Vitamin d and stroke: promise for prevention and better outcome.

The role of vitamin D (VitD) has recently been expanded beyond bone homeostasis and regulation of calcium levels. VitD deficiency has been proposed as a new risk factor for cardiovascular disease, including stroke. Low 25(OH)VitD levels are very common among post-stroke patients, probably due to their limited mobility and decreased sunlight exposure along with a higher prevalence of malnutrition, and they have been associated with previous and incident cerebrovascular events. Contributing mechanisms have been linked to the association of VitD deficiency with the presence of hypertension, diabetes mellitus and atherosclerosis. Moreover, there is experimental evidence demonstrating that VitD exerts neuroprotective effects, such as stimulation of neurotrophic factors, quenching of oxidative hyperactivity and regulation of neuronal death, as well as antithrombotic properties. It is plausible that VitD supplementation could be a beneficial intervention for the prevention and/or treatment of cerebrovascular disease possibly by decreasing the aforementioned cerebrovascular risk factors and simultaneously by improving neurologic and cognitive functions, thereby reducing falls and fractures in post-stroke patients. However, study results are still conflicting and data from large, randomized clinical trials are needed to clarify these speculations.

Assessing the associations between mental disorders, cardiovascular risk factors, and cardiovascular disease : the CoLaus/PsyCoLaus study

Background: Cardio-vascular diseases (CVD), their well established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, the pathogenic mechanisms and course determinants of both CVD and mental disorders have only been partially identified.Methods/Design: Comprehensive follow-up of CVRF and CVD with a psychiatric exam in all subjects who participated in the baseline cross-sectional CoLaus study (2003-2006) (n=6'738) which also included a comprehensive genetic assessment. The somatic investigation will include a shortened questionnaire on CVRF, CV events and new CVD since baseline and measurements of the same clinical and biological variables as at baseline. In addition, pro-inflammatory markers, persistent pain and sleep patterns and disorders will be assessed. In the case of a new CV event, detailed information will be abstracted from medical records. Similarly, data on the cause of death will be collected from the Swiss National Death Registry. The comprehensive psychiatric investigation of the CoLaus/PsyCoLaus study will use contemporary epidemiological methods including semi-structured diagnostic interviews, experienced clinical interviewers, standardized diagnostic criteria including threshold according to DSM-IV and sub-threshold syndromes and supplementary information on risk and protective factors for disorders. In addition, screening for objective cognitive impairment will be performed in participants older than 65 years.Discussion: The combined CoLaus/PsyCoLaus sample provides a unique opportunity to obtain prospective data on the interplay between CVRF/CVD and mental disorders, overcoming limitations of previous research by bringing together a comprehensive investigation of both CVRF and mental disorders as well as a large number of biological variables and a genome-wide genetic assessment in participants recruited from the general population.

How do the different components of episodic memory develop? Role of executive functions and short-term feature-binding abilities.

This study investigated the development of all 3 components of episodic memory (EM), as defined by Tulving, namely, core factual content, spatial context, and temporal context. To this end, a novel, ecologically valid test was administered to 109 participants aged 4-16 years. Results showed that each EM component develops at a different rate. Ability to memorize factual content emerges early, whereas context retrieval abilities continue to improve until adolescence, due to persistent encoding difficulties (isolated by comparing results on free recall and recognition tasks). Exploration of links with other cognitive functions revealed that short-term feature-binding abilities contribute to all EM components, and executive functions to temporal and spatial context, although ability to memorize temporal context is predicted mainly by age.

Molecular Mechanisms of Acute Brain Injury and Ensuing Neurodegeneration

Injury to the central nervous system (CNS), including stroke, traumatic brain injury andspinal cord injury, cause devastating and irreversible damage and loss of function. Forexample, stroke affects very large patient populations, results in major suffering for the patients and their relatives, and involves a significant cost to society. CNS damage implies disruption of the intricate internal circuits involved in cognition, the sensory-motor functions, and other important functions. There are currently no treatments available to properly restore such lost functions. New therapeutic proposals will emerge from an understanding of the interdependence of molecular and cellular responses to CNS injury, in particular the inhibitory mechanisms that block regeneration and those that enhanceneuronal plasticity...

Iron-deficiency anemia and hematochezia: when is colonoscopy appropriate?

