New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.     

Variations in use of second-generation antipsychotic medication by race among adult psychiatric patients

OBJECTIVE: This study examined variations in the use of second-generation antipsychotic medication among African-American and non-Hispanic white patients in a national sample of adults who were treated by psychiatrists. METHODS: This study used data from studies of psychiatric patients and treatments that were conducted by the American Psychiatric Institute for Research and Education's (APIRE's) Practice Research Network (PRN). Psychiatrists provided detailed clinical data for 126 African-American patients and 574 white patients who were randomly selected and for whom antipsychotic medications were prescribed. The study assessed differences by race in the use of second-generation antipsychotic medication, adjusting for clinical, sociodemographic, and health-system characteristics, including patients' source of payment for treatment. RESULTS: African-American patients were less likely than white patients to receive second-generation antipsychotic medications (49 percent compared with 66 percent). After the analysis statistically adjusted for clinical, sociodemographic, and health-system characteristics, African-American patients remained less likely than white patients to receive second-generation antipsychotics. CONCLUSIONS: Because African Americans tended to receive medications that are not first-line recommended treatments and that have a greater risk of producing tardive dyskinesia and extrapyramidal side effects, African Americans could be expected to suffer diminished clinical status. This disparity may also contribute to lower rates of adherence and to more frequent emergency department visits and psychiatric hospitalizations among African Americans     

Gender differences in anxiety-related traits in patients with panic disorder

This study examined gender differences in anxiety-related personality traits in patients with panic disorder with or without agoraphobia (PD+/-AG). Outpatients (101 total) with SCID confirmed PD+/-AG completed the Anxiety Sensitivity Index (ASI), the Trait form of the State-Trait Anxiety Inventory (STAI-T), the NEO Personality Inventory Revised (NEO PI-R), and the Retrospective Self-Report of Inhibition (RSRI) as part of their assessment. Significant gender differences were not detected for the total ASI scores. Females scored significantly higher than males on the Physical Concerns subscale of the ASI, whereas males scored significantly higher than women on the Social Concerns subscale. Women scored higher than men on the Extraversion scale of the NEO PI-R as well as on certain subscales of this domain. Although a significant gender difference was not detected on the Neuroticism subscale, men scored higher on the angry hostility and depression facets of this trait. Significant gender differences were not found for the STAI-T or the RSRI. These findings suggest that gender differences exist among patients with PD+/-AG in the feared consequences of anxiety symptoms as well as in the personality characteristics of extraversion.     

Intracerebral infection with murine cytomegalovirus induces CXCL10 and is restricted by adoptive transfer of splenocytes

The brain's intrinsic immune system consists of glial cells that produce cytokines and chemokines in response to stimulation with cytomegalovirus (CMV). The present experiments were undertaken to determine whether this intrinsic glial cell response alone is sufficient to control CMV infection of the central nervous system (CNS) or whether effector cells from the somatic immune system are also required. Following stereotactic, intracerebroventricular (icv), injection of murine cytomegalovirus (MCMV) into immunocompetent (C.B-17) mice, viral spread in the brain was limited to the cells of the ventricular walls and the infection was resolved by 10 days post infection (p.i.). In contrast, icv infection of immunodeficient (C.B-17 SCID/bg) mice resulted in viral spread from the ventricles throughout the brain parenchyma and these mice succumbed to lethal disease. Adoptive transfer of total splenocytes from major histocompatibility complex (MHC)-matched, MCMV-primed animals restricted intracerebral viral infection to the periventricular cells and reduced levels of reporter gene expression from the viral genome. Peripheral immune cell transfer also protected immunodeficient animals from lethal disease. Depletion of Thy 1.2(+) cells from MCMV-primed splenocytes abolished the protective effect of adoptive transfer. Viral expression was found to be fourfold greater in the brains of animals given Thy 1.2-depleted splenocytes than from those receiving total undepleted cells. As MCMV infection proceeded in the brains of immunodeficient mice, levels of the T-cell chemoattractants CXCL10 and CCL2 remained elevated, whereas CXCL10 levels waned in the brains of animals receiving transferred splenocytes. Taken together, these results demonstrate the ability of T lymphocytes to restrict intracerebral viral spread and indicate that intrinsic glial cell responses alone are insufficient to control MCMV brain infection.     

Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation

BACKGROUND: The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder. OBJECTIVES: To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD. DESIGN: We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures. SETTING: An academic referral setting, drawing from the Bay Area of San Francisco, Calif. RESULTS: Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation. CONCLUSIONS: Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.     

