Risky single-occasion drinking: bingeing is not bingeing

Aims To review the concept of binge drinking as a measure of risky single occasion drinking (RSOD), to illustrate its differential impact on selected health outcomes and to identify research gaps.Methods Narrative literature review with focus on conceptual and methodological differences, trajectories of RSOD and effects of RSOD on fetal outcomes, coronary heart disease (CHD) and injuries.Results Effects ascribed commonly to RSOD may often be the effects of an undifferentiated mixture of risky single occasions and regular heavy volume drinking, constituted by frequent, successive RSOD. This leads to the problem that additional risks due to RSOD are mis-specified and remain unidentified or underestimated in some cases, such as for injuries or CHD, but are probably overstated for some chronic consequences or for effects of maternal drinking on newborns.Conclusion A stronger focus should be placed upon methods that can differentiate the effects of RSOD from those due to frequent occasions of heavy drinking that result in heavy volume drinking.

Hypoglycémie et traitement du diabète de type 2. Le retour à une normoglycémie n'est pas nécessairement la meilleure stratégie thérapeutique [Hypoglycemia and diabetes treatment: the return to normal glucose level is not always the best therapeutic strategy].

Recent clinical trials with type 2 diabetic patients and the quest of normal glyceamic values, have revealed difficulties and limitations. These too normal glyceamic targets corresponding to the physiological standards are associated with very high rate of hypoglycemia and an increase of mortality. A too simplistic view of treatment: "the lowest, the better is in the diabetes" is no longer defensible. The knowledge from complex systems behavior invites us to search targets adapted to a new state of equilibrium due to loss of self-regulation. These targets should not aim the physiological standards but to be adapted to patient's situation. Shared decision-making and consensus are the two pillars of this new strategy supported by the new ADA-EASD guidelines.

Schizotypy : do not worry, it is not all worrisome

A long-standing tradition in personality research in psychology, and nowadays increasingly in psychiatry, is that psychotic and psychotic-like thoughts are considered common experiences in the general population. Given their widespread occurrence, such experiences cannot merely reflect pathological functioning. Moreover, reflecting the multi-dimensionality of schizotypy, some dimensions might be informative for healthy functioning while others less so. Here, we explored these possibilities by reviewing research that links schizotypy to favourable functioning such as subjective wellbeing, cognitive functioning (major focus on creativity) and personality correlates. This research highlights the existence of healthy people with psychotic-like traits who mainly experience positive schizotypy (but also affective features mapping onto bipolar disorder). These individuals seem to benefit from a healthy way to organise their thoughts and experiences, i.e. they employ an adaptive cognitive framework to explain and integrate their unusual experiences. We conclude that, instead of focussing only on the pathological, future studies should explore the behavioural, genetic, imaging and psychopharmacological correlates that define the healthy expression of psychotic-like traits. Such studies would inform on protective or compensatory mechanisms of psychosis-risk and could usefully inform us on the evolutionary advantages of the psychosis dimension.

PFAPA syndrome is not a sporadic disease.

OBJECTIVES: To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. METHOD: For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. RESULTS: We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. CONCLUSION: These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.

Ultramarathon is an outstanding model for the study of adaptive responses to extreme load and stress.

ABSTRACT: Ultramarathons comprise any sporting event involving running longer than the traditional marathon length of 42.195 km (26.2 miles). Studies on ultramarathon participants can investigate the acute consequences of ultra-endurance exercise on inflammation and cardiovascular or renal consequences, as well as endocrine/energetic aspects, and examine the tissue recovery process over several days of extreme physical load. In a study published in BMC Medicine, Schütz et al. followed 44 ultramarathon runners over 4,487 km from South Italy to North Cape, Norway (the Trans Europe Foot Race 2009) and recorded daily sets of data from magnetic resonance imaging, psychometric, body composition and biological measurements. The findings will allow us to better understand the timecourse of degeneration/regeneration of some lower leg tissues such as knee joint cartilage, to differentiate running-induced from age-induced pathologies (for example, retropatelar arthritis) and finally to assess the interindividual susceptibility to injuries. Moreover, it will also provide new information about the complex interplay between cerebral adaptations/alterations and hormonal influences resulting from endurance exercise and provide data on the dose-response relationship between exercise and brain structure/function. Overall, this study represents a unique attempt to investigate the limits of the adaptive response of human bodies.Please see related article: http://www.biomedcentral.com/1741-7015/10/78.

