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Biomedical subjects

M M Byrne

Publications and source records attributed to M M Byrne.

At least 19 recordsLinked to original sources
PubMed2006

Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function.

AIMS/HYPOTHESIS: Inactivating mutations in Tcf1, which encodes the transcription factor hepatocyte nuclear factor (HNF)-1alpha, cause maturity-onset diabetes of the young-3. We have previously shown that a dominant-negative mutant (DN-HNF-1alpha) renders INS-1 insulinoma cells sensitive to the mitochondrial apoptosis pathway, but the underlying alterations in signal transduction remain unknown. MATERIALS AND METHODS: Using a reverse tetracycline-dependent transactivator system, DN-HNF-1alpha-induced apoptosis was assessed by immunoblotting and caspase assays. Alterations in AKT1 kinase/protein kinase B (AKT1) survival signalling during DN-HNF-1alpha-induced apoptosis were investigated by phospho-specific immunodetection and transient transfection experiments. RESULTS: Induction of DN-HNF-1alpha caused significant changes in the activation-specific phosphorylation status of AKT1 that were preceded by a downregulation of Ins1 gene transcription. Phosphorylation of AKT1 at Ser473 was dramatically reduced after 36 to 48 h of DN-HNF-1alpha induction and coincided with maximal apoptosis activation. Overexpression of a constitutively active mutant of Akt1 rescued INS-1 cells from DN-HNF-1alpha-induced apoptosis, while ectopic expression of a dominant-negative mutant mimicked the effect of DN-HNF-1alpha on apoptosis activation. Pharmacological suppression of growth factor survival signalling through administration of the phosphatidylinositol-3 kinase (PI-3K) inhibitor wortmannin accelerated the induction of apoptosis by DN-HNF-1alpha. CONCLUSIONS/INTERPRETATION: These data suggest that a decrease in PI-3K/AKT1 survival signalling mediates DN-HNF-1alpha-induced apoptosis in insulin-secreting cells.

Androstadienes↗
PubMed2005

Glucagon-like peptide-1 reduces the pulsatile component of testosterone secretion in healthy males.

BACKGROUND: Glucagon-like-peptide-1 (7-36) amide (GLP-1), a potent regulator of glucose homeostasis, has been implicated in the control of hypothalamic-pituitary function. In vivo it is a relevant neuroendocrine modulator of gonadotropin-releasing hormone release, suggesting its possible role as a metabolic signal to the reproductive system. The present study was undertaken to establish its effect on luteinizing hormone (LH) and testosterone secretion in nine healthy male volunteers. MATERIALS AND METHODS: Each subject underwent an oral glucose tolerance test to establish LH, testosterone, and GLP-1 responses to glucose. Euglycaemic clamp experiments (6 h) were performed on two occasions with saline or with a constant infusion of GLP-1 (0.4 pmol kg(-1) min (-1)). Blood samples were drawn at 10-min intervals to measure the pulsatile pattern of LH and testosterone secretion. RESULTS: Ingestion of oral glucose resulted in a reduction in plasma testosterone levels at 30 min compared with baseline (P < 0.004) despite unaltered LH levels (P = 0.5). Constant GLP-1 infusion resulted in no change in LH (P = 0.83), testosterone (P = 0.96), follicle stimulating hormone (FSH) (P = 0.86) and leptin levels (P = 0.3). Pulse analysis revealed no significant difference in the number (P = 0.1) or median absolute amplitude (P = 0.3) of the LH pulses. However, there was a significant decrease in the number (3.0 +/- 0.6 vs. 1.3 +/- 0.4; P < 0.05) and a tendency for increased duration of testosterone pulses (97.4 +/- 16.7 vs. 170 +/- 27.1 min; P = 0.06). CONCLUSION: Oral glucose ingestion and intravenous GLP-1 infusion reduce the pulsatile component of testosterone secretion by a mechanism independent of LH release.

Administration, Oral↗
PubMed2002

Maternal recall bias, obstetric history and schizophrenia.

