Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.

OBJECTIVES: To compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs haloperidol (HAL) in a double blind, randomized trial. METHODS: Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05. RESULTS: HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties. CONCLUSIONS: In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was haloperidol. Olanzapine was equivalent to haloperidol for anticholinergic-like side effects when corrected for anticholingergic agents.

Genetic and environmental parameters for steer ultrasound and carcass traits.

Carcass measurements for weight, longissimus muscle area, 12-13th-rib fat thickness, and marbling score, as well as for live animal measurements of weight at the time of ultrasound, ultrasound longissimus muscle area, ultrasound 12-13th-rib fat thickness, and ultrasound-predicted percentage ether extract were taken on 2,855 Angus steers. The average ages for steers at the time of ultrasound and at slaughter were 391 and 443 d, respectively. Genetic and environmental parameters were estimated for all eight traits in a multivariate animal model. In addition to a random animal effect, the model included a fixed effect for contemporary group and a covariate for measurement age. Heritabilities for carcass weight, carcass longissimus muscle area, carcass fat thickness, carcass marbling score, ultrasound weight, ultrasound longissimus muscle area, ultrasound fat thickness, and ultrasound-predicted percentage ether extract were 0.48, 0.45, 0.35, 0.42, 0.55, 0.29, 0.39, and 0.51, respectively. Genetic correlations between carcass and ultrasound longissimus muscle area, carcass and ultrasound fat thickness, carcass marbling score and ultrasound-predicted percentage ether extract, and carcass and ultrasound weight were 0.69, 0.82, 0.90, and 0.96, respectively. Additional estimates were derived from a six-trait multivariate animal model, which included all traits except those pertaining to weight. This model included a random animal effect, a fixed effect for contemporary group, as well as covariates for both measurement age and weight. Heritabilities for carcass longissimus muscle area, carcass fat thickness, carcass marbling score, ultrasound longissimus muscle area, ultrasound fat thickness, and ultrasound-predicted percentage ether extract were 0.36, 0.39, 0.40, 0.17, 0.38, and 0.49, respectively. Genetic correlations between carcass and ultrasound longissimus muscle area, carcass and ultrasound fat thickness, and carcass marbling and ultrasound-predicted percentage ether extract were 0.58, 0.86, and 0.94, respectively. The high, positive genetic correlations between carcass and the corresponding real-time ultrasound traits indicate that real-time ultrasound imaging is an alternative to carcass data collection in carcass progeny testing programs.

A bootstrap approach to confidence regions for genetic parameters from Method R estimates.

Confidence regions (CR) for heritability (h2) and fraction of variance accounted for by permanent environmental effects (c2) from Method R estimates were obtained from simulated data using a univariate, repeated measures, full animal model, with 50% subsampling. Bootstrapping techniques were explored to assess the optimum number of subsamples needed to compute Method R estimates of h2 and c2 with properties similar to those of exact estimators. One thousand estimates of each parameter set were used to obtain 90, 95, and 99% CR in four data sets including 2,500 animals with four measurements each. Two approaches were explored to assess CR accuracy: a parametric approach assuming bivariate normality of h2 and c2 and a nonparametric approach based on the sum of squared rank deviations. Accuracy of CR was assessed by the average loss of confidence (LOSS) by number of estimates sampled (NUMEST). For NUMEST = 5, bootstrap estimates of h2 and c2 were within 10(-3) of the asymptotic ones. The same degree of convergence in the estimates of SE was achieved with NUMEST = 20. Correlation between estimates of h2 and c2 ranged from -.83 to -.98. At NUMEST < 10, the nonparametric CR were more accurate than parametric CR. However, with the parametric CR, LOSS approached zero at rate NUMEST(-1). This rate was an order of magnitude larger for the nonparametric CR. These results suggested that when the computational burden of estimating genetic parameters limits the number of Method R estimates that can be obtained to, say, 10 or 20, reliable CR can still be obtained by processing Method R estimates through bootstrapping techniques.

The role of different pedigree structures on the sampling variance of heritability estimates.

