Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort

Jane Salmon and colleagues studied 250 pregnant patients with SLE and/or antiphospholipid antibodies and found an association of risk variants in complement regulatory proteins in patients who developed preeclampsia, as well as in preeclampsia patients lacking autoimmune disease

Explanation and relations. How do general practitioners deal with patients with persistent medically unexplained symptoms: a focus group study

Contains fulltext : 80758.pdf (publisher's version ) (Open Access)BACKGROUND: Persistent presentation of medically unexplained symptoms (MUS) is troublesome for general practitioners (GPs) and causes pressure on the doctor-patient relationship. As a consequence, GPs face the problem of establishing an ongoing, preferably effective relationship with these patients. This study aims at exploring GPs' perceptions about explaining MUS to patients and about how relationships with these patients evolve over time in daily practice. METHODS: A qualitative approach, interviewing a purposive sample of twenty-two Dutch GPs within five focus groups. Data were analyzed according to the principles of constant comparative analysis. RESULTS: GPs recognise the importance of an adequate explanation of the diagnosis of MUS but often feel incapable of being able to explain it clearly to their patients. GPs therefore indicate that they try to reassure patients in non-specific ways, for example by telling patients that there is no disease, by using metaphors and by normalizing the symptoms. When patients keep returning with MUS, GPs report the importance of maintaining the doctor-patient relationship. GPs describe three different models to do this; mutual alliance characterized by ritual care (e.g. regular physical examination, regular doctor visits) with approval of the patient and the doctor, ambivalent alliance characterized by ritual care without approval of the doctor and non-alliance characterized by cutting off all reasons for encounter in which symptoms are not of somatic origin. CONCLUSION: GPs feel difficulties in explaining the symptoms. GPs report that, when patients keep presenting with MUS, they focus on maintaining the doctor-patient relationship by using ritual care. In this care they meticulously balance between maintaining a good doctor-patient relationship and the prevention of unintended consequences of unnecessary interventions

Protein Architecture of the Human Kinetochore Microtubule Attachment Site

Centromeric chromatin – spindle microtubule interactions mediated by kinetochores drive chromosome segregation. We have developed a two-color fluorescence light microscopy method that measures average label separation, Delta, at < 5 nm accuracy — to elucidate the protein architecture of human metaphase kinetochores. Delta analysis, when correlated with tension states of spindle-attached sister kinetochore pairs, provided information on mechanical properties of protein linkages within kinetochores. Treatment with taxol—which suppresses microtubule dynamics, eliminates tension at kinetochores, and activates the spindle checkpoint—resulted in specific large-scale changes in kinetochore architecture. Cumulatively, Delta analysis revealed compliant linkages close to the centromeric chromatin, suggests a model for how the KMN (KNL1/Mis12 complex/Ndc80 complex) network provides microtubule attachment and generates pulling forces from depolymerization, and reveals architectural changes induced by taxol treatment. The methods described here should also be applicable to other intermediate-scale biological machines in cells

Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

RELICS: A Strong Lens Model for SPT-CLJ0615-5746, a z=0.972 Cluster

We present a lens model for the cluster SPT-CLJ0615$-$5746, which is the highest redshift ($z=0.972$) system in the Reionization of Lensing Clusters Survey (RELICS), making it the highest redshift cluster for which a full strong lens model is published. We identify three systems of multiply-imaged lensed galaxies, two of which we spectroscopically confirm at $z=1.358$ and $z=4.013$, which we use as constraints for the model. We find a foreground structure at $z\sim0.4$, which we include as a second cluster-sized halo in one of our models; however two different statistical tests find the best-fit model consists of one cluster-sized halo combined with three individually optimized galaxy-sized halos, as well as contributions from the cluster galaxies themselves. We find the total projected mass density within $r=26.7"$ (the region where the strong lensing constraints exist) to be $M=2.51^{+0.15}_{-0.09}\times 10^{14}$~M$_{\odot}$. If we extrapolate out to $r_{500}$, our projected mass density is consistent with the mass inferred from weak lensing and from the Sunyaev-Zel'dovich effect ($M\sim10^{15}$~M$_{\odot}$). This cluster is lensing a previously reported $z\sim10$ galaxy, which, if spectroscopically confirmed, will be the highest-redshift strongly lensed galaxy known.Comment: 15 pages, 8 figures 4 tables. ApJ Accepte

“Medically unexplained” symptoms and symptom disorders in primary care: prognosis-based recognition and classification

