A Th17- and Th2-skewed Cytokine Profile in Cystic Fibrosis Lungs Represents a Potential Risk Factor for Pseudomonas aeruginosa Infection.

Rationale: Cystic fibrosis (CF) is characterized by progressive pulmonary inflammation that is infection-triggered. Pseudomonas aeruginosa represents a risk factor for deterioration of lung function and reduced life expectancy. Objectives: To assess T-cell cytokine/chemokine production in clinically stable children with CF and evaluate the association between T-cell subtypes and susceptibility for infection with P. aeruginosa. Methods: T-cell cytokine/chemokine profiles were measured in bronchoalveolar lavage fluid (BALF) from children with CF (n = 57; 6.1 ± 5.9 yr) and non-CF control subjects (n = 18; 5.9 ± 4.3 yr). Memory responses to Aspergillus fumigatus and P. aeruginosa were monitored. High-resolution computed tomography-based Helbich score was assessed. In a prospective observational trial the association between BALF cytokine/chemokine profiles and subsequent infection with P. aeruginosa was studied. Measurements and Main Results: Th1- (INF-γ), Th2- (IL-5, IL-13), Th17- (IL-17A), and Th17-related cytokines (IL-1β, IL-6) were significantly up-regulated in airways of patients with CF. IL-17A, IL-13, and IL-5 were significantly higher in BALF of symptomatic as compared with clinically asymptomatic patients with CF. IL-17A and IL-5 correlated with the percentage of neutrophils in BALF (r = 0.41, P < 0.05 and r = 0.46, P < 0.05, respectively). Th17- (IL-17A, IL-6, IL-1β, IL-8) and Th2-associated cytokines and chemokines (IL-5, IL-13, TARC/CCL17), but not IFN-γ levels, significantly correlated with high-resolution computed tomography changes (Helbich score; P < 0.05). P. aeruginosa- and A. fumigatus-specific T cells from patients with CF displayed significantly higher IL-5 and IL-17A mRNA expression. IL-17A and TARC/CCL17 were significantly augmented in patients that developed P. aeruginosa infection within 24 months. Conclusions: We propose a role for Th17 and Th2 T cells in chronic inflammation in lungs of patients with CF. High concentrations of these cytokines/chemokines in CF airways precede infection with P. aeruginosa.

Mutism and Amnesia following High-Voltage Electrical Injury: Psychogenic Symptomatology Triggered by Organic Dysfunction?

Background: Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. Methods: M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. Findings: M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. Discussion: This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient.

Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene - phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: case report.

BACKGROUND: Multiple epiphyseal dysplasia (MED) is one of the more common generalised skeletal dysplasias. Due to its clinical heterogeneity diagnosis may be difficult. Mutations of at least six separate genes can cause MED. Joint deformities, joint pain and gait disorders are common symptoms. CASE PRESENTATION: We report on a 27-year-old male patient suffering from clinical symptoms of autosomal recessive MED with habitual dislocation of a multilayered patella on both sides, on the surgical treatment and on short-term clinical outcome. Clinical findings were: bilateral hip and knee pain, instability of femorotibial and patellofemoral joints with habitual patella dislocation on both sides, contractures of hip, elbow and second metacarpophalangeal joints. Main radiographic findings were: bilateral dislocated multilayered patella, dysplastic medial tibial plateaus, deformity of both femoral heads and osteoarthritis of the hip joints, and deformity of both radial heads. In the molecular genetic analysis, the DTDST mutation g.1984T > A (p.C653S) was found at the homozygote state. Carrier status was confirmed in the DNA of the patient's parents. The mutation could be considered to be the reason for the patient's disease. Surgical treatment of habitual patella dislocation with medialisation of the tibial tuberosity led to an excellent clinical outcome. CONCLUSIONS: The knowledge of different phenotypes of skeletal dysplasias helps to select genes for genetic analysis. Compared to other DTDST mutations, this is a rather mild phenotype. Molecular diagnosis is important for genetic counselling and for an accurate prognosis. Even in case of a multilayered patella in MED, habitual patella dislocation could be managed successfully by medialisation of the tibial tuberosity.

