Biomedical subjects

Gary O Zerbe

Publications and source records attributed to Gary O Zerbe.

9 recordsLinked to original sources

PubMed2007

Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic beta-cells.

We measured the impact of chronic late gestation hypoglycemia on pancreatic islet structure and function to determine the cause of decreased insulin secretion in this sheep model of fetal nutrient deprivation. Late gestation hypoglycemia did not decrease pancreas weight, insulin content, beta-cell area, beta-cell mass, or islet size. The pancreatic islet isolation procedure selected a group of islets that were larger and had an increased proportion of beta-cells compared with islets measured in pancreatic sections, but there were no morphologic differences between islets isolated from control and hypoglycemic fetuses. The rates of glucose-stimulated pancreatic islet glucose utilization (126.2 +/- 25.3 pmol glucose.islet(-1).h(-1), hypoglycemic, vs. 93.5 +/- 5.5 pmol glucose.islet(-1).h(-1), control, P = 0.47) and oxidation (10.5 +/- 1.7 pmol glucose.islet(-1).h(-1), hypoglycemic, vs. 10.6 +/- 1.6 pmol glucose.islet(-1).h(-1), control) were not different in hypoglycemic fetuses compared with control fetuses. Chronic late gestation hypoglycemia decreased insulin secretion in isolated pancreatic islets by almost 70% in response to direct nonnutrient membrane depolarization and in response to increased extracellular calcium entry. beta-Cell ultrastructure was abnormal with markedly distended rough endoplasmic reticulum in three of the seven hypoglycemic fetuses studied, but in vitro analysis of hypoglycemic control islets showed no evidence that these changes represented endoplasmic reticulum stress, as measured by transcription of glucose regulatory protein-78 and processing of X-box binding protein-1. In conclusion, these studies show that chronic hypoglycemia in late gestation decreases insulin secretion by inhibiting the later steps of stimulus-secretion coupling after glucose metabolism, membrane depolarization, and calcium entry.

Animals↗

PubMed2006

Non-linear random effects model for multivariate responses with missing data.

The use of random-effects models for the analysis of longitudinal data with missing responses has been discussed by several authors. In this paper, we extend the non-linear random-effects model for a single response to the case of multiple responses, allowing for arbitrary patterns of observed and missing data. Parameters for this model are estimated via the EM algorithm and by the first-order approximation available in SAS Proc NLMIXED. The set of equations for this estimation procedure is derived and these are appropriately modified to deal with missing data. The methodology is illustrated with an example using data coming from a study involving 161 pregnant women presenting to a private obstetrics clinic in Santiago, Chile.

Algorithms↗

PubMed2006

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Adult↗

PubMed2006

Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening.

OBJECTIVES: To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. STUDY DESIGN: We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. RESULTS: Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. CONCLUSIONS: IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.

Biomarkers↗

PubMed2005

Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction.

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the beta-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

Animals↗

PubMed2005

Responder cell frequency estimation and binomial three-level nonlinear mixed effects model in limiting dilution assays.

Responder cell frequencies (RCF), which describe vaccine-boosted immune responses in herpes zoster (HZ) prevention studies, have been estimated by using limiting dilution assays (LDA). The theoretical linearity assumption between the logarithm of the proportion of nonresponding wells (s) and the cell concentration (N) (or dilution level) in LDA, based on the single-hit Poisson model, is often violated with observed data resulting in biased estimates of RCF. In this article, the Poisson assumption is modified by applying a mixture of Poisson and gamma distributions, resulting in a negative binomial assumption, which presents a better fit between s and N. In LDA for HZ prevention studies, binary responses (responder or non-responder wells) are measured repeatedly at different cell concentrations and over time. To account for the correlation between responses to varying dilution levels from individuals, and the correlation between repeated assays of individuals over time simultaneously, a binomial three-level nonlinear mixed-effects model is proposed. For parameter estimation, a maximum likelihood method is applied via adaptive Gaussian quadrature. There is a lack of non-Gaussian multilevel nonlinear mixed-effects software, which can execute such a complicated fit. In this article, an algorithm for the three-level nonlinear mixed-effects model, which can be inserted into the code in the SAS procedure NLMIXED, is suggested.

Cell Count↗

PubMed2005

Saccadic eye movement task identifies cognitive deficits in children with schizophrenia, but not in unaffected child relatives.

BACKGROUND: The delayed oculomotor response (DOR) task requires response inhibition followed by movement of gaze towards a known spatial location without a current stimulus. Abnormalities in response inhibition and in the spatial accuracy of the eye movement are found in individuals with schizophrenia and in many of their relatives, supporting the use of these saccadic abnormalities as endophenotypes in genetic studies. It is unknown whether school-age children, either with psychosis or as relatives of a schizophrenic proband, can be included. METHOD: One hundred eighty-seven children, ages 5.8-16.0 years - 45 children with childhood-onset schizophrenia, 64 children with a first-degree relative with schizophrenia, and 84 typically developing children - completed DOR tasks with 1 and 3 second delays. RESULTS: Children with childhood-onset schizophrenia demonstrated impaired response inhibition and impaired spatial accuracy compared to both relatives and typicals; however, relatives and typicals did not differ from each other. CONCLUSIONS: Children with childhood-onset schizophrenia have saccadic abnormalities similar to those found in adults with schizophrenia, supporting the continuity of executive function deficits in childhood-onset with adolescent and adult-onset schizophrenia. However, saccadic tasks are not sensitive to genetic risk in non-psychotic children and 6-15-year-old children should not be included in genetic studies utilizing this endophenotype.

Adolescent↗

PubMed2003

Comparing linear and nonlinear mixed model approaches to cosinor analysis.

The cosinor model, used for variables governed by circadian and other biological rhythms, is a nonlinear model in the amplitude and acrophase parameters that has a linear representation upon transformation. With linear cosinor analysis, amplitude and acrophase for each harmonic can be computed as nonlinear functions of the estimated linear regression coefficients. Here a flexible mixed model approach to cosinor analysis is considered, where the fixed effect parameters may enter nonlinearly as acrophase and amplitude for each harmonic or linearly after transformation to regression coefficients. In addition, the random effects may enter nonlinearly as subject-specific deviations from the acrophases and amplitudes or linearly as subject-specific deviations from the regression coefficients. It is also possible for the fixed effects to enter nonlinearly while the random effects enter linearly. Additionally, we evaluate whether including higher order linear harmonic terms as random effects, that is, Rao-Khatri 'covariance adjustment', improves precision. Applying the delta method to nonlinear functions of the parameters from linear mixed cosinor models to obtain approximate variances produces results that are often identical to results from nonlinear mixed models. Consequently, traditional linear cosinor analysis can often be used to estimate and compare the nonlinear parameters of interest, that is, amplitudes and acrophases, via the delta method. This is advantageous since the nonlinear mixed model may have convergence difficulties for more complex models. However, for some multiple-group analyses, the linear cosinor transformation should not be used and we clarify when the two methods are equivalent and when they differ.

Circadian Rhythm↗

PubMed2002

Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes.

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.

Adolescent↗