Age above 60 years is not a negative predictive factor for combined antiviral therapy with pegylated interferon alpha and ribavirin in hepatitis C patients

Background: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral hepatitis C therapy. However, elderly patients often show relevant fibrosis or cirrhosis which is a known negative predictive factor, making it difficult to interpret age as an independent predictive factor. Methods: From the framework of the Swiss hepatitis C cohort (SCCS), we collected data from 545 antiviral hepatitis C therapies, including data from 67 hepatitis C patients ≥ 60 y who had been treated with PEG-interferon and ribavirin. We analyzed host factors (age, gender, fibrosis, haemoglobin, depression, earlier hepatitis C treatment), viral factors (genotype, viral load) and treatment course (early virological response, end of treatment response, SVR). Generalised estimating equations (GEE) regression modelling was used for the primary end point (SVR), with age ≥ 60 y and < 60 y as independent variable and gender, presence of cirrhosis, genotype, earlier treatment and viral load as confounders. SVR was analysed in young and elderly patients after matching for these confounders. Additionally, classification tree analysis was done in elderly patients using these confounders. Results: SVR analyzed in 545 patients was 55%. In genotype 1/4, SVR was 42.9% in 259 patients < 60 y and 26.1% in 46 patients ≥ 60 y. In genotype 2/3, SVR was 74.4% in 215 patients < 60 y and 84% in 25 patients ≥ 60 y. However, GEE model showed that age had no influence on achieving SVR (Odds ratio 0.91). Confounders influenced SVR as known from previous studies (cirrhosis, genotype 1/4, previous treatment and viral load >600'000 IE/ml as negative predictive factors). When young and elderly patients were matched (analysis in 59 elderly patients), SVR was not different in these patient groups (54.2% and 55.9%, resp.; p=0.795 in binomial test). The classification tree-derived best criterion for SVR in elderly patients was genotype, with no further criteria relevant for predicting SVR in genotype 2/3. In patients with genotype 1/4, further criteria were presence of cirrhosis and low viral load <600'000 IE/ml in non-cirrhotic patients. Conclusions: Age is not a relevant predictive factor for achieving SVR, when confounders were taken into account. In terms of effectiveness of antiviral therapy, age does not play a major role and should not be regarded as relevant negative predictive factor. Since life expectancy in Switzerland at age 60 is more than 22 y, hepatitis C therapy is reasonable in elderly patients with known relevant fibrosis or cirrhosis, because interferon-based hepatitis C therapy improves survival and reduces carcinogenesis.

When federalism is not enough? Paths to cooperation in Federal democracies

This paper explores an overlooked issue in the literature on federations and federalism: the relationship between federalism and democracy. Starting from the assumption that federalism per se is not enough to guarantee cooperative intergovernmental dynamics between different levels of governments, this article analyzes how democracy reinforces cooperative intergovernmental relations under a federal design. Drawing from empirical evidence of federations in the making – Brazil, India, Malaysia, Mexico, South Africa and Spain – this article shows that in countries where the federal design was built under democratization, namely Brazil, Spain and South Africa, intergovernmental dynamics evolved under an increasingly cooperative mode of interaction.

A Single High Dose of Oral Vitamin D3 Is Not Enough to Correct Insufficiency and Deficiency in a Rheumatologic Population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 μg/l), vitamin D insufficiency (10 to 30 μg/l) or normal vitamin D (>30 μg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300000 IU or 600000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1 g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30 μg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months. Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

Genetic diversity in widespread species is not congruent with species richness in alpine plant communities.

