249 research outputs found
Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.
PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05).ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves
Exercise augmentation compared to usual care for Post Traumatic Stress Disorder: A Randomised Controlled Trial (The REAP study: Randomised Exercise Augmentation for PTSD)
<p>Abstract</p> <p>Background</p> <p>The physical wellbeing of people with mental health conditions can often be overlooked in order to treat the primary mental health condition as a priority. Exercise however, can potentially improve both the primary psychiatric condition as well as physical measures that indicate risk of other conditions such as diabetes mellitus and cardiovascular disease. Evidence supports the role of exercise as an important component of treatment for depression and anxiety, yet no randomised controlled trials (RCT's) have been conducted to evaluate the use of exercise in the treatment of people with post traumatic stress disorder (PTSD).</p> <p>This RCT will investigate the effects of structured, progressive exercise on PTSD symptoms, functional ability, body composition, physical activity levels, sleep patterns and medication usage.</p> <p>Methods and design</p> <p>Eighty participants with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of PTSD will be recruited. Participants will have no contraindications to exercise and will be cognitively able to provide consent to participate in the study.</p> <p>The primary outcome measures will be PTSD symptoms, measured through the PTSD Checklist Civilian (PCL-C) scale. Secondary outcome measures will assess depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage. All outcomes will be assessed by a health or exercise professional masked to group allocation at baseline and 12 weeks after randomisation.</p> <p>The intervention will be a 12 week individualised program, primarily involving resistance exercises with the use of exercise bands. A walking component will also be incorporated. Participants will complete one supervised session per week, and will be asked to perform at least two other non-supervised exercise sessions per week. Both intervention and control groups will receive all usual non-exercise interventions including psychotherapy, pharmaceutical interventions and group therapy.</p> <p>Discussion</p> <p>This study will determine the effect of an individualised and progressive exercise intervention on PTSD symptoms, depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage among people with a DSM-IV diagnosis of PTSD.</p> <p>Trial Registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12605000567628.aspx">ACTRN12610000579099</a></p
Identification of a Phosphorylation-Dependent Nuclear Localization Motif in Interferon Regulatory Factor 2 Binding Protein 2
Background - Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a muscle-enriched transcription factor required to activate vascular endothelial growth factor-A (VEGFA) expression in muscle. IRF2BP2 is found in the nucleus of cardiac and skeletal muscle cells. During the process of skeletal muscle differentiation, some IRF2BP2 becomes relocated to the cytoplasm, although the functional significance of this relocation and the mechanisms that control nucleocytoplasmic localization of IRF2BP2 are not yet known. // Methodology/Principal Findings - Here, by fusing IRF2BP2 to green fluorescent protein and testing a series of deletion and site-directed mutagenesis constructs, we mapped the nuclear localization signal (NLS) to an evolutionarily conserved sequence 354ARKRKPSP361 in IRF2BP2. This sequence corresponds to a classical nuclear localization motif bearing positively charged arginine and lysine residues. Substitution of arginine and lysine with negatively charged aspartic acid residues blocked nuclear localization. However, these residues were not sufficient because nuclear targeting of IRF2BP2 also required phosphorylation of serine 360 (S360). Many large-scale phosphopeptide proteomic studies had reported previously that serine 360 of IRF2BP2 is phosphorylated in numerous human cell types. Alanine substitution at this site abolished IRF2BP2 nuclear localization in C2C12 myoblasts and CV1 cells. In contrast, substituting serine 360 with aspartic acid forced nuclear retention and prevented cytoplasmic redistribution in differentiated C2C12 muscle cells. As for the effects of these mutations on VEGFA promoter activity, the S360A mutation interfered with VEGFA activation, as expected. Surprisingly, the S360D mutation also interfered with VEGFA activation, suggesting that this mutation, while enforcing nuclear entry, may disrupt an essential activation function of IRF2BP2. // Conclusions/Significance - Nuclear localization of IRF2BP2 depends on phosphorylation near a conserved NLS. Changes in phosphorylation status likely control nucleocytoplasmic localization of IRF2BP2 during muscle differentiation
The Thyroid Hormone Receptors Modulate the Skin Response to Retinoids
[Background]: Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice.