Altruism, dispersal, and phenotype-matching kin recognition.

We investigate the coevolution between philopatry and altruism in island-model populations when kin recognition occurs through phenotype matching. In saturated environments, a good discrimination ability is a necessary prerequisite for the emergence of sociality. Discrimination decreases not only with the average phenotypic similarity between immigrants and residents (i.e., with environmental homogeneity and past gene flow) but also with the sampling variance of similarity distributions (a negative function of the number of traits sampled). Whether discrimination should rely on genetically or environmentally determined traits depends on the apportionment of phenotypic variance and, in particular, on the relative values of e (the among-group component of environmental variance) and r (the among-group component of genetic variance, which also measures relatedness among group members). If r exceeds e, highly heritable cues do better. Discrimination and altruism, however, remain low unless philopatry is enforced by ecological constraints. If e exceeds r, by contrast, nonheritable traits do better. High e values improve discrimination drastically and thus have the potential to drive sociality, even in the absence of ecological constraints. The emergence of sociality thus can be facilitated by enhancing e, which we argue is the main purpose of cue standardization within groups, as observed in many social insects, birds, and mammals, including humans.

Mapping the structural core of human cerebral cortex.

Structurally segregated and functionally specialized regions of the human cerebral cortex are interconnected by a dense network of cortico-cortical axonal pathways. By using diffusion spectrum imaging, we noninvasively mapped these pathways within and across cortical hemispheres in individual human participants. An analysis of the resulting large-scale structural brain networks reveals a structural core within posterior medial and parietal cerebral cortex, as well as several distinct temporal and frontal modules. Brain regions within the structural core share high degree, strength, and betweenness centrality, and they constitute connector hubs that link all major structural modules. The structural core contains brain regions that form the posterior components of the human default network. Looking both within and outside of core regions, we observed a substantial correspondence between structural connectivity and resting-state functional connectivity measured in the same participants. The spatial and topological centrality of the core within cortex suggests an important role in functional integration.

