Bayesian QTL analyses using pedigreed families of an outcrossing species, with application to fruit firmness in apple.

KEY MESSAGE: Proof of concept of Bayesian integrated QTL analyses across pedigree-related families from breeding programs of an outbreeding species. Results include QTL confidence intervals, individuals' genotype probabilities and genomic breeding values. Bayesian QTL linkage mapping approaches offer the flexibility to study multiple full sib families with known pedigrees simultaneously. Such a joint analysis increases the probability of detecting these quantitative trait loci (QTL) and provide insight of the magnitude of QTL across different genetic backgrounds. Here, we present an improved Bayesian multi-QTL pedigree-based approach on an outcrossing species using progenies with different (complex) genetic relationships. Different modeling assumptions were studied in the QTL analyses, i.e., the a priori expected number of QTL varied and polygenic effects were considered. The inferences include number of QTL, additive QTL effect sizes and supporting credible intervals, posterior probabilities of QTL genotypes for all individuals in the dataset, and QTL-based as well as genome-wide breeding values. All these features have been implemented in the FlexQTL(™) software. We analyzed fruit firmness in a large apple dataset that comprised 1,347 individuals forming 27 full sib families and their known ancestral pedigrees, with genotypes for 87 SSR markers on 17 chromosomes. We report strong or positive evidence for 14 QTL for fruit firmness on eight chromosomes, validating our approach as several of these QTL were reported previously, though dispersed over a series of studies based on single mapping populations. Interpretation of linked QTL was possible via individuals' QTL genotypes. The correlation between the genomic breeding values and phenotypes was on average 90 %, but varied with the number of detected QTL in a family. The detailed posterior knowledge on QTL of potential parents is critical for the efficiency of marker-assisted breeding.

Low-temperature phase and morphology transformations in noble metal nanocatalysts.

In situ real-time x-ray diffraction was used to study temperature-induced structural changes of 1-5 nm Au, Pt, and AuPt nanocatalysts supported on silicon substrates. Synchrotron-based x-ray diffraction indicates that the as-synthesized Au and Au(64)Pt(36) nanoparticles have a non-crystalline structure, while the Pt nanoparticles have the expected cubic structure. The nanoparticles undergo dramatic structural changes at temperatures as low as 120 °C. During low-temperature annealing, the Au and AuPt nanoparticles first melt and then immediately coalesce to form 4-5 nm crystalline structures. The Pt nanoparticles also aggregate but with limited intermediate melting. The detailed mechanisms of nucleation and growth, though, are quite different for the three types of nanoparticles. Most interestingly, solidification of high-density AuPt nanoparticles involves an unusual transient morphological transformation that affects only the surface of the particles. AuPt nanoparticles on silicon undergo partial phase segregation only upon annealing at extremely high temperatures (800 °C).

An in situ real-time x-ray diffraction study of phase segregation in Au-Pt nanoparticles.

In situ real-time x-ray diffraction was used to study phase segregation and coarsening of Au-Pt nanoparticles supported on silica powder, and porous alumina membranes. Contrary to the expectations from the bulk phase diagram, silica supported Au-Pt nanoparticles have an alloyed structure that is preserved even after extensive annealing at temperatures as high at 700 degrees C. In stark contrast, alumina supported Au-Pt nanoparticles exhibit a rich phase behaviour that is sensitive to alloy composition and the details of the synthesis process. In particular, low-density as-prepared Au(41)Pt(59) nanoparticles exhibit the signature of incipient phase segregation that develops into full phase separation during annealing at high temperature.

Detection and evolution of resistance to the pyrethroid cypermethrin in Helicoverpa zea (Lepidoptera: Noctuidae) populations in Texas.

