Glial S100B Positive Vacuoles In Purkinje Cells: Earliest Morphological Abnormality In SCA1 Transgenic Mice

Spinocerebellar ataxia-1 (SCA1) is caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-1. The overexpression of mutant ataxin-1 in SCA1 transgenic mice results in the formation of cytoplasmic vacuoles in Purkinje neurons (PKN) of the cerebellum. PKN are closely associated with neighboring Bergmann glia. To elucidate the role of Bergmann glia in SCA1 pathogenesis, cerebellar tissue from 7 days to 6 wks old SCA1 transgenic and wildtype mice were used. We observed that Bergmann glial S100B protein is localized to the cytoplasmic vacuoles in SCA1 PKN. These S100B positive cytoplasmic vacuoles began appearing much before the onset of behavioral abnormalities, and were negative for other glial and PKN marker proteins. Electron micrographs revealed that vacuoles have a double membrane. In the vacuoles, S100B colocalized with receptors of advanced glycation end-products (RAGE), and S100B co-immunoprecipated with cerebellar RAGE. In SCA1 PKN cultures, exogenous S100B protein interacted with the PKN membranes and was internalized. These data suggest that glial S100B though extrinsic to PKN is sequestered into cytoplasmic vacuoles in SCA1 mice at early postnatal ages. Further, S100B may be binding to RAGE on Purkinje cell membranes before these membranes are internalized.     

Attempted suicide in bipolar disorder pedigrees: evidence for linkage to 2p12.

BACKGROUND: We are interested in identifying susceptibility genes that predispose subjects to attempted suicide. METHODS: We conducted a secondary analysis of genome-wide linkage data from 162 bipolar pedigrees that incorporated attempted suicide as a clinical covariate. RESULTS: The strongest covariate-based linkage signal was seen on 2p12 at marker D2S1777. The logarithm of odds (LOD) score at marker D2S1777 rose from 1.56 to 3.82 after inclusion of the suicide covariate, resulting in significant chromosome-wide empirically derived p-values for the overall linkage finding (p = .01) and for the change in LOD score after the inclusion of the covariate (p = .02). CONCLUSIONS: The finding on chromosome 2 replicates results from two previous studies of attempted suicide in pedigrees with alcohol dependence and in pedigrees with recurrent early-onset depression. Combined, these three studies provide compelling evidence for a locus influencing attempted suicide on 2p12.     

Sensorimotor gating deficits in adults with autism.

BACKGROUND: Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is impaired in a family of neuropsychiatric disorders characterized by abnormalities of inhibitory function. Adults with autistic disorder (AD) exhibit clinical features of inhibitory deficits, such as restrictive and repetitive behaviors, that may be explained by deficits in sensorimotor gating. METHODS: Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-msec interstimulus intervals) were assessed in 14 adult men diagnosed with AD and 16 typically developing normal comparison (NC) participants. All participants were administered measures of intelligence and frontal-executive functioning. RESULTS: Adults with AD exhibited significantly less PPI in the 60-msec condition than NC participants, which was correlated with increased ratings of restricted and repetitive behaviors. The groups did not differ on measures of startle amplitude or overall habituation. There was, however, a significant group-by-block habituation effect. Furthermore, PPI was not related to intelligence but was moderately associated with performance on a measure of frontal-executive functioning. CONCLUSIONS: Adults with AD have sensorimotor gating deficits similar to other neurodevelopmental disorders, implicating a failure of normal inhibitory regulation of sensory, motor, and attentional mechanisms. Thus, PPI deficits may be indirectly linked to one of the hallmark features of AD.     

Propofol versus traditional sedative agents for gastrointestinal endoscopy: a meta-analysis.

