Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders.

BACKGROUND: Deficits in gamma aminobutyric acid (GABA) neuron-related markers, including the GABA-synthesizing enzyme GAD67, the calcium-binding protein parvalbumin, the neuropeptide somatostatin, and the transcription factor Lhx6, are most pronounced in a subset of schizophrenia subjects identified as having a 'low GABA marker' (LGM) molecular phenotype. Furthermore, schizophrenia shares degrees of genetic liability, clinical features and cortical circuitry abnormalities with schizoaffective disorder and bipolar disorder. Therefore, we determined the extent to which a similar LGM molecular phenotype may also exist in subjects with these disorders. METHOD: Transcript levels for GAD67, parvalbumin, somatostatin, and Lhx6 were quantified using quantitative PCR in prefrontal cortex area 9 of 184 subjects with a diagnosis of schizophrenia (n = 39), schizoaffective disorder (n = 23) or bipolar disorder (n = 35), or with a confirmed absence of any psychiatric diagnoses (n = 87). A blinded clustering approach was employed to determine the presence of a LGM molecular phenotype across all subjects. RESULTS: Approximately 49% of the subjects with schizophrenia, 48% of the subjects with schizoaffective disorder, and 29% of the subjects with bipolar disorder, but only 5% of unaffected subjects, clustered in the cortical LGM molecular phenotype. CONCLUSIONS: These findings support the characterization of psychotic and bipolar disorders by cortical molecular phenotype which may help elucidate more pathophysiologically informed and personalized medications.

Acquisition and baseline performance of working memory tasks by adolescent rhesus monkeys.

Adolescence is a transitional stage of development characterized by protracted refinements in the neural circuits required for adult level proficiency of working memory. Because impaired working memory is a hallmark feature of several psychiatric disorders that have their onset during adolescence, model systems that can be used to assess the maturation of working memory function, and of disease-related risk factors that disrupt its development, are of particular importance. However, few studies have investigated the maturation of working memory in nonhuman primates. Thus in the present study, we adapted two working memory tests that are among the most widely used in human and adult nonhuman primates, for adolescent rhesus monkeys. Using a touch-screen apparatus, monkeys were trained on a spatial delayed-response task to assess spatial working memory and a delayed match-to-sample task to assess object working memory. The results indicate that adolescent rhesus monkeys readily and efficiently acquire the ability to perform touch-screen based, complex tests of working memory. These data establish that distinct components of adult prefrontal cortex-dependent cognitive functions can be effectively modeled and evaluated in adolescent monkeys. As such, this approach should be useful for assessing the influence of environmental risk factors on the protracted maturation of working memory in adolescent macaques.

Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.

Cocaine abusers show impaired performance on cognitive tasks that engage prefrontal cortex. These deficits may contribute to impaired control and relapse in abusers. Understanding the neuronal substrates that lead to these deficits requires animal models that are relevant to the human condition. However, to date, models have mostly focused on behaviors mediated by subcortical systems. Here we evaluated the impact of long-term self-administration of cocaine in the rhesus monkey on cognitive performance. Tests included stimulus discrimination (SD)/reversal and delayed alternation tasks. The chronic cocaine animals showed marked deficits in ability to organize their behavior for maximal reward. This was demonstrated by an increased time needed to acquire SDs. Deficits were also indicated by an increased time to initially learn the delayed alternation task, and to adapt strategies for bypassing a reliance on working memory to respond accurately. Working memory per se (delay dependent performance) was not affected by chronic self-administration. This pattern of cognitive deficits suggests dysfunction that extends beyond localized prefrontal cortical areas. In particular, it appears that temporal cortical function is also compromised. This agrees with other recent clinical and preclinical findings, and suggests further study into addiction related dysfunction across more widespread cortical networks is warranted.

Surgeon and type of anesthesia predict variability in surgical procedure times.

BACKGROUND: Variability in surgical procedure times increases the cost of healthcare delivery by increasing both the underutilization and overutilization of expensive surgical resources. To reduce variability in surgical procedure times, we must identify and study its sources. METHODS: Our data set consisted of all surgeries performed over a 7-yr period at a large teaching hospital, resulting in 46,322 surgical cases. To study factors associated with variability in surgical procedure times, data mining techniques were used to segment and focus the data so that the analyses would be both technically and intellectually feasible. The data were subdivided into 40 representative segments of manageable size and variability based on headers adopted from the common procedural terminology classification. Each data segment was then analyzed using a main-effects linear model to identify and quantify specific sources of variability in surgical procedure times. RESULTS: The single most important source of variability in surgical procedure times was surgeon effect. Type of anesthesia, age, gender, and American Society of Anesthesiologists risk class were additional sources of variability. Intrinsic case-specific variability, unexplained by any of the preceding factors, was found to be highest for shorter surgeries relative to longer procedures. Variability in procedure times among surgeons was a multiplicative function (proportionate to time) of surgical time and total procedure time, such that as procedure times increased, variability in surgeons' surgical time increased proportionately. CONCLUSIONS: Surgeon-specific variability should be considered when building scheduling heuristics for longer surgeries. Results concerning variability in surgical procedure times due to factors such as type of anesthesia, age, gender, and American Society of Anesthesiologists risk class may be extrapolated to scheduling in other institutions, although specifics on individual surgeons may not. This research identifies factors associated with variability in surgical procedure times, knowledge of which may ultimately be used to improve surgical scheduling and operating room utilization.

Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.

BACKGROUND: Markers of gamma-aminobutyric acid (GABA) neurotransmission seem to be altered in the prefrontal cortex (PFC) of subjects with schizophrenia. We sought to determine whether the expression of the messenger RNA (mRNA) for the synthesizing enzyme of GABA, glutamic acid decarboxylase67 (GAD67), is decreased in the PFC of subjects with schizophrenia, whether this change is present in all or only some GABA neurons, and whether long-term treatment with haloperidol decanoate contributes to altered GAD67 mRNA expression. METHODS: Tissue sections from 10 pairs of subjects with schizophrenia and control subjects and 4 pairs of haloperidol-treated and control monkeys were processed for in situ hybridization histochemical analysis with sulfur-35-labeled oligonucleotide probes for GAD67 mRNA and exposed to nuclear emulsion. Within each layer of PFC area 9, neurons expressing a detectable level of GAD67 mRNA were quantified for cell density and the relative level of mRNA expression per cell (grain density per neuron). RESULTS: In subjects with schizophrenia, the density of labeled neurons was significantly (P<.05) decreased by 25% to 35% in cortical layers 3 to 5. In contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-term haloperidol treatment on either the density of the labeled neurons or the grain density per labeled neuron. CONCLUSIONS: These findings indicate that in subjects with schizophrenia, GAD67 mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered GABA neurotransmission in this subset may contribute to PFC dysfunction in subjects with schizophrenia.

Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies.

The results of a combined analysis and separate analyses of four multicenter, randomized, parallel group studies that evaluated the effects of once-daily topical administration of becaplermin gel for the treatment of chronic, full thickness, lower extremity diabetic ulcers are presented. The four studies included a total of 922 patients with nonhealing lower extremity diabetic ulcers of at least 8 weeks' duration. Following initial complete sharp debridement of the ulcer, patients were randomized to receive a standardized regimen of good ulcer care alone, good ulcer care plus placebo gel, or good ulcer care plus becaplermin gel-30 microg/g, or good ulcer care plus becaplermin gel-100 microg/g, with various combinations of regimens used in the four studies. Safety was assessed by monitoring adverse events and by clinical laboratory evaluations. Meta-analytic statistical techniques were used in the combined analysis to establish homogeneity of treatment comparisons across studies. Based on an analysis of patients with baseline ulcer area common to all trials (

Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects.

OBJECTIVE: Abnormalities in dopamine neurotransmission in the prefrontal cortex have been implicated in the pathophysiology of schizophrenia. However, the integrity of the dopamine projections to the prefrontal cortex in this disorder has not been directly examined. METHOD: The authors employed immunocytochemical methods and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, and the dopamine membrane transporter to examine dopamine axons in the dorsomedial prefrontal cortex (area 9) from 16 pairs of schizophrenic and matched control subjects. RESULTS: Compared to the control subjects, the total length of tyrosine hydroxylase-immunoreactive axons was unchanged in the superficial and middle layers of the schizophrenic subjects but was reduced by an average of 33.6% in layer 6. The total length of tyrosine hydroxylase-positive axons in layer 6 was decreased in 13 of the schizophrenic subjects compared to their control subjects. Axons immunoreactive for the dopamine membrane transporter showed a similar pattern of change. In contrast, axons labeled for the serotonin transporter did not differ between schizophrenic and control subjects in any layer examined. In addition, the density of tyrosine hydroxylase-containing axons did not differ between monkeys chronically treated with haloperidol and matched control animals. CONCLUSIONS: These findings reveal that schizophrenia is associated with an altered dopamine innervation of prefrontal cortex area 9 that is lamina- and neurotransmitter-specific and that does not appear to be a consequence of pharmacological treatment. Together, these data provide direct evidence for a disturbance in dopamine neurotransmission in the prefrontal cortex of schizophrenic subjects.

A regression model for multivariate random length data.

