Gary O. Zerbe

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study

The relationship between elevated blood pressure and cardiovascular and cerebrovascular disease risk is well accepted. Both systolic and diastolic hypertension are associated with this risk increase, but systolic blood pressure appears to be a more important determinant of cardiovascular risk than diastolic blood pressure. Subjects for this study are derived from the Framingham Heart Study data set. Each subject had five records of clinical data of which systolic blood pressure, age, height, gender, weight, and hypertension treatment were selected to characterize the phenotype in this analysis.We modeled systolic blood pressure as a function of age using a mixed modeling methodology that enabled us to characterize the phenotype for each individual as the individuals deviation from the population average rate of change in systolic blood pressure for each year of age while controlling for gender, body mass index, and hypertension treatment. Significant (p = 0.00002) evidence for linkage was found between this normalized phenotype and a region on chromosome 1. Similar linkage results were obtained when we estimated the phenotype while excluding values obtained during hypertension treatment. The use of linear mixed models to define phenotypes is a methodology that allows for the adjustment of the main factor by covariates. Future work should be done in the area of combining this phenotype estimation directly with the linkage analysis so that the error in estimating the phenotype can be properly incorporated into the genetic analysis, which, at present, assumes that the phenotype is measured (or estimated) without error.

Randomization Analysis of the Completely Randomized Design Extended to Growth and Response Curves

Abstract A randomization analysis of a completely randomized growth (or response) curve model is derived from the basic assumptions of the design in the manner of Kempthorne (1955). Best linear unbiased estimators for mean growth and contrast curves are obtained. Kempthornes discussion of a univariate randomization test is generalized to the case of unequal group sizes and adapted to the problem of testing for treatment effects at a point in time. A similar randomization test for treatment effects over a specified interval of time is motivated and approximated by a standard F test. The proposed analysis is applied to experimental data.

Use of a Live Attenuated Varicella Vaccine to Boost Varicella-Specific Immune Responses in Seropositive People 55 Years of Age and Older: Duration of Booster Effect

Varicella-zoster virus (VZV)-specific T cell immunity was measured in 130 persons > or = 55 years of age 6 years after they received a live attenuated VZV vaccine. Circulating T cells, which proliferated in vitro in response to VZV antigen, were enumerated (VZV responder cell frequency assay). Six years after the booster vaccination, the VZV-responding cell frequency (1/61,000 circulating cells) was still significantly (P < .05) improved over the baseline measurements (1/70,000) and appears to have diminished the expected decline in frequency as these vaccinees aged (to 1/86,000). Ten herpes-zoster--like clinical events were recorded. Although the frequency of these events, approximately 1/100 patient-years, is within the expected range of such events for this age cohort, the number of lesions was small, there was very little pain, and there was no postherpetic neuralgia. These results support the development of a vaccine to prevent or attenuate herpes zoster.

The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference.

Objective To test whether the human fetus accommodates to the increasing glucose requirements of late pregnancy with an increased maternal-fetal glucose concentration gradient and whether there are differences in pregnancies with fetal growth restriction (FGR) according to clinical severity. Methods Umbilical venous glucose concentration was measured in 77 normal pregnancies (appropriate for gestational age [AGA]) and 42 pregnancies complicated by FGR at the time of fetal blood sampling. In 40 AGA and in all FGR cases, a maternal “arterialized” blood sample was collected simultaneously. Growth-restricted fetuses were subdivided into three groups according to fetal heart rate (FHR) recordings and Doppler measurements of the umbilical artery pulsatility index (PI): group 1 (normal FHR and PI; 12 cases), group 2 (normal FHR, abnormal PI; 17 cases) and group 3 (abnormal FHR and PI; 13 cases). Results In normal pregnancies with increasing gestational age, there was a significant decrease (P < .001) of umbilical venous glucose concentration and a significant increase of the maternal-fetal glucose concentration difference (P < .001). In addition, there was a significant relation between fetal and maternal glucose concentrations (P < .001). In FGR pregnancies, the maternal-fetal glucose concentration difference was significantly higher in fetuses of groups 2 and 3 compared with normal pregnancies and FGR pregnancies of group 1. Conclusion In human pregnancy, the fetal glucose concentration is a function of both gestational age and the maternal glucose concentration. In FGR pregnancies, as an accommodation of the fetus to a restricted placental size and placental glucose transport capacity, the maternal-fetal glucose concentration difference is increased, and this increase is a function of the clinical severity.

DETERMINANTS OF SURVIVAL AND RECOVERY IN ACUTE RENAL FAILURE PATIENTS DIALYZED IN INTENSIVE-CARE UNITS

The survival rate of critically ill patients who develop acute renal failure is extremely low, in spite of the sophisticated support systems, including dialysis. Therefore, it would be advantageous to identify, early in the disease course, those few survivors. We reviewed the clinical course of 43 consecutive critically ill patients who developed acute renal failure and were first dialyzed in an intensive-care unit setting to define comorbid conditions, present at the time of first dialysis, that were predictive of outcome. Mortality rate was 88%. Adult respiratory distress syndrome (p less than 0.05), requirement for antibiotics (p less than 0.01) and ventilatory failure (p less than 0.01) impacted negatively on recovery of renal function. The most powerful predictor of mortality was the need for ventilatory support (p less than 0.001). The presence of ventilatory failure at the initiation of dialysis predicted a 100% mortality (89-100%; 95% confidence limits). The initiation of dialysis in intensive-care unit patients with acute renal failure requiring ventilatory support did not alter the uniformly fatal outcome.

