Controversies about a common etiology for eating and mood disorders.

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors.

Viral envelope glycoprotein processing by proprotein convertases.

The proprotein convertases (PCs) are a family of nine mammalian enzymes that play key roles in the maintenance of cell homeostasis by activating or inactivating proteins via limited proteolysis under temporal and spatial control. A wide range of pathogens, including major human pathogenic viruses can hijack cellular PCs for their own purposes. In particular, productive infection with many enveloped viruses critically depends on the processing of their fusion-active viral envelope glycoproteins by cellular PCs. Based on their crucial role in virus-host interaction, PCs can be important determinants for viral pathogenesis and represent promising targets of therapeutic antiviral intervention. In the present review we will cover basic aspects and recent developments of PC-mediated maturation of viral envelope glycoproteins of selected medically important viruses. The molecular mechanisms underlying the recognition of PCs by viral glycoproteins will be described, including recent findings demonstrating differential PC-recognition of viral and cellular substrates. We will further discuss a possible scenario how viruses during co-evolution with their hosts adapted their glycoproteins to modulate the activity of cellular PCs for their own benefit and discuss the consequences for virus-host interaction and pathogenesis. Particular attention will be given to past and current efforts to evaluate cellular PCs as targets for antiviral therapeutic intervention, with emphasis on emerging highly pathogenic viruses for which no efficacious drugs or vaccines are currently available.

Contrôle de la qualité des soins: aspects épidémiologiques. [Quality control of health care: epidemiological aspects].

Quality control in health care should be performed by health professionals. To do so they must define indicators, set up studies aimed at measuring and analyzing quality of care, and implement quality assurance programs in health care systems. The elements of a quality improvement program of this kind are described, with special emphasis on the contribution of epidemiology in this field.

Actualités en hépatologie [Highlights in hepatology]

This review highlights recent advances in hepatology, including new insights into the clinical penetrance of hereditary hemochromatosis, the development of non-immunosuppressive cyclosporin A analogs for the treatment of chronic hepatitis C, thrombopoietin receptor agonists for thrombocytopenia in cirrhosis, the development of vasopressin V2 receptor antagonists (vaptans) for the management of ascites and hyponatremia in portal hypertension, the description of chronic hepatitis E in immunosuppressed patients, and the development of sorafenib as the first molecularly targeted therapy with a demonstrated benefit in the treatment of advanced hepatocellular carcinoma. These new developments will be summarized and discussed critically, with a particular emphasis on their potential implications for current and future clinical practice.

Scientific Evidence in Europe : Admissibility, Evaluation and Equality of Arms

This study was commissioned by the European Committee on Crime Problems at the Council of Europe to describe and discuss the standards used to asses the admissibility and appraisal of scientific evidence in various member countries. After documenting cases in which faulty forensic evidence seems to have played a critical role, the authors describe the legal foundations of the issues of admissibility and assessment of the probative value in the field of scientific evidence, contrasting criminal justice systems of accusatorial and inquisitorial tradition and the various risks that they pose in terms of equality of arms. Special attention is given to communication issues between lawyers and scientific experts. The authors eventually investigate possible ways of improving the system. Among these mechanisms, emphasis is put on the adoption of a common terminology for expressing the weight of evidence. It is also proposed to adopt an harmonized interpretation framework among forensic experts rooted in good practices of logical inference.

Docking, virtual high throughput screening and in silico fragment-based drug design.

ABSTRACT The drug discovery process has been profoundly changed recently by the adoption of computational methods helping the design of new drug candidates more rapidly and at lower costs. In silico drug design consists of a collection of tools helping to make rational decisions at the different steps of the drug discovery process, such as the identification of a biomolecular target of therapeutical interest, the selection or the design of new lead compounds and their modification to obtain better affinities, as well as pharmacokinetic and pharmacodynamic properties. Among the different tools available, a particular emphasis is placed in this review on molecular docking, virtual high throughput screening and fragment-based ligand design.