Background: Colonoscopy is usually proposed for the evaluation of lower gastrointestinal blood loss (hematochezia) or iron deficiency anemia (IDA). Clinical practice guidelines support this approach but formal evidence is lacking. Real clinical scenarios made available on the web would be of great help in decision-making in clinical practice as to whether colonoscopy is appropriate for a given patient. Method: A multidisciplinary multinational expert panel (EPAGE II) developed appropriateness criteria based on best published evidence (systematic reviews, clinical trials, guidelines) and experts' judgement. Using the explicit RAND Appropriateness Method (3 round of experts' votes and a panel meeting) 102 clinical scenarios were judged inappropriate, uncertain, appropriate, or necessary. Results: In IDA, colonoscopy was appropriate in patients >50 years and necessary in the presence of lower abdominal symptoms. In both men and women aged <50 years, colonoscopy was appropriate if prior sigmoidoscopy and/or gastroscopy did not explain the IDA, and necessary if lower gastrointestinal symptoms were present. In women <50 years with a potential gynecological cause, additional lower gastrointestinal symptoms rendered colonoscopy appropriate. In patients >50 years with hematochezia, colonoscopy was always appropriate and mostly necessary, except if a prior colonoscopy was normal within the previous 5 years. Under age 50 years, the presence of any risk factor for colorectal cancer (CRC) and no previous normal colonoscopy (within the last 5 years) made this procedure appropriate and necessary. Conclusion: Colonoscopy is appropriate and even necessary for many indications related to iron deficiency anemia or hematochezia, in particular in patients aged >50 years. The main factors influencing appropriateness are age, results of prior investigations (sigmoidoscopy, gastroscopy, previous colonoscopy), CRC risk and sex. EPAGE II appropriateness criteria are available on www.epage.ch

Developing psychosis and its risk States through the lens of schizotypy.

Starting from the early descriptions of Kraepelin and Bleuler, the construct of schizotypy was developed from observations of aberrations in nonpsychotic family members of schizophrenia patients. In contemporary diagnostic manuals, the positive symptoms of schizotypal personality disorder were included in the ultra high-risk (UHR) criteria 20 years ago, and nowadays are broadly employed in clinical early detection of psychosis. The schizotypy construct, now dissociated from strict familial risk, also informed research on the liability to develop any psychotic disorder, and in particular schizophrenia-spectrum disorders, even outside clinical settings. Against the historical background of schizotypy it is surprising that evidence from longitudinal studies linking schizotypy, UHR, and conversion to psychosis has only recently emerged; and it still remains unclear how schizotypy may be positioned in high-risk research. Following a comprehensive literature search, we review 18 prospective studies on 15 samples examining the evidence for a link between trait schizotypy and conversion to psychosis in 4 different types of samples: general population, clinical risk samples according to UHR and/or basic symptom criteria, genetic (familial) risk, and clinical samples at-risk for a nonpsychotic schizophrenia-spectrum diagnosis. These prospective studies underline the value of schizotypy in high-risk research, but also point to the lack of evidence needed to better define the position of the construct of schizotypy within a developmental psychopathology perspective of emerging psychosis and schizophrenia-spectrum disorders.

Defining risk thresholds for a 10-year probability of hip fracture model that combines clinical risk factors and quantitative ultrasound: results using the EPISEM cohort.

Using a large prospective cohort of over 12,000 women, we determined 2 thresholds (high risk and low risk of hip fracture) to use in a 10-yr hip fracture probability model that we had previously described, a model combining the heel stiffness index measured by quantitative ultrasound (QUS) and a set of easily determined clinical risk factors (CRFs). The model identified a higher percentage of women with fractures as high risk than a previously reported risk score that combined QUS and CRF. In addition, it categorized women in a way that was quite consistent with the categorization that occurred using dual X-ray absorptiometry (DXA) and the World Health Organization (WHO) classification system; the 2 methods identified similar percentages of women with and without fractures in each of their 3 categories, but the 2 identified only in part the same women. Nevertheless, combining our composite probability model with DXA in a case findings strategy will likely further improve the detection of women at high risk of fragility hip fracture. We conclude that the currently proposed model may be of some use as an alternative to the WHO classification criteria for osteoporosis, at least when access to DXA is limited.