The bollworm, Helicoverpa zea (Boddie), is a key pest of cotton in Texas. Bollworm populations are widely controlled with pyrethroid insecticides in cotton and exposed to pyrethroids in other major crops such as grain sorghum, corn, and soybeans. A statewide program that evaluated cypermethrin resistance in male bollworm populations using an adult vial test was conducted from 2003 to 2006 in the major cotton production regions of Texas. Estimated parameters from the most susceptible field population currently available (Burleson County, September 2005) were used to calculate resistance ratios and their statistical significance. Populations from several counties had statistically significant (P < or = 0.05) resistance ratios for the LC(50), indicating that bollworm-resistant populations are widespread in Texas. The highest resistance ratios for the LC(50) were observed for populations in Burleson County in 2000 and 2003, Nueces County in 2004, and Williamson and Uvalde Counties in 2005. These findings explain the observed pyrethroid control failures in various counties in Texas. Based on the assumption that resistance is caused by a single gene, the Hardy-Weinberg equilibrium formula was used for estimation of frequencies for the putative resistant allele (q) using 3 and 10 microg/vial as discriminatory dosages for susceptible and heterozygote resistant insects, respectively. The influence of migration on local levels of resistance was estimated by analysis of wind trajectories, which partially clarifies the rapid evolution of resistance to cypermethrin in bollworm populations. This approach could be used in evaluating resistance evolution in other migratory pests.

Open probability of homomeric murine 5-HT3A serotonin receptors depends on subunit occupancy.

1. The time course of macroscopic current responses of homomeric murine serotonin 5-HT3A receptors was studied in whole cells and excised membrane patches under voltage clamp in response to rapid application of serotonin. 2. Serotonin activated whole cell currents with an EC(50) value for the peak response of 2 microM and a Hill slope of 3.0 (n = 12), suggesting that the binding of at least three agonist molecules is required to open the channel. 3. Homomeric 5-HT3A receptors in excised membrane patches had a slow activation time course (mean +/- S.E.M. 10-90 % rise time 12.5 +/- 1.6 ms; n = 9 patches) for 100 microM serotonin. The apparent activation rate was estimated by fitting an exponential function to the rising phase of responses to supramaximal serotonin to be 136 s(-1). 4. The 5-HT3A receptor response to 100 microM serotonin in outside-out patches (n = 19) and whole cells (n = 41) desensitized with a variable rate that accelerated throughout the experiment. The time course for desensitization was described by two exponential components (for patches tau(slow) 1006 +/- 139 ms, amplitude 31 %; tau(fast) 176 +/- 25 ms, amplitude 69 %). 5. Deactivation of the response following serotonin removal from excised membrane patches (n = 8) and whole cells (n = 29) was described by a dual exponential time course with time constants similar to those for desensitization (for patches tau(slow) 838 +/- 217 ms, 55 % amplitude; tau(fast) 213 +/- 44 ms, 45 % amplitude). 6. In most patches (6 of 8), the deactivation time course in response to a brief 1-5 ms pulse of serotonin was similar to or slower than desensitization. This suggests that the continued presence of agonist can induce desensitization with a similar or more rapid time course than agonist unbinding. The difference between the time course for deactivation and desensitization was voltage independent over the range -100 to -40 mV in patches (n = 4) and -100 to +50 mV in whole cells (n = 4), suggesting desensitization of these receptors in the presence of serotonin does not reflect a voltage-dependent block of the channel by agonist. 7. Simultaneously fitting the macroscopic 5-HT3A receptor responses in patches to submaximal (2 microM) and maximal (100 microM) concentrations of serotonin to a variety of state models suggests that homomeric 5-HT3A receptors require the binding of three agonists to open and possess a peak open probability greater than 0.8. Our modelling also suggests that channel open probability varies with the number of serotonin molecules bound to the receptor, with a reduced open probability for fully liganded receptors. Increasing the desensitization rate constants in this model can generate desensitization that is more rapid than deactivation, as observed in a subpopulation of our patches.

Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes.

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among those whose mothers were diabetic during pregnancy. To define the metabolic abnormalities predisposing individuals in these high-risk groups to diabetes, we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subjects, acute insulin secretory response (AIR) to a 25-g intravenous glucose challenge correlated with the age at onset of diabetes in the mother (r = 0.23, P = 0.03) and, in multiple regression analyses, the age at onset of diabetes in the father (P = 0.02), after adjusting for maternal age at onset and after allowing for an interaction between these terms. In contrast, insulin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabetes in the parents affected insulin secretion in the offspring across a range of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compared with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% CI] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lower in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the birth of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant offspring of people with early onset type 2 diabetes. This impairment may be worsened by exposure to a diabetic environment in utero.

Use of labor economic theory to examine hours worked by male and female pharmacists.