Three essays in control, entrepreneurship and innovation

One of the key emphases of these three essays is to provide practical managerial insight. However, good practical insight, can only be created by grounding it firmly on theoretical and empirical research. Practical experience-based understanding without theoretical grounding remains tacit and cannot be easily disseminated. Theoretical understanding without links to real life remains sterile. My studies aim to increase the understanding of how radical innovation could be generated at large established firms and how it can have an impact on business performance as most businesses pursue innovation with one prime objective: value creation. My studies focus on large established firms with sales revenue exceeding USD $ 1 billion. Usually large established firms cannot rely on informal ways of management, as these firms tend to be multinational businesses operating with subsidiaries, offices, or production facilities in more than one country. I. Internal and External Determinants of Corporate Venture Capital Investment The goal of this chapter is to focus on CVC as one of the mechanisms available for established firms to source new ideas that can be exploited. We explore the internal and external determinants under which established firms engage in CVC to source new knowledge through investment in startups. We attempt to make scholars and managers aware of the forces that influence CVC activity by providing findings and insights to facilitate the strategic management of CVC. There are research opportunities to further understand the CVC phenomenon. Why do companies engage in CVC? What motivates them to continue "playing the game" and keep their active CVC investment status. The study examines CVC investment activity, and the importance of understanding the influential factors that make a firm decide to engage in CVC. The main question is: How do established firms' CVC programs adapt to changing internal conditions and external environments. Adaptation typically involves learning from exploratory endeavors, which enable companies to transform the ways they compete (Guth & Ginsberg, 1990). Our study extends the current stream of research on CVC. It aims to contribute to the literature by providing an extensive comparison of internal and external determinants leading to CVC investment activity. To our knowledge, this is the first study to examine the influence of internal and external determinants on CVC activity throughout specific expansion and contraction periods determined by structural breaks occurring between 1985 to 2008. Our econometric analysis indicates a strong and significant positive association between CVC activity and R&D, cash flow availability and environmental financial market conditions, as well as a significant negative association between sales growth and the decision to engage into CVC. The analysis of this study reveals that CVC investment is highly volatile, as demonstrated by dramatic fluctuations in CVC investment activity over the past decades. When analyzing the overall cyclical CVC period from 1985 to 2008 the results of our study suggest that CVC activity has a pattern influenced by financial factors such as the level of R&D, free cash flow, lack of sales growth, and external conditions of the economy, with the NASDAQ price index as the most significant variable influencing CVC during this period. II. Contribution of CVC and its Interaction with R&D to Value Creation The second essay takes into account the demands of corporate executives and shareholders regarding business performance and value creation justifications for investments in innovation. Billions of dollars are invested in CVC and R&D. However there is little evidence that CVC and its interaction with R&D create value. Firms operating in dynamic business sectors seek to innovate to create the value demanded by changing market conditions, consumer preferences, and competitive offerings. Consequently, firms operating in such business sectors put a premium on finding new, sustainable and competitive value propositions. CVC and R&D can help them in this challenge. Dushnitsky and Lenox (2006) presented evidence that CVC investment is associated with value creation. However, studies have shown that the most innovative firms do not necessarily benefit from innovation. For instance Oyon (2007) indicated that between 1995 and 2005 the most innovative automotive companies did not obtain adequate rewards for shareholders. The interaction between CVC and R&D has generated much debate in the CVC literature. Some researchers see them as substitutes suggesting that firms have to choose between CVC and R&D (Hellmann, 2002), while others expect them to be complementary (Chesbrough & Tucci, 2004). This study explores the interaction that CVC and R&D have on value creation. This essay examines the impact of CVC and R&D on value creation over sixteen years across six business sectors and different geographical regions. Our findings suggest that the effect of CVC and its interaction with R&D on value creation is positive and significant. In dynamic business sectors technologies rapidly relinquish obsolete, consequently firms operating in such business sectors need to continuously develop new sources of value creation (Eisenhardt & Martin, 2000; Qualls, Olshavsky, & Michaels, 1981). We conclude that in order to impact value creation, firms operating in business sectors such as Engineering & Business Services, and Information Communication & Technology ought to consider CVC as a vital element of their innovation strategy. Moreover, regarding the CVC and R&D interaction effect, our findings suggest that R&D and CVC are complementary to value creation hence firms in certain business sectors can be better off supporting both R&D and CVC simultaneously to increase the probability of generating value creation. III. MCS and Organizational Structures for Radical Innovation Incremental innovation is necessary for continuous improvement but it does not provide a sustainable permanent source of competitiveness (Cooper, 2003). On the other hand, radical innovation pursuing new technologies and new market frontiers can generate new platforms for growth providing firms with competitive advantages and high economic margin rents (Duchesneau et al., 1979; Markides & Geroski, 2005; O'Connor & DeMartino, 2006; Utterback, 1994). Interestingly, not all companies distinguish between incremental and radical innovation, and more importantly firms that manage innovation through a one-sizefits- all process can almost guarantee a sub-optimization of certain systems and resources (Davila et al., 2006). Moreover, we conducted research on the utilization of MCS along with radical innovation and flexible organizational structures as these have been associated with firm growth (Cooper, 2003; Davila & Foster, 2005, 2007; Markides & Geroski, 2005; O'Connor & DeMartino, 2006). Davila et al. (2009) identified research opportunities for innovation management and provided a list of pending issues: How do companies manage the process of radical and incremental innovation? What are the performance measures companies use to manage radical ideas and how do they select them? The fundamental objective of this paper is to address the following research question: What are the processes, MCS, and organizational structures for generating radical innovation? Moreover, in recent years, research on innovation management has been conducted mainly at either the firm level (Birkinshaw, Hamel, & Mol, 2008a) or at the project level examining appropriate management techniques associated with high levels of uncertainty (Burgelman & Sayles, 1988; Dougherty & Heller, 1994; Jelinek & Schoonhoven, 1993; Kanter, North, Bernstein, & Williamson, 1990; Leifer et al., 2000). Therefore, we embarked on a novel process-related research framework to observe the process stages, MCS, and organizational structures that can generate radical innovation. This article is based on a case study at Alcan Engineered Products, a division of a multinational company provider of lightweight material solutions. Our observations suggest that incremental and radical innovation should be managed through different processes, MCS and organizational structures that ought to be activated and adapted contingent to the type of innovation that is being pursued (i.e. incremental or radical innovation). More importantly, we conclude that radical can be generated in a systematic way through enablers such as processes, MCS, and organizational structures. This is in line with the findings of Jelinek and Schoonhoven (1993) and Davila et al. (2006; 2007) who show that innovative firms have institutionalized mechanisms, arguing that radical innovation cannot occur in an organic environment where flexibility and consensus are the main managerial mechanisms. They rather argue that radical innovation requires a clear organizational structure and formal MCS.