The PsyCoLaus study: methodology and characteristics of the sample of a population-based survey on psychiatric disorders and their association with genetic and cardiovascular risk factors.

ABSTRACT: BACKGROUND: The Psychiatric arm of the population-based CoLaus study (PsyCoLaus) is designed to: 1) establish the prevalence of threshold and subthreshold psychiatric syndromes in the 35 to 66 year-old population of the city of Lausanne (Switzerland); 2) test the validity of postulated definitions for subthreshold mood and anxiety syndromes; 3) determine the associations between psychiatric disorders, personality traits and cardiovascular diseases (CVD), 4) identify genetic variants that can modify the risk for psychiatric disorders and determine whether genetic risk factors are shared between psychiatric disorders and CVD. This paper presents the method as well as somatic and sociodemographic characteristics of the sample. METHODS: All 35 to 66 year-old persons previously selected for the population-based CoLaus survey on risk factors for CVD were asked to participate in a substudy assessing psychiatric conditions. This investigation included the Diagnostic Interview for Genetic Studies to elicit diagnostic criteria for threshold disorders according to DSM-IV and algorithmically defined subthreshold syndromes. Complementary information was gathered on potential risk and protective factors for psychiatric disorders, migraine and on the morbidity of first-degree family members, whereas the collection of DNA and plasma samples was part of the original somatic study (CoLaus). RESULTS: A total of 3,691 individuals completed the psychiatric evaluation (67% participation). The gender distribution of the sample did not differ significantly from that of the general population in the same age range. Although the youngest 5-year band of the cohort was underrepresented and the oldest 5-year band overrepresented, participants of PsyCoLaus and individuals who refused to participate revealed comparable scores on the General Health Questionnaire, a self-rating instrument completed at the somatic exam. CONCLUSIONS: Despite limitations resulting from the relatively low participation in the context of a comprehensive and time-consuming investigation, the PsyCoLaus study should significantly contribute to the current understanding of psychiatric disorders and comorbid somatic conditions by: 1) establishing the clinical relevance of specific psychiatric syndromes below the DSM-IV threshold; 2) determining comorbidity between risk factors for CVD and psychiatric disorders; 3) assessing genetic variants associated with common psychiatric disorders and 4) identifying DNA markers shared between CVD and psychiatric disorders.

Monitoring bank performance in the presence of risk

This paper proposes a managerial control tool that integrates risk in efficiency scores. Building on existing efficiency specifications, our proposal reflects the real banking technology and accurately models the relationship between desirable and undesirable outputs. Specifically, the undesirable output is defined as non-performing loans to capture credit risk, and is linked only to the relevant dimension of the output set. We empirically illustrate how our efficiency measure functions for managerial control purposes. The application considers a unique dataset of Costa Rican banks during 1998-2012. Efficiency scores? implications are mostly discussed at bank-level, and their interpretations are enhanced by using accounting ratios. We also show the usefulness of our tool for corporate governance by examining performance changes around executive turnover. Results confirm that appointing CEOs from outside the bank significantly improves performance, thus suggesting the potential benefits of new organisational practices.

Redundant functions of TCF-1 and LEF-1 during T and NK cell development, but unique role of TCF-1 for Ly49 NK cell receptor acquisition.

Members of the TCF/LEF (T cell factor / lymphoid enhancer factor) family of DNA-binding factors play important roles during embryogenesis, the establishment and/or maintenance of self-renewing tissues such as the immune system and for malignant transformation. Specifically, it has been shown that TCF-1 is required for T cell development. A role for LEF-1 became apparent when mice harbored two hypomorphic TCF-1 alleles and consequently expressed low levels of TCF-1. Here we show that NK cell development is similarly regulated by redundant functions of TCF-1 and LEF-1, whereby TCF-1 contributes significantly more to NK cell development than LEF-1. Despite this role for NK cell development, LEF-1 is not required for the establishment of a repertoire of MHC class I-specific Ly49 receptors on NK cells. The proper formation of this repertoire depends to a large extent on TCF-1. These findings suggest common and distinct functions of TCF-1 and LEF-1 during lymphocyte development.

Infection and chronic allograft dysfunction.

