood disorder in 1.3%, and uncomplicated bereavement in 2.6%. Of patients with major depression, all had symptoms of mild-to-moderate severity. The most common presenting symptoms were insomnia, psychomotor agitation, difficulty concentrating, and loss of energy. Depression was more prevalent among women, general medicine patients, staff (vs. private) patients, and those who were functionally disabled or had multiple serious medical conditions. When other patient characteristics were controlled, however, only health factors were independently associated with depression.