Evolution of Y chromosomes : lessons from mammals and amphibians

RÉSUMÉ : Le sexe des individus peut être déterminé par l'environnement ou la génétique. Lorsque la détermination du sexe est génétique, il y a dans le génome, la présence de chromosomes spécifiques qui détermineront le sexe. Dans cette thèse, j'ai étudié l'évolution des chromosomes sexuels et dans quel contexte des marqueurs sur ces chromosomes peuvent être utilisés. Pour explorer la formation du chromosome Y, nous avons étudié les caractéristiques des chromosomes sexuels chez la rainette verte, Hyla arborea. Dans un premier temps, nous avons utilisé un marqueur situé sur les chromosomes sexuels X et Y chez plusieurs espèces appartenant au groupe de la rainette verte. Cela nous a permis de révéler chez toutes ces espèces une hétérogamétie mâle. Dans un deuxième temps, nous avons tiré profit de deux autres marqueurs situés sur les chromosomes sexuels pour montrer que la recombinaison est supprimée chez les mâles mais pas chez les femelles. Pour expliquer la réduction de la variabilité sur le chromosome Y, il n'est pas nécessaire d'invoquer le balayage sélectif ou la sélection d'arrière-plan : le nombre de copies plus petit du chromosome Y dans le génome et l'absence de recombinaison suffisent à l'expliquer. Nous avons également analysé plus en détail la suppression de la recombinaison chez les mâles de H. arborea. Les modèles classiques de l'évolution des chromosomes sexuels supposent que la taille de la région non-recombinante augmente progressivement pendant l'évolution du chromosome Y, due à l'accumulation de changements structuraux. Dans cette étude, nous montrons un modèle différent, à savoir que la recombinaison est supprimée ou diminuée non seulement sur les chromosomes sexuels mais aussi sur les autosomes chez les mâles, dû à l'action de modificateurs généraux. En utilisant des marqueurs localisés sur le chromosome Y, ainsi que sur l'ADN mitochondrial et le chromosome X, nous avons étudié l'histoire évolutive de la musaraigne musette, Crocidura russula. Cette étude illustre que les analyses génétiques avec plusieurs types de marqueurs génétiques peuvent faciliter l'interprétation de l'histoire évolutive des espèces, mais que l'utilisation des marqueurs sur les chromosomes X et Y pour des études phylogéographiques est limitée par le peu de polymorphisme observé sur ces deux types de marqueurs. Le même jeu de données combiné avec des simulations a été employé pour comprendre les facteurs responsables de la faible variabilité sur le chromosome Y qui peut être expliqué, dans notre étude, par la démographie et les traits d'histoire de vie de C. russula. SUMMARY The sex of an individual is determined either by its environment or its genetics. Genetic sex determination relies on the presence of specific chromosomes that will determine the sex of their bearer. In this thesis, I studied the evolution of the sex chromosomes and the context in which markers on this type of chromosomes can be used. To explore the evolution of a Y chromosome, we studied the nascent sex chromosomes in the European tree frog Hyla arborea. First; we amplified a sex specific marker in several related species of European tree frog and found a homogeneous pattern of male heterogamety. Secondly, we used two additional sex-specific markers to show that recombination is suppressed in males but not in females. There is, therefore, no need to invoke background selection or selective sweeps to explain the reduced genetic variability on the Y chromosome, because the lower number of copies of the Y chromosomes per breeding pair and the absence of recombination are sufficient. To further analyze the suppression of recombination in male European. tree frogs, we constructed a microsatellite linkage map for this species. Classical models of sex-chromosome evolution assume that the non-recombining region expands progressively during the long-term evolution of the Y chromosome, owing to the accumulation of structural changes. Here we show a strikingly different pattern: recombination is suppressed or depressed both on sex chromosomes and autosomes in the heterogametic sex, presumably due to the action of general modifiers. We investigated the evolutionary history of the greater white-toothed shrew, Crocidura russula, using markers on both sex chromosomes and mtDNA. This study illustrates that multilocus genetic analyses facilitates the interpretation of a species' evolutionary history. It also demonstrates that phylogeographic inferences from X and Y chromosomal markers are restricted by the low levels of observed polymorphism. Combining this genetic study with simulations, we determined that the demography and the life-history traits of this species can alone be responsible for the low Y diversity. In conclusion, this thesis shows that sex chromosomes, in combination with autosomes or mtDNA, are necessary to understand the evolution of sex chromosomes and to precisely infer the population history of a species.

