A crucial sequence for transglutaminase type 2 extracellular trafficking in renal tubular epithelial cells lies in its N-terminal {beta}-sandwich domain

Transglutaminase type 2 (TG2) catalyzes the formation of an -( -glutamyl)-lysine isopeptide bond between adjacent peptides or proteins including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlie tissue scarring and fibrosis. The extracellular trafficking of TG2 is crucial to its role in ECM homeostasis; however, the mechanism by which TG2 escapes the cell is unknown as it has no signal leader peptide and therefore cannot be transported classically. Understanding TG2 transport may highlight novel mechanisms to interfere with the extracellular function of TG2 as isoform-specific TG2 inhibitors remain elusive. Mammalian expression vectors were constructed containing domain deletions of TG2. These were transfected into three kidney tubular epithelial cell lines, and TG2 export was assessed to identify critical domains. Point mutation was then used to highlight specific sequences within the domain required for TG2 export. The removal of -sandwich domain prevented all TG2 export. Mutations of Asp94 and Asp97 within the N-terminal -sandwich domain were identified as crucial for TG2 externalization. These form part of a previously identified fibronectin binding domain (88WTATVVDQQDCTLSLQLTT106). However, siRNA knockdown of fibronectin failed to affect TG2 export. The sequence 88WTATVVDQQDCTLSLQLTT106 within the -sandwich domain of TG2 is critical to its export in tubular epithelial cell lines. The extracellular trafficking of TG2 is independent of fibronectin

A pharmacist-led intervention for increasing the uptake of Home Medicines Review (HMR) among residents of retirement villages (PHARMER): protocol for a cluster randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The majority of retirement village residents are at risk of medication misadventure. In a recent survey of retirement village residents in Victoria, two-thirds had at least one medication-related risk factor, and hence were eligible to receive a government-subsidised Home Medicines Review (HMR). However, only 6% of eligible residents had received a HMR in the previous 12 months. Reasons for the poor uptake of HMR, and interventions for improving HMR uptake, have been identified and developed with input from stakeholders. The trial will test the effect of <b>P</b>harmacist-conducted <b>H</b>MR to <b>A</b>ddress the <b>R</b>isk of <b>M</b>edication-related <b>E</b>vents in <b>R</b>etirement Villages (PHARMER) in improving the uptake of HMRs among retirement village residents.</p> <p>Methods/Design</p> <p>This is a multicentre prospective cluster randomised controlled trial. Ten retirement villages in Victoria, Australia will be recruited for this trial. Retirement villages will be selected in consultation with the Residents of Retirement Villages Victoria Inc. (RRVV), based on geographical locations (e.g. northeast or southwest), size and other factors. Residents from selected villages will be recruited with the help of RRVV Resident Liaison Officers using a range of strategies. Randomisation will be by geographical location to minimise contamination. Participating villages and residents will be allocated to either Pharmacist Intervention Group (PIG) or Usual Care Group (UCG). Each group will include five retirement villages and will have at least 77 residents in total. The intervention (PHARMER) comprises educating residents regarding HMR, and using a risk assessment checklist by residents to notify their General Practitioners of their medication risk. Uptake of HMR and medication adherence will be assessed in both PIG and UCG at three and six months using telephone interviews and questionnaires.</p> <p>Discussion</p> <p>This study is the first to develop and test an intervention to improve the uptake of HMR among Australian residents in retirement villages, with a view to decreasing medication risk. A multi-faceted interventional approach will be used as suggested by stakeholders. The trial is expected to be complete by late 2011 and results will be available in 2012.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry (<a href="http://www.anzctr.org.au/ACTRN12611000109909.aspx">ACTRN12611000109909</a>)</p

