ß-cell metabolic alterations under chronic nutrient overload in rat and human islets.

The aim of this study was to assess multifactorial ß-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in ß-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in ß-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 µM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets.

A sequence of introductory pharmacy practice experiences to address the new standards for experiential learning.

OBJECTIVE: To implement an introductory pharmacy practice experience (IPPE) curricular sequence in a manner that optimized preceptor availability, fostered significant learning, and addressed the new standards for experiential education. DESIGN: A 4-course, 300+ hour IPPE sequence was developed with 1 module in each semester of the first 2 professional years. Semesters were 18 weeks in length with IPPE taking place in the middle weeks as dedicated time blocks when no concurrent didactic courses were scheduled. Learning exercises were developed to build a progressive foundation in preparation for advanced pharmacy practice experiences (APPE). ASSESSMENT: During 2 academic years, 161 students participated in the IPPE program. Eighty-one students completed the 4-course sequence and another 80 students completed the first 2 courses. Collectively, 486 individual IPPE placements were made at over 120 community pharmacies and 60 hospital pharmacies or alternative practice sites located over a broad geographic region. Student evaluations by preceptors, evaluation of student journals by faculty, and surveys of students and preceptors demonstrated that course objectives were being achieved. CONCLUSION: An innovative approach to scheduling IPPE optimized preceptor availability, exceeded the minimum number of IPPE hours required by current accreditation standards, and achieved development of desired competencies.

Fluctuations in vancomycin CNS tissue concentrations following intermittent and continuous infusions in the rat.

The purpose of this investigation was to compare the variability of vancomycin concentrations in the serum and CNS when administered continuously or as intermittent intravenous infusions in the rat. The hypothesis for this investigation was that the magnitude of change in serum vancomycin concentrations directly relates to the extent of vancomycin concentration fluctuations in the CNS. Microdialysis and serum sampling techniques were employed and biologic samples were analysed for vancomycin using HPLC. Over the dosing interval, the mean changes in concentrations were 71.8 +/- 9.8% and 13.6 +/- 9.3% for serum and 61.7 +/- 7.8% and 6.8 +/- 3.5% for brain extracellular fluid in the intermittent and continuously infused groups, respectively. Accordingly, the relative changes in vancomycin concentrations in brain extracellular fluid were closely associated with corresponding changes in serum concentrations (R2=0.94). Thus, continuous intravenous administration of vancomycin results in minimal serum and CNS tissue concentration changes as compared to traditional intermittent dosing methods and allows for more consistent vancomycin concentrations in the CNS.

Ischemic stroke prevention: an update on antiplatelet therapy.

Stroke is the third leading cause of mortality in the United States. As the leading cause of neurological deficits worldwide, stroke is associated with tremendous costs both to society and to the individuals and families stroke impacts. Antiplatelet agents have demonstrated efficacy in preventing recurrent atherothrombotic strokes and are the principal pharmacologic modality employed. With the recent development of the thienopyridines and the resurgence of dipyridamole, recommendations for antiplatelet therapy have undergone several iterations over the past decade. The focus of this review is to provide an update on the individual antiplatelet agents and recapitulate the current guidelines for antiplatelet selection and use in either transient ischemic attack or noncardiogenic ischemic stroke patients. Mechanisms of action, demonstrated efficacy, adverse effect profiles, and current consensus recommendations are reviewed for four conventional antiplatelet strategies, aspirin, ticlopidine, clopidogrel, and the combination of aspirin and extended-release dipyridamole.