Effects of intraovarian injection of autologous platelet rich plasma on ovarian reserve and IVF outcome parameters in women with primary ovarian insufficiency.
We aimed to determine whether intraovarian injection of autologous platelet rich plasma (PRP) improves response to ovarian stimulation and in vitro fertilization (IVF) outcome in women with primary ovarian insufficiency (POI). Women (N=311; age 24-40) diagnosed with POI based on ESHRE criteria underwent intraovarian PRP injection. Markers of ovarian reserve, and IVF outcome parameters were followed. PRP treatment resulted in increased antral follicle count (AFC) and serum antimullerian hormone (AMH), while serum follicle stimulating hormone (FSH) did not change significantly. After PRP injection, 23 women (7.4%) conceived spontaneously, 201 (64.8%) developed antral follicle(s) and attempted IVF, and 87 (27.8%) had no antral follicles and therefore did not receive additional treatment. Among the 201 women who attempted IVF, 82 (26.4% of total) developed embryos; 25 of these women preferred to cryopreserve embryos for transfer at a later stage, while 57 underwent embryo transfer resulting in 13 pregnancies (22.8% per transfer, 4% of total). In total, of the 311 women treated with PRP, 25 (8.0%) achieved livebirth/sustained implantation (spontaneously or after IVF), while another 25 (8.0%) cryopreserved embryos. Our findings suggest that in women with POI, intraovarian injection of autologous PRP might be considered as an alternative experimental treatment option.


Mutational analysis of the ribonuclease H activity of human immunodeficiency virus 1 reverse transcriptase.
We have constructed a series of plasmids that, when introduced into Escherichia coli, induce the expression of high levels of either wild-type or mutated forms of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). Mutant forms of RT that had been previously analyzed for their RNA-dependent DNA polymerase activity were tested for RNase H activity using an in situ polyacrylamide gel assay. Mutations affecting the RNase H are not clustered in a single region of the 66-kDa RT molecule. With only few exceptions, mutations that affect the RNase H activity also cause a substantial decrease in the DNA polymerase function. This suggests that, unlike the RT from murine leukemia virus (MuLV), it is difficult to genetically separate the catalytic domains responsible for the RNase H and DNA polymerase functions of HIV-1 RT. Those few mutations that differentially affect the RNase H and the polymerase activities of HIV-1 RT suggest that, as in MuLV, the polymerase domain is in the amino-terminus and the RNase H domain is in the carboxy-terminus. We have also generated chimeric molecules that are composed of sequences from the RT of HIV-1 and MuLV and these hybrid RTs were analyzed for their enzymatic properties. Two of these chimeric RTs possess RNase H activity but lack detectable DNA polymerase activity.


An online database of infant functional near infrared spectroscopy studies: a community-augmented systematic review.
Until recently, imaging the infant brain was very challenging. Functional Near InfraRed Spectroscopy (fNIRS) is a promising, relatively novel technique, whose use is rapidly expanding. As an emergent field, it is particularly important to share methodological knowledge to ensure replicable and robust results. In this paper, we present a community-augmented database which will facilitate precisely this exchange. We tabulated articles and theses reporting empirical fNIRS research carried out on infants below three years of age along several methodological variables. The resulting spreadsheet has been uploaded in a format allowing individuals to continue adding new results, and download the most recent version of the table. Thus, this database is ideal to carry out systematic reviews. We illustrate its academic utility by focusing on the factors affecting three key variables: infant attrition, the reliability of oxygenated and deoxygenated responses, and signal-to-noise ratios. We then discuss strengths and weaknesses of the DBIfNIRS, and conclude by suggesting a set of simple guidelines aimed to facilitate methodological convergence through the standardization of reports.


Optimization of integer wavelet transforms based on difference correlation structures.
In this paper, a novel lifting integer wavelet transform based on difference correlation structure (DCCS-LIWT) is proposed. First, we establish a relationship between the performance of a linear predictor and the difference correlations of an image. The obtained results provide a theoretical foundation for the following construction of the optimal lifting filters. Then, the optimal prediction lifting coefficients in the sense of least-square prediction error are derived. DCCS-LIWT puts heavy emphasis on image inherent dependence. A distinct feature of this method is the use of the variance-normalized autocorrelation function of the difference image to construct a linear predictor and adapt the predictor to varying image sources. The proposed scheme also allows respective calculations of the lifting filters for the horizontal and vertical orientations. Experimental evaluation shows that the proposed method produces better results than the other well-known integer transforms for the lossless image compression.


An Effective Approach for Glycan Structure De Novo Sequencing From HCD Spectra.
Mass spectrometry has become a widely used analytical technique for proteomics study because of its high throughput and sensitivity. Among those applications, a specific one is to characterize glycan structure. Glycosylation is a frequently occurred post-translational modification of proteins which is relevant to humans' health. Therefore, it is significant to develop effective computational methods to automate the identification of glycan structures from mass spectral data. In our research, we mathematically formulated the glycan de novo sequencing problem and proposed a heuristic algorithm for glycan de novo sequencing from HCD MS/MS spectra of N-linked glycopeptides. The algorithm proceeds in a carefully designate pathway to construct the best matched tree structure from MS/MS spectrum. Experimental results showed that our proposed approach can effectively identify glycan structures from HCD MS/MS spectra.


Signal-to-noise ratio trade-offs associated with coarsely sampled Fourier transform spectroscopy.
We derive the spectral signal-to-noise ratio (SNR) trade-offs associated with coarsely sampled Fourier transform spectroscopy using a step-and-integrate measurement scheme. We show that there is no SNR penalty in the shot noise limit and a slight SNR benefit in the detector noise limit for the case of coarse sampling to achieve the same spectral resolution as a baseline Nyquist sampling scenario, where the total detector integration time is the same for both sampling cases.


A step-by-step protocol for generating human fibroblast cell-derived completely biological extracellular matrix scaffolds.
Native extracellular matrix (ECM) based scaffolds are far more superior in structural and compositional complexity than other engineered scaffolding materials such as hydrogels, electrospun fibers, and three-dimensional (3D) printed substrates. Due to the presence of native structural proteins and other macromolecules, native ECM can better restore the crucial cell-ECM crosstalk and provide a highly biomimetic microenvironment to cells. Allogenic or xenogeneic tissues have been derived by decellularization to obtain native ECM scaffolds. However, their applicability is limited by batch to batch variation, risk of pathogen transfer, undesirable immune response and scarcity of donors. Human dermal fibroblasts (hDFs) can be prescreened and maintained in a pathogen-free condition. Herein, we have described a step-by-step protocol to generate a completely biological ECM scaffold by decellularization of hDF cell sheets. Decellularization was achieved by using an anionic surfactant sodium dodecyl sulfate (SDS) and ethylene diamine tetraacetate (EDTA). The resulting ECM sheet was organized into a nanofibrous scaffold, containing major ECM structural proteins as well as other macromolecules including collagens, fibronectin, laminin and elastin. This cell-derived nanofibrous ECM is a promising scaffold material for constructing highly biomimetic functional tissues.