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys

Effect of preoperative thoracic duct drainage on canine kidney transplantation

Chronic drainage of the thoracic duct to the esophagus was developed in dogs, and its efficacy in immunomodulation was tested using kidney transplantation. Compared to 9.7 days in the control, the mean animal survival was prolonged to 9.9 days, 17.8 days, and 18.5 days when TDD was applied preoperatively for 3 weeks, 6 weeks, and 9 weeks, respectively. Prolongation was significant after 6 weeks. Patency of the fistula was 93.5, 80.4, and 76.1% at respective weeks. Number of peripheral T-lymphocytes determined by a new monoclonal antibody diminished after 3 weeks. All animals were in normal health, requiring no special care for fluid, electrolyte, or protein replacement

Accuracy of magnetic resonance studies in the detection of chondral and labral lesions in femoroacetabular impingement : systematic review and meta-analysis

Background: Several types of Magnetic resonance imaging (MRI) are commonly used in imaging of femoroacetabular impingement (FAI), however till now there are no clear protocols and recommendations for each type. The aim of this meta-analysis is to detect the accuracy of conventional magnetic resonance imaging (cMRI), direct magnetic resonance arthrography (dMRA) and indirect magnetic resonance arthrography (iMRA) in the diagnosis of chondral and labral lesions in femoroacetabular impingement (FAI). Methods: A literature search was finalized on the 17th of May 2016 to collect all studies identifying the accuracy of cMRI, dMRA and iMRA in diagnosing chondral and labral lesions associated with FAI using surgical results (arthroscopic or open) as a reference test. Pooled sensitivity and specificity with 95% confidence intervals using a random-effects meta-analysis for MRI, dMRA and iMRA were calculated also area under receiver operating characteristic (ROC) curve (AUC) was retrieved whenever possible where AUC is equivocal to diagnostic accuracy. Results: The search yielded 192 publications which were reviewed according inclusion and exclusion criteria then 21 studies fulfilled the eligibility criteria for the qualitative analysis with a total number of 828 cases, lastly 12 studies were included in the quantitative meta-analysis. Meta-analysis showed that as regard labral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.864, 0.833 and 0.88 and for dMRA were 0.91, 0.58 and 0.92. While in chondral lesions the pooled sensitivity, specificity and AUC for cMRI were 0.76, 0.72 and 0.75 and for dMRA were 0.75, 0.79 and 0.83, while for iMRA were sensitivity of 0.722 and specificity of 0.917. Conclusions: The present meta-analysis showed that the diagnostic test accuracy was superior for dMRA when compared with cMRI for detection of labral and chondral lesions. The diagnostic test accuracy was superior for labral lesions when compared with chondral lesions in both cMRI and dMRA. Promising results are obtained concerning iMRA but further studies still needed to fully assess its diagnostic accuracy

Beta defensin-2 is reduced in central but not in distal airways of smoker COPD patients

Background: Altered pulmonary defenses in chronic obstructive pulmonary disease (COPD) may promote distal airways bacterial colonization. The expression/activation of Toll Like receptors (TLR) and beta 2 defensin (HBD2) release by epithelial cells crucially affect pulmonary defence mechanisms. Methods: The epithelial expression of TLR4 and of HBD2 was assessed in surgical specimens from current smokers COPD (s-COPD; n = 17), ex-smokers COPD (ex-s-COPD; n = 8), smokers without COPD (S; n = 12), and from non-smoker non-COPD subjects (C; n = 13). Results: In distal airways, s-COPD highly expressed TLR4 and HBD2. In central airways, S and s-COPD showed increased TLR4 expression. Lower HBD2 expression was observed in central airways of s-COPD when compared to S and to ex-s-COPD. s-COPD had a reduced HBD2 gene expression as demonstrated by real-time PCR on micro-dissected bronchial epithelial cells. Furthermore, HBD2 expression positively correlated with FEV1/FVC ratio and inversely correlated with the cigarette smoke exposure. In a bronchial epithelial cell line (16 HBE) IL-1β significantly induced the HBD2 mRNA expression and cigarette smoke extracts significantly counteracted this IL-1 mediated effect reducing both the activation of NFkB pathway and the interaction between NFkB and HBD2 promoter. Conclusions: This study provides new insights on the possible mechanisms involved in the alteration of innate immunity mechanisms in COPD. © 2012 Pace et al

MARK4 controls ischaemic heart failure through microtubule detyrosination.