Notch signaling in hematopoiesis and lymphopoiesis: lessons from Drosophila.

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self-renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH signaling is frequently linked to the induction of T leukemia in humans will also be discussed.

Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents.

In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.

Acknowledgment and psychiatric symptoms in police officers in Switzerland

The way supervisors acknowledge specific contribution and efforts of their employees has an impact on occupational health and wellbeing. Acknowledgement is a protective factor when it is sufficiently provided. We carried out a study about occupational health in police officers with special emphasis on acknowledgment and reward. A questionnaire was sent to 1000 police officers and inspectors working for a cantonal administration in Switzerland. In total, 695 participants answered the questionnaire. We used the TST questionnaire (French version of the Langner's questionnaire on psychiatric symptoms) to identify cases characterized by potential mental health problems. Multiple choice items (5 modalities ranging from "not at all" to "tremendously") were used to measure acknowledgment. The score for psychiatric symptoms was high (TST score >or= 9) for 86 police officers and inspectors for whom health might be at risk. Compared with police officers having low or medium scores for psychiatric symptoms (TST score < 9), police officers with high TST scores were more likely to report the lack of support and attention from the supervisors (odds ratio [OR] 3.2, 95% confidence interval [CI] 2.0 to 5.1) and the lack of acknowledgment by the hierarchy (OR 3.0, 95% CI 1.9 to 4.8). They were also more likely to mention that judicial authorities have a low consideration for police officers (OR 2.7, 95% CI 1.7 to 4.3) and that the public in general have a low appreciation of police officers (OR 1.8, 95% CI 1.2 to 2.9). Preserving mental health in occupations characterized by high emotional demand is challenging. Our results show that acknowledgment and mental health are associated. Further research should address a potential causal relation of acknowledgment on mental health in police officers and inspectors.

Knowledge of Glasgow coma scale by air-rescue physicians.

OBJECTIVE: To assess the theoretical and practical knowledge of the Glasgow Coma Scale (GCS) by trained Air-rescue physicians in Switzerland. METHODS: Prospective anonymous observational study with a specially designed questionnaire. General knowledge of the GCS and its use in a clinical case were assessed. RESULTS: From 130 questionnaires send out, 103 were returned (response rate of 79.2%) and analyzed. Theoretical knowledge of the GCS was consistent for registrars, fellows, consultants and private practitioners active in physician-staffed helicopters. The clinical case was wrongly scored by 38 participants (36.9%). Wrong evaluation of the motor component occurred in 28 questionnaires (27.2%), and 19 errors were made for the verbal score (18.5%). Errors were made most frequently by registrars (47.5%, p = 0.09), followed by fellows (31.6%, p = 0.67) and private practitioners (18.4%, p = 1.00). Consultants made significantly less errors than the rest of the participating physicians (0%, p < 0.05). No statistically significant differences were shown between anesthetists, general practitioners, internal medicine trainees or others. CONCLUSION: Although the theoretical knowledge of the GCS by out-of-hospital physicians is correct, significant errors were made in scoring a clinical case. Less experienced physicians had a higher rate of errors. Further emphasis on teaching the GCS is mandatory.

Ambulatory Blood Pressure and Adherence Monitoring: Diagnosing Pseudoresistant Hypertension.