A computer-intensive process was performed to simulate 12,600 data sets each with n = 5,000 individuals from distinct pedigree structures to assess the effect of pedigree information on the sampling variance of heritability (h2) estimates. Pedigree structures were determined by varying the proportion of foundation animals (PF), percentage replacement rates for males (RM) and females (RF), and ratio of females to male (F2M). A 2(3) factorial design was modeled; levels of RM and RF were 10 and 20%, and levels of F2M were 10 and 20. For each of the eight cells, 60 foundation animals were simulated, each with 10 replicates. The required mating seasons (MS) to obtain the number of individuals was simulated based on PF and F2M. A REML algorithm was used to estimate h2 and its associated SE. The effect of all factors was analyzed in a regression model with linear and quadratic components for PF. An alternative model with MS replacing PF was also investigated. There was a non-monotonic association (P < .01) between PF and h2 SE. The minimum h2 SE occurred when PF ranged from 20 to 40%. Here, the proportion of first-generation progeny was near its maximum with rapid increases in the proportion of subsequent descendants. Among the class effects, F2M yielded the highest mean square (P < .001). When considering more than one MS, h2 SE was positively associated (P < .01) with RF and F2M and negatively associated with RM. Results suggest that h2 is most accurately estimated when there is performance information on many animals closely related to foundation animals.

Inhibition of lymphocyte proliferation by aqueous humor.

Antigens introduced into the anterior chamber (AC) of the eye elicit systemic, antigen-specific suppression of delayed hypersensitivity combined with primed cytotoxic T cells and elevated levels of serum antibodies, a unique immune response termed anterior chamber associated immune deviation (ACAID). Among the mechanisms that have been implicated in the induction of this response is the possibility that T cells first recognize antigen within the AC, where-upon they then escape to initiate the induction of systemic suppression. Because this possibility implies that T-cell recognition of antigen could occur in the aqueous humor (AqH) that normally fills the AC, we tested the effects of freshly obtained AqH on lymphocyte proliferative responses in vitro. The results indicate that AqH from mice and rabbits profoundly inhibits (1) T-lymphocyte proliferation to antigens, (2) T- and B-lymphocyte responses to polyclonal mitogens, and (3) growth-factor-driven lymphocyte proliferation. The antiproliferative activity of AqH was also effective on some, but not all, neoplastic cells. The activity was shown to be neither species specific nor directly cytotoxic to cells. The activity was distinct from the growth inhibitory effects of normal mouse serum. We conclude that AqH contains a soluble factor(s) that is a potent inhibitor of cell proliferation. The potential role(s) of this activity in ocular wound healing and in intraocular immune responses are discussed.

Polypeptide synthesis in human fibroblasts infected with DNA-negative mutants of cytomegalovirus.

Two DNA-negative temperature-sensitive mutants of human cytomegalovirus strain AD169 were shown to be deficient in induction of several prominent viral polypeptides when grown in human foreskin fibroblasts under nonpermissive conditions. The use of a monospecific polyclonal antiserum allowed recognition of a further defect in processing of an 'early' viral polypeptide of 135 kD.

Dynamically stable 0 degrees phase mode operation of a grating-surface-emitting diode-laser array.

A coherent grating-surface-emitting diode-laser array has demonstrated dynamically stable operation in the 0 degrees phase mode. The array was operated under pulsed conditions, had a peak power output of 44 mW and a large central lobe on axis in the far field, and exhibited single-mode spectral output with better than 18-dB side-mode rejection.

Inhibition by monensin of human cytomegalovirus DNA replication.

Monensin, at concentrations which depended on the multiplicity of infection, was found to prevent DNA replication of human cytomegalovirus (HCMV) as well as production of viral progeny in human foreskin fibroblasts. The drug did not affect DNA replication of herpes simplex virus. Inhibition of consecutive HCMV DNA synthesis was also observed following delayed addition of the drug within 12-24 hours postinfection, but was fully reversible upon its removal. Viral replication proceeded, however, without impairment in cultures treated with monensin prior to infection. Induction of viral DNA polymerase activity was not impeded by the inhibitor. Analysis of protein- and glycoprotein synthesis revealed that monensin interfered with the production of a number of HCMV-specific polypeptides. Furthermore, evidence was obtained that the drug may hinder intracellular transport of a 135 kd glycopolypeptide.

