A placebo controlled trial of remoxipride in the prevention of relapse in chronic schizophrenia

Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D₂)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150–300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively (P=0.015). Efficacy analyses using clinical global impression (P=0.04) and change in BPRS scores (P=0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients.     

Impact of clinical history on fracture detection with radiography

The effect of knowledge of localizing symptoms and signs in the detection of fractures was studied. Forty radiographs of the extremities were examined twice by seven radiologists; the sessions were separated by 4 months. In 26 cases, a subtle fracture was present; 14 cases were normal. In half of the cases at each session, the precise location of pain, tenderness, or swelling was provided. The observer was asked to determine if the case was normal or abnormal (provide the exact location of the fracture) and to indicate the degree of confidence in the diagnosis. Responses were converted to a numeric scale for analysis. Analysis of receiver operator characteristic parameters indicates that clues regarding location of trauma facilitate detection of fractures. The improvement is based largely on an increased true-positive rate without an increased false-positive rate, regardless of the decision criteria of the radiologist (overall willingness to "overread" or "underread"). This has direct clinical applicability and reinforces the plea of radiologists for precise clinical information.     

Evidence that background GABAergic tone and possible ligand release may alter the action of the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788, in hypothalamic self-stimulation

Upward or downward shifts in the level of brain GABAergictransmission have been held to be necessary and sufficient to promote release of endogenous ligands ('endocoids') for the benzodiazepine (BZD) recognition site. To investigate this possibility, variable-interval self-stimulation performance was used to monitor 'intrinsic' benzodiazepine-like and anti- benzodiazepine activity by the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788 (flumazenil) (10 or 30 mg/kg intraperitoneally). Rats were pretreated with either a GABA synthesis blocking agent (isoniazid, 130 mg/kg subcutaneously), or with a GABA agonist (progabide, 30 or 100 mg/kg intraperitoneally). The lower dose of Ro 15-1788 (10 mg/kg), without pretreatment, did not affect self-stimulation; higher doses (30 mg/kg) caused a brief (<20 min) depression. Isoniazid (130 mg/kg) depressed self-stimulation, but did not modify the activity of Ro 15-1788. In rats pretreated with progabide (100 mg/kg), low doses of Ro 15- 1788 (10 mg/kg) that were previously without effect now caused a sharp fall in responding. These findings can be interpreted as showing that even low doses of Ro 15-1788 may affect self-stimulation under certain conditions, and that they do so by competing with an endogenous ligand for the benzodiazepine site, released by upward shifts in GABAergic activity. Alternative explanations in terms of altered receptor function seem less feasible. The results imply that the action of the endogenous ligand would not resemble that of a typical benzodiazepine, but that of an inverse agonist (that is, proconflict and proconvulsant); this conclusion agrees with recent biochemical evidence.     

A cDNA for the estradiol-regulated 24K protein: Control of mRNA levels in MCF-7 cells

We have previously demonstrated an estradiol-regulated 24 kDa (24K) protein in human breast cancer tissue culture cells and human tumor biopsies. The presence of 24K correlates well with the presence of steroid hormone receptors. In order to further study the hormonal regulation of the 24K protein and gene, we have isolated cDNA clones corresponding to the 24K mRNA.Poly(A)⁺ RNA isolated from the MCF-7 human breast cancer cell line was translated in a cell-free translation system containing [³⁵S]-methionine. The translation products were immunoprecipitated with a 24K monoclonal antibody, and thein vitro synthesis of 24K protein was confirmed by sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis. The same poly(A)⁺ RNA was used to construct an oligo(dT)-primed cDNA library in thegt11 expression vector system. The library was screened with a highly specific polyclonal antibody raised against 24K protein purified by immunoaffinity chromatography. Four recombinant clones reacting with the antibody by virtue of antigen expression were isolated and three were used in hybridization-selected translation. Three clones were able to hybridize specifically to a messenger RNA (mRNA) that yielded a Mr 24,000 protein when translatedin vitro and analyzed by SDS/polyacrylamide gel electrophoresis. This protein was also immunoprecipitable by the 24K monoclonal antibody. MCF-7 mRNA size fractionated by formaldehyde-agarose gel electrophoresis was transferred to nitrocellulose paper and hybridized to a nick-translated 24K cDNA clone. A single band of hybridization corresponding to a mRNA size of approximately 0.9–1.0 kilobase (kb) was observed. Using this same technique, 24K cDNA was hybridized to mRNA extracted from MCF-7 cells that had been treated for varying periods with either estradiol, nafoxidine, or tamoxifen. The 24K mRNA was elevated by the addition of estradiol, and clearly diminished by nafoxidine and tamoxifen.These results demonstrate that we have isolated cDNA clones for the study of the hormonal regulation of the 24K gene in breast cancer cells, and have shown that the mRNA is regulated by estradiol.     

Behavioural specificity of 8-OH-DPAT-induced feeding

8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) has been reported to increase food intake. This effect was confirmed in rats consuming plain or sweetened wet mash. However, the consumption of a 35% sucrose solution or of a range of other flavoured liquids was enhanced marginally if at all by a single low dose of 8-OH-DPAT, and the drug actually decreased the consumption of a high protein liquid diet. 8-OH-DPAT did, however, increase gnawing on a wooden block. These results suggest that 8-OH-DPAT-induced hyperphagia may to some extent be secondary to the elicitation of chewing behaviour. 8-OH-DPAT also caused certain other behavioural changes, including a suppression of grooming.     