A small proportion of the treated hypertensive population consistently has a blood pressure greater than 140/90 mm Hg despite a triple therapy including a diuretic, a calcium channel blocker, and a blocker of the renin-angiotensin system. According to guidelines, these patients have so-called resistant hypertension. The prevalence of this clinical condition is higher in tertiary than primary care centers and often is associated with chronic kidney disease, diabetes, obesity, and sleep apnea syndrome. Exclusion of pseudoresistant hypertension using ambulatory or home blood pressure monitoring is a crucial step in the investigation of patients with resistant hypertension. Thus, among the multiple factors to consider when investigating patients with resistant hypertension, ambulatory blood pressure monitoring should be performed very early. Among other factors to consider, physicians should investigate patient adherence to therapy, assess the adequacy of treatment, exclude interfering factors, and, finally, look for secondary forms of hypertension. Poor adherence to therapy accounts for 30% to 50% of cases of resistance to therapy depending on the methodology used to diagnose adherence problems. This review discusses the clinical factors implicated in the pathogenesis of resistant hypertension with a particular emphasis on pseudoresistance, drug adherence, and the use of ambulatory blood pressure monitoring for the diagnosis and management of resistant hypertension.

Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care : A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine.

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.

The nuclear matrix: a critical appraisal.

It is becoming increasingly clear that the cell nucleus is a highly structurized organelle. Because of its tight compartmentalization, it is generally believed that a framework must exist, responsible for maintaining such a spatial organization. Over the last twenty years many investigations have been devoted to identifying the nuclear framework. Structures isolated by different techniques have been obtained in vitro and are variously referred to as nuclear matrix, nucleoskeleton or nuclear scaffold. Many different functions, such as DNA replication and repair, mRNA transcription, processing and transport have been described to occur in close association with these structures. However, there is still much debate as to whether or not any of these preparations corresponds to a nuclear framework that exists in vivo. In this article we summarize the most commonly-used methods for obtaining preparations of nuclear frameworks and we also stress the possible artifacts that can be created in vitro during the isolation procedures. Emphasis is placed also on the protein composition of the frameworks as well as on some possible signalling functions that have been recently described to occur in tight association with the nuclear matrix.

The metaphysics of quantum gravity : a causal approach

The dissertation investigates some relevant metaphysical issues arising in the context of spacetime theories. In particular, the inquiry focuses on general relativity and canonical quantum gravity. A formal definition of spacetime theory is proposed and, against this framework, an analysis of the notions of general covariance, symmetry and background independence is performed. It is argued that many conceptual issues in general relativity and canonical quantum gravity derive from putting excessive emphasis on general covariance as an ontological prin-ciple. An original metaphysical position grounded in scientific essential- ism and causal realism (weak essentialism) is developed and defended. It is argued that, in the context of general relativity, weak essentialism supports spacetime substantivalism. It is also shown that weak essentialism escapes arguments from metaphysical underdetermination by positing a particular kind of causation, dubbed geometric. The proposed interpretive framework is then applied to Bohmian mechanics, pointing out that weak essentialism nicely fits into this theory. In the end, a possible Bohmian implementation of loop quantum gravity is considered, and such a Bohmian approach is interpreted in a geometric causal fashion. Under this interpretation, Bohmian loop quantum gravity straightforwardly commits us to an ontology of elementary extensions of space whose evolution is described by a non-local law. The causal mechanism underlying this evolution clarifies many conceptual issues related to the emergence of classical spacetime from the quantum regime. Although there is as yet no fully worked out physical theory of quantum gravity, it is argued that the proposed approach sets up a standard that proposals for a serious ontology in this field should meet.

Paper money and national distress: William Huskisson and the early theories of credit, speculation and crises

This paper examines the explanation of commercial crises offered by William Huskisson in 1810 in the wake of the debate on the Bullion Report. Huskisson argued that the suspension of convertibility made it possible to extend issues of paper currency beyond its proper limits. Such an expansion, being in the interest of all parties concerned, would actually take place and stimulate excessive speculations, which would eventually prove unsustainable and bring generalized ruin and distress. Although some elements of this explanations were not new (having been anticipated by writers sucha as James Currie in 1793, William Roscoe in 1793, William Anderson in 1797 and an anonymous in 1796), Huskisson's explanation is more systematic and better organized, and his emphasis on the endogenous character of the crisis and on the instability of the dynamics of trade and credit makes it an interesting foreshadower of the theories of crises that were advanced half a century later.