[Methodology/Principal Findings]: We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.
[Conclusions/significance]: Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds
could have not only physiological but also therapeutic implications.This work was supported by grants BFU2007-62402 and SAF2008-00121 from Ministerio de Ciencia e Innovación, RD06/0020/0036 and RD06/0020/0029 from the Fondo de Investigaciones Sanitarias and by the European Grant CRESCENDO (FP-018652).Peer reviewe
Loss of Col3a1, the Gene for Ehlers-Danlos Syndrome Type IV, Results in Neocortical Dyslamination
It has recently been discovered that Collagen III, the encoded protein of the type IV Ehlers-Danlos Syndrome (EDS) gene, is one of the major constituents of the pial basement membrane (BM) and serves as the ligand for GPR56. Mutations in GPR56 cause a severe human brain malformation called bilateral frontoparietal polymicrogyria, in which neurons transmigrate through the BM causing severe mental retardation and frequent seizures. To further characterize the brain phenotype of Col3a1 knockout mice, we performed a detailed histological analysis. We observed a cobblestone-like cortical malformation, with BM breakdown and marginal zone heterotopias in Col3a1−/− mouse brains. Surprisingly, the pial BM appeared intact at early stages of development but starting as early as embryonic day (E) 11.5, prominent BM defects were observed and accompanied by neuronal overmigration. Although collagen III is expressed in meningeal fibroblasts (MFs), Col3a1−/− MFs present no obvious defects. Furthermore, the expression and posttranslational modification of α-dystroglycan was undisturbed in Col3a1−/− mice. Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations
Hypoxia and Prostaglandin E Receptor 4 Signalling Pathways Synergise to Promote Endometrial Adenocarcinoma Cell Proliferation and Tumour Growth
The prostaglandin endoperoxide synthase (PTGS) pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG) E2. PTGS2 expression and PGE2 biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE2 regulate endometrial tumour growth is unknown. Here we investigated (a) the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3) and PGE receptors (PTGER1–4) in endometrial adenocarcinomas compared with normal endometrium and (b) the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells) xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE2 and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE2 and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells
Alumina-on-Polyethylene Bearing Surfaces in Total Hip Arthroplasty
The long-term durability of polyethylene lining total hip arthroplasty (THA) mainly depends on periprosthetic osteolysis due to wear particles, especially in young active patients. In hip simulator study, reports revealed significant wear reduction of the alumina ceramic-on-polyethylene articulation of THA compared with metal-on-polyethylene bearing surfaces. However, medium to long-term clinical studies of THA using the alumina ceramic-on-polyethylene are few and the reported wear rate of this articulation is variable. We reviewed the advantages and disadvantages of ceramicon- polyethylene articulation in THA, hip simulator study and retrieval study for polyethylene wear, in vivo clinical results of THA using alumina ceramic-on-polyethylene bearing surfaces in the literature, and new trial alumina ceramic-onhighly cross linked polyethylene bearing surfaces
Postnatal Changes in the Expression Pattern of the Imprinted Signalling Protein XLαs Underlie the Changing Phenotype of Deficient Mice
The alternatively spliced trimeric G-protein subunit XLαs, which is involved in cAMP signalling, is encoded by the Gnasxl transcript of the imprinted Gnas locus. XLαs deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy and fertile adults, which remain lean despite elevated food intake. The adult metabolic phenotype can be attributed to increased energy expenditure, which appears to be caused by elevated sympathetic nervous system activity. To better understand the changing phenotype of Gnasxl deficient mice, we compared XLαs expression in neonatal versus adult tissues, analysed its co-localisation with neural markers and characterised changes in the nutrient-sensing mTOR1-S6K pathway in the hypothalamus. Using a newly generated conditional Gnasxl lacZ gene trap line and immunohistochemistry we identified various types of muscle, including smooth muscle cells of blood vessels, as the major peripheral sites of expression in neonates. Expression in all muscle tissues was silenced in adults. While Gnasxl expression in the central nervous system was also