PURPOSE: The objectives of this study were to develop a theoretically derived model of hours worked by pharmacists and estimate the model separately for male and female pharmacists. METHODS: A systematic random sample of 1,600 pharmacists from four states was mailed a survey asking about current and past employment information. Two dependent variables were studied: weekly hours worked and annual hours worked. Independent variables were categorized as economic variables (hourly wage rate, other income, total debt) and demographic variables (employment position, age, degree earned, marital status, number of children at home). A two equation multiple regression model was estimated with two-stage least squares regression. RESULTS: A total of 541 pharmacists responded to the survey and data from 442 of the respondents were used in the analysis. Hourly wage rates were negatively associated with weekly hours worked for males. Other income and total debt were significantly negatively and positively associated, respectively, with annual hours worked by female pharmacists. The number of young children at home significantly reduced weekly and annual hours worked by female pharmacists. Female pharmacists earning a Pharm.D. degree worked significantly more hours weekly and annually. Age was significantly negatively associated with male pharmacists weekly and annual hours worked. CONCLUSIONS: Economic variables had a relatively small effect on hours worked by male and female pharmacists suggesting that increased wage rates may not increase hours worked. Strategies to increase hours worked by females likely should focus on benefits to help females handle childcare issues.

A national survey of U.S. pharmacists in 2000: assessing nonresponse bias of a survey methodology.

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.

Treatment of gingival recession with collagen membranes.

Periodontal plastic surgical techniques to obtain root coverage traditionally have utilized autogenous soft tissue grafts. Guided tissue regeneration (GTR) increasingly is being used as an alternative to soft tissue grafting in attempting root coverage. Resorbable membranes in GTR therapy prevent the need for a second surgery to harvest donor tissue. GTR membranes composed of collagen are effective barriers that add to the thickness of the overlying gingiva and possess platelet-aggregating properties that may help in early wound healing. The cases presented here demonstrate the treatment of gingival recession with a resorbable collagen membrane.

Periodontal plastic surgical technique for gingival fenestration closure.

Gingival fenestration is an opening through oral keratinized tissue, usually unattached, that is observed in thin gingiva with usually thick subgingival calculus deposits. This lesion is seen infrequently but may be more common than has been reported; lack of symptoms may inhibit patient awareness. Because surgical correction usually is not required, there are very few reports in the literature concerning this lesion. The following report describes a case of gingival fenestration and surgical treatment with a connective tissue/periosteal graft.

A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance.

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.

Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects.

Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 microM palmitate in cultured myoblasts correlated with the fasting glucose (r = 0.71, P = 0.001), log fasting insulin (r = 0.52, P = 0.03), and insulin-mediated glucose storage rate (r = -0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 microM palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 microM palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor.

Pharmacist job turnover, length of service, and reasons for leaving, 1983-1997.

Pharmacist job turnover from 1983 to 1997 was studied. Data were collected from a randomized 1997 mail survey of 1600 licensed pharmacists in four states (Ohio, Massachusetts, Oregon, and Alabama). The survey instrument included questions on pharmacist demographics, work schedules, salary, and work history. A total of 541 pharmacists responded, yielding an adjusted response rate of 34.5%. Information was provided on a total of 1697 jobs with start dates from 1931 to 1997. Pharmacist job turnover was fairly steady across the 1983-1997 period, averaging 11% annually. The average median tenure of pharmacists who left jobs was 32 months. The percentage of pharmacists leaving jobs and ranking stress as the reason for leaving increased, and the percentage of leavers ranking salary as the reason decreased. Women had a significantly higher annual turnover rate (15%) than men (9.7%), and they stayed in jobs for significantly less time (25.2 months) than men (56.5 months). There were no differences in turnover rates across practice settings. A larger percentage of pharmacists leaving jobs in large chain and institutional settings ranked stress as a reason for leaving than pharmacists leaving independent or small chain pharmacies. A larger percentage of pharmacists leaving independent or small chain pharmacies ranked salary as a reason than pharmacists in the other two settings. Pharmacist job turnover averaged 11% per year between 1983 and 1997. Pharmacists who left jobs typically stayed less than three years. The percentage citing stress as a reason for leaving increased, and the percentage citing salary decreased.

Referral characteristics of primary care physicians for seizure patients.

