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1.  The Development of a Community-Based, Pharmacist-Provided Falls Prevention MTM Intervention for Older Adults: Relationship Building, Methods, and Rationale 
Innovations in pharmacy  2014;5(1):140-.
The objectives of this article are to discuss the process of community engagement experienced to plan and implement a pilot study of a pharmacist-provided MTM intervention focused on reducing the use of medications associated with falling, and to present the research methods that emerged from the community engagement process to evaluate the feasibility, acceptance, and preliminary impact of the intervention. Key lessons learned from the community engagement process also are presented and discussed. The relationship building and planning process took twelve months. The RE-AIM framework broadly guided the planning process since an overarching goal for the community partners was developing a program that could be implemented and sustained in the future. The planning phase focused on identifying research questions that were of most interest to the community partners, the population to study, the capacity of partners to perform activities, process evaluation. Much of the planning phase was accomplished with face-to-face meetings. After all study processes, study materials, and data collection tools were developed, a focus group of older adults who represented the likely targets of the MTM intervention provided feedback related to the concept and process of the intervention. Nine key lessons were identified from the community engagement process. One key to successful community engagement is partners taking the time to educate each other about experiences, processes, and success and failures. Additionally, partners must actively listen to each other to better understand barriers and facilitators that likely will impact the planning and implementation process. Successful community engagement will be important to develop both formative and summative evaluation processes that will help to produce valid evidence about the effectiveness of pharmacists in modifying drug therapy and preventing falls as well as promote adoption and implementation of the intervention in other communities.
PMCID: PMC4190035  PMID: 25309809
Falls Prevention; Community Pharmacy; Medication Therapy Management; Community Engagement
2.  pH-Dependent Inhibition of Kainate Receptors by Zinc 
Kainate receptors contribute to synaptic plasticity and rhythmic oscillatory firing of neurons in corticolimbic circuits including hippocampal area CA3. We use zinc chelators and mice deficient in zinc transporters to show that synaptically released zinc inhibits postsynaptic kainate receptors at mossy fiber synapses and limits frequency facilitation of kainate, but not AMPA EPSCs during thetapattern stimulation. Exogenous zinc also inhibits the facilitatory modulation of mossy fiber axon excitability by kainate but does not suppress the depressive effect of kainate on CA3 axons. Recombinant kainate receptors are inhibited in a subunit-dependent manner by physiologically relevant concentrations of zinc, with receptors containing the KA1 subunit being sensitive to submicromolar concentrations of zinc. Zinc inhibition does not alter receptor desensitization nor apparent agonist affinity and is only weakly voltage dependent, which points to an allosteric mechanism. Zinc inhibition is reduced at acidic pH. Thus, in the presence of zinc, a fall in pH potentiates kainate receptors by relieving zinc inhibition. Acidification of the extracellular space, as occurs during repetitive activity, may therefore serve to unmask kainate receptor neurotransmission. We conclude that zinc modulation of kainate receptors serves an important role in shaping kainate neurotransmission in the CA3 region.
PMCID: PMC4100615  PMID: 18272686
zinc; kainate receptor; CA3; glutamate receptor; mossy fiber; hippocampus; pH
3.  Effects of Medicare Part D on Drug Affordability and Utilization: Are Seniors with Prior High Out-of-Pocket Drug Spending Affected More? 
Medicare Part D was expected to have differential impacts on patient drug expenditures and utilization based on beneficiaries’ levels of pre-Part D patient drug spending, but it is unknown whether these projections have borne out
We sought to evaluate whether and how the policy effect of Medicare Part D on drug expenditures and utilization was modified by levels of pre-Part D drug spending.
A quasi-experimental, pretest-posttest, nonequivalent control group design was used. Data were obtained from a regional supermarket chain for all prescriptions dispensed between January 1, 2005 and December 31, 2007 (n =1,230,612) to patients age 60 and older as of January 1, 2005 (n = 51,305) to construct 12-month pre-Part D and post-Part D periods. The treatment group was defined as individuals who were eligible via age, for Part D coverage on January 1, 2006 (ages 65+). The control group included individuals aged 60 through 62 on January 1, 2006. Annual medication utilization was measured as the total number of pill-days acquired. Annual drug expenditures were measured as total expenditures, patient out-of-pocket expenditures, and the proportion of total expenditures paid out of pocket by the patient.