Background: Many patients consult their GP because they experience bodily symptoms. In a substantial proportion of cases, the clinical picture does not meet the existing diagnostic criteria for diseases or disorders. This may be because symptoms are recent and evolving or because symptoms are persistent but, either by their character or the negative results of clinical investigation cannot be attributed to disease: so-called “medically unexplained symptoms” (MUS). MUS are inconsistently recognised, diagnosed and managed in primary care. The specialist classification systems for MUS pose several problems in a primary care setting. The systems generally require great certainty about presence or absence of physical disease, they tend to be mind-body dualistic, and they view symptoms from a narrow specialty determined perspective. We need a new classification of MUS in primary care; a classification that better supports clinical decision-making, creates clearer communication and provides scientific underpinning of research to ensure effective interventions. Discussion: We propose a classification of symptoms that places greater emphasis on prognostic factors. Prognosis-based classification aims to categorise the patient’s risk of ongoing symptoms, complications, increased healthcare use or disability because of the symptoms. Current evidence suggests several factors which may be used: symptom characteristics such as: number, multi-system pattern, frequency, severity. Other factors are: concurrent mental disorders, psychological features and demographic data. We discuss how these characteristics may be used to classify symptoms into three groups: self-limiting symptoms, recurrent and persistent symptoms, and symptom disorders. The middle group is especially relevant in primary care; as these patients generally have reduced quality of life but often go unrecognised and are at risk of iatrogenic harm. The presented characteristics do not contain immediately obvious cut-points, and the assessment of prognosis depends on a combination of several factors. Conclusion: Three criteria (multiple symptoms, multiple systems, multiple times) may support the classification into good, intermediate and poor prognosis when dealing with symptoms in primary care. The proposed new classification specifically targets the patient population in primary care and may provide a rational framework for decision-making in clinical practice and for epidemiologic and clinical research of symptoms

Sustainable prevention of obesity through integrated strategies: The SPOTLIGHT project's conceptual framework and design

<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight and obesity in Europe is high. It is a major cause of the overall rates of many of the main chronic (or non communicable) diseases in this region and is characterized by an unequal socio-economic distribution within the population. Obesity is largely determined by modifiable lifestyle behaviours such as low physical activity levels, sedentary behaviour and consumption of energy dense diets. It is increasingly being recognised that effective responses must go beyond interventions that only focus on a specific individual, social or environmental level and instead embrace system-based multi-level intervention approaches that address both the individual and environment. The EU-funded project “sustainable prevention of obesity through integrated strategies” (SPOTLIGHT) aims to increase and combine knowledge on the wide range of determinants of obesity in a systematic way, and to identify multi-level intervention approaches that are strong in terms of Reach, Efficacy, Adoption, Implementation and Maintenance (RE-AIM).</p> <p>Methods/Design</p> <p>SPOTLIGHT comprises a series of systematic reviews on: individual-level predictors of success in behaviour change obesity interventions; social and physical environmental determinants of obesity; and on the RE-AIM of multi-level interventions. An interactive web-atlas of currently running multi-level interventions will be developed, and enhancing and impeding factors for implementation will be described. At the neighbourhood level, these elements will inform the development of methods to assess obesogenicity of diverse environments, using remote imaging techniques linked to geographic information systems. The validity of these methods will be evaluated using data from surveys of health and lifestyles of adults residing in the neighbourhoods surveyed. At both the micro- and macro-levels (national and international) the different physical, economical, political and socio-cultural elements will be assessed.</p> <p>Discussion</p> <p>SPOTLIGHT offers the potential to develop approaches that combine an understanding of the obesogenicity of environments in Europe, and thus how they can be improved, with an appreciation of the individual factors that explain why people respond differently to such environments. Its findings will inform governmental authorities and professionals, academics, NGOs and private sector stakeholders engaged in the development and implementation of policies to tackle the obesity epidemic in Europe.</p

Gendering the careers of young professionals: some early findings from a longitudinal study. in Organizing/theorizing: developments in organization theory and practice

Wonders whether companies actually have employees best interests at heart across physical, mental and spiritual spheres. Posits that most organizations ignore their workforce – not even, in many cases, describing workers as assets! Describes many studies to back up this claim in theis work based on the 2002 Employment Research Unit Annual Conference, in Cardiff, Wales

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal fring as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family signifcantly linked to 7q36. We identifed and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identifed signifcantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value=0.03, OR=2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p=0.006, OR=2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p<0.001 and p<0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to caus