m-CPP-induced self-grooming is mediated by 5-HT2C receptors

m-Chlorophenylpiperazine (m-CPP), a potent 5-HT receptor agonist, is known to induce self-grooming in rats and exacerbate symptoms in patients with obsessive-compulsive disorder (OCD). To characterise the possible role, 5-HT(2B) and 5-HT(2C) receptors play in m-CPP-induced self-grooming, subtype-selective receptor antagonists were used. m-CPP significantly increased the amount of self-grooming in male Sprague-Dawley rats. This effect followed a bell-shaped dose-response curve with a peak at 0.6 mg/kg, i.p. Pretreatment with SB-242084, a subtype-selective 5-HT(2C) receptor antagonist (0.1-0.5 mg/kg, i.p.), reversed m-CPP-induced self-grooming. In contrast, pretreatment with the subtype-selective 5-HT(2B) receptor antagonist SB-215505 (1 mg/kg, i.p) did not block the effect of m-CPP. Two days after depletion of brain 5-HT by p-chlorophenylalanine (p-CPA, 2 x 50, 2 x 100 mg/kg, i.p.) m-CPP-induced responses were significantly enhanced compared to controls. Our studies provide evidence that direct activation of 5-HT(2C) receptors mediate m-CPP-induced self-grooming and the depletion of brain 5-HT sensitizes these receptors.     

Interaction between LIS1 and doublecortin, two lissencephaly gene products

Mutations in either LIS1 or DCX are the most common cause for type I lissencephaly. Here we report that LIS1 and DCX interact physically both in vitro and in vivo. Epitope-tagged DCX transiently expressed in COS cells can be co-immunoprecipitated with endogenous LIS1. Furthermore, endogenous DCX could be co-immunoprecipitated with endogenous LIS1 in embryonic brain extracts, demonstrating an in vivo association. The two protein products also co-localize in transfected cells and in primary neuronal cells. In addition, we demonstrate homodimerization of DCX in vitro. Using fragments of both LIS1 and DCX, the domains of interaction were mapped. LIS1 and DCX interact with tubulin and microtubules. Our results suggest that addition of DCX and LIS1 to tubulin enhances polymerization in an additive fashion. In in vitro competition assays, when LIS1 is added first, DCX competes with LIS1 in its binding to microtubules, but when DCX is added prior to the addition of LIS1 it enhances the binding of LIS1 to microtubules. We conclude that LIS1 and DCX cross-talk is important to microtubule function in the developing cerebral cortex.     

Prognostic models: evidence-based approach to predicting disease outcome

BACKGROUND: A thorough understanding of the techniques underlying prognostic modelling, the potential shortcomings of prognostic models, and their applicability to dermatology are important for both clinicians and researchers. OBJECTIVE: This article distinguishes between prognostic and explanatory (causal) models, discusses some of the techniques used in developing a prognostic model, and addresses the importance of model generalizability. CONCLUSION: Prognostic models may be useful to the clinician, but must be used with care. It is important to critically appraise prognostic models and to assure that they are relevant to the population of interest. The ability to critically appraise prognostic models is predicated on a thorough understanding of the techniques used in their development and evaluation.     

Strategies in the development of recombinant vaccines for colon cancer

A new era involving the evaluation of recombinant vaccines for colon cancer has begun with the concurrent emergence of insights and technologies in the fields of molecular biology and immunology. These advances include (I) the identification and cloning of an array of genes associated with the neoplastic process, such as oncogenes, suppressor genes, genes encoding oncofetal antigens, and tissue lineage determinants; (2) the development of a variety of viral and bacterial vectors to deliver and present gene products; (3) the identification of numerous T-cell costimulatory molecules and the knowledge of their mode of action; (4) the cloning and analysis of the modes of action of an array of cytokines and other immunomodulatory molecules; and (5) a more sophisticated knowledge of the mode(s) of antigen presentation and T-cell activation.     

Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes

We have reported that inhibition of protein kinase C blocks the Ca(2+)-independent reverse transport of dopamine mediated by amphetamine. In this study we investigated whether activation of protein kinase C by 12-O-tetradecanoyl phorbol-13-acetate (TPA) would mediate dopamine release through the plasmalemmal dopamine transporter. TPA, at 250 nM, increased the release of dopamine from rat striatal slices and synaptosomes while the inactive phorbol ester, 4alpha-phorbol, was ineffective. The TPA-mediated dopamine release was independent of extracellular calcium and was blocked by a selective protein kinase C inhibitor, Ro31-8220. The dopamine transporter antagonists, cocaine and GBR 12935 blocked the TPA-mediated dopamine release. In addition, cocaine blocked TPA-mediated phosphorylation of the plasmalemmal dopamine transporter. These results suggest that activation of protein kinase C results in reverse transport of dopamine through the plasmalemmal dopamine transporter and the phosphorylated substrate could be the dopamine transporter.     

The relationship between premature rupture of the membranes and the respiratory distress syndrome. An update and plan of management

The records of 340 infants of 36 weeks' gestational age or less were reviewed to study the relationship between premature rupture of the membranes (PRM) and the development of the respiratory distress syndrome (RDS). Twins and infants of diabetic mothers were excluded from the data analysis. PRM of 16 hours or more was associated with statistically significant reduction in the incidence of RDS in infants of 31 weeks' gestational age and older. The association between PRM in excess of 16 hours and survival, however, was only statistically significant for infants of 33 weeks' gestational age and older. The implications of these results and a proposed plan of management for premature infants with PRM are discussed.     

ACUPUNCTURE CHANNELS - MYTH OR REALITY GS Sekhon School of Surgery and Allied Sciences

Spurred by recent advances in the ancient science of acupuncture in China, world interest in the subject has renewed. While the benefits of acupuncture are evident, its. mode of action and the existence of channels and collaterals are major controversial subjects. Based on personal experience and that of some of their colleagues and patients, the authors believe that channels and collaterals exist. These channels not only play a role in the treatment of deep seated dis- eases and analgesia induction and probably a.lso moderate normal healthy perception. The ex- istence of channels and their collaterals has not been proved anatomically.     

High-performance liquid chromatographic determination of components of bleomycin preparations

A fast and sensitive method was developed for the quantitative determination of at least 10 components of pharmaceutical bleomycin sulfate preparations. The method is based on the reversed-phase high-performance liquid chromatographic (HPLC) separation of the components on a muBondapak C18 column with a mobile phase having a linear gradient of 10--40% methanol in aqueous 0.005 M 1-pentanesulfonic acid at pH 4.3. With this assay, the average standard deviations for components A2 and B2 are 0.92 and 0.87, respectively, for a 7.5--22.5 x 10(-3)-mg sample. Regulatory agencies presently use the official Code of Federal Regulations (CFR) method, which is based on CM-Sephadex column chromatography. It was demonstrated that this CFR method does not separate the bleomycin A2 component from some other minor bleomycin components. After elution from the CM-Sephadex column, the "A2 component" was separated into five components by the HPLC method. Bleomycin A2 is stable under these HPLC conditions.     

Urinary tract infection and risk of bladder cancer

In an epidemiologic study of 2982 bladder carcinoma patients and 5782 population controls from 10 geographic areas of the United States, the role of urinary tract infection and inflammation in the etiology of this neoplasm was evaluated. A history of urinary tract infection significantly elevated the risk of bladder cancer, particularly in individuals who reported three or more infections (relative risk (RR) = 2.0). Significantly increased bladder cancer risk was also found for bladder stones (RR = 1.8), while kidney stones showed no relation. A history of three or more urinary tract infections was strongly related to squamous cell carcinoma in particular (RR = 4.8).     

Classification using ensemble learning under weighted misclassification loss

Binary classification rules based on covariates typically depend on simple loss functions such as zero-one misclassification. Some cases may require more complex loss functions. For example, individual-level monitoring of HIV-infected individuals on antiretroviral therapy requires periodic assessment of treatment failure, defined as having a viral load (VL) value above a certain threshold. In some resource limited settings, VL tests may be limited by cost or technology, and diagnoses are based on other clinical markers. Depending on scenario, higher premium may be placed on avoiding false-positives, which brings greater cost and reduced treatment options. Here, the optimal rule is determined by minimizing a weighted misclassification loss/risk. We propose a method for finding and cross-validating optimal binary classification rules under weighted misclassification loss. We focus on rules comprising a prediction score and an associated threshold, where the score is derived using an ensemble learner. Simulations and examples show that our method, which derives the score and threshold jointly, more accurately estimates overall risk and has better operating characteristics compared with methods that derive the score first and the cutoff conditionally on the score especially for finite samples.