A qualitative study of patient views on discontinuing long-term selective serotonin reuptake inhibitors.
There is concern that patients may be remaining on selective serotonin reuptake inhibitors (SSRIs) longer than is clinically indicated. Previous research has explored patients' experiences of taking SSRIs and decisions about starting medication. There has been less research into patients' reasons for long-term use and their views and experiences of discontinuation. To explore patient experiences of and beliefs about their long-standing SSRI use and understand the barriers and facilitators to discontinuation. Face-to-face semi-structured qualitative interview study. One group general practice in Southampton, UK. Three overarching themes were identified: (i) patient uncertainty about the benefits of, and continued need for, SSRI medication; (ii) barriers to stopping, including fear of withdrawal symptoms and fear of relapse; and (iii) the importance of the GP's role in facilitating cessation. Uncertainty and fear about withdrawal symptoms and what patients would be like without their medication were key barriers to stopping, even among patients who felt no discernible benefit from taking SSRIs. Patients indicated a need to share the decision to stop with their GP. However, the majority of patients interviewed had received repeat prescriptions of SSRIs without being reviewed by the GP. Patients prescribed SSRI medication need to be reassured that, as with starting medication, thinking about or actually stopping medication is a task that will not be managed in isolation, but with the support of their GP.


The Thriving of Older People Assessment Scale: validity and reliability assessments.
To explore construct validity and reliability of the Thriving of Older People Assessment Scale. The concept of thriving emphasizes person-environment interaction in relation to well-being. The Thriving of Older People Assessment Scale has been developed and evaluated as a self-report and proxy scale based on the theory of thriving. Cross-sectional survey design. The Thriving of Older People Assessment Scale was completed by a sample of 259 residents, 146 family members and 52 staff from 13 long-term care facilities in Norway and Sweden. Data were collected between April 2010-December 2011. Exploratory factor analysis was applied to explore construct validity in terms of factor structure and dimensionality of the 32-item scale in relation to the thriving theory. Reliability was explored through internal consistency estimation using Cronbach's alpha and through homogeneity evaluation using corrected item-total correlations. Exploratory factor analysis resulted in five factors (subscales) that corresponded meaningfully with the thriving theory and were labelled 1: Resident' attitudes towards being in long-term care; 2: Quality of care and caregivers; 3: Resident engagement and peer relationships; 4: Keeping in touch with people and places; and 5: Quality of the physical environment. The scale had satisfactory internal consistency and homogeneity estimates. The 32-item Thriving of Older People Assessment Scale can be regarded as construct valid and reliable. Its factor structure corresponded logically to the thriving theory and its factors showed satisfactory internal consistency and homogeneity. Nevertheless, the TOPAS would benefit from further testing in other populations and contexts.


Serological implications of germinal center-like structures in primary Sjögren's syndrome.
To determine serological implications of germinal center (GC)-like structures in primary Sjögren's syndrome (pSS). Retrospectively, minor salivary gland biopsies (n = 269) with focal lymphoid aggregates corresponding to focus score > 1 were evaluated for the presence of GC-like morphology. Relevant clinical information was obtained from medical records. Of 269 patients, 169 fulfilled the American-European criteria for pSS. GC-like features were observed in 47/169 (28%) biopsies. In the majority of cases, GC-like lesions were confirmed by CD21-positive follicular dendritic cell networks. Mean inflammatory focus score was significantly higher in GC-positive compared to GC-negative samples (p < 0.001). GC-positive patients had lower mean salivary secretion (p < 0.001) and a higher frequency of patients with unstimulated salivary secretion < or = 1.5 ml/15 min (p < 0.01). In addition, elevated titers of rheumatoid factor, serum anti-Ro/SSA and anti-La/SSB (p < 0.05), and IgG levels > or = 15.3 g/l (p < 0.05) were more common in GC-positive compared to GC-negative. Enlarged salivary glands were observed in 46/163 (28%) patients, but could not be linked to either presence or absence of GC-like features. Inflammatory infiltrates with GC-like morphology were observed in 28% of the investigated patients with pSS, and was particularly noted in patients with higher focus score. The observed serological aberrations in patients with ectopic GC-like structures in the minor salivary glands warrant further prospective studies.


Interleukin-6 in acute exercise and training: what is the biological relevance?
It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercise involving a significant muscle mass in the contractile activity is necessary in order to produce a marked systemic IL-6 response. Furthermore, exercise training may reduce basal IL-6 production as well as the magnitude of the acute exercise IL-6 response by counteracting several potential stimuli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation.


CDC42 and Rac1 control different actin-dependent processes in the Drosophila wing disc epithelium.
Cdc42 and Rac1 are members of the rho family of small guanosinetriphosphatases and are required for a diverse set of cytoskeleton-membrane interactions in different cell types. Here we show that these two proteins contribute differently to the organization of epithelial cells in the Drosophila wing imaginal disc. Drac1 is required to assemble actin at adherens junctions. Failure of adherens junction actin assembly in Drac1 dominant-negative mutants is associated with increased cell death. Dcdc42, on the other hand, is required for processes that involve polarized cell shape changes during both pupal and larval development. In the third larval instar, Dcdc42 is required for apico-basal epithelial elongation. Whereas normal wing disc epithelial cells increase in height more than twofold during the third instar, cells that express a dominant-negative version of Dcdc42 remain short and are abnormally shaped. Dcdc42 localizes to both apical and basal regions of the cell during these events, and mediates elongation, at least in part, by effecting a reorganization of the basal actin cytoskeleton. These observations suggest that a common cdc42-based mechanism may govern polarized cell shape changes in a wide variety of cell types.


Investigating the dynamics of nurse migration in early career: a longitudinal questionnaire survey of variation in regional retention of diploma qualifiers in England.
Increasing mobility of healthcare professionals has led to concerns that certain countries or regions are depleted of sufficient staff to meet healthcare needs. In formulating appropriate strategies to ensure better retention locally, human resource managers are hindered by lack of information about migration patterns. Purposes included studying movement of diploma nurses qualifying in England and contributing to literature on developing methods for obtaining migration data. Specific aims ascertained: regional variation in retention of locally trained nurses; associations between nurses' profile and retention in training region; and impact on each region of inter-regional movement of nurses. Questionnaires sent to a nationally representative cohort of adult branch nurses at qualification (n=1596) and at subsequent intervals thereafter provided data on all employment and other activities and geographical location of each. Event histories constructed from chart data were used to analyse length of retention in region of training and movements between regions. Retention was operationalised through developing the construct 'engagement with nursing'. Older entrants and those with children were more likely to nurse in their training region than younger and childless counterparts. Regions differed in retention of locally trained nurses and in the impact on their diplomate workforce of inter-regional movement. Regional variations were insufficiently explained by differences in nurses' profiles; hence influences of regional characteristics were also considered. Retention strategies should include maintaining the policy of recruiting greater diversity of entrants, particularly mature entrants and those who have children. In developing local strategies, each region needs: information about retention of different components of their workforce; and an understanding of how regional characteristics can facilitate or constrain retention. National and international workforce organisations need to plan how best to obtain accurate and comparable nurse migration data.


