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.     

Fetal relative lung volume: quantification by using prenatal MR imaging lung volumetry

PURPOSE: To retrospectively determine a biometric algorithm for calculating relative lung volume in fetuses with normal lungs and of a wide range of gestational ages by using proved independent variables and to retrospectively investigate the use of this algorithm in fetuses with pulmonary hypoplasia. MATERIALS AND METHODS: Total lung volume (TLV) was measured by using planimetry on single-shot rapid acquisition with relaxation enhancement magnetic resonance (MR) images obtained in 91 fetuses with ultrasonographically (US) normal chests and 28 fetuses with US-determined pulmonary hypoplasia. All fetuses were aged between 18 and 38 weeks gestation. Analysis of covariance was used to identify parameters that were not different between the fetuses with US-determined normal and those with US-determined abnormal chests, and these variables were used to construct an algorithm for calculating predicted lung volume. The relative lung volume-that is, the observed lung volume expressed as a percentage of the predicted lung volume-was then calculated in fetuses with pulmonary hypoplasia. RESULTS: There was no significant difference in mean maternal or gestational age between the two fetus groups. Stepwise regression analysis was used to generate the following equation for predicting fetal lung volume on the basis of independent biometric indexes, with a correlation coefficient of 0.93: TLV = (0.52 . LV) + (0.33 . BD) - (0.06 . FL) - 13.7, with TLV and liver volume (LV) in milliliters and biparietal diameter (BD) and femoral length (FL) in centimeters. In the fetuses with normal chests, relative lung volume varied between 51% and 134%. In the fetuses with pulmonary hypoplasia, relative lung volume varied between 6% and 70%. CONCLUSION: The predicted lung volume in fetuses of a wide range of gestational ages can be calculated with a high degree of accuracy, enabling prenatal MR imaging lung volumetry in which relative lung volume is used to quantify fetal pulmonary hypoplasia.     

A novel model of HPV infection in meshed human foreskin grafts

The present study describes a novel meshing procedure that provided successful low-risk papillomavirus propagation and reproducible wart induction in human foreskin xenografts. The initial HPV6 and/or 11 inocula were collected from clinically excised human wart tissues and confirmed to be free of HPV16, 18 and 31 by PCR analysis. Human foreskin grafts were collected from a circumcision clinic, and pre-inoculated with HPV virions by scarification. Meshing was carried out with a Zimmer Skin Grafter Mesher. Grafts were cut to appropriate size (1cm x 1cm or 5mm x 5mm) for cutaneous or subcutaneous grafting to NIH-nu-bg-xid mice under halothane anesthesia. Cutaneous xenografts were dressed with antibiotics and protective band-aids for 3 weeks. In the paralleled experiment using the same viral stock containing both HPV6 and 11, and matched grafts, no visible papillomas were observed in non-meshed cutaneous xenografts (n = 4 up to 6 months). In comparison, six of eight cutaneous xenografts treated with the meshing procedure formed visible papillomas within 4 months. This high frequency of distinct papilloma induction over the surface of meshed xenografts were reproduced in subsequent experiments with viral stocks containing both HPV11 and 6 (8 out of 10 grafts), or with a single-type HPV11 inoculum (80-100%). In contrast, an initial viral stock of single-type HPV6 provided lower frequency and more delayed papilloma induction. Serial passage of HPV6 in the meshed xenograft appeared to improve both the induction frequency and growth rate up to the 3rd generation. Histology, in situ hybridization, and immunohistochemical analysis revealed similarity of xenograft warts to those observed in the clinic. The highly reproducible papilloma induction rate and successful viral stock propagation associated with the meshing procedure provide a novel feature in the HPV xenograft model.     

Onset of pain relief with rofecoxib in chronic low back pain: results of two four-week, randomized, placebo-controlled trials

OBJECTIVE: We recently reported the efficacy of rofecoxib in two randomized controlled trials in chronic low back pain (CLBP). The objectives of this report are to present data regarding the onset of efficacy of rofecoxib from these trials and propose methods for reporting onset. RESEARCH DESIGN AND METHODS: Patients were aged 18-75, with non-radicular CLBP for >or= 3 months. Patients were randomized to rofecoxib 25mg, 50 mg, or placebo once daily for 4 weeks. Assessments included Low Back Pain and Bothersomeness scales every morning and Relief from Starting Pain after the first dose at 0.5, 1, 2, 3, 4 h, bedtime, and next morning. Onset of meaningful relief was measured by Time to Confirmed 50% Reduction in Pain and Time to Confirmed 'Slightly' or 'Not At All' Bothersome Pain. Onset of perceptible pain relief was measured by Time to At Least 'A Little' Confirmed Pain Relief. RESULTS: 690 patients entered. Significantly more patients treated with rofecoxib had compared with 1/3 receiving placebo. Median meaningful relief compared to placebo: 60.4, 58.4, and 34.7% for rofecoxib 25mg, 50 mg, and placebo (p< 0.001). Median time to meaningful relief for rofecoxib was 2 days, 1 day sooner than placebo. Rofecoxib was superior to placebo by bedtime after the first dose. CONCLUSIONS: Approximately 2/3 of patients achieved meaningful pain relief with rofecoxib time to onset of meaningful relief was about 2 days, but superior relief over placebo was seen by bedtime after the first dose. Onset of perceptible pain relief was within 2 h. We propose that measures of onset of analgesic effect include the proportion of patients who achieve meaningful pain relief and in this subgroup, the time-to-onset of confirmed meaningful reduction in pain intensity, time-to-onset of confirmed pain relief, and time to first separation from placebo in the proportion of patients who achieve meaningful pain relief.     

Large submacular hemorrhages after verteporfin therapy

PURPOSE: To report the occurrence of large submacular hemorrhages after photodynamic therapy with verteporfin in age-related macular degeneration patients with subfoveal choroidal neovascularization (CNV) composed of occult with no classic CNV in whom the hemorrhage precluded determining if additional therapy should be given within 3 months after initiation of treatment. DESIGN: Retrospective, noncomparative case series. METHODS: The records of all age-related macular degeneration patients who received verteporfin therapy for subfoveal lesions composed of occult with no classic CNV between February and July 2001 at The Wilmer Eye Institute were reviewed. Subjects who reported either having undergone a procedure to remove intraocular blood before a month 3 follow-up visit, or who had submacular hemorrhage at the month 3 visit that was severe enough to preclude determining if additional verteporfin therapy should be given were identified. RESULTS: Fifty-five eyes of 52 patients were reviewed. Five eyes (9% [95% confidence interval, 1.4%-16.6%]) developed submacular hemorrhage that precluded determining if additional verteporfin therapy should be given. Visual acuity 3 months after documentation of the hemorrhage decreased a median of 8.5 lines compared with pretreatment acuity. CONCLUSIONS: Even in the absence of acute severe visual acuity decrease, submacular hemorrhage after verteporfin therapy can be associated with severe vision loss and preclude determining if additional therapy should be given.