Reliability of an isokinetic test of muscle strength and endurance

Funding for this study was provided by the U.S. Army Medical Research and Development Command, Project No. 85PP5866, under the Joint Working Group on Drug Dependent Degradation in Military Performance Program. The opinions or assertions contained herein are private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. The reliability of an isokinetic test of muscle strength and endurance was evaluated. Eleven males and 9 females underwent testing on three separate occasions, 2-4 days apart. The protocol included a velocity spectrum test (VST-5 repetitions at velocities ranging from 90-330 degrees /sec) and a muscle endurance test (number of contractions performed in 45 sec at 180 degrees /sec). In the VST, no significant within-subject test day differences were noted at any velocity. Reliability was generally higher at slower velocities and higher for knee extension than flexion. Mean intraclass correlation coefficients (ICCs) for peak torque across velocities were 0.88 for extension and 0.79 for flexion. For the endurance test, two reliable measures were total work performed and average power (ICCs = 0.92); relative endurance measures had ICCs of less than 0.80. Thresholds for demonstrating experimental effects and the number of subjects to test at different detection levels are-recommended.J Orthop Sports Phys Ther 1989;10(8):315-322.     

Prophylaxis in recurrent unipolar depression: a new indication for treatment studies

Antidepressants are used for long periods of time and until recently there were no formal requirements for establishing efficacy in the maintenance phase or the prophylactic phase of the treatment of depression. The CPMP guidelines advise regulatory authorities in the EEC to consider the efficacy of antidepressants in the medium and the long term separately from efficacy in the treatment of the acute episode. This paper reviews the efficacy of antidepressants in continuation treatment and prophylactic treatment of unipolar depression. Prophylactic studies are difficult and time consuming and it is important to adopt adequate trial methodology. The minimum criteria for the demonstration of prophylactic efficacy are presented.     

IL-6–174G/C genotype is associated with the bone mineral density response to oestrogen replacement therapy in post-menopausal women

A reduction in interleukin-6 (IL-6) activity may contribute to the beneficial effects of hormone replacement therapy (HRT) on the menopausal decline in bone mineral density (BMD). We have examined this hypothesis using a genetic strategy. The –174C (rather than G) IL-6 gene variant is associated with lower IL-6 expression. As such, we might anticipate the C allele to be associated with a greater response to HRT. We have tested this hypothesis. Mean three-site [spine (L1-L4), neck of femur, and Wards triangle] BMD was measured in 65 women in a 1-year randomised controlled trial of HRT with 0.625 mg oestrogen/day and 0.15 mg norgestrel (n=30). Baseline BMD was genotype-independent for both the control and HRT group. In the control group, the percentage change in BMD after 1 year was similar between genotypes (P=0.45). In contrast, in the HRT group, the rise was genotype-dependent. Those homozygous for the G allele showed a 3.62 (2.14)% increase in BMD compared with 10.44 (4.68)% for the C-homozygous group. Heterozygotes had an intermediate BMD increase of 5.6 (2.82)% [P=0.006 (P value for interaction between HRT and genotype was 0.04)] Although the study was limited by its small sample size, these are the first data to demonstrate the importance of IL-6 genotype in determining response to oestrogen therapy, rather than its physiological withdrawal.     

Socioeconomic disparities in intimate partner violence against Native American women: a cross-sectional study

Background

Intimate partner violence (IPV) against women is a global public health problem, yet data on IPV against Native American women are extremely limited. We conducted a cross-sectional study of Native American women to determine prevalence of lifetime and past-year IPV and partner injury; examine IPV in relation to pregnancy; and assess demographic and socioeconomic correlates of past-year IPV.

Methods

Participants were recruited from a tribally-operated clinic serving low-income pregnant and childbearing women in southwest Oklahoma. A self-administered survey was completed by 312 Native American women (96% response rate) attending the clinic from June through August 1997. Lifetime and past-year IPV were measured using modified 18-item Conflict Tactics Scales. A socioeconomic index was created based on partner's education, public assistance receipt, and poverty level.

Results

More than half (58.7%) of participants reported lifetime physical and/or sexual IPV; 39.1% experienced severe physical IPV; 12.2% reported partner-forced sexual activity; and 40.1% reported lifetime partner-perpetrated injuries. A total of 273 women had a spouse or boyfriend during the previous 12 months (although all participants were Native American, 59.0% of partners were non-Native). Among these women, past-year prevalence was 30.1% for physical and/or sexual IPV; 15.8% for severe physical IPV; 3.3% for forced partner-perpetrated sexual activity; and 16.4% for intimate partner injury. Reported IPV prevalence during pregnancy was 9.3%. Pregnancy was not associated with past-year IPV (odds ratio = 0.9). Past-year IPV prevalence was 42.8% among women scoring low on the socioeconomic index, compared with 10.1% among the reference group. After adjusting for age, relationship status, and household size, low socioeconomic index remained strongly associated with past-year IPV (odds ratio = 5.0; 95% confidence interval: 2.4, 10.7).

Conclusions

Native American women in our sample experienced exceptionally high rates of lifetime and past-year IPV. Additionally, within this low-income sample, there was strong evidence of socioeconomic variability in IPV. Further research should determine prevalence of IPV against Native American women from diverse tribes and regions, and examine pathways through which socioeconomic disadvantage may increase their IPV risk.