Identifying patients with chronic widespread pain in primary care.

Chronic widespread pain (CWP) is common in the general population. It is unclear how people reporting this problem present in primary care; they may regularly consult for regional pains without being recognized as having a generalized condition. Our objectives were to determine the prevalence of people consulting in primary care for musculoskeletal conditions in different body regions on different occasions (recurrent regional pain consultation), the proportion with diagnosed generalized pain and survey-reported widespread pain, and if they have features characteristic of CWP. Phase 1 used electronic records from 12 general practices in North Staffordshire (Consultations in Primary Care Archive) from 2005 to 2009. Phase 2 used linked self-reported health and primary healthcare data from 8,286 people aged 50 plus in eight general practices (North Staffordshire Osteoarthritis Project) between 2002 and 2005. In Phase 1, 11% of registered patients fulfilled criteria for recurrent regional pain consultation. Three-quarters had no recorded CWP-related generalized pain condition (e.g. fibromyalgia). In Phase 2, 53% of recurrent regional pain consulters had survey-reported widespread pain and 88% had consulted for somatic symptoms. Self-reported general health was worse in recurrent regional pain consulters than in single-region consulters, and poorest in those who also reported persistent widespread pain. Recurrent regional pain consulters are a heterogeneous group of frequent consulters sharing features with CWP (e.g. somatic symptoms) but including those less severely affected. They lie on the spectrum of polysymptomatic distress characteristic of CWP and represent a group whose needs may be better met by earlier diagnosis of multi-site pain.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Identifying patients with chronic widespread pain in primary care.

Chronic widespread pain (CWP) is common in the general population. It is unclear how people reporting this problem present in primary care; they may regularly consult for regional pains without being recognized as having a generalized condition. Our objectives were to determine the prevalence of people consulting in primary care for musculoskeletal conditions in different body regions on different occasions (recurrent regional pain consultation), the proportion with diagnosed generalized pain and survey-reported widespread pain, and if they have features characteristic of CWP. Phase 1 used electronic records from 12 general practices in North Staffordshire (Consultations in Primary Care Archive) from 2005 to 2009. Phase 2 used linked self-reported health and primary healthcare data from 8,286 people aged 50 plus in eight general practices (North Staffordshire Osteoarthritis Project) between 2002 and 2005. In Phase 1, 11% of registered patients fulfilled criteria for recurrent regional pain consultation. Three-quarters had no recorded CWP-related generalized pain condition (e.g. fibromyalgia). In Phase 2, 53% of recurrent regional pain consulters had survey-reported widespread pain and 88% had consulted for somatic symptoms. Self-reported general health was worse in recurrent regional pain consulters than in single-region consulters, and poorest in those who also reported persistent widespread pain. Recurrent regional pain consulters are a heterogeneous group of frequent consulters sharing features with CWP (e.g. somatic symptoms) but including those less severely affected. They lie on the spectrum of polysymptomatic distress characteristic of CWP and represent a group whose needs may be better met by earlier diagnosis of multi-site pain.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Association networks and social temporal dynamics in ewes and lambs

This is the final version. Available on open access from Elsevier via the DOI in this recordSheep are highly social domesticated animals that evolved to live in large and structured groups. As in other group-living species, individuals differ in the level of association they have with others, and these associations often result in lasting and stable social bonds. However, there are substantial gaps in our knowledge of the temporal social dynamics in sheep, and how their social bonds vary in relation to environmental changes. Here, we aimed to assess the social relationships between ewes and lambs, collecting dyadic associations data of 41 ewes and 55 lambs through the use of proximity loggers on a commercial farm. We computed association indices between each pair of animals to estimate the proportion of time any two individuals associated. We first generated an aggregated network of the whole 13-day observation period, and we compared the values of association indices between different types of dyads (i.e., lamb-mother, lamb-ewe non-mother, lambs littermates, lambs non-littermates, ewe-ewe). We generated aggregated contact networks on a daily scale to compare the ego-networks of individuals obtained in successive time windows to determine how stable social associations were over time. As would be expected, the highest values of association indices were found in dyads formed by dams and lambs (0.17±0.11) and by lambs of the same litter (0.32±0.09). Both single-born and twin-born lambs showed high association values with their dams (single-born: 0.24±0.11; twin-born: 0.1±0.05), although twin-born lambs had stronger associations with their littermates compared with those with their mothers (p-value < 0.001). At a temporal level, the flock exhibited periods of high network stability at the beginning and at the end of the study period. However, periods of social instability occurred one-two days after management interventions, such as changes in field size. These transitory periods of social instability were driven by changes in the association patterns of ewes and single born lambs. In contrast, the ego-networks of twin-born lambs remained relatively stable, supported by strong association levels between twins. Thus, the social instability of the social network was not a global one, but some parts of the network remained stable while others underwent important changes. Our study represents a first step to track social associations within an ewe-lamb group using proximity tags and advances our understanding of the social organisation of sheep. We highlight the importance of detecting social network instability as a consequence of different types of perturbations in order to identify the presence of social rearrangements.Biotechnology & Biological Sciences Research Council (BBSRC)CRT Foundatio

