Allosteric modulation of beta1 integrin function induces lung repair in animal model of emphysema.

Emphysema is a progressive lung disease characterised by loss of lung parenchyma with associated functional changes including decreased tissue elastance. Here we report beta1 integrin is a novel target for tissue repair and regeneration in emphysema. We show a single dose of a monoclonal antibody against beta1 integrin induced both functional and structural reversal of elastase-induced lung injury in vivo, and we found that similar matrix remodelling changes occurred in human lung tissue. We also identified a potential mechanism of action as this allosteric modulation of beta1 integrin inhibited elastase-induced caspase activation, F-actin aggregate formation and changes in cellular ATP levels. This was accompanied by maintenance of beta1?integrin levels and inhibition of caveolin-1 phosphorylation. We propose that allosteric modulation of beta1 integrin-mediated mechanosensing prevents cell death associated with lung injury and progressive emphysema, thus allowing cells to survive and for repair and regeneration to ensue

Screening for gestational diabetes : a systematic review and economic evaluation

Background Screening for gestational diabetes mellitus (GDM) has been controversial, with some expert bodies advising universal screening, others selective screening, and yet others advising against screening at all. This has partly been a result of debate about the definition of GDM, and partly because of the profusion of different tests available, both for screening and definite diagnosis. In the UK, there is no national policy on screening, and a variety of practices exist in different parts of the country. There have also been doubts about the treatment of GDM, and particularly about management of minor degrees of glucose elevation, which are better described as glucose intolerance rather than true diabetes. Objectives To provide an updated review of current knowledge, to clarify research needs, and to assist with policy making in the interim, pending future research. Methods A literature review was carried out, with a particular focus on screening methods and costs, and an appraisal of screening for GDM against the criteria for assessing screening programmes used by the UK National Screening Committee (NSC). Results There is still debate about what is meant by GDM – the threshold for diagnosis is not soundly based; the terms GDM and impaired glucose tolerance are not used in a standard fashion in pregnancy; there is almost certainly a continuum of risk to the baby, rather than there being separate normal and abnormal groups; and the key risk factor in most women may be maternal overweight, with glucose intolerance being an associate of that. In addition there are some rare genetic conditions, which affect a few women, such as glucokinase and hepatic nuclear factor disorders. GDM is usually defined according to divergence from normal glucose levels, but glucose levels are usually raised in pregnancy, and so diagnosis by normal levels in non-pregnant women may misclassify many normal pregnant women as abnormal. This may lead to anxiety and the inconvenience of extra investigations and ‘disease’ care. The Caesarean section rate appears to be increased by the diagnosis alone. Ideally, the condition should be defined by the incidence of adverse effects. However, the most common reported complication of GDM is ‘macrosomia’ in the baby. This is usually defined by arbitrary weight cut-offs (usually a birth weight of 4000 g, but sometimes 4500 g), but such neat thresholds fail to distinguish between larger than average healthy babies and those that have the abnormal growth patterns associated with high insulin levels in the womb. Screening for GDM fails to meet some of the NSC criteria. A number of screening tests have been used but some, such as glycosylated haemoglobin and fructosamine, have proved unsatisfactory and can be discarded. Others, such as urine testing or random blood glucose, are far from satisfactory, although they may be cheap to do. There is marked international variation. Risk factors such as weight, age and family history are useful for selective screening but some patients with GDM would be missed. Fasting plasma glucose (FPG) is convenient and reliable, but some pregnant women have normal fasting levels but raised levels of glucose after meals, and would be missed by screening based on FPG alone. Glucose challenge tests (GCTs) are based on glucose levels after a glucose drink, but also have shortcomings. The definitive diagnosis is usually by oral glucose tolerance test (OGTT), but the glucose load and timing vary in different countries; taking a 75 g glucose load is unnatural, makes some women sick, and the reproducibility of the test is poor. More natural methods such as test meals have been used, but not widely. Conclusions Interim conclusions There are clearly some women whose glucose levels rise sufficiently in pregnancy to cause harm to their babies. However, there are also many women with lower levels of glucose intolerance whose babies are not at risk, but who may suffer anxiety and inconvenience as a result of being classed as abnormal. On balance, the present evidence suggests that we should not have universal screening, but a highly selective policy, based on age and overweight. The best test at present, for those deemed to need testing, is probably the GCT, preferably combined with an FPG. The benefits of a follow-up OGTT are doubtful

Analysis of breastfeeding policies and practices in childcare centres in Adelaide, South Australia