PURPOSE: To investigate primary care physicians' behavior with respect to referral patterns, antiepileptic drug (AED) initiation, and level of comfort in managing seizure patients. METHODS: A cross-sectional descriptive study design was used for collecting and analyzing data. A 20-item survey was developed and mailed to 8,195 primary care physicians including family practitioners, internal medicine physicians, and obstetrics-gynecologists throughout the state of Ohio; 504 primary care physicians that interact regularly with epilepsy patients responded to the survey. RESULTS: Two patterns of referral emerged. Data showed that the majority (n = 382) of physicians refer >/=50% of their patients, but a minority of physicians (n = 122) refer <50% of their patients. Differences between the two groups existed in three of the four research questions asked: who initiates AED therapy, comfort level, and percentage of patients referred to a neurologist. Influence of managed care on decision making was not different between the two groups. CONCLUSIONS: A minority of primary care physicians rate themselves very comfortable with seizure patients. These same physicians refer a minority of their patients to a neurologist. As a whole, however, primary care physicians refer a majority of their seizure patients to a neurologist. Neurologists evaluate most seizure patients because most primary care physicians claim not to be extremely comfortable with evaluation and treatment of seizures. We conclude that neurologists play an essential role in the treatment of most seizure patients.

Functional analyses of amino acid substitutions Arg883Ser and Asp905Tyr of protein phosphatase-1 G-subunit.

The PPP1R3 gene encoding the G-subunit of protein phosphatase-1 has three polymorphisms in linkage disequilibrium in the Pima Indians: an mRNA-destabilizing element in the 3'-untranslated region (ARE1/ARE2 alleles), Arg883Ser, and Asp905Tyr substitutions. The ARE2 allele, Arg883, and Asp905 variants are associated with insulin resistance and higher prevalence of type 2 diabetes in the Pima Indians. The ARE2 allele is associated with lower PPP1R3 transcript and protein levels in muscle tissue. Here we determined the functional contribution of the amino acid substitutions independent of the ARE alleles to insulin-stimulated glycogen synthesis by adenoviral-mediated gene expression in L6 myotubes. Similar overexpression levels of the G-subunit variants increased glycogen synthase fractional activity in the presence ( approximately 1. 5-fold) of insulin compared to control myotubes transduced with adenovirus encoding beta-galactosidase. The glycogen synthesis rate of myotubes overexpressing the G-subunit variants also increased by approximately 1.7-fold over the control with and without insulin. However, these measures were not significantly different among the variants. This study does not support a role for Arg883 and Asp905 variants independent of the ARE2 allele in the impaired insulin-stimulated glycogen synthesis in the muscle of Pima Indians.

Evaluating prescriptions for the elderly: drug/age criteria as a tool to help community pharmacists.

OBJECTIVES: To use drug/age criteria to determine (1) the prevalence of dispensing of drugs potentially inappropriate for use in elderly patients; (2) the dispensing rate of individual drugs considered potentially inappropriate for use in elderly patients; (3) the association between selected patient characteristics and the prevalence of potentially inappropriate drug dispensing. DESIGN, SETTING, PARTICIPANTS: A secondary database of 6,380 new prescription orders dispensed to patients of all ages in ambulatory pharmacies in a mid-western state was used retrospectively for the analysis. A total of 1,530 (23.9%) of the new prescription orders were dispensed to 1,185 elderly patients. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Name, strength, and daily dose of each drug dispensed were compared with drug/age criteria to determine whether a dispensed drug was inappropriate for use in elderly patients. The association of the rate of dispensing of potentially inappropriate drugs with characteristics of the elderly patients, including age, sex, race, number of comorbidities, and prescription drug insurance coverage type, was determined. RESULTS: A total of 170 patients (14.3%) were dispensed potentially inappropriate medications. The three most common medications were propoxyphene and propoxyphene combinations, prescription and nonprescription antihistamines, and digoxin at doses > 0.125 mg/day. There was no statistically significant association between inappropriate drug dispensing and patient age, sex, race, number of comorbidities, and prescription drug insurance coverage type. CONCLUSION: Pharmacists can use drug/age criteria as a tool for an initial check to assess the appropriateness of drugs used by the elderly. Elderly patients appear equally at risk of using potentially inappropriate medications regardless of demographic, disease, or insurance characteristics.

Radiotherapy for carcinoma of the posterior pharyngeal wall.

