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BACKGROUND: To date, gene expression studies related to chronic heart failure (CHF) have mainly involved microarray analysis of myocardial tissues. The potential utility of blood to infer the etiology, pathogenesis, and course of CHF remains unclear. Further, the use of proteomic and metabolomic platforms for molecular profiling of CHF is relatively unexplored. METHODS: Microarray genomic, iTRAQ proteomic, and nuclear magnetic resonance metabolomic analyses were carried out on blood samples from 29 end-stage CHF patients (16 ischemic heart disease [IHD], 13 nonischemic cardiomyopathy [NICM]), and 20 normal cardiac function (NCF) controls. Robust statistical tests and bioinformatical tools were applied to identify and compare the molecular signatures among these subject groups. RESULTS: No genes or proteins, and only two metabolites, were differentially expressed between IHD and NICM patients at end stage. However, CHF versus NCF comparison revealed differential expression of 7,426 probe sets, 71 proteins, and 8 metabolites. Functional enrichment analyses of the CHF versus NCF results revealed several in-common biological themes and potential mechanisms underlying advanced heart failure. CONCLUSION: Multiple '-omic' analyses support the convergence of dramatic changes in molecular processes underlying IHD and NICM at end stage. [ABSTRACT FROM AUTHOR]

Background: The Prospective Research In MEmory clinics (PRIME) is a three-year non-prescriptive, observational study identifying and measuring relationships among predictor and outcome variables.Methods: Patients from nine memory clinics, diagnosed with dementia or mild cognitive impairment (MCI), living in the community with <40 hours/week nursing care were divided into diagnostic groups defined at baseline as Alzheimer's disease (AD) early or late onset, frontotemporal dementia (FTD), vascular dementia (VaD), mixed (AD and VaD) and other dementia. To achieve outcome measures, baseline and change over six months in all measures by diagnostic group, and predictors of change at six months were examined.Results: Of the 970 patients enrolled, 967 were eligible for analysis. The most common disorder was AD (late onset) accounting for 46.5% of this population. Patients had an overall slight worsening on all assessment scales over the six-month period. Patients with FTD had a more marked change (decline) in cognition, function and behavior over six months compared to other diagnostic groups. However, in the regression analysis the difference was not significant between groups. Predictors of decline in Mini-Mental State Examination (MMSE) scores were not robust at six months, and longer follow-up is required. Patients with FTD were more likely to be prescribed psychotropics.Conclusion: The PRIME study is continuing and will provide important data on predictors of decline along with differences between diagnosis groups on the rate of change. [ABSTRACT FROM AUTHOR]

Objectives: to characterize the cost of caring for an outpatient in Canada with Alzheimer disease (AD) based on disease severity, and to describe how costs change with increases in disease severity.Method: community-dwelling patients with mild-to-moderate AD were enrolled in a 3-year, naturalistic, observational study. Assessments included cognition (Mini Mental Status Examination), global ratings (Global Deterioration Scale [GDS]), and daily function (Functional Autonomy Measurement System) as part of the Canadian Outcomes Study in Dementia. Direct (medical and nonmedical) and indirect costs were collected using resource use questionnaires. Costs at baseline were compared with costs at follow-up and correlated with disease severity.Results: total costs associated with treating AD were significantly higher with greater disease severity. The mean total cost to treat patients with very mild AD (GDS = 2) was $367 per month, compared with $4063 per month for patients with severe or very severe AD (GDS = 6). From baseline to follow-up, the greatest changes in cost were observed in the group of patients with the most severe AD as measured by all scales. The largest component of total cost was indirect costs at most severity levels, though medication costs contributed the most in patients with very mild AD. Significant independent contributors to cost were being female, having more impaired activities of daily living, and exhibiting more neuropsychiatric symptoms.Conclusions: costs for treating a patient with AD were strongly associated with disease severity, even though none of the patients were institutionalized. Delaying the progression of AD may reduce indirect costs and burden to caregivers. [ABSTRACT FROM AUTHOR]

Background The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice. Aim To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naïve patients with HCV genotype 1 infection enrolled in a large expanded access programme. Methods Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated. Results Mean ribavirin exposure in week 0–12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received ( P < 0.001 for both). Conclusions Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3 mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than in adults, with an AUC of 861 ± 805 vs2629 ± 1487 μmg × h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59 ± 0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077 ± 1551 μg × h/l compared to 1795 ± 973 μg × h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These... [ABSTRACT FROM AUTHOR]