Sit-to-Stand Symmetry

Asymmetric sit-to-stand (STS) and static standing mechanics may be related to fall risk and function after hip fracture. Even in those individuals who achieve an independent status in rising from STS, asymmetric movement strategies are frequently adopted. Previous research has revealed that the asymmetry is not fully explained by strength deficits alone. Stroke literature suggests that STS asymmetry is a function of perceptual deficits, such as sense of effort, however, this concept has not yet been explored following a hip fracture

The health informatics cohort enhancement project (HICE): using routinely collected primary care data to identify people with a lifetime diagnosis of psychotic disorder

Background: We have previously demonstrated that routinely collected primary care data can be used to identify potential participants for trials in depression [1]. Here we demonstrate how patients with psychotic disorders can be identified from primary care records for potential inclusion in a cohort study. We discuss the strengths and limitations of this approach; assess its potential value and report challenges encountered. Methods: We designed an algorithm with which we searched for patients with a lifetime diagnosis of psychotic disorders within the Secure Anonymised Information Linkage (SAIL) database of routinely collected health data. The algorithm was validated against the "gold standard" of a well established operational criteria checklist for psychotic and affective illness (OPCRIT). Case notes of 100 patients from a community mental health team (CMHT) in Swansea were studied of whom 80 had matched GP records. Results: The algorithm had favourable test characteristics, with a very good ability to detect patients with psychotic disorders (sensitivity > 0.7) and an excellent ability not to falsely identify patients with psychotic disorders (specificity > 0.9). Conclusions: With certain limitations our algorithm can be used to search the general practice data and reliably identify patients with psychotic disorders. This may be useful in identifying candidates for potential inclusion in cohort studies

The Effect of Microcosm Biofilm Decontamination on Surface Topography, Chemistry, and Biocompatibility Dynamics of Implant Titanium Surfaces

Since the inception of dental implants, a steadily increasing prevalence of peri-implantitis has been documented. Irrespective of the treatment protocol applied for the management of peri-implantitis, this biofilm-associated pathology, continues to be a clinical challenge yielding unpredictable and variable levels of resolution, and in some cases resulting in implant loss. This paper investigated the effect of microcosm biofilm in vitro decontamination on surface topography, wettability, chemistry, and biocompatibility, following decontamination protocols applied to previously infected implant titanium (Ti) surfaces, both micro-rough -Sandblasted, Large-grit, Acid-etched (SLA)-and smooth surfaces -Machined (M). Microcosm biofilms were grown on SLA and M Ti discs. These were treated with TiBrushes (TiB), combination of TiB and photodynamic therapy (PDT), combination of TiB and 0.2%CHX/1%NaClO, plus or minus Ultraviolet-C (UV-C) radiation. Surface topography was evaluated by Scanning Electron Microscopy (SEM) and Laser Surface Profilometry. Surface function was analysed through wettability analysis. Surface chemistry evaluation of the discs was performed under SEM/Energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS). Biocompatibility was tested with the cytocompatibility assay using human osteoblast-like osteosarcoma cell line (MG-63) cells. Elemental analysis of the discs disclosed chemical surface alterations resulting from the different treatment modalities. Titanium, carbon, oxygen, sodium, aluminium, silver, were identified by EDX as the main components of all the discs. Based on the data drawn from this study, we have shown that following the decontamination of Ti surfaces the biomaterial surface chemistry and topography was altered. The type of treatment and Ti surface had a significant effect on cytocompatibility (p = 0.0001). Although, no treatment modality hindered the titanium surface biocompatibility, parameters such as the use of chemical agents and micro-rough surfaces had a higher cytotoxic effect in MG-63 cells. The use of smooth surfaces, and photofunctionalisation of the TiO2 layer had a beneficial effect on cytocompatibility following decontamination

Sol-gel synthesis of quaternary (P2O5)(55)-(CaO)(25)-(Na2O)((20-x))-(TiO2)(x) bioresorbable glasses for bone tissue engineering applications (x=0, 5, 10, or 15)

In the present study, we report a new and facile sol–gel synthesis of phosphate-based glasses with the general formula of (P2O5)55–(CaO)25–(Na2O)(20−x)–(TiO2) x , where x = 0, 5, 10 or 15, for bone tissue engineering applications. The sol–gel synthesis method allows greater control over glass morphology at relatively low processing temperature (200 °C) in comparison with phosphate-based melt-derived glasses (~1000 °C). The glasses were analyzed using several characterization techniques, including x-ray diffraction (XRD), 31P magic angle spinning nuclear magnetic resonance (31P MAS-NMR), Fourier transform infrared (FTIR) spectroscopy and energy-dispersive x-ray (EDX) spectroscopy, which confirmed the amorphous and glassy nature of the prepared samples. Degradation was assessed by measuring the ion release and pH change of the storage medium. Cytocompatibility was also confirmed by culturing osteoblast-like osteosarcoma cell line MG-63 on the glass microparticles over a seven-day period. Cell attachment to the particles was imaged using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The results revealed the potential of phosphate-based sol–gel derived glasses containing 5 or 10 mol% TiO2, with high surface area, ideal dissolution rate for cell attachment and easily metabolized dissolution products, for bone tissue engineering applications