BACKGROUND: This study sought to clarify the role of obstetric complications (OCs) and maternal recall bias for patients with first episodes of schizophrenia and those at increased risk of the disorder. METHOD: Subjects at high risk of schizophrenia were compared with people with first-episode schizophrenia and with healthy volunteers. Consenting mothers of subjects were interviewed using a standardised questionnaire for the recall of OCs, and OCs were also measured from records collected at the time of pregnancy and delivery. RESULTS: High-risk subjects and first-episode patients had higher rates of OCs recalled by their mother than controls, but hospital records showed no differences in OCs between groups. The number of OCs recalled by mothers of the high-risk group was not related to whether the mother had schizophrenia or not, but was related to the maternally rated abnormal childhood behaviour as measured by the Child Behaviour Checklist. CONCLUSIONS: These results suggest that studies that rely on maternal recall alone are susceptible to bias. The excess of OCs recalled by the mother could be related to abnormal behaviour in their child rather than maternal illness, family history or psychotic symptoms.

Adolescent↗
PubMed2001

Evaluating the findings of qualitative research.

This article provides an overview of strategies used to support and evaluate qualitative research. Research consumers should critique qualitative research to see how the concepts of credibility, transferability, and confirmability are met in a study. Further, as qualitative research evolves and transforms the understanding of phenomena, the strategies for evaluating credibility may evolve and change, as well. Qualitative research just as personal knowing, is a dynamic process.

Evaluation Studies as Topic↗
PubMed2001

A positive analysis of financial incentives for cadaveric organ donation.

Financial incentives of various kinds have been suggested to alleviate the chronic shortage of transplantable organs in the United States. This paper analyzes the possible consequences of financial incentives on organ supply. We show that under current practice and current law (which are not the same), inducements to donate organs or to register as an organ donor may lead to a decline in the supply of organs. Furthermore, some financial incentives that have been proposed lead to time inconsistent choices.

Cadaver↗
PubMed2001

Screening and preventable illness.

If an agent does not discount the future at a constant rate, as in some forms of myopia, her optimal strategy is unattainable without some commitment device. We apply this familiar idea to a model of screening and disease prevention, and explore how financial incentives can correct suboptimal health choices. In general, myopia need not imply under-screening. While the optimal intervention for prevention effort is a state-invariant subsidy, the optimal intervention for screening may involve a tax or a subsidy. When screening and prevention are coincident, a simple and practical subsidy equal to one minus the discount factor to both screening and intervention is indicated.

Cost of Illness↗
PubMed2001

A psychometric analysis of the measurement level of the rating scale, time trade-off, and standard gamble.

A fundamental assumption of utility-based analyses is that patient utilities for health states can be measured on an equal-interval scale. This assumption, however, has not been widely examined. The objective of this study was to assess whether the rating scale (RS), standard gamble (SG), and time trade-off (TTO) utility elicitation methods function as equal-interval level scales. We wrote descriptions of eight prostate-cancer-related health states. In interviews with patients who had newly diagnosed, advanced prostate cancer, utilities for the health states were elicited using the RS, SG, and TTO methods. At the time of the study, 77 initial and 73 follow-up interviews had. been conducted with a consecutive sample of 77 participants. Using a Rasch model, the boundaries (Thurstone Thresholds) between four equal score sub-ranges of the raw utilities were mapped onto an equal-interval logit scale. The distance between adjacent thresholds in logit units was calculated to determine whether the raw utilities were equal-interval. None of the utility scales functioned as interval-level scales in our sample. Therefore, since interval-level estimates are assumed in utility-based analyses, doubt is raised regarding the validity of findings from previous analyses based on these scales. Our findings need to be replicated in other contexts, and the practical impact of non-interval measurement on utility-based analyses should be explored. If cost-effectiveness analyses are not found to be robust to violations of the assumption that utilities are interval, serious doubt will be cast upon findings from utility-based analyses and upon the wisdom of expending millions in research dollars on utility-based studies.

Cost-Benefit Analysis↗
PubMed2001

GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve.

The present study was undertaken to establish in normal volunteers the alterations in beta-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol x kg(-1) x min(-1)) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 +/- 12.4 pmol x min(-1) x mM(-1) during the saline study to 241.7 +/- 36.6 pmol x min(-1) x mM(-1) during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta-cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

Adult↗
PubMed2001

Intestinal proliferation and delayed intestinal transit in a patient with a GLP-1-, GLP-2- and PYY-producing neuroendocrine carcinoma.

