Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia

Objectives:

This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia.

Methods:

In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18–65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score.

Results:

SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5mg, 2-tailed P = .159; 50mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated.

Conclusion:

These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.Key words: schizophrenia, negative symptoms, cognition     

First-time anterior shoulder dislocations: should they be arthroscopically stabilised?

The glenohumeral joint is inherently unstable because the large humeral head articulates with the small shadow glenoid fossa. Traumatic anterior dislocation of the shoulder is a relatively common athletic injury, and the high frequency of recurrent instability in young athletes after shoulder dislocation is discouraging to both the patient and the treating physician. Management of primary traumatic shoulder dislocation remains controversial. Traditionally, treatment involves initial immobilisation for 4–6 weeks, followed by functional rehabilitation. However, in view of the high recurrence rates associated with this traditional approach, there has been an escalating interest in determining whether immediate surgical intervention can lower the rate of recurrent shoulder dislocation, improving the patient’s quality of life. This review article aims to provide an overview of the nature and pathogenesis of first-time primary anterior shoulder dislocations, the widely accepted management modalities, and the efficacy of primary surgical intervention in first-time primary anterior shoulder dislocations.     

鸟氨酸脱羧酶的生理病理特点及其药物研究概况

鸟氨酸脱羧酶(ornithinedecarboxylase,ODC)是多胺代谢中的关键酶,广泛存在于人体和动物各组织细胞内,其中对肠细胞的增生、移行和分化起重要作用.机体调节因素比较复杂.在黏膜损伤性疾病及某些癌前病变等细胞大量增生的病理情况下ODC的表达发生改变,可以作为这些疾病分期、预后及药物作用靶点或疗效的指标.寻找对ODC有作用的药物对于治疗其相关疾病是非常有意义的.     

A review of studies of parent-child communication about sexuality and HIV/AIDS in sub-Saharan Africa

Parent-child sexuality communication has been identified as a protective factor for adolescent sexual and reproductive health, including HIV infection. The available literature on this topic in sub-Saharan Africa is increasing; however a systematic review of studies has not been conducted. This article reviews the literature in the area of parental or caregiver and child communication about sexuality and HIV/AIDS in sub-Saharan Africa. A review of peer reviewed literature published between 1980 and April 2011 was conducted. Communication process studies investigating the frequency, content, style, tone of discussions, preferences, as well as associations with and barriers to sexuality communication are reviewed. In addition, studies which examine behavioral associations with parent-child sexuality communication, and intervention studies to improve parent-child sexuality communication are examined. The findings from process studies suggest wide variation in terms of frequency of discussions, with a range of socio-demographic and other factors associated with sexuality communication. Overall, findings demonstrate that discussions tend to be authoritarian and uni-directional, characterized by vague warnings rather than direct, open discussion. Moreover, parents and young people report a number of barriers to open dialogue, including lack of knowledge and skills, as well as cultural norms and taboos. Findings are less clear when it comes to associations between parental communication and adolescent sexual activity and contraception use. However, nascent indications from intervention research suggest positive findings with increases in frequency and comfort of discussions, among other outcomes. Gaps in the research are identified and discussed with implications for future studies.     

Activation of the CPP32 protease in apoptosis induced by 1-beta-D- arabinofuranosylcytosine and other DNA-damaging agents

The response of human myeloid leukemia cells to treatment with 1-beta- arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD- pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA- insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.     

Importance of recurrence rating,morphology, hernial gap size,and risk factors in ventral and incisional hernia classification

Background

There is limited evidence on the natural course of ventral and incisional hernias and the results of hernia repair, what might partially be explained by the lack of an accepted classification system. The aim of the present study is to investigate the association of the criteria included in the Wuerzburg classification system of ventral and incisional hernias with postoperative complications and long-term recurrence.

Methods

In a retrospective cohort study, the data on 330 consecutive patients who underwent surgery to repair ventral and incisional hernias were analyzed. The following four classification criteria were applied: (a) recurrence rating (ventral, incisional or incisional recurrent); (b) morphology (location); (c) size of the hernial gap; and (d) risk factors. The primary endpoint was the occurrence of a recurrence during follow-up. Secondary endpoints were incidence of postoperative complications. Independent association between classification criteria, type of surgical procedures and postoperative complications was calculated by multivariate logistic regression analysis and between classification criteria, type of surgical procedures and risk of long-term recurrence by Cox regression analysis.

Results

Follow-up lasted a mean 47.7 ± 23.53 months (median 45 months) or 3.9 ± 1.96 years. The criterion “recurrence rating” was found as predictive factor for postoperative complications in the multivariate analysis (OR 2.04; 95 % CI 1.09–3.84; incisional vs. ventral hernia). The criterion “morphology” had influence neither on the incidence of the critical event “recurrence during follow-up” nor on the incidence of postoperative complications. Hernial gap “width” predicted postoperative complications in the multivariate analysis (OR 1.98; 95 % CI 1.19–3.29; ≤5 vs. >5 cm). Length of the hernial gap was found to be an independent prognostic factor for the critical event “recurrence during follow-up” (HR 2.05; 95 % CI 1.25–3.37; ≤5 vs. >5 cm). The presence of 3 or more risk factors was a consistent predictor for “recurrence during follow-up” (HR 2.25; 95 % CI 1.28–9.92). Mesh repair was an independent protective factor for “recurrence during follow-up” compared to suture (HR 0.53; 95 % CI 0.32–0.86).

Conclusions

The ventral and incisional hernia classification of Dietz et al. employs a clinically proven terminology and has an open classification structure. Hernial gap size and the number of risk factors are independent predictors for “recurrence during follow-up”, whereas recurrence rating and hernial gap size correlated significantly with the incidence of postoperative complications. We propose the application of these criteria for future clinical research, as larger patient numbers will be needed to refine the results.     

Isolation and characterization of covalently closed circular proviral DNA molecules of several type D retroviruses isolated from human cell lines

Infection of a human lymphoblastoid B cell line (Raji cells) with type D retroviruses, originally isolated either from subhuman primates (MPMV, LV) or from permanent human cell lines (PMFV, HeLaV, HEp-2V) led to the production of type D retrovirus particles. Subsequent cocultivation of uninfected and virus-producing Raji cells was employed for the generation of sufficient amounts of covalently closed circular DNA molecules (cccDNA). Highest amounts of cccDNA were obtained after cocultivation of virus-producing Raji cells and homologous uninfected cells at a ratio of 1 to 3 for 72 hr. The cccDNAs of type D retroviruses migrated at about 4.3 kbp compared to lambda DNA/HindIII markers. Digestion of cccDNAs with restriction endonucleases which have one recognition site generated molecules of approximately 8 kbp. The restriction endonuclease site analysis of the cccDNA of type D retroviruses revealed a genomic heterogeneity among the different isolates.