Myocardial infarction is a major cause of premature death in adults. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate1. Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure2,3 or have shown a very modest reduction of risk of heart failure4. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility5. Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction.BHF fellowship grant (FS/14/28/30713), Issac Newton Trust Grant (18.40u), and Cambridge BHF Centre of Research Excellence grants (RE/13/6/30180 and RE/18/1/34212)

Excess healthcare burden during 1918-1920 influenza pandemic in Taiwan: implications for post-pandemic preparedness

<p>Abstract</p> <p>Background</p> <p>It is speculated that the 2009 pandemic H1N1 influenza virus might fall into a seasonal pattern during the current post-pandemic period with more severe clinical presentation for high-risk groups identified during the 2009 pandemic. Hence the extent of likely excess healthcare needs during this period must be fully considered. We will make use of the historical healthcare record in Taiwan during and after the 1918 influenza pandemic to ascertain the scope of potential excess healthcare burden during the post-pandemic period.</p> <p>Methods</p> <p>To establish the healthcare needs after the initial wave in 1918, the yearly healthcare records (hospitalizations, outpatients, etc.) in Taiwan during 1918-1920 are compared with the corresponding data from the adjacent "baseline" years of 1916, 1917, 1921, and 1922 to estimate the excess healthcare burden during the initial outbreak in 1918 and in the years immediately after.</p> <p>Results</p> <p>In 1918 the number of public hospital outpatients exceeded the yearly average of the baseline years by 20.11% (95% CI: 16.43, 25.90), and the number of hospitalizations exceeded the corresponding yearly average of the baseline years by 12.20% (10.59, 14.38), while the excess number of patients treated by the public medics was statistically significant at 32.21% (28.48, 39.82) more than the yearly average of the baseline years. For 1920, only the excess number of hospitalizations was statistically significant at 19.83% (95% CI: 17.21, 23.38) more than the yearly average of the baseline years.</p> <p>Conclusions</p> <p>Considerable extra burden with significant loss of lives was reported in 1918 by both the public medics system and the public hospitals. In comparison, only a substantial number of excess hospitalizations in the public hospitals was reported in 1920, indicating that the population was relatively unprepared for the first wave in 1918 and did not fully utilize the public hospitals. Moreover, comparatively low mortality was reported by the public hospitals and the public medics during the second wave in 1920 even though significantly more patients were hospitalized, suggesting that there had been substantially less fatal illnesses among the hospitalized patients during the second wave. Our results provide viable parameters for assessing healthcare needs for post-pandemic preparedness.</p

Inherent Signals in Sequencing-Based Chromatin-ImmunoPrecipitation Control Libraries

The growth of sequencing-based Chromatin Immuno-Precipitation studies call for a more in-depth understanding of the nature of the technology and of the resultant data to reduce false positives and false negatives. Control libraries are typically constructed to complement such studies in order to mitigate the effect of systematic biases that might be present in the data. In this study, we explored multiple control libraries to obtain better understanding of what they truly represent.First, we analyzed the genome-wide profiles of various sequencing-based libraries at a low resolution of 1 Mbp, and compared them with each other as well as against aCGH data. We found that copy number plays a major influence in both ChIP-enriched as well as control libraries. Following that, we inspected the repeat regions to assess the extent of mapping bias. Next, significantly tag-rich 5 kbp regions were identified and they were associated with various genomic landmarks. For instance, we discovered that gene boundaries were surprisingly enriched with sequenced tags. Further, profiles between different cell types were noticeably distinct although the cell types were somewhat related and similar.We found that control libraries bear traces of systematic biases. The biases can be attributed to genomic copy number, inherent sequencing bias, plausible mapping ambiguity, and cell-type specific chromatin structure. Our results suggest careful analysis of control libraries can reveal promising biological insights