Phenotypic variability of retinocytomas: preregression and postregression growth patterns.

AIM: To describe the incidence of retinocytomas, their variability at presentation and their growth patterns both before and after regression.¦METHODS: Medical notes of the 525 patients of the Jules-Gonin Eye Hospital Retinoblastoma Clinic between 1964 and 2008 were reviewed and the charts of 36 patients with retinocytomas and/or phthisis bulbi were selected.¦RESULTS: The proportion of patients with retinocytomas and/or phthisis bulbi was 3.2%. The mean age at diagnosis was 28.7±17 years. Five tumours presented a cystic pattern (5.8%). Evidence of aggressive exophytic disease prior to spontaneous regression was documented in two eyes, and of invasive endophytic disease (regressed vitreous seeding or internal limiting membrane disruption) in three eyes. Twenty patients were followed with a mean follow-up of 44±60 months. Tumour growth was observed in 16% cases, benign cystic enlargement in 4% and malignant transformation in 12%.¦CONCLUSION: This large study of retinocytomas substantially expands the published features of retinocytoma by describing the cystic nature of some retinocytomas as well as clinical characteristics of the endophytic and exophytic preregression growth patterns. The authors report two different patterns of reactivation: benign cystic enlargement and malignant transformation with or without cystic growth. Higher than previously reported frequency of growth and possible life-threatening complications impose close lifetime follow-up of retinocytoma patients.

Use of high-frequency jet ventilation for percutaneous tumor ablation.

PURPOSE: To report feasibility and potential benefits of high-frequency jet ventilation (HFJV) in tumor ablations techniques in liver, kidney, and lung lesions. METHODS: This prospective study included 51 patients (14 women, mean age 66 years) bearing 66 tumors (56 hepatic, 5 pulmonary, 5 renal tumors) with a median size of 16 ± 8.7 mm, referred for tumor ablation in an intention-to-treat fashion before preoperative anesthesiology visit. Cancellation and complications of HFJV were prospectively recorded. Anesthesia and procedure duration, as well as mean CO2 capnea, were recorded. When computed tomography guidance was used, 3D spacial coordinates of an anatomical target <2 mm in diameter on 8 slabs of 4 slices of 3.75-mm slice thickness were registered. RESULTS: HFJV was used in 41 of 51 patients. Of the ten patients who were not candidate for HFJV, two patients had contraindication to HFJV (severe COPD), three had lesions invisible under HFJV requiring deep inspiration apnea for tumor targeting, and five patients could not have HFJV because of unavailability of a trained anesthetic team. No specific complication or hypercapnia related to HFJV were observed despite a mean anesthetic duration of 2 h and ventilation performed in procubitus (n = 4) or lateral decubitus (n = 6). Measured internal target movement was 0.3 mm in x- and y-axis and below the slice thickness of 3.75 mm in the z-axis in 11 patients. CONCLUSIONS: HFJV is feasible in 80 % of patients allowing for near immobility of internal organs during liver, kidney, and lung tumor ablation.