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract). Rarer infectious causes of chronic allograft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein-Barr virus-associated posttransplant lymphoproliferative disease, and direct cytotoxicity from adenoviral infection or parvovirus B19.

Official Positions for FRAX® Bone Mineral Density and FRAX® simplification from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Tools to predict fracture risk are useful for selecting patients for pharmacological therapy in order to reduce fracture risk and redirect limited healthcare resources to those who are most likely to benefit. FRAX® is a World Health Organization fracture risk assessment algorithm for estimating the 10-year probability of hip fracture and major osteoporotic fracture. Effective application of FRAX® in clinical practice requires a thorough understanding of its limitations as well as its utility. For some patients, FRAX® may underestimate or overestimate fracture risk. In order to address some of the common issues encountered with the use of FRAX® for individual patients, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) assigned task forces to review the medical evidence and make recommendations for optimal use of FRAX® in clinical practice. Among the issues addressed were the use of bone mineral density (BMD) measurements at skeletal sites other than the femoral neck, the use of technologies other than dual-energy X-ray absorptiometry, the use of FRAX® without BMD input, the use of FRAX® to monitor treatment, and the addition of the rate of bone loss as a clinical risk factor for FRAX®. The evidence and recommendations were presented to a panel of experts at the Joint ISCD-IOF FRAX® Position Development Conference, resulting in the development of Joint ISCD-IOF Official Positions addressing FRAX®-related issues.

Assessment of the 10-year probability of osteoporotic hip fracture combining clinical risk factors and heel bone ultrasound: the EPISEM prospective cohort of 12,958 elderly women.

This study aimed to develop a hip screening tool that combines relevant clinical risk factors (CRFs) and quantitative ultrasound (QUS) at the heel to determine the 10-yr probability of hip fractures in elderly women. The EPISEM database, comprised of approximately 13,000 women 70 yr of age, was derived from two population-based white European cohorts in France and Switzerland. All women had baseline data on CRFs and a baseline measurement of the stiffness index (SI) derived from QUS at the heel. Women were followed prospectively to identify incident fractures. Multivariate analysis was performed to determine the CRFs that contributed significantly to hip fracture risk, and these were used to generate a CRF score. Gradients of risk (GR; RR/SD change) and areas under receiver operating characteristic curves (AUC) were calculated for the CRF score, SI, and a score combining both. The 10-yr probability of hip fracture was computed for the combined model. Three hundred seven hip fractures were observed over a mean follow-up of 3.2 yr. In addition to SI, significant CRFs for hip fracture were body mass index (BMI), history of fracture, an impaired chair test, history of a recent fall, current cigarette smoking, and diabetes mellitus. The average GR for hip fracture was 2.10 per SD with the combined SI + CRF score compared with a GR of 1.77 with SI alone and of 1.52 with the CRF score alone. Thus, the use of CRFs enhanced the predictive value of SI alone. For example, in a woman 80 yr of age, the presence of two to four CRFs increased the probability of hip fracture from 16.9% to 26.6% and from 52.6% to 70.5% for SI Z-scores of +2 and -3, respectively. The combined use of CRFs and QUS SI is a promising tool to assess hip fracture probability in elderly women, especially when access to DXA is limited.

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia.

Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry.

Salt, blood pressure and cardiovascular risk : what is the most adequate preventive strategy? A Swiss perspective

Among the various strategies to reduce the incidence of non-communicable diseases reduction of sodium intake in the general population has been recognized as one of the most cost-effective means because of its potential impact on the development of hypertension and cardiovascular diseases. Yet, this strategic health recommendation of the WHO and many other international organizations is far from being universally accepted. Indeed, there are still several unresolved scientific and epidemiological questions that maintain an ongoing debate. Thus what is the adequate low level of sodium intake to recommend to the general population and whether national strategies should be oriented to the overall population or only to higher risk fractions of the population such as salt-sensitive patients are still discussed. In this paper, we shall review the recent results of the literature regarding salt, blood pressure and cardiovascular risk and we present the recommendations recently proposed by a group of experts of Switzerland. The propositions of the participating medical societies are to encourage national health authorities to continue their discussion with the food industry in order to reduce the sodium intake of food products with a target of mean salt intake of 5-6 grams per day in the population. Moreover, all initiatives to increase the information on the effect of salt on health and on the salt content of food are supported.