Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells

) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells.This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment

Using Ontario's "Telehealth" health telephone helpline as an early-warning system: a study protocol

BACKGROUND: The science of syndromic surveillance is still very much in its infancy. While a number of syndromic surveillance systems are being evaluated in the US, very few have had success thus far in predicting an infectious disease event. Furthermore, to date, the majority of syndromic surveillance systems have been based primarily in emergency department settings, with varying levels of enhancement from other data sources. While research has been done on the value of telephone helplines on health care use and patient satisfaction, very few projects have looked at using a telephone helpline as a source of data for syndromic surveillance, and none have been attempted in Canada. The notable exception to this statement has been in the UK where research using the national NHS Direct system as a syndromic surveillance tool has been conducted. METHODS/DESIGN: The purpose of our proposed study is to evaluate the effectiveness of Ontario's telephone nursing helpline system as a real-time syndromic surveillance system, and how its implementation, if successful, would have an impact on outbreak event detection in Ontario. Using data collected retrospectively, all "reasons for call" and assigned algorithms will be linked to a syndrome category. Using different analytic methods, normal thresholds for the different syndromes will be ascertained. This will allow for the evaluation of the system's sensitivity, specificity and positive predictive value. The next step will include the prospective monitoring of syndromic activity, both temporally and spatially. DISCUSSION: As this is a study protocol, there are currently no results to report. However, this study has been granted ethical approval, and is now being implemented. It is our hope that this syndromic surveillance system will display high sensitivity and specificity in detecting true outbreaks within Ontario, before they are detected by conventional surveillance systems. Future results will be published in peer-reviewed journals so as to contribute to the growing body of evidence on syndromic surveillance, while also providing an non US-centric perspective

Treatment of diaphyseal non-unions of the ulna and radius

Non-unions of the forearm often cause severe dysfunction of the forearm as they affect the interosseus membrane, elbow and wrist. Treatment of these non-unions can be challenging due to poor bone stock, broken hardware, scarring and stiffness due to long-term immobilisation. We retrospectively reviewed a large cohort of forearm non-unions treated by using a uniform surgical approach during a period of 33 years (1975-2008) in a single trauma centre. All non-unions were managed following the AO-principles of compression plate fixation and autologous bone grafting if needed. The study cohort consisted of 47 patients with 51 non-unions of the radius and/or ulna. The initial injury was a fracture of the diaphyseal radius and ulna in 22 patients, an isolated fracture of the diaphyseal ulna in 13, an isolated fracture of the diaphyseal radius in 5, a Monteggia fracture in 5, and a Galeazzi fracture-dislocation of the forearm in 2 patients. Index surgery for non-union consisted of open reduction and plate fixation in combination with a graft in 30 cases (59%), open reduction and plate fixation alone in 14 cases (27%), and only a graft in 7 cases (14%). The functional result was assessed in accordance to the system used by Anderson and colleagues. Average follow-up time was 75 months (range 12-315 months). All non-unions healed within a median of 7 months. According to the system of Anderson and colleagues, 29 patients (62%) had an excellent result, 8 (17%) had a satisfactory result, and 10 (21%) had an unsatisfactory result. Complications were seen in six patients (13%). Our results show that treatment of diaphyseal forearm non-unions using classic techniques of compression plating osteosynthesis and autologous bone grafting if needed will lead to a high union rate (100% in our series). Despite clinical and radiographic bone healing, however, a substantial subset of patients will have a less than optimal functional outcom

Biochemical Characterization of a Structure-Specific Resolving Enzyme from Sulfolobus islandicus Rod-Shaped Virus 2

Sulfolobus islandicus rod shaped virus 2 (SIRV2) infects the archaeon Sulfolobus islandicus at extreme temperature (70°C–80°C) and acidity (pH 3). SIRV2 encodes a Holliday junction resolving enzyme (SIRV2 Hjr) that has been proposed as a key enzyme in SIRV2 genome replication. The molecular mechanism for SIRV2 Hjr four-way junction cleavage bias, minimal requirements for four-way junction cleavage, and substrate specificity were determined. SIRV2 Hjr cleaves four-way DNA junctions with a preference for cleavage of exchange strand pairs, in contrast to host-derived resolving enzymes, suggesting fundamental differences in substrate recognition and cleavage among closely related Sulfolobus resolving enzymes. Unlike other viral resolving enzymes, such as T4 endonuclease VII or T7 endonuclease I, that cleave branched DNA replication intermediates, SIRV2 Hjr cleavage is specific to four-way DNA junctions and inactive on other branched DNA molecules. In addition, a specific interaction was detected between SIRV2 Hjr and the SIRV2 virion body coat protein (SIRV2gp26). Based on this observation, a model is proposed linking SIRV2 Hjr genome resolution to viral particle assembly

Work-life conflict and associations with work- and nonwork-related factors and with physical and mental health outcomes: a nationally representative cross-sectional study in Switzerland