Part D resulted in significantly greater reductions in absolute and relative out-of-pocket spending for individuals in the highest pre-Part D drug spending group relative to the moderate and low pre-Part D drug spending groups.
Our findings suggest that, as expected, Part D facilitated access to medications for patients who previously experienced the greatest costs without adversely increasing use and costs among those with the lowest prior cost.
PMCID: PMC4087326  PMID: 20511108
Medicare Part D; Utilization; Out-of-pocket Spending; Access
4.  Use of pharmacists or pharmacies as Medicare Part D information sources 
To characterize beneficiaries who used a pharmacy or pharmacist as a Medicare Part D information source.
This cross-sectional descriptive study involved 4,724 Medicare Part D beneficiaries who graduated from Wisconsin high schools in 1957. The main outcome measure was beneficiary self-reported use of a pharmacy or pharmacist as a Medicare Part D information source.
Only 13% of the total sample and 15% of those with three or more medications used a pharmacy or pharmacist for Medicare Part D information. Adjusted logistic regression revealed that beneficiaries living in rural communities, compared with metropolitan areas, and with higher out-of-pocket prescription costs were more likely to use a pharmacy or pharmacist for Medicare Part D information. Beneficiaries with lower educational attainment were less likely to use a pharmacy or pharmacist for Medicare Part D information.
Pharmacists have the knowledge and are in the position in the community to effectively educate beneficiaries about the Medicare Part D program. However, this study suggests that few beneficiaries are using pharmacists or pharmacies for Medicare Part D information.
PMCID: PMC3774520  PMID: 23229982
Medicare Part D; community pharmacies; pharmacists; information sources; rural setting; prescription costs
5.  The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABAA receptors 
Neuropharmacology  2012;62(8):2507-2514.
The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABAA receptors, consistent with their biological effects. The GABAA receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABAA receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor’s subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the α, β, or γ subunit subtype, although the compounds showed particularly high efficacy at δ-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABAA receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected.
PMCID: PMC3652012  PMID: 22445602
GABA; anxiolytic; natural product; Magnolia
6.  The auxiliary subunits Neto1 and Neto2 reduce voltage-dependent inhibition of recombinant kainate receptors 
Kainate receptors can be subject to voltage-dependent block by intracellular polyamines, which causes inward rectification of the current-voltage relationship. Sensitivity to polyamine block is largely determined by the identity of a residue within the pore domain that can be altered through RNA editing. This process causes replacement of the encoded glutamine(Q) with a positively charged arginine(R), eliminating polyamine inhibition and thus inward rectification. In neurons, kainate receptors can associate with the auxiliary subunits Neto1 or Neto2. These transmembrane proteins alter the trafficking, channel kinetics, and pharmacology of the receptors in a subunit-dependent manner. We found that co-expression of Neto subunits with recombinant GluK2(Q) kainate receptors greatly reduced inward rectification, without altering calcium permeability. This effect was separate from modulation of channel kinetics, as mutations within the extracellular LDLa domain of the Neto proteins completely eliminated their effects on desensitization but only reduced their effects on rectification. Conversely, deletion of the intracellular C-terminal domain of Neto1 or Neto2 or neutralization of positively charged residues within this domain prevented the reduction in rectification, but did not alter effects on channel kinetics. These results demonstrate new roles for Neto1 and Neto2 in regulating kainate receptor function and identify domains within these auxiliary subunits important for mediating their effects.
PMCID: PMC3652014  PMID: 22973017
8.  The Auxiliary Subunits Neto1 and Neto2 Reduce Voltage-Dependent Inhibition of Recombinant Kainate Receptors 
The Journal of Neuroscience  2012;32(37):12928-12933.
Kainate receptors can be subject to voltage-dependent block by intracellular polyamines, which causes inward rectification of the current–voltage relationship. Sensitivity to polyamine block is largely determined by the identity of a residue within the pore domain that can be altered through RNA editing. This process causes replacement of the encoded glutamine(Q) with a positively charged arginine(R), eliminating polyamine inhibition and thus inward rectification. In neurons, kainate receptors can associate with the auxiliary subunits Neto1 or Neto2. These transmembrane proteins alter the trafficking, channel kinetics, and pharmacology of the receptors in a subunit-dependent manner. We found that coexpression of Neto subunits with recombinant GluK2(Q) kainate receptors greatly reduced inward rectification without altering calcium permeability. This effect was separate from modulation of channel kinetics, as mutations within the extracellular LDLa domain of the Neto proteins completely eliminated their effects on desensitization but only reduced their effects on rectification. Conversely, deletion of the intracellular C-terminal domain of Neto1 or Neto2 or neutralization of positively charged residues within this domain prevented the reduction in rectification but did not alter effects on channel kinetics. These results demonstrate new roles for Neto1 and Neto2 in regulating kainate receptor function and identify domains within these auxiliary subunits important for mediating their effects.