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

Annual consultation prevalence of regional musculoskeletal problems in primary care: an observational study

<p>Abstract</p> <p>Background</p> <p>Regional musculoskeletal pain such as back or shoulder pain are commonly reported symptoms in the community. The extent of consultation to primary care with such problems is unknown as a variety of labels may be used to record such consultations. The objective was to classify musculoskeletal morbidity codes used in routine primary care by body region, and to determine the annual consultation prevalence of regional musculoskeletal problems.</p> <p>Methods</p> <p>Musculoskeletal codes within the Read morbidity Code system were identified and grouped by relevant body region by four GPs. Consultations with these codes were then extracted from the recorded consultations at twelve general practices contributing to a general practice consultation database (CiPCA). Annual consultation prevalence per 10,000 registered persons for the year 2006 was determined, stratified by age and gender, for problems in individual regions and for problems affecting multiple regions.</p> <p>Results</p> <p>5,908 musculoskeletal codes were grouped into regions. One in seven of all recorded consultations were for a musculoskeletal problem. The back was the most common individual region recorded (591 people consulting per 10,000 registered persons), followed by the knee (324/10,000). In children, the foot was the most common region. Different age and gender trends were apparent across body regions although women generally had higher consultation rates. The annual consultation-based prevalence for problems encompassing more than one region was 556 people consulting per 10,000 registered persons and increased in older people and in females.</p> <p>Conclusions</p> <p>There is an extensive and varied regional musculoskeletal workload in primary care. Musculoskeletal problems are a major constituent of general practice. The output from this study can be used as a resource for planning future studies.</p

The radial arrangement of the human chromosome 7 in the lymphocyte cell nucleus is associated with chromosomal band gene density

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer-Verlag 2008.In the nuclei of human lymphocytes, chromosome territories are distributed according to the average gene density of each chromosome. However, chromosomes are very heterogeneous in size and base composition, and can contain both very gene-dense and very gene-poor regions. Thus, a precise analysis of chromosome organisation in the nuclei should consider also the distribution of DNA belonging to the chromosomal bands in each chromosome. To improve our understanding of the chromatin organisation, we localised chromosome 7 DNA regions, endowed with different gene densities, in the nuclei of human lymphocytes. Our results showed that this chromosome in cell nuclei is arranged radially with the gene-dense/GC-richest regions exposed towards the nuclear interior and the gene-poorest/GC-poorest ones located at the nuclear periphery. Moreover, we found that chromatin fibres from the 7p22.3 and the 7q22.1 bands are not confined to the territory of the bulk of this chromosome, protruding towards the inner part of the nucleus. Overall, our work demonstrates the radial arrangement of the territory of chromosome 7 in the lymphocyte nucleus and confirms that human genes occupy specific radial positions, presumably to enhance intra- and inter-chromosomal interaction among loci displaying a similar expression pattern, and/or similar replication timing

Changes in chromatin structure during processing of wax-embedded tissue sections

The use of immunofluorescence (IF) and fluorescence in situ hybridisation (FISH) underpins much of our understanding of how chromatin is organised in the nucleus. However, there has only recently been an appreciation that these types of study need to move away from cells grown in culture and towards an investigation of nuclear organisation in cells in situ in their normal tissue architecture. Such analyses, however, especially of archival clinical samples, often requires use of formalin-fixed paraffin wax-embedded tissue sections which need addition steps of processing prior to IF or FISH. Here we quantify the changes in nuclear and chromatin structure that may be caused by these additional processing steps. Treatments, especially the microwaving to reverse fixation, do significantly alter nuclear architecture and chromatin texture, and these must be considered when inferring the original organisation of the nucleus from data collected from wax-embedded tissue sections

Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds

Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

Background: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. Methods: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. Results: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. Conclusion: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration. Graphical Abstract: [Figure not available: see fulltext.]