BACKGROUND The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. METHODS Sixty-five ...patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. RESULTS The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. CONCLUSIONS These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.Arch Gen Psychiatry. 2000;57:249-258-->
Qualitative secondary research in Canada into the perceptions of women concerning their husbands' role in supporting them in postnatal depression. The women's vulnerability and the positive ...contribution made by their husbands' availability were studied. (BNI unique abstract) 66 references
In the absence of biological markers, dementia classification remains complex both in terms of characterization as well as early detection of the presence or absence of dementing symptoms, ...particularly in diseases with possible secondary dementia. An empirical, statistical approach using neuropsychological measures was therefore developed to distinguish demented from non-demented patients and to identify differential patterns of cognitive dysfunction in neurodegenerative disease. Age-scaled neurobehavioral test results (Wechsler Adult Intelligence Scale-Revised and Wechsler Memory Scale) from Alzheimer's (AD) and Huntington's (HD) patients, matched for intellectual disability, as well as normal controls were used to derive a classification formula. Stepwise discriminant analysis accurately (99% correct) distinguished controls from demented patients, and separated the two patient groups (79% correct). Variables discriminating between HD and AD patient groups consisted of complex psychomotor tasks, visuospatial function, attention and memory. The reliability of the classification formula was demonstrated with a new, independent sample of AD and HD patients which yielded virtually identical results (classification accuracy for dementia: 96%; AD versus HD: 78%). To validate the formula, the discriminant function was applied to Parkinson's (PD) patients, 38% of whom were classified as demented. The validity of the classification was demonstrated by significant PD subgroup differences on measures of dementia not included in the discriminant function. Moreover, a majority of demented PD patients (65%) were classified as having an HD-like pattern of cognitive deficits, in line with previous reports of the subcortical nature of PD dementia. This approach may thus be useful in classifying presence or absence of dementia and in discriminating between dementia subtypes in cases of secondary or coincidental dementia.
At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies ...had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US.
Randomised, placebo, controlled, trial.
The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50-69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 - 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease.
The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years.
The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding.
Objective: To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of ...subjects with plasma HIV-1 RNA less than or equal to 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. Design: One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts greater than or equal to 100 x 10 super(6)/l and plasma HIV-1 RNA of 400-50 000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. Methods: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. Results: At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA less than or equal to 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%; P < 0.001). A similar response was observed in both the lamivudine naive and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a greater than or equal to 1.0 log sub(10) copies/ml reduction in plasma HIV-1 RNA or had a value of less than or equal to 400 copies/ml by week 16. Conclusions: ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.
The bottleneck in elucidating gene function through high-throughput gain-of-function genome screening is the limited availability of comprehensive libraries for gene overexpression. Lentiviral ...vectors are the most versatile and widely used vehicles for gene expression in mammalian cells. Lentiviral supernatant libraries for genome screening are commonly generated in the HEK293T cell line, yet very little is known about the effect of introduced sequences on the produced viral titer, which we have shown to be gene dependent. We have generated an arrayed lentiviral vector library for the expression of 17,030 human proteins by using the GATEWAY#174; cloning system to transfer ORFs from the Mammalian Gene Collection into an EF1alpha promoter-dependent lentiviral expression vector. This promoter was chosen instead of the more potent and widely used CMV promoter, because it is less prone to silencing and provides more stable long term expression. The arrayed lentiviral clones were used to generate viral supernatant by packaging in the HEK293T cell line. The efficiency of transfection and virus production was estimated by measuring the fluorescence of IRES driven GFP, co-expressed with the ORFs. More than 90% of cloned ORFs produced sufficient virus for downstream screening applications. We identified genes which consistently produced very high or very low viral titer. Supernatants from select clones that were either high or low virus producers were tested on a range of cell lines. Some of the low virus producers, including two previously uncharacterized proteins were cytotoxic to HEK293T cells. The library we have constructed presents a powerful resource for high-throughput gain-of-function screening of the human genome and drug-target discovery. Identification of human genes that affect lentivirus production may lead to improved technology for gene expression using lentiviral vectors.
First generation antipsychotics induce extrapyramidal motor symptoms (EPS), presumably through dopamine D(2) receptor blockade at the dorsal striatum. This may also produce impairment of cognitive ...processes, such as procedural learning, that are dependent on this region. Haloperidol and, to a lesser extent, risperidone, are active in the dorsal striatum and may induce EPS and impairment of procedural learning. In contrast, the prototypical second-generation antipsychotic, clozapine, is less active in the dorsal striatum and does not induce EPS or impair procedural learning. Olanzapine is pharmacologically similar to clozapine and has a low incidence of EPS induction.
To assess the hypothesis that olanzapine would not have a deleterious effect on procedural learning.
Thirty-nine subjects with early phase schizophrenia were randomly assigned to double blind treatment with haloperidol, risperidone, or olanzapine. They were administered the Tower of Toronto test at an unmedicated baseline and again following 6 weeks and 6 months of treatment.
Procedural learning, defined as the improvement observed between two blocks of five trials of the Tower of Toronto, was preserved after 6 weeks of all three treatments but showed a substantial decline after 6 months of treatment with haloperidol or risperidone.
These data are consistent with the differential activity of the three medications in dorsal striatum structures and suggest that the advantages of olanzapine over haloperidol and risperidone in relation to extrapyramidal syndromes may also generalize to procedural learning. The results also suggest that the procedural learning disadvantages of haloperidol and risperidone accrue slowly but are apparent after 6 months of treatment.
This study examines the confidentiality practices of highly experienced, well-trained group psychotherapists. A provocative finding was that practitioners rarely inform prospective clients of ...confidentiality limitations. Their reluctance to do so appears to be based upon the belief that it might discourage persons from entering treatment, as well as having negative ramifications for the therapeutic process (e.g., members may be less likely to talk about unprotected topics). The prevalence and content of breaches in confidentiality are explored. Ethical, legal, clinical, and educational implications of these and other findings are addressed. Research recommendations are offered.
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