PMCID: PMC3652014  PMID: 22973017
9.  Interneuron loss reduces dendritic inhibition and GABA release in hippocampus of aged rats 
Neurobiology of aging  2011;33(2):431.e1-431.e13.
Aging is associated with impairments in learning and memory and a greater incidence of limbic seizures. These changes in the aged brain have been associated with increased excitability of hippocampal pyramidal cells caused by a reduced number of GABAergic interneurons. To better understand these issues, we performed cell counts of GABAergic interneurons and examined GABA efflux and GABAergic inhibition in area CA1 of the hippocampus of young (3-5 mo) and aged (26-30 mo) rats. Aging significantly reduced high K+/Ca2+-evoked GABA, but not glutamate efflux in area CA1. Immunostaining revealed a significant loss of GABAergic interneurons, but not inhibitory boutons in stratum oriens and stratum lacunosum moleculare. Somatostatin-immunoreactive oriens-lacunosum moleculare (O-LM) cells, but not parvalbumin-containing interneurons were selectively lost. O-LM cells project to distal dendrites of CA1 pyramidal cells, providing dendritic inhibition. Accordingly, inhibition of dendritic input to CA1 from entorhinal cortex was selectively reduced. These findings suggest that the age-dependent loss of interneurons impairs dendritic inhibition and dysregulates entorhinal cortical input to CA1, potentially contributing to cognitive impairment and seizures.
PMCID: PMC3110542  PMID: 21277654
Interneuron; aging; hippocampus; CA1; O-LM cells; temporoammonic pathway; GABA; inhibition; somatostatin; parvalbumin; entorhinal cortex; dendritic inhibition
Physiology & behavior  2011;105(1):138-144.
Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). While the vast majority of these studies have focused upon the hypothalamus, more recent studies suggest that the complications of obesity may also affect the structural and functional integrity of the hippocampus. A potential contributor to obesity-related CNS abnormalities is the adipocyte-derived hormone leptin. In this regard, decreases in CNS leptin activity may contribute to deficits in hippocampal synaptic plasticity and suggest that leptin resistance, a well described phenomenon in the hypothalamus, may also be observed in the hippocampus. Unfortunately, the myriad of metabolic and endocrine abnormalities in diabetes/obesity phenotypes makes it challenging to assess the role of leptin in hippocampal neuroplasticity deficits associated with obesity models. To address this question, we examined hippocampal morphological and behavioral plasticity following lentivirus-mediated downregulation of hypothalamic insulin receptors (hypo-IRAS). Hypo-IRAS rats exhibit increases in body weight, adiposity, plasma leptin and triglyceride levels. As such, hypo-IRAS rats develop a phenotype that is consistent with features of the metabolic syndrome. In addition, hippocampal morphological plasticity and performance of hippocampal-dependent tasks are adversely affected in hypo-IRAS rats. Leptin-mediated signaling is also decreased in hypo-IRAS rats. We will discuss these findings in the context of how hyperleptinemia and hypertriglyceridemia may represent mechanistic mediators of the neurological consequences of impaired hippocampal synaptic plasticity in obesity.
PMCID: PMC3129487  PMID: 21354191
triglycerides; leptin; adiposity; fear conditioning; STAT3; morphology; lentivirus
Physiology & behavior  2010;104(2):235-241.
Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA sequence (IRAS) that when injected into the hypothalamus selectively decreases IR signaling in hypothalamus, resulting in increased body weight, peripheral adiposity and plasma leptin levels. To test the hypothesis that this obesity/hyperleptinemic phenotype would impair hippocampal synaptic transmission, we examined short term potentiation (STP) and long term potentiation (LTP) in the hippocampus of rats that received the LV-IRAS construct or the LV-Control construct in the hypothalamus (hypo-IRAS and hypo-Con, respectively). Stimulation of the Schaffer collaterals elicits STP that develops into LTP in the CA1 region of hypo-Con rats; conversely, hypo-IRAS rats exhibit STP that fails to develop into LTP. To more closely examine the potential role of hyperleptinemia in these electrophysiological deficits, hypo-IRAS were subjected to mild food restriction paradigms that would either: 1) prevent the development of the obesity phenotype; or 2) reverse an established obesity phenotype in hypo-IRAS rats. Both of these paradigms restored LTP in the CA1 region and reversed the decreases in the phosphorylated/total ratio of GluA1 Ser845 AMPA receptor subunit expression observed in the hippocampus of hypo-IRAS rats. Collectively, these data support the hypothesis that obesity impairs hippocampal synaptic transmission and support the hypothesis that these deficits are mediated through impairment of hippocampal leptin activity.
PMCID: PMC3097290  PMID: 21036186
triglycerides; leptin; adiposity; long term potentiation; GluA1 receptor; lentivirus
12.  Distinct Functional Roles of Subunits within the Heteromeric Kainate Receptor 
Kainate receptors (KARs) have been implicated in a number of neurological disorders, including epilepsy. KARs are tetrameric, composed of a combination of GluK1–5 subunits. We examined the contribution of GluK2 and GluK5 subunits to activation and desensitization of the heteromeric receptor. Heteromeric GluK2/K5 receptors expressed in HEK 293T cells showed markedly higher glutamate sensitivity than GluK2 homomers and did not desensitize at low glutamate concentrations. Mutation of residue E738 in GluK2 substantially lowered its glutamate sensitivity. However, heteromeric KARs containing this mutant GluK2 [GluK2(E738D)] assembled with wild-type GluK5 showed no change in glutamate EC50 compared to wild-type heteromeric KARs. Instead, higher concentrations of glutamate were required to produce desensitization. This suggested that within the heteromeric receptor, glutamate binding to the high affinity GluK5 subunit alone was sufficient for channel activation but not desensitization, while agonist binding to the low affinity GluK2 subunit was not necessary to open the channel, but instead caused the channel to enter a closed, desensitized state. To test this hypothesis in wild-type receptors, we used the competitive antagonist kynurenate, which has higher affinity for the GluK2 than the GluK5 subunit. Co-application of kynurenate with glutamate to heteromeric receptors reduced the onset of desensitization without affecting the peak current response, consistent with our hypothesis. Our results suggest that GluK2 and GluK5 subunits can be individually activated within the heteromeric receptor and that these subunits serve dramatically different functional roles.
PMCID: PMC3237056  PMID: 22114280
kainate receptor; GluK5; GluK2; desensitization; glutamate; hippocampus
13.  A qualitative assessment of a community pharmacy cognitive pharmaceutical services program, using a work system approach 
Although lack of time, trained personnel, and reimbursement have been identified as barriers to pharmacists providing cognitive pharmaceutical services (CPS) in community pharmacies, the underlying contributing factors of these barriers have not been explored. One approach to better understand barriers and facilitators to providing CPS is to use a work system approach to examine different components of a work system and how the components may impact care processes.
The goals of this study were to identify and describe pharmacy work system characteristics that pharmacists identified and changed to provide CPS in a demonstration program.
A qualitative approach was used for data collection. A purposive sample of 8 pharmacists at 6 community pharmacies participating in a demonstration program was selected to be interviewed. Each semistructured interview was audio recorded and transcribed, and the text was analyzed in a descriptive and interpretive manner by 3 analysts. Themes were identified in the text and aligned with 1 of 5 components of the Systems Engineering Initiative for Patient Safety (SEIPS) work system model (organization, tasks, tools/technology, people, and environment).
A total of 21 themes were identified from the interviews, and 7 themes were identified across all 6 interviews. The organization component of the SEIPS model contained the most (n = 10) themes. Numerous factors within a pharmacy work system appear important to enable pharmacists to provide CPS. Leadership and foresight by the organization to implement processes (communication, coordination, planning, etc.) to facilitate providing CPS was a key finding across the interviews. Expanding technician responsibilities was reported to be essential for successfully implementing CPS.
To be successful in providing CPS, pharmacists must be cognizant of the different components of the pharmacy work system and how these components influence providing CPS.