Food deprivation after treatment blocks the multiple-day hyperphagic response to SHU9119 administration

The multiple-day hyperphagic effect of the melanocortin 3/4 receptor antagonist, SHU9119, is apparently abolished when rats are food-deprived for 24 h after central (4th-ventricular) injection. Here, we affirmed this indication, and addressed the possibility that the orexigenic potency of SHU9119 is simply masked by the refeeding hyperphagia that follows food deprivation. This explanation is discounted by our finding that the drug response in ad libitum-fed rats and the deprivation response are expressed at different, and non-overlapping, times of day. We then asked whether food consumption during a hypothesized critical period in the hours after treatment is necessary for expression of the hyperphagic response to SHU9119, or alternatively, whether blood-borne signals that emerge only after an extended period of food restriction underlie the drug-state interaction. Evidence favoring the latter interpretation was derived from a series of four experiments over which the timing and duration of food access after drug administration was varied. The results indicate an interaction between melanocortin receptor activity and the metabolic state of the animal, and constrain our thinking about the peripheral signals and central mechanisms that underlie this interaction.     

Changes in early psychosis service provision: a file audit

OBJECTIVE: To measure change in services provided to young people with first-episode psychosis following the introduction of specialized early psychosis teams and staff training. METHOD: A standardized tool was developed to audit services provided to young people with first-episode psychosis. The tool initially comprised 27 clinical indicators measuring aspects of optimal care derived from the Australian clinical guidelines for early psychosis. The first 12 months of treatment, as documented in the case records, were audited for all young people receiving their first treatment for psychosis during a 6-month period prior to the introduction of these service developments (n = 47). These subjects were compared with those who received treatment after the implementation of service development strategies (n = 70). A comparison was also made within the second group, between those receiving some treatment from a specialized early psychosis team and those being exclusively treated by other services. RESULTS: Inter-rater reliability was achieved for 24 of the 27 indicators. Improvements were found on 10 indicators which measured psychosocial interventions, prescribing practices, family interventions and continuity of care. There was no significant deterioration on any of the indicators. Clients who attended early psychosis teams were significantly more likely to receive psychoeducation. CONCLUSIONS: The services increased their provision of "guideline concordant" care for early psychosis. The audit proved useful to monitor performance, to demonstrate improvements in care and to identify those areas of service provision and documentation in need of improvement.     

Cross reactivity of polyclonal GFAP antiserum: implications for the in-vitro characterisation of brain endothelium

Following a recent claim, based on glial acidic fibrillary protein (GFAP) expression, that brain-derived astrocytes in culture are in fact endothelial cells, we immuno-labelled primary cultures of rat brain astrocytes and endothelium with various GFAP antisera. Both cell types stained positively with a polyclonal antibody, although monoclonal antiserum labelled only astrocytes. We conclude that staining of endothelial cells with the polyclonal GFAP antiserum is due to cross reactivity with another protein.     

Myasthenia in a patient with sarcoidosis and schizophrenia

A 44-year-old male patient was hospitalised with paranoid schizophrenia in 1985. Depot neuroleptic treatment was started which successfully prevented further psychotic relapses for the next ten years. His myasthenia gravis started with bulbar signs in 1997 and the symptoms soon became generalized. The diagnosis of myasthenia gravis was confirmed by electromyography, by positive anticholinesterase test and by the detection of anti-acetylcholine receptor antibodies in the serum. Mediastinal CT examination showed enlarged hilar lymph nodes on the left but no thymic pathology was observed. Mediastinoscopy was performed and biopsies were obtained from the affected nodes. Histology revealed sarcoidosis. The patient suffered respiratory crisis following the thoracic intervention (in September 1998). Combined oral corticosteroid (64 mg methylprednisolone/e.o.d.) and azathioprine (150 mg/day) treatment regimen was initiated and complete remission took place in both the myasthenic symptoms and the sarcoidosis. The follow-up CT scans showed no mediastinal pathology (January 2000). During steroid treatment a transient psychotic relapse occurred which was successfully managed by supplemental haloperidol medication added to his regular depot neuroleptics. The patient currently takes 150 mg/day azathioprine and receives 40 mg/month flupentixol depot i.m. His physical and mental status are stable and he has been completely symptom free in the last 24 months. The association of myasthenia gravis and sarcoidosis is very rare. To our best knowledge no case has been reported of a patient suffering from myasthenia gravis, sarcoidosis, and schizophrenia at the same time.     

Priming by natural category membership in the left and right cerebral hemispheres

The cerebral representation of category information was examined in a single word priming paradigm, during which the N400 component of the event-related potential (ERP) was recorded. The visual half-field paradigm was employed in order to selectively stimulate the two hemispheres. To investigate which aspects of category membership are relevant in producing priming, two types of related stimuli were presented. In one condition pairs of exemplars had a higher amount of feature overlap (e.g., MOSQUITO-FLEA) than in the other (e.g., SOFA–VASE). Significant priming was obtained only for stimuli in the high feature overlap condition and then only when these were presented to the left visual field (LVF)/right hemisphere (RH). This finding was interpreted within our recent model of semantic memory wherein the right hemisphere represents items on the basis of distributed individual features, whereas the left hemisphere (LH) represents semantic information locally, within a spreading activation system, where priming occurs exclusively through associative links. It was concluded that knowledge regarding category membership is maintained in the RH, on the basis of feature coding.