Multivariate random length data occur when we observe multiple measurements of a quantitative variable and the variable number of these measurements is also an observed outcome for each experimental unit. For example, for a patient with coronary artery disease, we may observe a number of lesions in that patient's coronary arteries, along with percentage of blockage of each lesion. Barnhart and Sampson first proposed the multiple population model to analyse multivariate random length data without covariates. This paper extends their approach to deal with multiple covariates. We propose a new multiple population regression model with covariates, and discuss the estimation issues. We analyse data from the TYPE II coronary intervention study to illustrate the methodology.

The predictive power of baseline hemoglobin for transfusion risk in surgery patients.

Preoperative hemoglobin concentration may be an important predictor of transfusion risk in surgical procedures with significant expected blood loss. Contemporary studies investigating transfusion risk with regard to the relationship between perioperative administration of Epoetin alfa and baseline hemoglobin provide data to test this hypothesis. The predictive power of seven preoperative variables (hemoglobin concentration, age, erythropoietin level, ferritin concentration, serum iron, total iron-binding capacity, and predicted blood volume) on transfusion risk was examined via retrospective logistic regression analysis of 276 orthopedic surgical patients. In the two studies used to perform the regression analysis, patients were treated daily with either Epoetin alfa or placebo. Based on the retrospective analyses, a prospective study was conducted to validate the hypothesis. Of the seven variables evaluated, baseline hemoglobin concentration and predicted blood volume were significantly predictive of transfusion risk in both Epoetin alfa- and placebo-treated patients. Further, an inverse correlation between hemoglobin concentration and transfusion risk was demonstrated in placebo-treated patients. Placebo-treated patients with hemoglobin > 10 to < or = 13 g/dL had an approximately twofold greater risk of transfusion than patients with hemoglobin > 13 g/dL. In contrast to placebo treatment, Epoetin alfa significantly reduced transfusion risk in patients with hemoglobin > 10 to < or = 13 g/dL. Baseline hemoglobin concentration is an excellent predictor of transfusion risk in orthopedic surgical patients. As a result, hemoglobin testing should be considered a part of routine preoperative testing for orthopedic surgical patients.

Effects of heteroscedasticity upon certain analyses when regression lines are not parallel.

The two sample analysis of covariance model is considered where the regression lines are found not to be parallel. There are two analyses often utilized in this case. One is to obtain a standard confidence interval for the covariate value where the two lines intersect, and the other is to find a simultaneous confidence region for the difference between the regression lines. The asymptotic robustness to heteroscedasticity of the regressions' errors of the coverage probability of each of these two confidence procedures is considered. When the sample sizes are approximately equal, and the covariate means and the covariate variances are similar between the samples, the unequal regression variances are shown to have little effect on the asymptotic coverage probabilities of these two confidence procedures. Discussions concerning the effects of unequal sample sizes and inequitably distributed covariate values are also presented. These results are illustrated in application to a clinical trial of recombinant human erythropoetin versus placebo to treat patients with anemia secondary to advanced cancer, who were not receiving chemotherapy.

Multiple population models for multivariate random length data--with applications in clinical trials.

This paper focuses on the development and study of multiple population models for multivariate random length data, of the type often encountered in clinical trials. If experimental outcomes per subject consist of multiple measurements of a quantitative variable and the number of these measurements, then a multivariate random length vector is observed. For this type of data, the experimental treatment is likely to affect both the quantitative measurements and the number of these measurements. One example of such data is from the National Heart, Lung and Blood Institute Type II coronary intervention study (Brensike et al. (1982; Controlled Clinical Trials 3, 91-111; 1984, Circulation 69, 313-324)). The outcome data consist of vectors of lesion sizes with lengths determined by the number of underlying lesions assessed from the patients' angiograms, where both the numbers and the lesion sizes depend on patients' overall disease status. We propose models which can realistically describe the relationships between the quantitative variables and the number of responses. The asymptotic covariance of the maximum likelihood estimators is obtained. Data from the Type II study are analyzed using this multiple population model.

Multiple correlation: exact power and sample size calculations.

This article discusses power and sample size calculations for observational studies in which the values of the independent variables cannot be fixed in advance but are themselves outcomes of the study. It reviews the mathematical framework applicable when a multivariate normal distribution can be assumed and describes a method for calculating exact power and sample sizes using a series expansion for the distribution of the multiple correlation coefficient. A table of exact sample sizes for level .05 tests is provided. Approximations to the exact power are discussed, most notably those of Cohen (1977). A rigorous justification of Cohen's approximations is given. Comparisons with exact answers show that the approximations are quite accurate in many situations of practical interest. More extensive tables and a computer program for exact calculations can be obtained from the authors.

A statistical methodology for postmarketing surveillance of adverse drug reaction reports.

This paper presents a statistically optimal exact hypothesis testing procedure for detecting changes in sales adjusted adverse drug reaction (ADR) rates between historical and current periods, with a computer program that implements this test appended. We provide discussions and illustrations on how to monitor ADR rates for product lines that consist of several pharmacologically equivalent dosage forms.