PMCID: PMC3351586  PMID: 21824822
Medication therapy management; Community pharmacy; Human factors; Work systems
14.  Subunit-Dependent Modulation of Kainate Receptors by Muscarinic Acetylcholine Receptors 
Brain research  2010;1352:61-69.
Interactions between cholinergic and glutamatergic neurotransmitter systems influence synaptic transmission and plasticity. While previous studies have examined cross-talk between acetylcholine (ACh) and NMDA or AMPA receptors, little is known about the effect of ACh on kainate receptors (KARs). We show that stimulation of m1 or m3 muscarinic ACh receptors (mAChRs) for 2 min potentiates recombinant KAR currents in a long lasting fashion. Muscarinic AChR activation potentiates heteromeric GluK2/GluK4 and GluK2/GluK5 receptors, but not homomeric GluK2 receptors. In hippocampal slices kainate potentiates mossy fiber axon excitability. Transient mAChR activation enhances this action of kainate, suggesting a novel mechanism through which acetylcholine could modulate synaptic transmission in the hippocampus. KAR over-activation has been implicated in excitotoxic cell death. To establish the functional significance of the interaction between mAChRs and KARs we examined the effect of mAChR activation on KAR-mediated excitotoxicity. We find that during pharmacological blockade of NMDA and AMPA receptors, KAR activation with AMPA produces significant cell death in primary cortical culture. Concanavalin A (Con A), which selectively blocks KAR desensitization, markedly increases this KAR-mediated neurotoxicity. Brief activation of mAChRs with pilocarpine significantly enhances KAR-mediated excitotoxicity both in the presence and absence of Con A. We conclude that KARs are modulated in a subunit dependent manner by mAChRs. We suggest that ACh may induce long lasting alterations in neuronal excitability and enhance excitotoxicity in part by potentiating KAR function.
PMCID: PMC2926221  PMID: 20655886
Excitotoxicity; GluK2; GluK5; Hippocampus; Glutamate; Acetylcholine
15.  Development of a Scale to Measure Pharmacists’ Self-Efficacy in Performing Medication Therapy Management Services 
Measuring community pharmacists’ self-efficacy in performing medication therapy management (MTM) services can be useful for tailoring interventions and predicting participation.
To identify relevant survey constructs related to the Wisconsin Pharmacy Quality Collaborative (WPQC) MTM program and to evaluate scale validity.
The 31-item MTM Self-efficacy Scale was developed using previous research, identifying critical program components, and beta-testing. After administration to pharmacists in the 53 WPQC pilot sites, summary statistics and exploratory factor analysis (EFA) were conducted. Parallel analysis was used to determine the optimal number of factors. Internal consistency reliabilities were calculated.
Baseline participation rate was 94% (N=76). The 11-point scale (0–10) item means ranged from 2.83±3.05 to 7.82±2.19. Parallel analysis produced a 3-factor solution, accounting for 56% of the variance. Low factor loadings or unacceptably high cross-loadings resulted in 17 item deletions. The final EFA on the remaining 14 items retained the original 3-factor solution and increased the proportion of explained variance (72%). The factors relate to MTM tasks (alpha = 0.92), personal interactions (alpha = 0.86), and goal setting (alpha = 0.84). Overall Cronbach’s alpha = 0.90.
Constructs for measuring self-efficacy were identified that may aid in future research predicting whether pharmacists engage in and persist in providing MTM services.
PMCID: PMC2904078  PMID: 20511114
Self-efficacy; Medication therapy management; Community pharmacy; Scale validation; Research methods
16.  Association Between Increased Number of US Pharmacy Graduates and Pharmacist Counts by State from 2000-2009 
To determine whether growth in the number of pharmacy graduates and newly accredited schools from 2000 to 2009 were larger in states with fewer pharmacists per population age ≥ 65 years.
States were aggregated into quartiles based on rank-ordered ratios of in-state pharmacists per 100,000 population aged ≥ 65 years. Quartiles were then compared with respect to the number of new graduates.
The mean cumulative number of graduates was highest in the first quartile of states (those with the greatest need for pharmacists) and lowest in the fourth quartile of states. States with the greatest need for pharmacists had the lowest positive growth in number of pharmacists per population ≥ 65 years. The majority of new schools in 2009 were located in states with relatively low numbers of pharmacists.
