5-HT 2C receptor sensitivity during treatment with selective serotonin re-uptake inhibitors

We studied the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRIs) on the sensitivity of brain 5-HT(2C) receptors, by measuring the decrease in slow wave sleep (SWS) that follows administration of meta-chlorophenylpiperazine (mCPP) (7.5 mg orally). mCPP significantly lowered SWS both in patients taking SSRIs and in a group of healthy controls. There was, however, no difference in the response between the two groups. The results do not support the suggestion that repeated SSRI treatment alters the sensitivity of 5-HT(2C) receptors in the human brain. The present study, however, cannot exclude the possibility that a decrease in 5-HT(2C) receptor sensitivity was offset by higher plasma levels of mCPP in the SSRI-treated group.     

Baclofen,a gamma-aminobutyric acid-b receptor agonist,delays diabetes onset in the non-obese diabetic mouse

Glutamic acid decarboxylase (GAD) is the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). GAD has been identified as a 64-kDa antigen expressed in pancreatic beta-cells, to which autoantibodies are generated prior to the onset of type 1 (insulin-dependent) diabetes mellitus. GAD may therefore be an initiating factor in beta-cell destruction. We administered baclofen, a GABA-B receptor agonist, to non-obese diabetic (NOD) mice in an attempt to down-regulate GAD expression and thereby reduce the incidence of diabetes. Twenty-four female NOD mice were given baclofen in their drinking water at a final dose of 50 mg/kg body weight daily from weaning to 30 weeks of age. Twentyfour sex-and litter-matched mice were used as controls. At 30 weeks there was no difference in the incidence of diabetes in the treated group compared with the controls. However, there was a significant delay in the onset of diabetes in the treated group (P<0.001, parallelism test). The degree of insulitis and the GAD activity in the pancreas per mg of protein were unchanged by baclofen treatment with respect to controls. These results suggest that baclofen may be effective in delaying diabetes onset in NOD mice by stimulating GABA activity, as this neurotransmitter, localised in the islets, may modulate insulin secretion and the antigen expression associated with it.     

Low back pain: cost-effective diagnosis and treatment

This systematic approach to low back pain limits the use of imaging studies and surgery. The natural history of this condition and its resolution show that such modalities are best restricted to a minority of patients.     

The activity of deoxyspergualin in multidrug-resistant cells

Deoxyspergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic spergualin, has been shown to possess potent in vitro and in vivo antitumour activity and is currently in the National Cancer Institute (NCI) decision network. Deoxyspergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multi-drug resistance. We therefore decided to examine the comparative activity of deoxyspergualin in parent and multidrug-resistant cells. Deoxyspergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxyspergualin. It appears that in the presence of horse serum, deoxyspergualin may exert its effect by a mechanism other than polyamine oxidation. Deoxyspergualin did not enhance the accumulation of [³H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxyspergualin (1–20 M) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [³H]-azidopine. Deoxyspergualin did not inhibit this labeling. Although deoxyspergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxyspergualin a promising candidate for development as an anti-cancer agent.     

Recovered memories of abuse in women with documented child sexual victimization histories

This study provides evidence that some adults who claim to have recovered memories of sexual abuse recall actual events that occurred in childhood. One hundred twenty-nine women with documented histories of sexual victimization in childhood were interviewed and asked about abuse history. Seventeen years following the initial report of the abuse, 80 of the women recalled the victimization. One in 10 women (16% of those who recalled the abuse) reported that at some time in the past they had forgotten about the abuse. Those with a prior period of forgetting—the women with recovered memories—were younger at the time of abuse and were less likely to have received support from their mothers than the women who reported that they had always remembered their victimization. The women who had recovered memories and those who had always remembered had the same number of discrepancies when their accounts of the abuse were compared to the reports from the early 1970s.     

Effect of dietary sodium on airways responsiveness and its importance in the epidemiology of asthma: an evaluation in three areas of northern England.

BACKGROUND--Although several investigations have shown a relationship between asthma (or its surrogate, airways responsiveness) and dietary or urinary sodium, others have not, and the matter remains controversial. This "salt effect" has been investigated during two recent epidemiological surveys of men in northern England. The first assessed the possible effect on airways responsiveness of occupational exposure to welding fumes, and the second characterised airways responsiveness in two geographically distinct residential areas. Thus, three separate study areas/populations were involved. METHODS--Investigation 1 involved 1059 shipyard workers aged 16-27 years who were exposed variously to welding fumes, and Investigation 2 involved 587 men aged 20-44 years who lived in rural West Cumbria or in urban Newcastle upon Tyne. In Investigation 1, a 24 hour urine specimen was requested from each subject with quantifiable airways responsiveness (PD20 < or = 6400 micrograms methacholine) and from an equal number of subjects without measurable airways responsiveness from the same occupational subgroup. In Investigation 2, every subject was asked to provide a 24 hour urine specimen. RESULTS--Of the men undergoing methacholine tests, satisfactory 24 hour urine specimens were obtained from 234 (22.1%) in Investigation 1 and 232 (39.5%) in Investigation 2. Analysis using multiple linear regression, multiple linear logistic regression, and multiple regression for censored data produced consistent results within each study population but conflicting results between them, such that there was no hint of a relationship between airways responsiveness and 24 hour urinary sodium excretion in the shipyard workers of Investigation 1 nor in the rural West Cumbrian population of Investigation 2, but an association was found in the urban Newcastle population of Investigation 2. All study populations were sufficiently large to demonstrate anticipated relationships between airways responsiveness and atopy, baseline FEV1, and (Newcastle only) age. CONCLUSIONS--If airways responsiveness is related to dietary sodium the relationship is not likely to be strong.     

Marijuana use among minority youths living in public housing developments

Youths residing in public housing developments appear to be at markedly heightened risk for drug use because of their constant exposure to violence, poverty, and drug-related activity. The purpose of this study was to develop and test a model of marijuana etiology with adolescents (N=624) residing in public housing. African-American and Hispanic seventh graders completed questionnaires about their marijuana use, social influences to smoke maijuana, and sociodemographic and psychosocial characteristics. Results indicated that social influences, such as friends' marijuana use and perceived ease of availability of marijuana, significantly predicted both occasional and future use of marijuana. Individual characteristics such as antimarijuana attitudes and drug refsul skills also predicted marijuana use. The findings imply that effective prevention approaches that target urban youths residing in public housing developments should provide them with an awareness of social influences to use marijuana, correct misperceptions about the prevalence of marijuana smoking, and train adolescents in relevant psychosocial skills.