Glucagon-like peptides (GLP) 1 and 2 are hormones derived from the post-translational processing of proglucagon in the intestinal L cells that influence intestinal motility and small bowel growth, respectively. We describe a patient with a neuroendocrine tumor of unknown primary origin with peritoneal carcinomatosis and diffuse liver metastases, who presented with constipation and nocturnal itching for over 3 years. Small bowel follow-through showed decreased small intestinal motility and marked intestinal hypertrophy. Biopsies from mesenterial lymph nodes showed, histologically, a well-differentiated neuroendocrine tumor (G1), with positive immunostaining for chromogranin A, GLP-1, GLP-2 and polypeptide YY (PYY). Jejunal biopsy demonstrated marked intestinal mucosal hypertrophy. HPLC analysis combined with RIA of tumor and serum extracts revealed that the tumor was producing and releasing fasting levels of GLP-1 of 738+/-20.7 pg/ml (normal levels (nl) <100 pg/ml), GLP-2 of 3,150+/-9 pg/ml (nl <100 pg/ml) as well as PYY 550 pg/ml (nl <100 pg/ml). Octreotide administration decreased levels of GLP-1 and GLP-2 and reduced small intestinal transit time from 150 to 50 min. However, tumor growth was not inhibited by octreotide, interferon or dacarbazine therapy and the patient died 8 months later. This is the first case report demonstrating the overproduction of GLP-1, GLP-2 and PYY from an neuroendocrine tumor, in a patient with intestinal hypertrophy and delayed intestinal transit time.

Cell Division↗
PubMed2000

A trial for comparing methods for eliciting treatment preferences from men with advanced prostate cancer: results from the initial visit.

OBJECTIVE: The objective of this study was to evaluate the convergent validity of 3 types of utility measures: standard gamble, time tradeoff, and rating scale. RESEARCH DESIGN: A prospective cohort of 120 men with advanced prostate cancer were first asked to rank order 8 health states, and then utility values were obtained from each participant for each of the 8 health states through 2 of the 3 techniques evaluated (standard gamble, time tradeoff and rating scale). Participants were randomly assigned to 1 of 3 possible pairs of techniques. The validity of the 3 methods, as measured by the convergence and raw score differences of the techniques, was assessed with ANOVA. The ability of the techniques to differentiate health states was determined. The inconsistencies between rankings and utility values were also measured. Proportions of illogical utility responses were assessed as the percent of times when states with more symptoms were given higher or equal utility values than states with fewer symptoms. RESULTS: There were significant differences in raw scores between techniques, but the values were correlated across health states. Utility values were often inconsistent with the rank order of health states. In addition, utility assessment did not differentiate the health states as well as the rank order. Furthermore, utility values were often illogical in that states with more symptoms received equal or higher utility values than states with fewer symptoms. CONCLUSIONS: Use of the utility techniques in cost-effectiveness analysis and decision making has been widely recommended. The results of this study raise serious questions as to the validity and usefulness of the measures.

Aged↗
PubMed1999

Assessing the performance of utility techniques in the absence of a gold standard.

BACKGROUND: Utility techniques are the most commonly used means to assess patient preferences for health outcomes. However, whether utility techniques produce valid measures of preference has been difficult to determine in the absence of a gold standard. OBJECTIVE: To introduce and demonstrate two methods that can be used to evaluate how well utility techniques measure patients' preferences. SUBJECTS AND DESIGN: Patients treated for advanced prostate cancer (n = 57) first ranked eight health states in order of preference. Four utility techniques were then used to elicit patients' utilities for each health state. MEASURES: The rating scale, standard gamble, time trade-off, and a modified version of willingness-to-pay techniques were used to elicit patients' utilities. Technique performance was assessed by computing a differentiation and inconsistency score for each technique. RESULTS: Differentiation scores indicated the rating scale permitted respondents to assign unique utility values to about 70% of the health states that should have received unique values. When the other techniques were used, about 40% or less of the health states that should have received unique utility scores actually did receive unique utility scores. Inconsistency scores, which indicate how often participants assign utility scores that contradict how they value health states, indicated that the willingness-to-pay technique produced the lowest rate of inconsistency (10%). However, this technique did not differ significantly from the rating scale or standard gamble on this dimension. CONCLUSIONS: Differentiation and inconsistency offer a means to evaluate the performance of utility techniques, thereby allowing investigators to determine the extent to which utilities they have elicited for a given decision problem are valid. In the current investigation, the differentiation and inconsistency methods indicated that all four techniques performed at sub-optimal levels, though the rating scale out-performed the standard gamble, time trade-off, and willingness-to-pay techniques.