On Fieller's Theorem and the General Linear Model

Abstract The purpose of this note is to indicate that Fiellers Theorem can be expressed in the matrix formulation of the general linear model. The practical consequence is that one general computer program which can estimate the parameters and test the validity of a pertinent model, can also compute confidence limits for the ratios of any linear combinations of the parameters.

Sulindac is not renal sparing in man

We investigated the claimed renal‐sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen‐induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2α (PGF‐M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24‐hour urinary PGE2 excretion (range −49% to −86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti‐inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen‐induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF‐M excretion. Peak plasma drug concentrations of indomethacin (1.9 ± 0.4 µg/ml) and sulindac sulfide (7.7 ± 1.9 µg/ml) were those associated with clinical efficacy. We conclude that sulindac has renal effects qualitatively comparable to those of indomethacin. Therefore, caution should continue to be exercised with the use of sulindac, as with other nonsteroidal anti‐inflammatory drugs, in clinical situations in which cyclooxygenase inhibitors have been associated with deterioration of renal function.

Influence of Age and Nature of Primary Infection on Varicella-Zoster Virus—Specific Cell-Mediated Immune Responses

BACKGROUND Varicella-zoster virus (VZV)-specific cell-mediated immunity is important for protection against VZV disease. We studied the relationship between VZV cell-mediated immunity and age after varicella or VZV vaccination in healthy and human immunodeficiency virus (HIV)-infected individuals. METHODS VZV responder cell frequency (RCF) determinations from 752 healthy and 200 HIV-infected subjects were used to identify group-specific regression curves on age. RESULTS In healthy individuals with past varicella, VZV RCF peaked at 34 years of age. Similarly, VZV-RCF after varicella vaccine increased with age in subjects aged <1 to 43 years. In subjects aged 61-90 years, VZV RCF after zoster vaccine decreased with age. HIV-infected children had lower VZV RCF estimates than HIV-infected adults. In both groups, VZV RCF results were low and constant over age. Varicella vaccination of HIV-infected children with CD4 levels 20% generated VZV RCF values higher than wild-type infection and comparable to vaccine-induced responses of healthy children. CONCLUSIONS In immunocompetent individuals with prior varicella, VZV RCF peaked in early adulthood. Administration of varicella vaccine to HIV-infected or uninfected individuals aged >5 years generated VZV RCF values similar to those of immunocompetent individuals with immunity induced by wild-type infection. A zoster vaccine increased the VZV RCF of elderly adults aged <75 years to values higher than peak values induced by wild-type infection.

Effects of Insulin and Glucose Concentrations on Glucose Utilization in Fetal Sheep

ABSTRACT: Glucose and insulin clamp experiments were performed in vivo in chronically catheterized, late-gestation fetal lambs to quantify the effects of glucose and insulin on fetal glucose metabolism. Fetal glucose uptake from the placenta via the umbilical circulation (umbilical glucose uptake) was measured by application of the Fick principle, and fetal glucose utilization rate (GUR) was measured using [U-14C]glucose tracer. Fetal plasma insulin concentrations ranged from 2 to 119 μU·ml−1 and fetal blood glucose concentrations ranged from 7.3 to 62.6 mg·dl−1. GUR varied from 2.82 to 15.12 mg/min/kg and the exogenous glucose entry rate (umbilical glucose uptake + glucose infusion) varied from 2.46 to 13.95 mg/min/kg. The mean GUR [6.53 ± 0.28 (SEM) mg/kg/min] was not different from the mean exogenous glucose entry rate [6.29 ± 0.30 (SEM) mg/kg/min]. Multiple linear regression analysis on a glucose-by-insulin surface demonstrated a best-fit model of fetal glucose utilization following the quadratic equation: GUR = −0.322 + [0.289 (glucose)] + [0.108 (insulin)] - [0.00319 (glucose)2] - [0.000673 (insulin)2], r = 0.883 (all terms significant at p < 0.02). This model predicted a GURmax of 10.56 mg/min/kg at blood glucose concentration = 45.3 mg/dl and plasma insulin concentration = 80 μU/ml and Km values for blood glucose concentration and plasma insulin concentration of 20.6 mg/dl and 10 μU/ml, respectively. According to this model, the glucose and insulin effects were additive. Furthermore, change in GUR was not proportionate to change in glucose concentration, accounting for a decreasing metabolic clearance rate at higher glucose concentrations. These results demonstrate the three-dimensional nature of the simultaneous additive effects of glucose and insulin on glucose utilization. These results also serve to emphasize that comparative studies of insulin and glucose metabolism in fetal lambs must be conducted at similar concentrations of glucose to avoid inaccurate estimates of the magnitude of insulin effect on glucose metabolism.