Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Metabolic clearance rates of androgens and oestrogens in ageing women

Using the constant infusion technique we have measured the metabolic clearance rates (MCR) for Δ⁴-androstenedione (A), testosterone (T), oestrone (E₁) and oestradiol (E₂) in a large group of postmenopausal women. Their mean ± SE age was 64.5 ± 1.6 yr, their ages ranged from 46–90 yr. When the MCRs for each steroid were related to age by linear regression analysis no significant correlation was found for any of the steroids. Similarly, when the women were grouped according to their age by decade, the mean MCR for each steroid showed no trend with increasing age.

There was no difference in the MCRs for A, T and E₁ of the post-menopausal women and a large group of pre-menopausal women. However, there was a significant decrease in the mean MCR for E₂ between the two groups which is probably related to the marked decrease in circulating E₂ in postmenopausal women. We conclude that for these steroids age, per se, does not appear to be a major determinant of the MCR.     

Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex

T cell responsiveness to an epitope is affected both by its affinity for the presenting MHC molecule and the affinity of the MHC-peptide complex for TCR. One limitation of cancer immunotherapy is that natural tumor antigens elicit relatively weak T cell responses, in part because high-affinity T cells are rendered tolerant to these antigens. We report here that amino acid substitutions in a natural MHC class I-restricted tumor antigen that increase the stability of the MHC-peptide-TCR complex are significantly more potent as tumor vaccines. The improved immunity results from enhanced in vivo expansion of T cells specific for the natural tumor epitope. These results indicate peptides that stabilize the MHC-peptide-TCR complex may provide superior antitumor immunity through enhanced stimulation of specific T cells.     

Buspirone as an antidote to SSRI-induced bruxism in 4 cases

BACKGROUND: One hypothesis to explain selective serotonin reuptake inhibitor (SSRI)-induced bruxism states that SSRIs increase extrapyramidal serotonin levels, thereby inhibiting dopaminergic pathways controlling movement. Previous reports have emphasized buspirone's postsynaptic dopaminergic effect as a partial antidote to the suppressed dopamine levels. CASE REPORTS: Four patients, recently started on treatment with the SSRI sertraline, presented with new-onset complaints attributable to SSRI-induced bruxism. All 4 responded to adjunctive buspirone, a serotonin-1A (5-HT1A) receptor agonist, with relief of bruxism and associated symptoms. DISCUSSION: We expand the hypothesis put forth in previous reports by proposing that buspirone is not only acting postsynaptically in the extrapyramidal system, but also presynaptically on serotonergic neurons that influence masticatory modulation in the mesocortical tract. Our 4 cases support the concept of buspirone acting as a full agonist at the presynaptic 5-HT1A somatodendritic receptors located on the cell bodies of raphe serotonergic neurons that project to the ventral tegmental area (VTA) of the midbrain. These serotonergic neurons modulate the firing of the mesocortical tract, which itself projects from the VTA to the prefrontal cortex and acts on masticatory muscle activity through inhibiting spontaneous movements such as bruxism. While the literature is confusing and contradictory on definitions of bruxism and etiologies of incompletely understood movement disorders, we believe SSRI-induced bruxism is best conceptualized as a form of akathisia.     

Promises and pitfalls in the development of biomarkers that can promote early intervention in children at risk

The cost to individuals and to society of psychopathology that emerges in childhood is substantial. Children whose problems are undiagnosed or inadequately treated struggle in school, experience rejection by peers, and become a source of stress for caregivers and teachers. As adults, their mental health problems tend to recur and their cognitive difficulties persist. Clinicians hold a well‐founded belief that early identification of children who are at risk for psychopathology is the key to prevention.     

Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.     

Prevention of ischemia during percutaneous transluminal coronary angioplasty by transcatheter infusion of oxygenated Fluosol DA 20%

Catheter balloon inflation performed during percutaneous transluminal coronary angioplasty (PTCA) results in temporary interruption of coronary blood flow and subsequent myocardial ischemia. This produces transient but profound regional left ventricular dysfunction. In an effort to mitigate this inflation-related dysfunction, oxygenated Fluosol DA 20%, a perfluorochemical oxygen transport fluid, was infused distal to the balloon through the central lumen of the dilating catheter during balloon inflation. Regional wall motion during PTCA was assessed by simultaneous continuous two-dimensional echocardiography and was quantified by computer analysis. During control inflations accompanied by no intracoronary infusion or by transcatheter infusion of Ringer's lactate solution or nonoxygenated Fluosol DA 20%, there was profound regional left ventricular dysfunction with a greater than 90% decrease in regional contraction. In contrast, regional contraction during transcatheter infusion of oxygenated Fluosol DA 20% remained at normal levels throughout balloon inflation. Distal infusion of Fluosol DA 20% during balloon inflation is a useful adjunct to PTCA, allowing longer inflation times and perhaps permitting PTCA to be performed safely in patients with significant myocardium at ischemic risk or with limited left ventricular reserve for whom the procedure is currently believed to be too hazardous.     

Peroral Cholangioscopy with Intracorporeal Electrohydraulic Lithotripsy for Choledocholithiasis

Five patients with choledocholithiasis refractory to standard extraction methods after endoscopic sphincterotomy underwent peroral cholangioscopy with the "mother-daughter" endoscopy system. Electrohydraulic lithotripsy of nine stones was performed successfully and without complication, other than minor transient bleeding in one patient. The outer sheath of the "daughter scope" sustained a linear burn in one instance. This method of stone fragmentation is a useful adjunct to achieve ductal clearance in difficult cases.