An Agenda for Addressing Multimorbidity and Racial and Ethnic Disparities in Alzheimer's Disease and Related Dementia.
Advancements in Alzheimer's disease and related dementias (ADRD) research on the U.S. population acknowledge the importance of the high burden of ADRD on segments of the population and yet-to-be characterized risks attributable to the burden of multiple chronic diseases (multimorbidity). These realizations suggest successful strategies in caring for people with ADRD and their caregivers will rely not only on clinical treatments but also on more refined and comprehensive models of ADRD that take its broad effects on the whole-person and the whole of society into consideration. To this end, it is critical to characterize and address the relationship between ADRD and multimorbidity combinations that complicate care and lead to poor outcomes, particularly with regard to racial and ethnic disparities in the occurrence, course, and effects of ADRD. Several research and policy recommendations are presented to address the intersection of ADRD, multimorbidity, and underrepresented populations most at risk for adverse outcomes.


Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b.
The family of the Casitas B-lineage Lymphoma (Cbl) proteins, c-Cbl, Cbl-b, and Cbl-3, function as E3 ubiquitin ligases and molecular adaptors. In particular, Cbl-b acts as a gatekeeper in T cell activation that controls activation thresholds and the requirement for co-stimulation. Loss of Cbl-b expression renders animals susceptible to antigen-triggered autoimmunity suggesting that Cbl-b is a key autoimmunity gene. In addition, Cbl-b plays a critical role in T cell anergy and escape from regulatory T cells (Treg) suppression. Modulation of Cbl-b might provide us with a unique opportunity for future immune treatment of human disorders such as autoimmunity, immunodeficiency, or cancer.


Inspiratory muscle training increases inspiratory muscle strength in patients weaning from mechanical ventilation: a systematic review.
Does inspiratory muscle training improve inspiratory muscle strength and endurance, facilitate weaning, improve survival, and reduce the rate of reintubation and tracheostomy in adults receiving mechanical ventilation? Systematic review of randomised or quasi-randomised controlled trials. Adults over 16 years of age receiving mechanical ventilation. Inspiratory muscle training versus sham or no inspiratory muscle training. Data were extracted regarding inspiratory muscle strength and endurance, the duration of unassisted breathing periods, weaning success and duration, reintubation and tracheostomy, survival, adverse effects, and length of stay. Three studies involving 150 participants were included in the review. The studies varied in time to commencement of the training, the device used, the training protocol, and the outcomes measured. Inspiratory muscle training significantly increased inspiratory muscle strength over sham or no training (weighted mean difference 8 cmH(2)O, 95% CI 6 to 9). There were no statistically significant differences between the groups in weaning success or duration, survival, reintubation, or tracheostomy. Inspiratory muscle training was found to significantly increase inspiratory muscle strength in adults undergoing mechanical ventilation. Despite data from a substantial pooled cohort, it is not yet clear whether the increase in inspiratory muscle strength leads to a shorter duration of mechanical ventilation, improved weaning success, or improved survival. Further large randomised studies are required to clarify the impact of inspiratory muscle training on patients receiving mechanical ventilation. PROSPERO CRD42011001132.


Family support and cardiac rehabilitation: a comparative study of the experiences of South Asian and White-European patients and their carer's living in the United Kingdom.
Effective lifestyle modification facilitated by cardiac rehabilitation is known to reduce the occurrence of adverse coronary events and mortality. South Asians have poorer outcomes after a myocardial infarction than the general UK population, but little is known about their experiences of family support, cardiac rehabilitation and lifestyle change. To explore the nature of family support available to a sample of South Asian and White-European cardiac patients and to highlight similarities and differences between these groups with regard to cardiac rehabilitation and lifestyle modification. Using a qualitative approach, semi-structured interviews (in 1 of 6 languages) were conducted by researchers with; 45 South Asian patients and 37 carers and 20 White-European patients and 17 carers. Interviews were conducted in a home setting, up to eighteen months after discharge from hospital following myocardial infarction, coronary artery bypass surgery or unstable angina. The main themes that emerged related to the provision of advice and information, family support and burden, dietary change and exercise regimes. Several cultural and ethnic differences were identified between patients and their families alongside similarities, irrespective of ethnicity. These may represent generic characteristics of recovery after a cardiac event. Health professionals should develop a cultural repertoire to engage with diversity and difference. Not every difficulty a person encounters as they try to access appropriate service delivery can be attributed to ethnic background. By improving services generally, support for South Asian populations can be improved. The challenge is to know when ethnicity makes a difference and mediates a person's relationship with service support and when it does not.


Long-term prevention of erosive or ulcerative gastro-oesophageal reflux disease relapse with rabeprazole 10 or 20 mg vs. placebo: results of a 5-year study in the United States.
Erosive gastro-oesophageal reflux disease (GERD) is a chronic condition requiring long-term maintenance treatment. However, few trials of proton pump inhibitors in maintaining healing of erosive or ulcerative GERD are conducted for longer than 1 year. To compare the efficacy and safety of 10- and 20-mg rabeprazole with placebo in the 5-year maintenance of healing in patients previously diagnosed with erosive/ulcerative GERD healed in an acute efficacy trial. Patients (N = 497) were randomized to receive once-daily doses of 10- or 20-mg rabeprazole or placebo. The primary efficacy measure was endoscopically documented absence of oesophageal erosions or ulcerations. After 5 years, relapse rates in both rabeprazole groups were significantly lower than with placebo (rabeprazole 20 mg, 11%; 10 mg, 23%; placebo, 63%; P < 0.001 for rabeprazole vs. placebo; P = 0.005 for rabeprazole 20 mg vs. 10 mg). Both rabeprazole doses were significantly superior to placebo in preventing relapse of heartburn frequency and improving patient quality of life. Analyses of adverse events, biopsy findings and laboratory values showed no evidence of clinically significant effects. Five-year maintenance therapy with rabeprazole is effective in preventing relapse of erosive or ulcerative GERD and is well tolerated.