The Convention on Biological Diversity (CBD) aims at the conservation of all three levels of biodiversity, that is, ecosystems, species and genes. Genetic diversity represents evolutionary potential and is important for ecosystem functioning. Unfortunately, genetic diversity in natural populations is hardly considered in conservation strategies because it is difficult to measure and has been hypothesised to co-vary with species richness. This means that species richness is taken as a surrogate of genetic diversity in conservation planning, though their relationship has not been properly evaluated. We tested whether the genetic and species levels of biodiversity co-vary, using a large-scale and multi-species approach. We chose the high-mountain flora of the Alps and the Carpathians as study systems and demonstrate that species richness and genetic diversity are not correlated. Species richness thus cannot act as a surrogate for genetic diversity. Our results have important consequences for implementing the CBD when designing conservation strategies.

A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

The CAP1/Prss8 catalytic triad is not involved in PAR2 activation and protease nexin-1 (PN-1) inhibition.

Serine proteases, serine protease inhibitors, and protease-activated receptors (PARs) are responsible for several human skin disorders characterized by impaired epidermal permeability barrier function, desquamation, and inflammation. In this study, we addressed the consequences of a catalytically dead serine protease on epidermal homeostasis, the activation of PAR2 and the inhibition by the serine protease inhibitor nexin-1. The catalytically inactive serine protease CAP1/Prss8, when ectopically expressed in the mouse, retained the ability to induce skin disorders as well as its catalytically active counterpart (75%, n=81). Moreover, this phenotype was completely normalized in a PAR2-null background, indicating that the effects mediated by the catalytically inactive CAP1/Prss8 depend on PAR2 (95%, n=131). Finally, nexin-1 displayed analogous inhibitory capacity on both wild-type and inactive mutant CAP1/Prss8 in vitro and in vivo (64% n=151 vs. 89% n=109, respectively), indicating that the catalytic site of CAP1/Prss8 is dispensable for nexin-1 inhibition. Our results demonstrate a novel inhibitory interaction between CAP1/Prss8 and nexin-1, opening the search for specific CAP1/Prss8 antagonists that are independent of its catalytic activity.-Crisante, G., Battista, L., Iwaszkiewicz, J., Nesca, V., Mérillat, A.-M., Sergi, C., Zoete, V., Frateschi, S., Hummler, E. The CAP1/Prss8 catalytic triad is not involved in PAR2 activation and protease nexin-1 (PN-1) inhibition.

The zebrafish is an animal model in ophthalmic diseases : Fleck corneal dystrophy and Schorderet-Munier syndrome

RAPPORT DE SYNTHÈSE : Pip5k3 : Pip5k3 is a kinase responsible for fleck corneal dystrophy when mutated. It is a well conserved gene that has only been characterized in human and mouse. Characterization of pip5k3 in zebrafish was necessary before using it as a model. The protein is 70 % similar to the human homologue. The full coding sequence encompasses 6303 by and presented four isoforms. They were differentially expressed during development. All the analyzed organs of the adult zebrafish expressed pip5k3. The adult eye expressed pip5k3 in the cornea, lens, ganglion cell layer (GCL), inner nuclear layer (INL) and outer limiting membrane (OLM). During development, pip5k3 was first uniformly expressed before to be restricted to the head region and to the somites. The expression of pip5k3 in the cornea of the larval eye could make possible the study of fleck corneal dystrophy on this animal. NkxS-3 : NKXS-3 is a transcription factor responsible for a new oculo-auricular syndrome in human when mutated. This recessive disorder is characterized by defects in ear lobule and multiple defects in eye, including microphthalmia and cataract. During development, the zebrafish expressed nkx5-3 in the lens, in the anterior retina and in otic vesicles. Knockdown experiments partially phenocopied the human disease. Microphthalmia and cataract were reproduced, but zebrafish showed also defects in the cartilage of the jaw associated with a microcephaly and fins abnormalities. The retinal cell differentiation was delayed, possibly linked with the delayed expression of at`h5 and crx also observed in morphants. Shh, a regulator of ath5, was normally expressed in morphant. Overexpression of nkx5-3 lead to an anophthalmia, suggesting a role at the early organogenesis of the eye. All the phenotypes observed in morphants and embryos overexpressing nkx5-3 suggest a potential involvement of the FGF and hedgehog signaling pathways.