Author version made available in accordance with publisher policy.Breastfeeding policies and practices were analysed in childcare settings in the metropolitan area of Adelaide, South Australia. Childcare centres were purposively selected based on their geographical location, type and socioeconomic score of the area. Qualitative inquiry approach was employed by undertaking interviews with childcare centres’ director or baby house coordinator to explore their perception towards breastfeeding practice and support within their centre. Breastfeeding related policy documents, where available, were also collected during the interviews to triangulate data. A total of 15 face-to-face interviews were conducted. Six childcare centres had a written policy specifically on breastfeeding support, although the technical issues of handling breastmilk were included in most centres’ food and nutrition guidelines. Most participants believed that decision to breastfeed is the personal choice of parents, and hence saw the childcare centre’s role as supporting parental choice whether it is breastfeeding or not. The provision of physical space to breastfeed and facilities to store the expressed breast milk were the most common practices in support of parents who had chosen to continue breastfeeding. Participants perceived mothers’ work-related issues such as distance from the centre, time, and unsupportive workplace the most important barriers that led to early introduction of bottle feeding or breastfeeding cessation. Most childcare centres support breastfeeding in a more passive than active way. Breastfeeding promotion needs to be an integral part of childcare centres training, policy and practice if an increased rate of breastfeeding is to be achieved particularly amongst working mothers.This work was made possible by a grant from the Faculty of Health Science, Flinders University

DATA SHARING TO DRIVE THE IMPROVEMENT OF TEACHER PREPARATION PROGRAMS

Background/Context: Teacher preparation programs (TPPs) face increasing pressure from the federal government, states, and accreditation agencies to improve the quality of their practices and graduates, yet they often do not possess enough data to make evidence-based reforms. Purpose/Objective: This manuscript has four objectives: (a) to present the strengths and shortcomings of accountability-based TPP evaluation systems; (b) to detail the individual-level data being shared with TPPs at public universities in North Carolina; (c) to describe how data sharing can lead to TPP improvement and the challenges that programs will need to overcome; and (d) to detail how three TPPs are using the data for program improvement. Setting: North Carolina public schools and schools of education at public universities in North Carolina. Importantly, this individual-level data sharing system can be instituted among TPPs in other states. Population/Participants/Subjects: Teachers initially-prepared b

Fasting Blood Glucose and Depressive Mood among Patients with Mental Illness in a Medicaid Managed Care Program

Objective. This study explores the relationship between depressive symptoms, as measured by the PHQ-9 depression screen and blood glucose levels among patients with diabetes enrolled in Gold Choice, a Medicaid managed care program for individuals with mental illness and/or substance abuse. Methods. The PHQ-9 was mailed to 454 Gold Choice members and a questionnaire was mailed to their physicians requesting current HbA1c% and fasting blood glucose (FBG) levels. The pearson product-moment correlation was used to describe the association between PHQ-9 scores and FBG levels. Results. The PHQ-9 response rate was 55% (N = 249). Laboratory results were received for 141 patients. The correlation between FBG and PHQ-9 scores was modest but statistically significant: r = 0.21 , P = 0.015. Conclusion. A statistically significant association was found between FBG and PHQ-9 depression scores. This finding supports current recommendations that physicians be alert to depressive symptoms among patients with diabetes or impaired glucose metabolism

The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease : systematic review

Coronary heart disease (CHD) is one of the main causes of mortality and morbidity in the UK and other Western countries. The disease can be asymptomatic until the first event, which may be a fatal myocardial infarction (heart attack). Half of all heart attacks occur in people who have had no prior warning of coronary disease, and almost half will die from the first attack. Risk scores based on well-known factors such as age, blood pressure, smoking, cholesterol and diabetes have been used to assess risk, but are imperfect: not all high-risk people develop heart disease, and many low-risk people do. Indeed, depending on which cut-off is used to define high risk, most heart attacks occur in low-risk people, because the number of people at low risk is much greater than the number at high risk. There is therefore a need for a better way of identifying those at risk so that they can treat themselves with lifestyle measures, or receive drug therapy such as statins and antihypertensive drugs as appropriate. Computed tomography (CT) is a form of radiological imaging that can detect calcium deposits in the coronary arteries. This calcification is a marker for CHD, and so CT imaging could be a way of detecting asymptomatic but serious CHD. CT is quick and non-invasive, but does involve a relatively large radiation dose

Allosteric Modulation of Beta1 Integrin Function Induces Lung Tissue Repair

The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against β1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of β1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung

RNA-seq: technical variability and sampling

<p>Abstract</p> <p>Background</p> <p>RNA-seq is revolutionizing the way we study transcriptomes. mRNA can be surveyed without prior knowledge of gene transcripts. Alternative splicing of transcript isoforms and the identification of previously unknown exons are being reported. Initial reports of differences in exon usage, and splicing between samples as well as quantitative differences among samples are beginning to surface. Biological variation has been reported to be larger than technical variation. In addition, technical variation has been reported to be in line with expectations due to random sampling. However, strategies for dealing with technical variation will differ depending on the magnitude. The size of technical variance, and the role of sampling are examined in this manuscript.</p> <p>Results</p> <p>In this study three independent Solexa/Illumina experiments containing technical replicates are analyzed. When coverage is low, large disagreements between technical replicates are apparent. Exon detection between technical replicates is highly variable when the coverage is less than 5 reads per nucleotide and estimates of gene expression are more likely to disagree when coverage is low. Although large disagreements in the estimates of expression are observed at all levels of coverage.</p> <p>Conclusions</p> <p>Technical variability is too high to ignore. Technical variability results in inconsistent detection of exons at low levels of coverage. Further, the estimate of the relative abundance of a transcript can substantially disagree, even when coverage levels are high. This may be due to the low sampling fraction and if so, it will persist as an issue needing to be addressed in experimental design even as the next wave of technology produces larger numbers of reads. We provide practical recommendations for dealing with the technical variability, without dramatic cost increases.</p

Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints : systematic review and economic evaluation

Objective: To support a review of the guidance issued by the National Institute for Health and Clinical Excellence (NICE) in December 2000 by examining the current clinical and cost-effectiveness evidence on autologous cartilage transplantation. Data sources: Electronic databases. Review methods: Evidence on clinical effectiveness was obtained from randomised trials, supplemented by data from selected observational studies for longer term results, and for the natural history of chondral lesions. Because of a lack of long-term results on outcomes such as later osteoarthritis and knee replacement, only illustrative modelling was done, using a range of assumptions that seemed reasonable, but were not evidence based. Results: Four randomised controlled trials were included, as well as observational data from case series. The trials studied a total of 266 patients and the observational studies up to 101 patients. Two studies compared autologous chondrocyte implantation (ACI) with mosaicplasty, the third compared ACI with microfracture, and the fourth compared matrix-guided ACI (MACI®) with microfracture. Follow-up was 1 year in one study, and up to 3 years in the remaining three studies. The first trial of ACI versus mosaicplasty found that ACI gave better results than mosaicplasty at 1 year. Overall, 88% had excellent or good results with ACI versus 69% with mosaicplasty. About half of the biopsies after ACI showed hyaline cartilage. The second trial of ACI versus mosaicplasty found little difference in clinical outcomes at 2 years. Disappointingly, biopsies from the ACI group showed fibrocartilage rather than hyaline cartilage. The trial of ACI versus microfracture also found only small differences in outcomes at 2 years. Finally, the trial of MACI versus microfracture contained insufficient long-term results at present, but the study does show the feasibility of doing ACI by the MACI technique. It also suggested that after ACI, it takes 2 years for full-thickness cartilage to be produced. Reliable costs per quality-adjusted life-year (QALY) could not be calculated owing to the absence of necessary data. Simple short-term modelling suggests that the quality of life gain from ACI versus microfracture would have to be between 70 and 100% greater over 2 years for it to be more cost-effective within the £20,000–30,000 per QALY costeffectiveness thresholds. However, if the quality of life gains could be maintained for a decade, increments relative to microfracture would only have to be 10–20% greater to justify additional treatment costs within the cost-effectiveness band indicated above. Follow-up from the trials so far has only been up to 2 years, with longer term outcomes being uncertain. Conclusions: There is insufficient evidence at present to say that ACI is cost-effective compared with microfracture or mosaicplasty. Longer term outcomes are required. Economic modelling using some assumptions about long-term outcomes that seem reasonable suggests that ACI would be cost-effective because it is more likely to produce hyaline cartilage, which is more likely to be durable and to prevent osteoarthritis in the longer term (e.g. 20 years). Further research is needed into earlier methods of predicting long-term results. Basic science research is also needed into factors that influence stem cells to become chondrocytes and to produce high-quality cartilage, as it may be possible to have more patients developing hyaline cartilage after microfracture. Study is also needed into cost-effective methods of rehabilitation and the effect of early mobilisation on cartilage growth

The Grizzly, September 20, 2018

Changes to Faculty Parking Disgruntle Students • Berman Opens Two New Exhibits for the Fall Semester • Inclusive Community Fellowships and Grants • Healing Hurt People at the Parlee Center • Two-Legged Dog Runs Away Then Finally Finds Forever Home: Meet Deuce, Professor Scudera\u27s Newest Dog • Help Wanted: UCARE Fall Volunteering Opportunities • Opinions: Greek Life at Ursinus is Dying; Anonymous New York Times Op-Ed is Cowardly • Football Dominates in First Three Games • UC Gymnastics has New Coach in Valentihttps://digitalcommons.ursinus.edu/grizzlynews/1602/thumbnail.jp