Advance in Plasma AD Core Biomarker Development: Current Findings from Immunomagnetic Reduction-Based SQUID Technology.
New super-sensitive biomarker assay platforms for measuring Alzheimer's disease (AD) core pathological markers in plasma have recently been developed and tested. Research findings from these technologies offer promising evidence for identifying the earliest stages of AD and correlating them with brain pathological progression. Here, we review findings using immunomagnetic reduction, one of these ultrasensitive technologies. The principles, technology and assays developed, along with selected published findings will be discussed. The major findings from this technology were significant increases of amyloid beta (Aβ) 42 and total tau (t-tau) levels in subjects clinically diagnosed with early AD when compared with cognitively normal control (NC) subjects. The composite marker of the product of Aβ42 and t-tau discriminated subjects with early AD from NC subjects with high accuracy. The potential of this technology for the purpose of early or preclinical disease stage detection has yet to be explored in subjects who have also been assessed with brain imaging and cerebrospinal fluid AD core biomarker measurements.


Serum fibroblast growth factor-23 is associated with incident kidney disease.
Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990-1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73 m(2). During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (>54.6 pg/ml) compared with the lowest quintile (<32.0 pg/ml) was associated with risk of developing ESRD (hazard ratio, 2.10; 95% confidence interval, 1.31 to 3.36; trend P<0.001). In a large, community-based study comprising a broad range of kidney function, higher baseline fibroblast growth factor-23 levels were associated with increased risk of incident ESRD independent of the baseline level of kidney function and a number of other risk factors.


IgA and IgG1 Specific to Vi Polysaccharide of Salmonella Typhi Correlate With Protection Status in a Typhoid Fever Controlled Human Infection Model.
Vaccination against Salmonella Typhi using the Vi capsular polysaccharide, a T-cell independent antigen, can protect from the development of typhoid fever. This implies that antibodies to Vi alone can protect in the absence of a T cell-mediated immune response; however, protective Vi antibodies have not been well-characterized. We hypothesized that variability in the biophysical properties of vaccine-elicited antibodies, including subclass distribution and avidity, may impact protective outcomes. To interrogate the relationship between antibody properties and protection against typhoid fever, we analyzed humoral responses from participants in a vaccine efficacy (VE) trial using a controlled human infection model (CHIM) who received either a purified Vi polysaccharide (Vi-PS) or Vi tetanus toxoid conjugate (Vi-TT) vaccine followed by oral challenge with live S. Typhi. We determined the avidity, overall magnitude, and vaccine-induced fold-change in magnitude from before immunization to day of challenge of Vi IgA and IgG subclass antibodies. Amongst those who received the Vi-PS vaccine, Vi IgA magnitude (FDR p = 0.01) and fold-change (FDR p = 0.02) were significantly higher in protected individuals compared with those individuals who developed disease ("diagnosed"). In the Vi-TT vaccine group, the responses of protected individuals had higher fold-change in Vi IgA (FDR p = 0.06) and higher Vi IgG1 avidity (FDR p = 0.058) than the diagnosed Vi-TT vaccinees, though these findings were not significant at p < 0.05. Overall, protective antibody signatures differed between the Vi-PS and Vi-TT vaccines, thus, we conclude that although the Vi-PS and Vi-TT vaccines were observed to have similar efficacies, these vaccines may protect through different mechanisms. These data will inform studies on mechanisms of protection against typhoid fever, including identification of antibody effector functions, as well as informing future vaccination strategies.


Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation.
Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis.


Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men.
We aimed to determine if any mechanistic differences exist between a single set (1SET) and multiple sets (i.e. 3 sets; 3SET) of resistance exercise by utilizing a primed constant infusion of [ring-13C6]phenylalanine to determine myofibrillar protein synthesis (MPS) and Western blot analysis to examine anabolic signalling molecule phosphorylation following an acute bout of resistance exercise. Eight resistance-trained men (24+/-5 years, BMI=25+/-4 kg m2) were randomly assigned to perform unilateral leg extension exercise at 70% concentric one repetition maximum (1RM) until volitional fatigue for 1SET or 3SET. Biopsies from the vastus lateralis were taken in the fasted state (Fast) and fed state (Fed; 20 g of whey protein isolate) at rest, 5 h Fed, 24 h Fast and 29 h Fed post-exercise. Fed-state MPS was transiently elevated above rest at 5 h for 1SET (2.3-fold) and returned to resting levels by 29 h post-exercise. However, the exercise induced increase in MPS following 3SET was superior in amplitude and duration as compared to 1SET at both 5 h (3.1-fold above rest) and 29 h post-exercise (2.3-fold above rest). Phosphorylation of 70 kDa S6 protein kinase (p70S6K) demonstrated a coordinated increase with MPS at 5 h and 29 h post-exercise such that the extent of p70S6K phosphorylation was related to the MPS response (r=0.338, P=0.033). Phosphorylation of 90 kDa ribosomal S6 protein kinase (p90RSK) and ribosomal protein S6 (rps6) was similar for 1SET and 3SET at 24 h Fast and 29 h Fed, respectively. However, 3SET induced a greater activation of eukaryotic translation initiation factor 2B (eIF2B) and rpS6 at 5 h Fed. These data suggest that 3SET of resistance exercise is more anabolic than 1SET and may lead to greater increases in myofibrillar protein accretion over time.


GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment.
Focal adhesions (FAs) undergo maturation that culminates in size and composition changes that modulate adhesion, cytoskeleton remodeling and differentiation. Although it is well recognized that stimuli for osteogenesis of mesenchymal stem cells (MSCs) drive FA maturation, actin organization and stress fiber polarization, the extent to which FA-mediated signals regulated by the FA protein composition specifies MSC commitment remains largely unknown. Here, we demonstrate that, upon dexamethasone (osteogenic induction) treatment, guanine nucleotide exchange factor H1 (GEF-H1, also known as Rho guanine nucleotide exchange factor 2, encoded by ARHGEF2) is significantly enriched in FAs. Perturbation of GEF-H1 inhibits FA formation, anisotropic stress fiber orientation and MSC osteogenesis in an actomyosin-contractility-independent manner. To determine the role of GEF-H1 in MSC osteogenesis, we explore the GEF-H1-modulated FA proteome that reveals non-muscle myosin-II heavy chain-B (NMIIB, also known as myosin-10, encoded by MYH10) as a target of GEF-H1 in FAs. Inhibition of targeting NMIIB into FAs suppresses FA formation, stress fiber polarization, cell stiffness and osteogenic commitments in MSCs. Our data demonstrate a role for FA signaling in specifying MSC commitment.


Modulating exercise-induced hormesis: Does less equal more?
Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.


Psychosocial determinants of out of school activity participation for children with and without physical disabilities.
Psychosocial determinants of children's out of school participation were examined, using secondary analyses of data from 427 children with physical disabilities (from 12 service locations in Ontario Canada) and 354 children without disabilities, ages 6 to 14. For both groups of children, hierarchical regression analyses indicated that psychosocial variables added significant incremental variance (6% to 14%) to the prediction of active physical intensity and social activity enjoyment, beyond that accounted for by family income, child age and sex, and physical functioning. As well, there were significant psychosocial determinants, with medium to large effect sizes. Athletic competence and hyperactivity had specific effects on active physical activities and social activities, respectively, for both groups of children. Disability-specific determinants included social acceptance, emotional functioning, and peer difficulties (only significant for children with disabilities). It was concluded that psychosocial variables play an important role in children's enjoyment and intensity of participation in leisure activities.


