Predicting the long-term outcome of schizophrenia

Predictors of long-term (13 year) outcome of schizophrenia are reported for a representative cohort of 'treated incidence' patients ascertained on their first contact with Nottingham psychiatric services between 1978-80. An initial (baseline) model including previously reported predictors of 2-year outcome (age, gender, ever married, acuteness of onset) and length of untreated illness was used to predict a range of outcome measures covering the domains of disability, psychopathology, hospitalization, employment, social activity, and global outcome. This model demonstrated significant prognostic ability across all non-hospitalization outcomes under both ICD-10 and ICD-9 diagnoses of schizophrenia, but was attenuated under broad (ICD-9 and CATEGO S, P or O) and restrictive (S+) diagnostic classifications. Female gender predicted more favourable outcome under all diagnostic classifications except S+. In an extended analysis, the addition of initial 2-year course type substantially increased the prognostic ability of the model under all diagnostic classifications and enabled over 30% of the variance in global ratings of disability and symptoms to be predicted. In this extended model female gender predicted more favourable outcome over and above the effect of course type, across most domains under ICD-10, and for disability and psychopathology under other diagnostic classifications. The inclusion of measures of psychopathology at the time of first assessment, pre-morbid functioning, and duration of index admission conferred only marginal additional predictive ability for respective outcomes in the domains of psychopathology, social activity, employment and hospitalization. Hospitalization during the past year was the most difficult outcome to predict under any model suggesting that resource utilization represents the 'administrative outcome' of schizophrenia and serves as a poor proxy for broader concerns in the era of community care. These data demonstrate that key demographic variables and the mode of onset influence the long-term course of schizophrenia, but that early course type is a particularly strong predictor.     

Glutathione synthetase is dispensable for growth under both normal and oxidative stress conditions in the yeast Saccharomyces cerevisiae due to an accumulation of the dipeptide gamma-glutamylcysteine

Glutathione (GSH) synthetase (Gsh2) catalyzes the ATP-dependent synthesis of GSH from gamma-glutamylcysteine (gamma-Glu-Cys) and glycine. GSH2, encoding the Saccharomyces cerevisiae enzyme, was isolated and used to construct strains that either lack or overproduce Gsh2. The identity of GSH2 was confirmed by the following criteria: 1) the predicted Gsh2 protein shared 37-39% identity and 58-60% similarity with GSH synthetases from other eukaryotes, 2) increased gene dosage of GSH2 resulted in elevated Gsh2 enzyme activity, 3) a strain deleted for GSH2 was dependent on exogenous GSH for wild-type growth rates, and 4) the gsh2 mutant lacked GSH and accumulated the dipeptide gamma-Glu-Cys intermediate in GSH biosynthesis. Overexpression of GSH2 had no effect on cellular GSH levels, whereas overexpression of GSH1, encoding the enzyme for the first step in GSH biosynthesis, lead to an approximately twofold increase in GSH levels, consistent with Gsh1 catalyzing the rate-limiting step in GSH biosynthesis. In contrast to a strain deleted for GSH1, which lacks both GSH and gamma-Glu-Cys, the strain deleted for GSH2 was found to be unaffected in mitochondrial function as well as resistance to oxidative stress induced by hydrogen peroxide, tert-butyl hydroperoxide, and the superoxide anion. Furthermore, gamma-Glu-Cys was at least as good as GSH in protecting yeast cells against an oxidant challenge, providing the first evidence that gamma-Glu-Cys can act as an antioxidant and substitute for GSH in a eukaryotic cell. However, the dipeptide could not fully substitute for the essential function of GSH in the cell as shown by the poor growth of the gsh2 mutant on minimal medium. We suggest that this function may be the detoxification of harmful intermediates that are generated during normal cellular metabolism.     

Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys

L-754,394 is a potent and specific inhibitor of the HIV-1 encoded protease that is essential for the maturation of the infectious virus. The drug exhibited dose-dependent kinetics in all species studied (rat, dog and monkey); the apparent clearance decreased when the dose was increased. However, the dose-dependency cannot be explained by Michaelis-Menten kinetics. L-754,394 in plasma declined log-linearly with time, but with an apparent half-life that increased with dose. The apparent terminal half-life of L-754,394 in rats increased from 20 min at 0.5 mg/kg i.v. to 118 min at 10 mg/kg i.v. Furthermore, L-754,394 exhibited time-dependent pharmacokinetics. After chronic i.v. doses for 7 days (1 mg/kg/dose/day), the apparent clearance of L-754,394 in rats decreased from 87 ml/min/kg after the first dose to 25 ml/min/kg after the last dose. Similar results were observed in dogs and monkeys. In vitro spectral studies indicated that approximately 40 to 60% of the content of cytochrome P-450 was inactivated when L-754,394 (10 microM) was incubated with rat, dog and monkey liver microsomes in the presence of NADPH. Little or no inactivation of cytochrome P-450 was observed when either NADPH or L-754,394 was omitted. In addition, L-754,394 selectively inhibited CYP 2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylase activity and CYP 3A1/2-dependent testosterone 6 beta-hydroxylase activity, but not CYP 2D1/2-dependent bufuralol 1'-hydroxylase activity nor CYP 1A2-dependent phenacetin O-deethylase activity in rat liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anxiety-performance relationships in cricketers: testing the zone of optimal functioning hypothesis

This study extended Hanin's 1980 Zone of Optimal Functioning hypothesis by assessing both intensity and direction components of competitive state anxiety. 20 volunteer semiprofessional cricketers responded to the modified Competitive State Anxiety Inventory-2 prior to ten matches. For each game, players' performances were intraindividually evaluated by three qualified cricket coaches using subjective criteria. Separate Cognitive Anxiety and Somatic Anxiety 'below,' 'in,' and 'above' zones for Intensity and Direction of state anxiety were identified via repeated empirical assessments. Two two-way analyses of variance were computed for Intensity and Direction of anxiety (Cognitive Anxiety Zone Level x Somatic Anxiety Zone Level) with standardized performance scores as the dependent variable. A significant interaction was found between the zone levels for Cognitive and Somatic Anxiety Direction and performance scores. Examination of the Zone of Optimal Functioning hypothesis that focuses on the interactions between Cognitive and Somatic Anxiety and in particular the directional elements of the modified inventory seems warranted.     

An active noise control algorithm for controlling multiple sinusoids

The filtered-x LMS algorithm and its modified versions have been successfully applied in suppressing acoustic noise such as single and multiple tones and broadband random noise. This paper presents an adaptive algorithm based on the filtered-x LMS algorithm which may be applied in attenuating tonal acoustic noise. In the proposed method, the weights of the adaptive filter and estimation of the phase shift due to the acoustic path from a loudspeaker to a microphone are computed simultaneously for optimal control. The algorithm possesses advantages over other filtered-x LMS approaches in three aspects: (1) each frequency component is processed separately using an adaptive filter with two coefficients, (2) the convergence parameter for each sinusoid can be selected independently, and (3) the computational load can be reduced by eliminating the convolution process required to obtain the filtered reference signal. Simulation results for a single-input/single-output (SISO) environment demonstrate that the proposed method is robust to the changes of the acoustic path between the actuator and the microphone and outperforms the filtered-x LMS algorithm in simplicity and convergence speed.     

Relation between encapsulation and various properties of Streptococcus suis

Encapsulation is thought to be a critical virulence factor for Streptococcus suis. In this study, encapsulation of a selected S. suis culture could be stimulated by cultivation conditions. After cultivation of the S. suis culture in fluid media supplemented with serum, the culture grew with short chains and a uniform turbidity of the growth medium. Autoclave extracts of this culture reacted with capsular type-1-specific antiserum. After cultivation of the S. suis culture in fluid media without serum, the bacteria generally formed longer chains, grew in fluid medium as granular sediment with clear supernatant, and were non-typeable. In addition, the unencapsulated variant appeared to have a more hydrophobic surface and adhered significantly more to HeLa cells. In contrast to the unencapsulated variant, the encapsulated S. suis was phagocytosed to a lesser extent by polymorphonuclear leucocytes. These findings might help to elucidate the role of encapsulation in infections with this bacterial organism.