Analysis of the enantiomers of citalopram and its demethylated metabolites using chiral liquid chromatography.

A procedure using a chirobiotic V column is presented which allows separation of the enantiomers of citalopram and its two N-demethylated metabolites, and of the internal standard, alprenolol, in human plasma. Citalopram, demethylcitalopram and didemethylcitalopram, as well as the internal standard, were recovered from plasma by liquid-liquid extraction. The limits of quantification were found to be 5 ng/ml for each enantiomer of citalopram and demethylcitalopram, and 7.5 ng/ml for each enantiomer of didemethylcitalopram. Inter- and intra-day coefficients of variation varied from 2.4% to 8.6% for S- and R-citalopram, from 2.9% to 7.4% for S- and R-demethylcitalopram, and from 5.6% to 12.4% for S- and R- didemethylcitalopram. No interference was observed from endogenous compounds following the extraction of plasma samples from 10 different patients treated with citalopram. This method allows accurate quantification for each enantiomer and is, therefore, well suited for pharmacokinetic and drug interaction investigations. The presented method replaces a previously described highly sensitive and selective high-performance liquid chromatography procedure using an acetylated 3-cyclobond column which, because of manufactural problems, is no longer usable for the separation of the enantiomers of citalopram and its demethylated metabolites.

Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Health correlates of overweight and obesity in adults aged 50 years and over: results from the Survey of Health, Ageing and Retirement in Europe (SHARE)

QUESTIONS UNDER STUDY: To examine the association between overweight/obesity and several self-reported chronic diseases, symptoms and disability measures. METHODS: Data from eleven European countries participating in the Survey of Health, Ageing and Retirement in Europe were used. 18,584 non-institutionalised individuals aged 50 years and over with BMI > or = 18.5 (kg/m2) were included. BMI was categorized into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9) and obesity (BMI > or = 30). Dependent variables were 13 diagnosed chronic conditions, 11 health complaints, subjective health and physical disability measures. For both genders, multiple logistic regressions were performed adjusting for age, socioeconomic status and behaviour risks. RESULTS: The odds ratios for high blood pressure, high cholesterol, diabetes, arthritis, joint pain and swollen legs were significantly increased for overweight and obese adults. Compared to normal-weight individuals, the odds ratio (OR) for reporting > or = 2 chronic diseases was 2.4 (95% CI 1.9-2.9) for obese men and 2.7 (95% CI 2.2-3.1) for obese women. Overweight and obese women were more likely to report health symptoms. Obesity in men (OR 0.5, 95% CI 0.4-0.6), and overweight (OR 0.5, 95% CI 0.4-0.6) and obesity (OR 0.4, 95% CI 0.3-0.5) in women, were associated with poorer subjective health (i.e. a decreased risk of reporting excellent, very good or good subjective health). Disability outcomes were those showing the greatest differences in strength of association across BMI categories, and between genders. For example, the OR for any difficulty in walking 100 metres was non-significant at 0.8 for overweight men, at 1.9 (95% CI 1.3-2.7) for obese men, at 1.4 (95% CI 1.1-1.8) for overweight women, and at 3.5 (95% CI 2.6-4.7) for obese women. CONCLUSIONS: These results highlight the impact of increased BMI on morbidity and disability. Healthcare stakeholders of the participating countries should be aware of the substantial burden that obesity places on the general health and autonomy of adults aged over 50.

Vertebral microarchitecture and fragility fracture in men: a TBS study.