Neuroeconomics: the consilience of brain and decision.
Economics, psychology, and neuroscience are converging today into a single, unified discipline with the ultimate aim of providing a single, general theory of human behavior. This is the emerging field of neuroeconomics in which consilience, the accordance of two or more inductions drawn from different groups of phenomena, seems to be operating. Economists and psychologists are providing rich conceptual tools for understanding and modeling behavior, while neurobiologists provide tools for the study of mechanism. The goal of this discipline is thus to understand the processes that connect sensation and action by revealing the neurobiological mechanisms by which decisions are made. This review describes recent developments in neuroeconomics from both behavioral and biological perspectives.


New Reference Genome Sequences for 17 Bacterial Strains of the Honey Bee Gut Microbiota.
We sequenced the genomes of 17 strains isolated from the gut of honey bees, including strains representing the genera Lactobacillus, Bifidobacterium, Gilliamella, Snodgrassella, Frischella, and Commensalibacter. These genome sequences represent an important step forward in the development of a comprehensive reference database to aid future analysis of this emerging gut microbiota model.


Exploring the Profile of Incidental Memory in Patients with Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease.
Incidental memory can be defined as the ability to acquire information unintentionally. The present study investigated incidental memory performance in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD) patients; additionally, hippocampal atrophy between groupswas examined. Twenty-nine aMCI patients (14 with hippocampal atrophy, measured by the Medial Temporal Lobe Atrophy scale), 15 mild AD patients, and 20 cognitively intact individuals underwent a detailed medical and neuropsychological assessment examining intentional memory, using the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test. Participants first took part in a driving simulator experiment, followed by an unexpected incidental memory questionnaire referring to elements related to the driving simulation. The mild AD group performed worse than the aMCI group and the control group both in incidental and intentional memory tasks, whereas the aMCI group differed significantly from the control group only in the intentional memory tasks. The incidental recognition memory task was the only measure that differed between aMCI patients with and without hippocampal atrophy. Moreover, incidental memory tasks were the only measures that correlated significantly with both left and right hippocampal atrophy. The current findings indicate that incidental memory testing may provide potentially useful information for detecting aMCI patients with greater hippocampal atrophy, who may be considered at higher risk of developing dementia due to AD.


Medial superior olive in the free-tailed bat: response to pure tones and amplitude-modulated tones.
In mammals with good low-frequency hearing and a moderate to large interear distance, neurons in the medial superior olive (MSO) are sensitive to interaural time differences (ITDs). Most small mammals, however, do not hear low frequencies and do not experience significant ITDs, suggesting that their MSOs participate in functions other than ITD coding. In one bat species, the mustached bat, the MSO is a functionally monaural nucleus, acting as a low-pass filter for the rate of sinusoidally amplitude-modulated (SAM) stimuli. We investigated whether the more typical binaural MSO of the MExican free-tailed bat also acts as an SAM filter. We recorded from 60 MSO neurons with their best frequencies covering the entire audiogram of this bat. The majority revealed bilateral excitation and indirect evidence for inhibition (EI/EI; 55%). The remaining neurons exhibited reduced inputs, mostly lacking ipsilateral inputs (28% I/EI; 12% O/EI; 5% EI/O). Most neurons (64%) responded with a phasic discharge to pure tones; the remaining neurons exhibited an additional sustained component. For stimulation with pure tones, two thirds of the cells exhibited monotonic rate-level functions for ipsilateral, contralateral, or binaural stimulation. In contrast, nearly all neurons exhibited nonmonotonic rate-level functions when tested with SAM stimuli. Eighty-eight percent of the neurons responded with a phase-locked discharge to SAM stimuli at low modulation rates and exhibited low-pass filter characteristics in the modulation transfer function (MTF) for ipsilateral, contralateral, and binaural stimulation. The MTF for ipsilateral stimulation usually did not match that for contralateral stimulation. Introducing interaural intensity differences (IIDs) changed the MTF in unpredictable ways. We also found that responses to SAMs depended on the carrier frequency. In some neurons we measured the time course of the ipsilaterally and contralaterally evoked inhibition by presenting brief frequency-modulated sweeps at different ITDs. The duration and timing of inhibition could be related to the SAM cutoff for binaural stimulation. We conclude that the response of the MSO in the free-tailed bat is created by a complex interaction of inhibition and excitation. The different time constants of inputs create a low-pass filter for SAM stimuli. However, the MSO output is an integrated response to the temporal structure of a stimulus as well as its azimuthal position, i.e., IIDs. There are no in vivo results concerning filter characteristics in a "classical" MSO, but our data confirm an earlier speculation about this interdependence based on data accessed from a gerbil brain slice preparation.


Urinary orosomucoid 1 protein to creatinine ratio as a potential biomarker for early screening of kidney impairment in type-2 diabetes patients.
Early screening of diabetic kidney disease (DKD) remains a major challenge. Our aim was to evaluate the value of urinary orosomucoid 1 protein (UORM1) in early renal impairment screening in type-2 diabetes patients. The concentration of UORM1, the UORM1-to-creatinine ratio (UORM1CR), the urinary albumin-to-creatinine ratio (ACR), the alpha-1-microglobulin-to-creatinine ratio (A1MCR) and estimated glomerular filtration rate (eGFR) were measured in 406 type-2 diabetes patients. Any positive values for ACR, A1MCR and/or eGFR were considered as indicative of renal impairment. On average, the levels of UORM1 and UORM1CR were about seven times higher in subjects with renal injury than in those without. Both UORM1 and UORM1CR, when adjusted via logarithm-transformation, were significantly related to ACR, A1MCR and eGFR levels. The highest correlation was observed between UORM1CR and A1MCR (r = 0.85, P < .001). The cut-off values for UORM1 (2.53 mg/L) and UORM1CR (3.69 mg/g) for the early diagnosis of kidney impairment were obtained from receiver operating characteristic curves. UORM1CR obviously had higher diagnostic efficiency corresponding to 83.26% sensitivity and 90.32% specificity than UORM1. Likewise, its sensitivity was higher than those of ACR, A1MCR and eGFR. Bad glycaemic control had the highest risk of increased UORM1CR (odds ratio [OR] = 2.81, P < .001), while high HDL-C (high-density lipoprotein cholesterol) decreased the risk of increased UORM1CR (OR = 0.38, P = .017). The UORM1CR (>3.69 mg/g) has the high diagnostic efficiency for the early screening of renal impairment in type-2 diabetes patients. Furthermore, good glycaemic control and high HDL-C might be protective factors against UORM1CR increase.