The growth in new pharmacy graduates created by expansion in schools as well as in graduates per school helped states meet demand between 2000 and 2009. However, tremendous variation remains in the number of graduates as well as the number of pharmacists across states. The quartile framework is useful for assessing the number of new pharmacy graduates based on pharmacists per population ratios. Based on current dynamics in the supply and demand of pharmacists, frequent monitoring is recommended.
PMCID: PMC3138339  PMID: 21769152
pharmacists; workforce; graduates; assessment; states
17.  Practice Characteristics of Bachelor of Science and Doctor of Pharmacy Degreed Pharmacists Based on the 2009 National Workforce Survey 
To compare practice settings and activities of pharmacists with bachelor of science (BS) in pharmacy and doctor of pharmacy (PharmD) degrees.
Data from the 2009 National Pharmacist Workforce Survey instrument were analyzed. Multivariate regression was used to examine the association of the PharmD degree with time spent in dispensing and patient care.
The survey response rate by pharmacists was 52%, and 562 usable responses met our inclusion criteria. Sixty-three percent of BS and 39% of PharmD pharmacists were employed in community pharmacies, compared with 21% of BS and 38% of PharmD pharmacists employed in hospital pharmacy settings. Practicing in a community setting had the strongest influence on time spent in dispensing and time spent in patient care. Among respondents with PharmD degrees, a residency was associated with less time in dispensing and more time in patient care.
Time spent in dispensing and patient care were influenced more by practice setting than by educational degree and residency training.
PMCID: PMC2996749  PMID: 21301593
degrees; graduates; pharmacist; workforce
18.  Two simple and rugged designs for creating microfluidic sheath flow 
Lab on a chip  2008;8(7):1097-1103.
A simple design capable of 2-dimensional hydrodynamic focusing is proposed and successfully demonstrated. In the past, most microfluidic sheath flow systems have often only confined the sample solution on the sides, leaving the top and bottom of the sample stream in contact with the floor and ceiling of the channel. While relatively simple to build, these designs increase the risk of adsorption of sample components to the top and bottom of the channel. A few designs have been successful in completely sheathing the sample stream, but these typically require multiple sheath inputs and several alignment steps. In the designs presented here, full sheathing is accomplished using as few as one sheath input, which eliminates the need to carefully balance the flow of two or more sheath inlets. The design is easily manufactured using current microfabrication techniques. Furthermore, the sample and sheath fluid can be subsequently separated for recapture of the sample fluid or re-use of the sheath fluid. Designs were demonstrated in poly(dimethylsiloxane) (PDMS) using soft lithography and poly(methyl methacrylate) (PMMA) using micromilling and laser ablation.
PMCID: PMC2751611  PMID: 18584084
19.  Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes 
Recent studies have suggested that abnormal regulation of protein phosphatase 2A (PP2A) is associated with Type 2 diabetes in rodent and human tissues. Results with cultured mouse myotubes support a mechanism for palmitate activation of PP2A, leading to activation of glycogen synthase kinase 3. Phosphorylation and inactivation of glycogen synthase by glycogen synthase kinase 3 could be the mechanism for long-chain fatty acid inhibition of insulin-mediated carbohydrate storage in insulin-resistant subjects. Here, we test the effects of palmitic acid on cultured muscle glycogen synthase and PP2A activities. Palmitate inhibition of glycogen synthase fractional activity is increased in subjects with high body mass index compared with subjects with lower body mass index (r = −0.43, P = 0.03). Palmitate action on PP2A varies from inhibition in subjects with decreased 2-h plasma glucose concentration to activation in subjects with increased 2-h plasma glucose concentration (r = 0.45, P < 0.03) during oral glucose tolerance tests. The results do not show an association between palmitate effects on PP2A and glycogen synthase fractional activity. We conclude that subjects at risk for Type 2 diabetes have intrinsic differences in palmitate regulation of at least two enzymes (PP2A and glycogen synthase), contributing to abnormal insulin regulation of glucose metabolism.
PMCID: PMC2268844  PMID: 18056794
skeletal muscle; cell culture; obesity; insulin resistance
20.  Exploring the demand for a voluntary medicare prescription drug benefit 
AAPS PharmSci  2003;5(2):99-110.