BACKGROUND & AIMS: Even though propofol has better recovery profile than traditional agents, its use is limited because of the perception of increased complication rates. Because an adequately powered trial comparing risk of propofol with traditional agents is lacking, we performed a meta-analysis of the current literature. METHODS: We searched Medline (1966-October 2004), EMBASE (1980-October 2004), and Cochrane controlled trials registry. The following 4 cardiopulmonary complications were assessed: hypoxia, hypotension, arrhythmias, and apnea. Procedures were divided into 3 groups: esophagogastroduodenoscopy group, colonoscopy group, and endoscopic retrograde cholangiopancreatography/endoscopic ultrasonography group. Pooled odds ratios for complications were calculated for all the procedures combined and then separately for the 3 groups. Random effects models were used for 2-proportion comparisons. RESULTS: Of the 90 citations identified, 12 original studies qualified for this meta-analysis and included 1161 patients. Of these, 634 received propofol, and 527 received midazolam, meperidine, and/or fentanyl. Most of the included studies were randomized trials of moderate quality and nonsignificant heterogeneity (Cochran Q = 4.81, P = .90). Compared with traditional sedative agents, the pooled odds ratio with the use of propofol for developing hypoxia or hypotension for all the procedures combined was 0.74 (95% confidence interval [CI], 0.44-1.24); for EGD, 0.85 (95% CI, 0.33-2.17); for colonoscopy, 0.4 (95% CI, 0.2-0.79); and for ERCP/EUS, 1.07 (95% CI, 0.38-3.01). CONCLUSIONS: Propofol sedation during colonoscopy appears to have lower odds of cardiopulmonary complications compared with traditional agents, but for other procedures, the risk of complications is similar.     

Psychological Functioning, Nonadherence and Health Outcomes After Pediatric Liver Transplantation

The present study empirically assessed the relationships between adherence behaviors and HRQOL, parent and child psychological functioning and family functioning, and investigated the relationship between adherence behaviors and health outcomes in children who were within 5 years of their liver transplantation. Participants included 38 children (mean = 8.5 years, range 28 months to 16 years) and their parent/guardian(s). HRQOL and psychological functioning were examined using well-validated assessment measures. Measures of adherence included the rate of clinic attendance and standard deviations (SDs) of consecutive tacrolimus blood levels, which were collected and evaluated retrospectively. Measures of child health status included the frequency of hospital admissions, liver biopsies, episodes of rejection and graft function for the year prior to study participation. Results indicated that nonadherence was related to lower physical HRQOL, more limitations in social and school activities related to emotional and behavioral problems, parental emotional distress and decreased family cohesion. Nonadherence was also related to frequency and duration of hospitalizations, liver biopsies and rejection episodes. These results suggest that empirically based assessment of HRQOL, parenting stress and family functioning may help identify patients at risk for nonadherence, and may allow for the need-based delivery of appropriate clinical interventions.     

A diagnostic algorithm for male genital oedema

Male genital oedema can be defined as swelling or the appearance of swelling of the scrotum and/or the penile shaft and prepuce. Despite the various causes of genital oedema reported in the published work, a concise approach to the evaluation and management has not been sufficiently addressed.     

Picotamide inhibition of excess in vitro thromboxane B2 release by colorectal mucosa in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A2 has been proposed as a possible inflammatory mediator; its suppression may be a useful therapeutic option. METHODS: Using a tissue incubation technique, we compared release of immunoreactive thromboxane B2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. RESULTS: Increased amounts of thromboxane B2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147- 325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61- 140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64- 206), 8). Incubation with picotamide at concentrations between 100 microM and 1 mM reduced thromboxane B2 release (IC50 890 microM). CONCLUSION: Since increased thromboxane A2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.     

A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains

Summary: Bovine immunoglobulins are made from genes belonging to a small family of closely related Vh, genes. In this respect cattle resemble all species of domesticated mammals, which also use one VH family The family, named BoVH1, is homologous to the mouse Q52 family, and there are no more than 20 genes of this family in the bovine genome. Another feature of bovine heavy chains is the use of long CDR3s, which have an average of 21 codons. It seems that there are several families of long, closely related D genes rich in glycine and tyrosine responsible for this length. Sequences described as targets for mutations in other species can be found in CDR1, CDR2, and the putative D genes. The mutation mechanism starts at some point between late fetal stage and birth and seems to be antigen Independent. Diversity seems to be generated by hypermutation, although other mechanistns cannot be discomited at this time. Contrary to humans and mice, which have several Vh gene families comprising more than 100 genes, cattle use only a few genes and long CDR3s followed by somatic mutation to generate the necessary diversity to recognize the universe of antigens they will encounter during their life.