Three-Dimensional Power Doppler Ultrasonography for Diagnosing Abnormally Invasive Placenta and Quantifying the Risk.
To test an objective ultrasound marker for diagnosing the presence and severity of abnormally invasive placenta. Women at risk of abnormally invasive placenta underwent a three-dimensional power Doppler ultrasound scan. The volumes were examined offline by a blinded observer. The largest area of confluent three-dimensional power Doppler signal (Area of Confluence [Acon], cm) at the uteroplacental interface was measured and compared in women subsequently diagnosed with abnormally invasive placenta and women in a control group who did not have abnormally invasive placenta. Receiver operating characteristic curves were plotted for prediction of abnormally invasive placenta and abnormally invasive placenta requiring cesarean hysterectomy. Ninety-three women were recruited. Results were available for 89. Abnormally invasive placenta was clinically diagnosed in 42 women; 36 required hysterectomy and had abnormally invasive placenta confirmed histopathologically. Median and interquartile range for Acon was greater for abnormally invasive placenta (44.2 [31.4-61.7] cm) compared with women in the control group (4.5 cm [2.9-6.6], P<.001) and even greater in the 36 requiring hysterectomy (46.6 cm [37.2-72.6], P<.001). Acon rose with histopathologic diagnosis: focal accreta (32.2 cm [17.2-57.3]), accreta (59.6 cm [40.1-89.9]), and percreta (46.6 cm [37.5-71.5]; P<.001 analysis of variance for linear trend). Receiver operating characteristic analysis for prediction of abnormally invasive placenta revealed that with an Acon of 12.4 cm or greater, 100% sensitivity (95% confidence interval [CI] 91.6-100) could be obtained with 92% specificity (95% CI 79.6-97.6); area under the curve is 0.99 (95% CI 0.94-1.0). For prediction of abnormally invasive placenta requiring hysterectomy, 100% sensitivity (95% CI 90.3-100) can be obtained with an Acon of 17.4 cm or greater with 87% specificity (95% CI 74.7-94.5; area under the curve 0.98 [0.93-1.0]). The marker Acon provides a quantitative means for diagnosing abnormally invasive placenta and assessing severity. If further validated, subjectivity could be eliminated from the diagnosis of abnormally invasive placenta. II.


Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure.
Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2 ) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced β-hydroxyacyl CoA dehydrogenase activity. Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.


Avatars and arrows in the brain.
In this Commentary article we critically assess the claims made by Schurz, Kronbichler, Weissengrubler, Surtees, Samson and Perner (2015) relating to the neural processes underlying theory of mind and visual perspective taking. They attempt to integrate research findings in these two areas of social neuroscience using a perspective taking task contrasting mentalistic agents ('avatars'), with non-mentalistic control stimuli ('arrows'), during functional Magnetic Resonance Imaging. We support this endeavour whole-heartedly, agreeing that the integration of findings in these areas has been neglected in research on the social brain. However, we cannot find among the behavioural or neuroimaging data presented by Schurz et al. evidence supporting their claim of 'implicit mentalizing'-the automatic ascription of mental states to another representing what they can see. Indeed, we suggest that neuroimaging methods may be ill-suited to address the existence of implicit mentalizing, and suggest that approaches utilizing neurostimulation methods are likely to be more successful.


Characterization of pinin, a novel protein associated with the desmosome-intermediate filament complex.
We have identified a protein named pinin that is associated with the mature desmosomes of the epithelia (Ouyang, P., and S.P. Sugrue. 1992. J. Cell Biol. 118:1477-1488). We suggest that the function of pinin is to pin intermediate filaments to the desmosome. Therefore, pinin may play a significant role in reinforcing the intermediate filament-desmosome complex. cDNA clones coding for pinin were identified, using degenerative oligonucleotide probes that were based on the internal amino acid sequence of pinin for the screening of a cDNA library. Immunoblotting of expressed recombinant proteins with the monoclonal 08L antibody localized the 08L epitope to the carboxyl end of the protein. Polyclonal antibodies directed against fusion proteins immunoidentified the 140-kD protein in tissue extracts. Immunofluorescence analysis, using the antifusion protein antibody, demonstrated pinin at lateral epithelial boundaries, which is consistent with desmosomal localization. The conceptual translation product of the cDNA clones contained three unique domains: (a) a serine-rich domain; (b) a glutamine-proline, glutamine-leucine repeat domain; and (c) an acidic domain rich in glutamic acid. Although the 3' end of the open reading frame of the clone for pinin showed near identity to a partial cDNA isolated for a pig neutrophil phosphoprotein (Bellavite, P., F. Bazzoni, et al. 1990. Biochem. Biophys. Res. Commun. 170:915-922), the remaining sequence demonstrated little homology to known protein sequences. Northern blots of mRNA from chicken corneal epithelium, MDCK cells, and various human tissues indicated that pinin messages exhibit tissue-specific variation in size, ranging from 3.2 to 4.1 kb. Genomic Southern blots revealed the existence of one gene for pinin, suggesting alternative splicing of the mRNA. Expression of the full-length cDNA clones in human 293 cells and monkey COS-7 cells demonstrated that a 140-kD immunoreactive species on Western blots corresponded to pinin. Pinin cDNA transfected into the transformed 293 cells resulted in enhanced cell-cell adhesion. Immunofluorescence staining revealed that the expressed pinin protein was assembled to the lateral boundaries of the cells in contact, which is consistent with the staining pattern of pinin in epithelial cells.


Poverty, birthweight, and infant weight gain in Hertfordshire, 1923-1939.
To investigate the association between poverty, birthweight, and infant weight gain in Hertfordshire, 1923-1939. Cohort study based on the Hertfordshire Health Visitors' Register (HHVR). The population of Hertfordshire, and a sub-sample of five Hertfordshire towns-Hoddesdon, Berkhampstead, Hertford, Hitchin, and Bishops Stortford-extracted from the HHVR. Some 71 201 live birth entries in the HHVR and a sample of 13,649 live birth entries for the five towns. MEASURE OF POVERTY: Rateable value of birth addresses reflecting market and rental value of housing. Birthweight, and infant weight gain (z score of weight at one year minus z score of birthweight). In Hertfordshire as a whole there was a reduction in mean birthweight from 7.7 pounds (lbs) in 1923 to 7.4 lbs in 1939. Over the same time period there was an increase in mean infant weight gain, although with a degree of variation within the trend. In the sample of five towns there was no association between rateable value and birthweight, but a significant association between rateable value and both weight at one year, and weight gain during the first year of life. In Hertfordshire average birthweight declined, whereas weight gain during the first year of life tended to increase, at a time when, nationally, calorific intake and per capita consumption of a range of nutritional ingredients was rising. Poverty, as measured by rateable value, did not correlate with birthweight but was associated with weight gain during the first year of life. These findings suggest that nutritional poverty had a more significant influence on post-natal weight gain than it did on birthweight.