Aged↗
PubMed1998

Inhibitory effects of hyperglycaemia on fed jejunal motility: potential role of hyperinsulinaemia.

BACKGROUND: Acute hyperglycaemia is known to inhibit jejunal interdigestive motility. This study was undertaken to establish the effects of hyperglycaemia on fed jejunal motility and small intestinal transit time, and to establish if the effects of hyperglycaemia are mediated in part by hyperinsulinaemia. METHODS: Nine healthy male volunteers were studied in random order using three experimental conditions: (a) euglycaemic clamp [glucose 5 mmol L(-1)]; (b) hyperglycaemic clamp [glucose 15 mmol L(-1)]; and (c) euglycaemic hyperinsulinaemic clamp [glucose 5 mmol L(-l)]. Fed jejunal motility was induced by an intrajejunal perfusion of lipid (Lipofundin medium-chained triglyceride 10%) at 1.5 mL min(-1) [1.5 kcal min(-1)] for 180 min through the most proximal port of a manometry catheter (eight ports spaced at 2-cm intervals) located just distal to the ligament of Treitz. One minute after starting the lipid perfusion, 15 g of lactulose dissolved in 20 mL of tap water was infused. Small intestinal transit time was measured by the hydrogen breath test. RESULTS: Acute hyperglycaemia reduced the total number of jejunal contractions and progradely propagated contractions, the motility index (P < 0.05) and the mean amplitude of contractions and delayed intestinal transit time. Hyperinsulinaemia reduced the total number of jejunal contractions, motility index (P < 0.05) and intestinal transit time. CONCLUSIONS: Thus, hyperinsulinaemia may contribute to the inhibitory effects of hyperglycaemia on jejunal motility. In addition, this study demonstrated that intrajejunal infusion of lipid stimulates sustained glucagon-like peptide-1 release. In contrast to fat-induced gastric inhibitory polypeptide release, this glucagon-like peptide-1 release is not inhibited by exogenous or endogenous hyperinsulinaemia (P = 0.59).

Adult↗
PubMed1998

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.

Administration, Oral↗
PubMed1997

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.

Administration, Oral↗
PubMed1997

Sleepiness, performance, and neuroendocrine function during sleep deprivation: effects of exposure to bright light or exercise.

The temporal profiles of subjective fatigue (as assessed by the Stanford Sleepiness Scale), of cognitive performance (on a digit symbol substitution test and a symbol copying task), of body temperature, and of the peripheral concentrations of melatonin, thyroid-stimulating hormone (TSH), and cortisol were obtained simultaneously at frequent intervals in 17 normal young subjects submitted to a 43-h period of constant routine conditions involving continuous wakefulness at bed rest in dim indoor light. The subjects had knowledge of time of day. Caloric intake was exclusively in the form of an intravenous glucose infusion, and plasma glucose levels were monitored continuously in 8 of the 17 subjects. Under these conditions, fluctuations in plasma glucose reflect primarily changes in glucose use because endogenous glucose production is suppressed by the exogenous infusion. Following the completion of a baseline constant routine study, the volunteers participated in two subsequent studies using the same protocol to determine the immediate psychophysiological effects of exposure to a 3-h pulse of bright light or to a 3-h pulse of physical exercise. Sleepiness and performance varied in a mirror image, with significant negative correlations. Sleepiness scores were minimal around noon and then increased at a modest rate throughout the rest of the normal waking period. Staying awake during usual bedtime hours was associated with an acceleration in the rate of increase in sleepiness, which coincided with decreasing body temperature, rapidly rising cortisol concentrations, and maximal levels of melatonin and TSH. When body temperature reached its nadir, a further major increase in sleepiness occurred in parallel with a pronounced decrease in plasma glucose (reflecting increased glucose use). Recovery from maximal sleepiness started when blood glucose levels stopped falling and when significant decreases in cortisol and melatonin concentrations were initiated. Lower levels of subjective sleepiness resumed when glucose concentrations and body temperature had returned to levels similar to those observed prior to sleep deprivation and when melatonin and TSH concentrations had returned to daytime levels. The synchrony of behavioral, neuroendocrine, and metabolic changes suggests that circulating hormonal levels could exert modulatory influences on sleepiness and that metabolic alterations may underlie the sudden increase in fatigue consistently occurring at the end of a night of sleep deprivation. Effects of bright light or exercise exposure on subjective sleepiness appeared to be critically dependent on the timing of exposure.

Adult↗