Induction of Group IVC Phospholipase A2 in Allergic Asthma: Transcriptional Regulation by TNF-α in Bronchoepithelial Cells

Airway inflammation in allergen-induced asthma is associated with eicosanoid release. These bioactive lipids exhibit anti- and pro-inflammatory activities with relevance to pulmonary pathophysiology. We hypothesized that sensitization/challenge using an extract from the ubiquitous fungus, Aspergillus fumigatus (Af), in a mouse model of allergic asthma would result in altered phospholipase gene expression, thus modulating the downstream eicosanoid pathway. We observed the most significant induction in the group IVC phospholipase A2 (cPLA2γ or PLA2G4C). Our results infer that Af extract can induce cPLA2γ levels directly in eosinophils while induction in lung epithelial cells is most likely a consequence of TNF-α secretion by Af-activated macrophages. The mechanism of TNF-α-dependent induction of cPLA2γ gene expression was elucidated through a combination of promoter deletions, ChIP and overexpression studies in human bronchoepithelial cells, leading to the identification of functionally relevant CRE, NF-κB and E-box promoter elements. ChIP analysis demonstrated that RNA polymerase II, c-Jun/ATF-2, p65/p65 and USF1/USF2 complexes are recruited to the cPLA2γ enhancer/promoter in response to TNF-α with overexpression and dominant negative studies implying a strong level of cooperation and interplay between these factors. Overall, our data link cytokine-mediated alterations in cPLA2γ gene expression with allergic asthma and outline a complex regulatory mechanism

Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders and known risk factors

Background Suicide is a leading cause of death worldwide, and non-fatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium. The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via mtCOJO, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with non-psychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders

Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk

Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock

Engineering protein processing of the mammary gland to produce abundant hemophilia B therapy in milk

Both the low animal cell density of bioreactors and their ability to post-translationally process recombinant factor IX (rFIX) limit hemophilia B therapy to transgenic pigs to make rFIX in milk at about 3,000-fold higher output than provided by industrial bioreactors. However, this resulted in incomplete γ-carboxylation and propeptide cleavage where both processes are transmembrane mediated. We then bioengineered the co-expression of truncated, soluble human furin (rFurin) with pro-rFIX at a favorable enzyme to substrate ratio. This resulted in the complete conversion of pro-rFIX to rFIX while yielding a normal lactation. Importantly, these high levels of propeptide processing by soluble rFurin did not preempt γ-carboxylation in the ER and therefore was compartmentalized to the Trans-Golgi Network (TGN) and also to milk. The Golgi specific engineering demonstrated here segues the ER targeted enhancement of γ-carboxylation needed to biomanufacture coagulation proteins like rFIX using transgenic livestock

Service use of older people who participate in primary care health promotion: a latent class analysis

Background: Recruiting patients to health promotion programmes who will benefit is crucial to success. A key policy driver for health promotion in older people is to reduce health and social care use. Our aim was to describe service use among older people taking part in the Multi-dimensional Risk Appraisal for Older people primary care health promotion programme. Methods: A random sample of 1 in 3 older people (≥65 years old) was invited to participate in the Multi-dimensional Risk Appraisal for Older people project across five general practices in London and Hertfordshire. Data collected included socio-demographic characteristics, well-being and functional ability, lifestyle factors and service use. Latent class analysis (LCA) was used to identify groups based on use of the following: secondary health care, primary health care, community health care, paid care, unpaid care, leisure and local authority resources. Differences in group characteristics were assessed using univariate logistic regression, weighted by probability of class assignation and clustered by GP practice. Results: Response rate was 34% (526/1550) with 447 participants presenting sufficient data for analysis. LCA using three groups gave the most meaningful interpretation and best model fit. About a third (active well) were fit and active with low service use. Just under a third (high NHS users) had high impairments with high primary, secondary and community health care contact, but low non-health services use. Just over a third (community service users) with high impairments used community health and other services without much hospital use. Conclusion: Older people taking part in the Multi-dimensional Risk Appraisal for Older people primary care health promotion can be described as three groups: active well, high NHS users, and community service users

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

A. Palotie on työryhmän UK10K Consortium jäsen.Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF similar to 0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 x 10(-3)), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.Peer reviewe