The purposes of this study were (1) to assess the utility of the economic theory of demand for insurance for modeling voluntary Medicare drug benefit enrollment decisions and (2) to explore the degree of adverse selection and crowd-out that might occur under a voluntary enrollment Medicare prescription benefit. Data were collected using a cross-sectional, mail survey of 2,100 community-dwelling adults aged 65 and older in Wisconsin. Respondents were asked to evaluate their likelihood of enrollment in any of 4 hypothetical drug benefit plans under the assumption that they could enroll in one of the hypothetical plans or maintain their current coverage. Data analyses included bivariate comparisons across enrollment likelihood categories and logit analysis of enrollment likelihood as a function of respondent characteristics. 1041 usable survey forms were returned for an adjusted response rate of 51.5%. Older adults with 4 or more chronic conditions were most likely to report that they were “very likely” to enroll in one of the hypothetical drug plans, as were those with the highest out-of-pocket drug spending in the previous 30 days. Respondents with no or self-purchased drug benefits were more likely than those with employer-based plans to express a higher likelihood of enrollment in one of the hypothetical plans. Adverse selection may be problematic for a voluntary enrollment Medicare drug benefit. Given that high out-of-pocket drug spending (secondary to drug coverage source) was a consistent predictor of enrollment likelihood, demand-side factors affecting the crowding out of employer-based drug coverage sources by a voluntary enrollment drug benefit appear minimal. However, the availability of a Medicare prescription benefit may still lead to crowd-out through employer incentives.
PMCID: PMC2751526  PMID: 12866945
prescription drug coverage; Medicare; older adults
21.  A national survey of U.S. pharmacists in 2000: Assessing nonresponse bias of a survey methodology 
AAPS PharmSci  2001;3(4):76-86.
The first objective of this study was to assess the existence of nonresponse bias to a national survey of licensed pharmacists conducted in 2000. Three methods were used to assess nonresponse bias. The second objective of the study was to examine reasons why sampled licensed pharmacists did not respond to the national survey of licensed pharmacists. We used data from 2204 respondents to a national survey of pharmacists and from 521 respondents to a survey of nonrespondents to the national survey. We made comparisons between respondents for 5 variables: employment status, gender, age, highest academic degree, and year of initial licensure. Chi-square tests were used to examine differences in the 5 variables between respondents to the first mailing and second mailing of the survey, early and late respondents to the survey, and respondents to the survey and respondents to the nonrespondent survey. There were no significant differences between first mailing and second mailing respondents, but there were differences in each variable except year of licensure between early and late respondents. These differences likely were due to regional bias possibly related to differences in mailing times. There were differences between respondents and nonrespondents in terms of employment status and year of licensure. The main reasons for not responding to the survey were that it was too long or that it was too intrusive. Overall, the survey methodology resulted in a valid sample of licensed pharmacists. Nonresponse bias should be assessed by surveying nonrespondents. Future surveys of pharmacists should consider the length of the survey and the address where it is sent.
PMCID: PMC2751222  PMID: 12049496
Pharmacy Workforce; Survey Methods; Nonresponse Bias
22.  A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance 
Journal of Clinical Investigation  2000;106(7):R69-R73.
Previous linkage studies in Mexican-Americans localized a major susceptibility locus for type 2 diabetes, NIDDM1, to chromosome 2q. This evidence for linkage to type 2 diabetes was recently found to be associated with a common G→A polymorphism (UCSNP-43) within the CAPN10 gene. The at-risk genotype was homozygous for the UCSNP-43 G allele. In the present study among Pima Indians, the UCSNP-43 G/G genotype was not associated with an increased prevalence of type 2 diabetes. However, Pima Indians with normal glucose tolerance, who have a G/G genotype at UCSNP-43, were found to have decreased rates of postabsorptive and insulin-stimulated glucose turnover that appear to result from decreased rates of glucose oxidation. In addition, G/G homozygotes were found to have reduced CAPN10 mRNA expression in their skeletal muscle. A decreased rate of insulin-mediated glucose turnover, or insulin resistance, is one mechanism by which the polymorphism in CAPN10 may increase susceptibility to type 2 diabetes mellitus in older persons.
PMCID: PMC387246  PMID: 11018080
23.  The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus 
Journal of Clinical Investigation  1999;104(6):787-794.
The pathogenesis of type 2 diabetes involves abnormalities in insulin action, insulin secretion, and endogenous glucose output (EGO). However, the sequence with which these abnormalities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. We measured insulin action, insulin secretion, and EGO longitudinally in 17 Pima Indians, in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic over 5.1 ± 1.4 years. Transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.
PMCID: PMC408438  PMID: 10491414

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