Posterior pharyngeal carcinoma has an extremely poor prognosis regardless of the method of treatment. The purpose of this study was to assess the local control and survival in patients with carcinoma of the posterior pharyngeal wall treated with definitive radiotherapy and to determine prognostic factors which may be relevant to the current UICC staging classification. Between January 1991 and December 1995, 22 patients with a mean age of 60 years (range 44-82) received definitive radiotherapy, using a homogeneous technique, for carcinoma of the posterior pharyngeal wall. The median follow-up was 42 months (range 25-66). The overall 3-year survival and local control for the whole group was 50% and 73% respectively. Patients with early stage (T1 and T2) disease had a significantly better overall 3-year survival rate of 77% compared to 11% for patients with advanced stage (T3 and T4) disease (p=0.0010). Similarly, patients with early stage disease had a significantly improved 3-year local control rate compared to patients with more advanced stage disease (92% and 44% respectively, p=0.0080). Patients with node positive disease had an inferior survival rate of 29% compared to 60% for those with node negative disease though the difference did not reach statistical significance. In addition only one patient with initial node negative disease had isolated nodal relapse. There was no significant late morbidity. For patients with early stage disease we have obtained local control and survival rates comparable to other groups with a once daily, short fractionation radiotherapy scheme but with reduced morbidity. In late stage disease altered fractionation schemes should be considered in order to achieve better local control and survival. Isolated nodal relapse was not a significant problem in this cohort of patients. Outcome correlates with primary tumour size and this is reflected in the current UICC staging classification.

Job matching in pharmacy labor markets: a study in four states.

PURPOSE: Reports from various pharmacy labor market sectors suggest that the United States may be experiencing a shortage of pharmacists. To guide policy making and planning with respect to this shortage, it is necessary to develop a better understanding of the process by which pharmacists choose jobs. Using the economic theory of job matching, this study sought to understand how (a) attributes of the practice setting, (b) characteristics of pharmacists, and (c) regional and urbanization variables are associated with pharmacy practice setting choices. METHODS: A secondary database containing information about employment characteristics and work histories of 541 pharmacists in four states was used. The data were augmented with information on the relative number of employment opportunities in each of three practice settings (large chain, institutional, and independent) in the year the respondent's most recent employment change occurred. Practice setting choices were modeled using multinomial conditional logit regression. RESULTS: A total of 477 pharmacists represented in the database met the inclusion criteria for the study. Multivariate analyses showed that the impact of search costs and wage differentials varied with the practice setting chosen. Pharmacists choosing independent settings over large chain settings were more likely to be white and to have worked in an independent setting in their prior job. Pharmacists living in Oregon were less likely to choose institutional settings compared to those living in Massachusetts, whereas those living in areas with populations greater than 50,000 were more likely to choose institutional settings. CONCLUSIONS: Pharmacist job matching appears to be a complex process in which diverse factors interact to produce a final match. Our results suggest that the pharmacy labor market may actually be composed of two distinct labor markets: an ambulatory market and an institutional market.

Pharmaceutical care and health outcomes in community settings: a matched pair analysis of perceptions of hypertensive patients versus pharmacists.

UNLABELLED: This study aimed to: (1) assess the level of pharmaceutical care delivered by pharmacists, and (2) compare patients' and pharmacists' health related quality of life (HRQOL) assessments for patients receiving antihypertensive therapy as an indicator of the delivery of pharmaceutical care. DESIGN: An exploratory, cross-sectional study using matched pair survey instruments. SETTING: Columbus, Ohio. PARTICIPANTS: Patients in a community setting prescribed antihypertensive medication and their pharmacists were selected for study participation. INTERVENTIONS: Parallel surveys distributed to patients and their pharmacists. MAIN OUTCOME MEASURES: Level of pharmaceutical care delivered by pharmacists, and perceived patient viewpoints on: clinical outcomes (blood pressure control, and side effects due to antihypertensive medication) and humanistic outcomes (overall, emotional and physical HRQOL) by patients and pharmacists. RESULTS: Analysis of 52 useable matching surveys of pharmacists and patients indicated that nearly all pharmacists counsel patients and two thirds of pharmacists counsel and monitor drug therapy. This is consistent with providing the minimal OBRA 90 requirements. When comparing patient and pharmacist perceived patient clinical as well as humanistic outcomes, a high level of association was reported between the two groups. CONCLUSIONS: The results of this study suggest that pharmacists are cognizant of patient clinical and humanistic outcomes and hence, they are in an excellent position to improve patient outcomes by making appropriate drug therapy changes.

The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.

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.