INTRODUCTION: Although osteoporosis is considered a disease of women, 25% of the individuals with osteoporosis are men. BMD measurement by DXA is the gold standard used to diagnose osteoporosis and assess fracture risk. Nevertheless, BMD does not take into account alterations of microarchitecture. TBS is an index of bone microarchitecture extracted from the spine DXA. Previous studies have reported the ability of the spine TBS to predict osteoporotic fractures in women. This is the first case-controlled study in men to evaluate the potential diagnostic value of TBS as a complement to bone mineral density (BMD), by comparing men with and without fractures. METHODS: To be eligible for this study, subjects had to be non-Hispanic US white men aged 40 and older. Furthermore, subjects were excluded if they have or have had previously any treatment or illness that may influence bone metabolism. Fractured subjects were included if the presence of at least one fracture was confirmed. Cases were matched for age (±3 years) and BMD (±0.04 g/cm(2)) with three controls. BMD and TBS were first retrospectively evaluated at AP spine (L1-L4) with a Prodigy densitometer (GE-Lunar, Madison, USA) and TBS iNsight® (Med-Imaps, France) in Lausanne University Hospital blinded from clinical outcome. Inter-group comparisons were undertaken using Student's t-tests or Wilcoxon signed rank tests. Odds ratios were calculated per one standard deviation decrease as well as areas under the receiver operating curve (AUC). RESULTS: After applying inclusion/exclusion criteria, a group of 180 male subjects was obtained. This group consists of 45 fractured subjects (age=63.3±12.6 years, BMI=27.1±4.2 kg/m(2)) and 135 control subjects (age=62.9±11.9 years, BMI=26.7±3.9 kg/m(2)) matched for age (p=0.86) and BMD (p=0.20). A weak correlation was obtained between TBS and BMD and between TBS and BMI (r=0.27 and r=-0.28, respectively, p<0.01). Subjects with fracture have a significant lower TBS compared to control subjects (p=0.013), whereas no differences were obtained for BMI, height and weight (p>0.10). TBS OR per standard deviation is 1.55 [1.09-2.20] for all fracture type. When considering vertebral fracture only TBS OR reached 2.07 [1.14-3.74]. CONCLUSION: This study showed the potential use of TBS in men. TBS revealed a significant difference between fractured and age- and spine BMD-matched nonfractured subjects. These results are consistent with those previously reported on for men of other nationalities.

Exposure of highway maintenance workers to fine particulate matter and noise

In this study, we assessed the mixed exposure of highway maintenance workers to airborne particles, noise, and gaseous co-pollutants. The aim was to provide a better understanding of the workers' exposure to facilitate the evaluation of short-term effects on cardiovascular health endpoints. To quantify the workers' exposure, we monitored 18 subjects during 50 non-consecutive work shifts. Exposure assessment was based on personal and work site measurements and included fine particulate matter (PM2.5), particle number concentration (PNC), noise (Leq), and the gaseous co-pollutants: carbon monoxide, nitrogen dioxide, and ozone. Mean work shift PM2.5 concentrations (gravimetric measurements) ranged from 20.3 to 321 μg m(-3) (mean 62 μg m(-3)) and PNC were between 1.6×10(4) and 4.1×10(5) particles cm(-3) (8.9×10(4) particles cm(-3)). Noise levels were generally high with Leq over work shifts from 73.3 to 96.0 dB(A); the averaged Leq over all work shifts was 87.2 dB(A). The highest exposure to fine and ultrafine particles was measured during grass mowing and lumbering when motorized brush cutters and chain saws were used. Highest noise levels, caused by pneumatic hammers, were measured during paving and guardrail repair. We found moderate Spearman correlations between PNC and PM2.5 (r = 0.56); PNC, PM2.5, and CO (r = 0.60 and r = 0.50) as well as PNC and noise (r = 0.50). Variability and correlation of parameters were influenced by work activities that included equipment causing combined air pollutant and noise emissions (e.g. brush cutters and chain saws). We conclude that highway maintenance workers are frequently exposed to elevated airborne particle and noise levels compared with the average population. This elevated exposure is a consequence of the permanent proximity to highway traffic with additional peak exposures caused by emissions of the work-related equipment.

Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.