developmentally silenced in some midbrain nuclei, it was upregulated in the preoptic area, the medial amygdala, several hypothalamic nuclei (e.g. arcuate, dorsomedial, lateral and paraventricular nuclei) and the nucleus of the solitary tract. Furthermore, expression was detected in the ventral medulla as well as in motoneurons and a subset of sympathetic preganglionic neurons of the spinal cord. In the arcuate nucleus of Gnasxl-deficient mice we found reduced activity of the nutrient sensing mTOR1-S6K signalling pathway, which concurs with their metabolic status. The expression in these brain regions and the hypermetabolic phenotype of adult Gnasxl-deficient mice imply an inhibitory function of XLαs in energy expenditure and sympathetic outflow. By contrast, the neonatal phenotype of mutant mice appears to be due to a transient role of XLαs in muscle tissues
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Working relationships between obstetric care staff and their managers: a critical incident analysis
Background
Malawi continues to experience critical shortages of key health technical cadres that can adequately respond to Malawi’s disease burden. Difficult working conditions contribute to low morale and frustration among health care workers. We aimed to understand how obstetric care staff perceive their working relationships with managers.
Methods
A qualitative exploratory study was conducted in health facilities in Malawi between October and December 2008. Critical Incident Analysis interviews were done in government district hospitals, faith-based health facilities, and a sample of health centres’ providing emergency obstetric care. A total of 84 service providers were interviewed. Data were analyzed using NVivo 8 software.
Results
Poor leadership styles affected working relationships between obstetric care staff and their managers. Main concerns were managers’ lack of support for staff welfare and staff performance, lack of mentorship for new staff and junior colleagues, as well as inadequate supportive supervision. All this led to frustrations, diminished motivation, lack of interest in their job and withdrawal from work, including staff seriously considering leaving their post.
Conclusions
Positive working relationships between obstetric care staff and their managers are essential for promoting staff motivation and positive work performance. However, this study revealed that staff were demotivated and undermined by transactional leadership styles and behavior, evidenced by management by exception and lack of feedback or recognition. A shift to transformational leadership in nurse-manager relationships is essential to establish good working relationships with staff. Improved providers’ job satisfaction and staff retentionare crucial to the provision of high quality care and will also ensure efficiency in health care delivery in Malawi
Correlations Between Gene Expression and Mercury Levels in Blood of Boys With and Without Autism
Gene expression in blood was correlated with mercury levels in blood of 2- to 5-year-old boys with autism (AU) compared to age-matched typically developing (TD) control boys. This was done to address the possibility that the two groups might metabolize toxicants, such as mercury, differently. RNA was isolated from blood and gene expression assessed on whole genome Affymetrix Human U133 expression microarrays. Mercury levels were measured using an inductively coupled plasma mass spectrometer. Analysis of covariance (ANCOVA) was performed and partial correlations between gene expression and mercury levels were calculated, after correcting for age and batch effects. To reduce false positives, only genes shared by the ANCOVA models were analyzed. Of the 26 genes that correlated with mercury levels in both AU and TD boys, 11 were significantly different between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression of a large number of genes (n = 316) correlated with mercury levels in TD but not in AU boys (P ≤ 0.05), the most represented biological functions being cell death and cell morphology. Expression of 189 genes correlated with mercury levels in AU but not in TD boys (P ≤ 0.05), the most represented biological functions being cell morphology, amino acid metabolism, and antigen presentation. These data and those in our companion study on correlation of gene expression and lead levels show that AU and TD children display different correlations between transcript levels and low levels of mercury and lead. These findings might suggest different genetic transcriptional programs associated with mercury in AU compared to TD children
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