States of maximum entropy production in a onedimensional vertical model with convective adjustment

We investigate the hypothesis that the atmosphere is constrained to maximize its entropy production by using a one-dimensional (1-D) vertical model. We prescribe the lapse rate in the convective layer as that of the standard troposphere. The assumption that convection sustains a critical lapse rate was absent in previous studies, which focused on the vertical distribution of climatic variables, since such a convective adjustment reduces the degrees of freedom of the system and may prevent the application of the maximum entropy production (MEP) principle. This is not the case in the radiative–convective model (RCM) developed here, since we accept a discontinuity of temperatures at the surface similar to that adopted in many RCMs. For current conditions, the MEP state gives a difference between the ground temperature and the air temperature at the surface ≈10 K. In comparison, conventional RCMs obtain a discontinuity ≈2 K only. However, the surface boundary layer velocity in the MEP state appears reasonable (≈3 m s-¹). Moreover, although the convective flux at the surface in MEP states is almost uniform in optically thick atmospheres, it reaches a maximum value for an optical thickness similar to current conditions. This additional result may support the maximum convection hypothesis suggested by Paltridge (1978)

Robotic Gait Training Is not Superior to Conventional Treadmill Training in Parkinson Disease: A Single-Blind Randomized Controlled Trial.

BACKGROUND: The use of robots for gait training in Parkinson disease (PD) is growing, but no evidence points to an advantage over the standard treadmill. METHODS: In this randomized, single-blind controlled trial, participants aged <75 years with early-stage PD (Hoehn-Yahr <3) were randomly allocated to 2 groups: either 30 minutes of gait training on a treadmill or in the Lokomat for 3 d/wk for 4 weeks. Patients were evaluated by a physical therapist blinded to allocation before and at the end of treatment and then at the 3- and 6-month follow-up. The primary outcome measure was the 6-minute walk test. RESULTS: Of 334 screened patients, the authors randomly allocated 30 to receive gait training with treadmill or the Lokomat. At baseline, the 2 groups did not differ. At the 6-month follow-up, both groups had improved significantly in the primary outcome measure (treadmill: mean = 490.95 m, 95% confidence interval [CI] = 448.56-533.34, P = .0006; Lokomat: 458.6 m, 95% CI = 417.23-499.96, P = .01), but no significant differences were found between the 2 groups (P = .53). DISCUSSION: Robotic gait training with the Lokomat is not superior to treadmill training in improving gait performance in patients with PD. Both approaches are safe, with results maintained for up to 6 months.

Social Cognition is not Reducible to Theory of Mind. When Children use Deontic Rules to Predict Others' Behaviors

The objective of this paper is to discuss whether children have a capacity for deonticreasoning that is irreducible to mentalizing. The results of two experiments point tothe existence of such non-mentalistic understanding and prediction of the behaviourof others. In Study 1, young children (3- and 4-year-olds) were told different versionsof classic false-belief tasks, some of which were modified by the introduction of a ruleor a regularity. When the task (a standard change of location task) included a rule, theperformance of 3-year-olds, who fail traditional false-belief tasks, significantly improved.In Study 2, 3-year-olds proved to be able to infer a rule from a social situation and touse it in order to predict the behaviour of a character involved in a modified versionof the false-belief task. These studies suggest that rules play a central role in the socialcognition of young children and that deontic reasoning might not necessarily involvemind reading.