Mycobacterium tuberculosis H2S Functions as a Sink to Modulate Central Metabolism, Bioenergetics, and Drug Susceptibility.
H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and it functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.


Collection of the Abstracts of the 2019Sp PMD: Translational Myology and Mobility Medicine.
The Interdepartmental Research Centre of Myology (CIR-Myo), Department of Biomedical Sciences, University of Padova, Italy and the A&C M-C Foundation for Translational Myology, Padova, Italy organized with the scientific support of Helmut Kern, Jonathan C. Jarvis, Viviana Moresi, Marco Narici, Feliciano Protasi, Marco Sandri and Ugo Carraro, the 2019SpringPaduaMuscleDays: Translational Myology and Mobility Medicine, an International Conference held March 28-30, 2019 in Euganei Hills and Padova (Italy). Presentations and discussions of the Three Physiology Lectures and of the seven Sessions (I: Spinal Cord Neuromodulation and h-bFES in SC; II: Muscle epigenetics in aging and myopathies; III: Experimental approaches in animal models; IV: Face and Voice Rejuvenation; V: Muscle Imaging; VI: Official Meeting of the EU Center of Active Aging; VII: Early Rehabilitation after knee and hip replacement) were at very high levels. This was true in the past and will be true in future events thanks to researchers and clinicians who were and are eager to attend the PaduaMuscleDays.


Radiological impact of airborne effluents of coal and nuclear plants.
Radiation doses from airborne effluents of model coal-fired and nuclear power plants (1000 megawatts electric) are compared. Assuming a 1 percent ash release to the atmosphere (Environmental Protection Agency regulation) and 1 part per million of uranium and 2 parts per million of thorium in the coal (approximately the U.S. average), population doses from the coal plant are typically higher than those from pressurized-water or boiling-water reactors that meet government regulations. Higher radionuclide contents and ash releases are common and would result in increased doses from the coal plant. The study does not assess the impact of non-radiological pollutants or the total radiological impacts of a coal versus a nuclear economy.


Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation.
Transforming growth factor beta (TGF beta) is a multifunctional polypeptide that regulates proliferation, differentiation, and other functions of many cell types. The pathway of TGF beta signal transduction in cells is unknown. We report here that an early effect of TGF beta is an enhancement of the expression of two genes encoding serum- and phorbol ester tumor promoter-regulated transcription factors: the junB gene and the c-jun proto-oncogene, respectively. This stimulation was observed in human lung adenocarcinoma A549 cells which were growth inhibited by TGF beta, AKR-2B mouse embryo fibroblasts which were growth stimulated by TGF beta, and K562 human erythroleukemia cells, which were not appreciably affected in their growth by TGF beta. The increase in jun mRNA occurred with picomolar TGF beta concentrations within 1 h of TGF beta stimulation, reached a peak between 1 and 5 h in different cells, and declined gradually to base-line levels. This mRNA response was followed by a large increase in the biosynthesis of the c-jun protein (AP-1), as shown by metabolic labeling and immunoprecipitation analysis. However, differential and cell type-specific regulation appeared to determine the timing and magnitude of the response of each jun gene in a given cell. In AKR-2B and NIH 3T3 cells, only junB was induced by TGF beta, evidently in a protein synthesis-independent fashion. The junB response to TGF beta was maintained in c-Ha-ras and neu oncogene-transformed cells. Thus, one of the earliest genomic responses to TGF beta may involve nuclear signal transduction and amplification by the junB and c-jun transcription factors in concert with c-fos, which is also induced. The differential activation of the jun genes may explain some of the pleiotropic effects of TGF beta.


Catalase and superoxide dismutase secreted from Helicobacter pylori.
Previously, we have reported that toxic oxidants produced by activated neutrophils play a pivotal role in the development of Helicobacter pylori-induced gastric mucosal damage. Microorganisms, however, are characterized by their ability to produce a variety of antioxidant enzymes. This study is designed to measure the oxygen radical scavenging enzymes, such as catalase and superoxide dismutase (SOD), and urease in the supernatant of H. pylori (NCTC11637) suspension. H. pylori was inoculated on a sheep blood agar plate and harvested. Bacterial suspensions (10(9) cfu/ml phosphate buffer) were washed twice and incubated at 37 degrees C for 1, 2, 12, and 24 hours or were sonicated in ice. Their supernatants were obtained by centrifugation and filtration. SOD activity was measured spectrophotometrically by the cytochrome c method. Catalase activity was assayed by the fall in absorbance at 240 nm as H2O2 is degraded. Urease activity was determined by measuring the release of ammonia using Berthelot reaction. Activities of both SOD and catalase were detected in the supernatants of 1-hour microaerophilic incubation. Their activities were almost constant in 4-, 12-, and 24-hour microaerobic incubation or sonication. Urease activity was increased dramatically in proportion to the period of microaerobic incubation. Although H. pylori possesses antioxidant as a constitutive compartment, the magnitude of its secretion was below the detectable level. It is not likely that SOD and catalase play a significant role for scavenging the oxidants from injured gastric mucosa, such as infiltrated leukocytes.


Ribavirin in the treatment of chronic hepatitis C.
Current practice guidelines recommend that individuals chronically infected with the hepatitis C virus (HCV) be treated with pegylated interferon plus ribavirin. Ribavirin, however, is associated with serious adverse events (AE), especially anemia. We review its mechanism of action, its importance in treating chronic hepatitis C (CHC) patients, the AE associated with its use, and techniques used to lessen these AE. Medline searches were performed using the keywords ribavirin and hepatitis, together with the keywords mechanism, anemia, liver transplant, renal function, pharmacokinetics, and dose reduction. Searches of abstracts of recent Digestive Diseases Week, American Association for the Study of Liver Diseases, and European Association for the Study of Liver Diseases meetings were also performed. Ribavirin may be effective in treating CHC by affecting the virus or the host; for example by inducing viral mutations, blocking cellular enzymes, or affecting the host immune response. Although the pegylated interferons are the primary drugs used to treat CHC, a combination with ribavirin is more effective than pegylated interferon alone. Ribavirin-associated AE may be lessened by ribavirin dose reductions and by maintenance of the hematocrit. Treatments of ribavirin toxicities, especially anemia, can allow patients to continue full-dose combination therapy with peginterferon and ribavirin, enhancing their probability of attaining a sustained virologic response (SVR). Treatment of CHC should be tailored to individual patients, especially those with renal dysfunction, and should include agents that treat the side-effects of CHC treatment. Monitoring of plasma ribavirin concentrations during treatment may help in the future.