BACKGROUND: The aim of the present cross-sectional study was to examine work- and nonwork-related factors and physical and mental health outcomes associated with combined time- and strain-based work-life conflict (WLC) among adult employees living and working in Switzerland as well as possible gender differences in this regard. METHODS: The data used for the study were taken from wave 6 of the nationally representative Swiss Household Panel (SHP) collected in 2004. The analysis was restricted to 4'371 employees aged 20 to 64 years. Trivariate crosstabulations and multivariate linear and logistic regression analyses stratified by gender were performed in order to calculate gender-specific prevalence rates (%), beta coefficients (SZ) and crude as well as multiple adjusted odds ratios (OR) as measures of association. RESULTS: Every eighth person (12.5%) within the study population has a high or very high WLC score. Prevalence rates are clearly above average in men and women with higher education, in executive positions or managerial functions, in full-time jobs, with variable work schedules, regular overtime, long commuting time to work and job insecurity. Working overtime regularly, having variable work schedules and being in a management position are most strongly associated with WLC in men, whereas in women the level of employment is the strongest explanatory variable by far, followed by variable work schedules and high job status (managerial position). In both men and women, WLC is associated with several physical and mental health problems. Employees with high or very high WLC show a comparatively high relative risk of self-reported poor health, anxiety and depression, lack of energy and optimism, serious backache, headaches, sleep disorders and fatigue. While overall prevalence rate of (very) high WLC is higher in men than in women, associations between degrees of WLC and most health outcomes are stronger in women than in men. CONCLUSIONS: This important issue which up to now has been largely neglected in public health research needs to be addressed in future public health research and, if the findings are confirmed by subsequent (longitudinal) studies, to be considered in workplace health promotion and interventions in Switzerland as elsewhere

Dynamical analysis of three distant trans-Neptunian objects with similar orbits

This paper reports the discovery and orbital characterization of two extreme trans-Neptunian objects (ETNOs), 2016 QV 89 and 2016 QU 89 , which have orbits that appear similar to that of a previously known object, 2013 UH 15 . All three ETNOs have semi-major axes a≈172 AU and eccentricities e≈0.77 . The angular elements (i,ω,Ω) vary by 6, 15, and 49 deg, respectively between the three objects. The two new objects add to the small number of TNOs currently known to have semi-major axes between 150 and 250 AU, and serve as an interesting dynamical laboratory to study the outer realm of our Solar System. Using a large ensemble of numerical integrations, we find that the orbits are expected to reside in close proximity in the (a,e) phase plane for roughly 100 Myr before diffusing to more separated values. We then explore other scenarios that could influence their orbits. With aphelion distances over 300 AU, the orbits of these ETNOs extend far beyond the classical Kuiper Belt, and an order of magnitude beyond Neptune. As a result, their orbital dynamics can be affected by the proposed new Solar System member, referred to as Planet Nine in this work. With perihelion distances of 35-40 AU, these orbits are also influenced by resonant interactions with Neptune. A full assessment of any possible, new Solar System planets must thus take into account this emerging class of TNOs

Effects of circadian disruption on physiology and pathology: from bench to clinic (and back)

Nested within the hypothalamus, the suprachiasmatic nuclei (SCN) represent a central biological clock that regulates daily and circadian (i.e., close to 24 h) rhythms in mammals. Besides the SCN, a number of peripheral oscillators throughout the body control local rhythms and are usually kept in pace by the central clock. In order to represent an adaptive value, circadian rhythms must be entrained by environmental signals or zeitgebers, the main one being the daily light?dark (LD) cycle. The SCN adopt a stable phase relationship with the LD cycle that, when challenged, results in abrupt or chronic changes in overt rhythms and, in turn, in physiological, behavioral, and metabolic variables. Changes in entrainment, both acute and chronic, may have severe consequences in human performance and pathological outcome. Indeed, animal models of desynchronization have become a useful tool to understand such changes and to evaluate potential treatments in human subjects. Here we review a number of alterations in circadian entrainment, including jet lag, social jet lag (i.e., desynchronization between body rhythms and normal time schedules), shift work, and exposure to nocturnal light, both in human subjects and in laboratory animals. Finally, we focus on the health consequences related to circadian/entrainment disorders and propose a number of approaches for the management of circadian desynchronization.Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Mesenchymal stem cells lack efficacy in the treatment of experimental autoimmune neuritis despite in vitro inhibition of T-cell proliferation.

Mesenchymal stem cells have been demonstrated to ameliorate experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, prompting clinical trials in multiple sclerosis which are currently ongoing. An important question is whether this therapeutic effect generalises to other autoimmune neurological diseases. We performed two trials of efficacy of MSCs in experimental autoimmune neuritis (EAN) in Lewis (LEW/Han (M)Hsd) rats, a model of human autoimmune inflammatory neuropathies. No differences between the groups were found in clinical, histological or electrophysiological outcome measures. This was despite the ability of mesenchymal stem cells to inhibit proliferation of CD4+ T-cells in vitro. Therefore the efficacy of MSCs observed in autoimmune CNS demyelination models do not necessarily generalise to the treatment of other forms of neurological autoimmunity