Systemic hypertension induces disparate localized left ventricular action potential lengthening and altered sensitivity to verapamil in left ventricular myocardium.

Previously, we demonstrated that acute exposure to superfusate containing verapamil suppresses action potential plateau to a greater degree in cells at the tip of the anterior papillary muscle compared to those at its base in normal cat left ventricle (LV) studied in tissue bath. To determine the effects of chronic pressure overload brought about by renal hypertension on papillary muscle electrophysiology and regional sensitivity to verapamil, LV were isolated from cats subjected to unilateral nephrectomy and contralateral kidney wrapping. After 3 months, systemic hypertension (mean increase = 60.2 +/- 1.4 mmHg) was associated with moderate LV hypertrophy of approximately equal to 18% (LV weight/body weight). Transmembrane action potentials recorded from the endocardial surface (including anterior papillary muscle) in pressure overloaded LV in vitro (800 ms stimulus cycle length) showed increased action potential duration at 25, 75 and 90% of repolarization (APD25, APD75 and APD90, respectively) relative to controls (LV from normal and sham operated cats). With respect to the anterior papillary muscle in pressure overloaded LV, APD25, APD75 and APD90 were increased to a greater extent in cells at the base of the muscle compared to those increases observed at the tip (P less than 0.05). In contrast to its effects in controls, verapamil (2 micrograms/ml) significantly reduced APD25 at both the base and the tip of the papillary muscle in pressure overloaded preparations, but particularly at the base; also, the disparities between the APD75 or APD90 at tip and base were decreased. Thus, regional electrophysiologic disparities were induced in systemic hypertension, and these differences were subsequently reduced by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium butyrate selectively inhibits host cell glycoprotein synthesis in human fibroblasts infected with cytomegalovirus.

Host cell as well as viral DNA synthesis in human fibroblasts infected with human cytomegalovirus was found to be largely resistant even to high concentrations of sodium butyrate. Likewise, production of viral progeny was reduced by 1-2 orders of magnitude but not abolished. On the other hand, the drug allowed (modified) glycosylation only of viral polypeptides whereas that of host proteins was suppressed. Immunofluorescence studies on living cells suggested that butyrate may interfere with processing and intracellular transport of virus-specific surface membrane antigens.

Histamine modification of spontaneous rate and rhythm in infarcted canine ventricle.

Histamine (10(-3) M) increased the spontaneous rate similarly in isolated preparations of normal left ventricular tissue from control, i.e. normal and sham-operated, dogs (control preparations) and in preparations consisting of normal and contiguous infarcted left ventricular tissue from dogs with subacute, i.e. 24 hours after left coronary artery ligation, myocardial infarction (infarcted preparations). Histamine (10(-3) M) markedly enhanced the irregular rhythm of infarcted preparations. The H1-receptor antagonist, chlorpheniramine (10(-4) M), and the H2-receptor antagonist, cimetidine (10(-3) M), antagonized the effects of histamine (10(-3) M) on the spontaneous rate of both control and infarcted preparations. The H1-receptor agonist, 2-pyridyl ethylamine (PEA, 10(-4) M), increased the spontaneous rate of control and infarcted preparations; these effects were antagonized by chlorpheniramine (10(-4) M). The H2-receptor agonist, dimaprit, had no effect. Similar to histamine (10(-3) M), PEA (10(-4) M) enhanced the irregular rhythm of infarcted preparations; dimaprit had no effect. High local concentrations of histamine may occur in poorly perfused ischemic tissue. The enhancement of irregular rhythm produced by histamine, and the specific H1-receptor agonist, PEA, leads us to suggest its involvement in arrhythmias associated with subacute myocardial infarction.