In situ dissection of the Fab-7 region of the bithorax complex into a chromatin domain boundary and a Polycomb-response element.
Parasegmental (PS)-specific expression of the homeotic genes of the bithorax-complex (BX-C) appears to depend upon the subdivision of the complex into a series of functionally independent cis-regulatory domains. Fab-7 is a regulatory element that lies between iab-6 and iab-7 (the PS11- and PS12-specific cis-regulatory domains, respectively). Deletion of Fab-7 causes ectopic expression of iab-7 in PS11 (where normally only iab-6 is active). Two models have been proposed to account for the dominant Fab-7 phenotype. The first considers that Fab-7 functions as a boundary element that insulates iab-6 and iab-7. The second model envisages that Fab-7 contains a silencer element that keeps iab-7 repressed in parasegments anterior to PS12. Using a P-element inserted in the middle of the Fab-7 region (the bit transposon), we have generated an extensive collection of new Fab-7 mutations that allow us to subdivide Fab-7 into a boundary element and a Polycomb-respond element (PRE). The boundary lies within 1 kb of DNA on the proximal side of the bit transposon (towards iab-6). Deletions removing this element alone cause a complex gain- and loss-of-function phenotype in PS11; in some groups of cells, both iab-6 and iab-7 are active, while in others both iab-6 and iab-7 are inactive. Thus, deletion of the boundary allows activating as well as repressing activities to travel between iab-6 and iab-7. We also provide evidences that the boundary region contains an enhancer blocker element. The Polycomb-response element lies within 0.5 kb of DNA immediately distal to the boundary (towards iab-7). Deletions removing the PRE alone do not typically cause any visible phenotype as homozygotes. Interestingly, weak ectopic activation of iab-7 is observed in hemizygous PRE deletions, suggesting that the mechanisms that keep iab-7 repressed in the absence of this element may depend upon chromosome pairing. These results help to reconcile the previously contradictory models on Fab-7 function and to shed light on how a chromatin domain boundary and a nearby PRE concur in the setting up of the appropriate PS-specific expression of the Abd-B gene of the BX-C.


Cumulative incidence of false-positive results in repeated, multimodal cancer screening.
Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program. Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period. After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%) for men, and 48.8% (95% CI, 48.1%-49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%) for men and 22.1% (95% CI, 21.4%-22.7%) for women. For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.


Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.


Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions.
The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11-mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by ∼5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease.


Vulnerability to longline fisheries of three hammerhead shark Sphyrna species in the south-western and equatorial Atlantic Ocean.
Catch and effort data from 29 418 longline sets from Brazilian tuna longline vessels operating in the south-western and equatorial Atlantic Ocean between 2004 and 2011 were analysed to investigate the distribution, catch rate and size of three species of hammerhead sharks (Sphyrna lewini, Sphyrna mokarran and Sphyrna zygaena). During that period, 6172 hammerhead sharks were caught. Among the elasmobranchs, the highest percentage of hammerhead sharks were caught in 2007, when they accounted for 3·90% of the group, while the lowest value of 0·40% was recorded in 2010. In general, the spatial distribution of the mean catch per unit effort (CPUE) by years and quarters showed a trend of higher catches near the equatorial region and in southern Brazil. The nominal mean CPUE was 0·12 Sphyrna spp. 1000(-1) hooks, with the highest value being recorded in 2007 (0·30 Sphyrna spp. 1000(-1) hooks). The standardized yearly CPUE estimated by a generalized linear model assuming a zero inflated negative binomial (ZINB) distribution were not much different from nominal values. Of the 205 sexed specimens, 117 were females and 88 were males, resulting in a sex ratio with a predominance of females (1·30:1·00), although not statistically significant. The total length of females ranged from 1200 to 2800 mm and of males from 1100 to 3100 mm. Juvenile hammerhead sharks represented 82 and 54% of the sexed female and male specimens, respectively.


Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers.
Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs), while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics. In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS) SNPs ranked by Random Forests (RF) importance score for the CAMP (Childhood Asthma Management Program) population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group. Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC)=0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors. Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.


Adsorption and diffusion of lithium polysulfides over blue phosphorene for Li-S batteries.
Lithium-sulphur (Li-S) batteries suffer from capacity loss due to the dissolution of lithium polysulfides (LiPSs). Although finding cathodes that can trap LiPSs strongly is a possible solution to suppress the "shuttle" effect, fast diffusion of lithium and LiPSs is also pivotal to prevent agglomeration. We report that monolayer blue phosphorene (BP), a recently synthesized two-dimensional material, possesses these characteristics as a cathode in Li-S batteries. Density functional theory calculations showed that while the adsorption energies (Eb) of various LiPSs over pristine BP are reasonably strong (from -0.86 eV to -2.45 eV), defect engineering of the lattice by introducing a single vacancy (SV) increased the binding strength significantly, with Eb in the range of -1.41 eV to -4.34 eV. Ab-initio molecular dynamics simulations carried out at 300 K showed that the single vacancies trap the Li atoms in the LiPSs compared to pristine BP. Projected density of states revealed that the creation of an SV induces metallicity in the cathode. Furthermore, an increase in the adsorption strength did not cause significant structural deformation, implying that the soluble large LiPSs did not decompose, which is essential to suppress capacity fading. The energy barriers for LiPSs' migration over pristine BP are minimal to ensure ultrafast diffusion, with the lowest diffusion energy barriers being 0.23 eV, 0.13 eV and 0.18 eV for Li2S4, Li2S6 and Li2S8, respectively. Furthermore, the energy barrier associated with the catalytic oxidation of Li2S over pristine and defective BP was found to be greater than three times smaller compared to graphene, which suggests that charging processes could be faster by orders of magnitude. Therefore, BP with a suitable combination of defects would be an excellent cathode material in Li-S batteries.


Population structure and physiological changes within a hot spring microbial mat community following disturbance.
The influence of disturbance on a hot spring cyanobacterial mat community was investigated by physically removing the top 3.0 mm, which included the entire cyanobacterial layer. Changes in 16S rRNA-defined populations were monitored by denaturing gradient gel electrophoresis analysis of PCR-amplified 16S rRNA gene segments. Some previously absent cyanobacterial populations colonized the disturbed areas, while some populations which were present before the disturbance remained absent for up to 40 days. Changes in physiological activity were measured by oxygen microelectrode analyses and by 14CO2 incorporation into cyanobacterial molecular components. These investigations indicated substantial differences between the disturbed and undisturbed mats, including an unexplained light-induced oxygen consumption in the freshly exposed mat, increased carbon partitioning by phototrophs into growth-related macromolecules, bimodal vertical photosynthesis profiles, and delayed recovery of respiration relative to photosynthesis.


Conditional cooperation and costly monitoring explain success in forest commons management.
Recent evidence suggests that prosocial behaviors like conditional cooperation and costly norm enforcement can stabilize large-scale cooperation for commons management. However, field evidence on the extent to which variation in these behaviors among actual commons users accounts for natural commons outcomes is altogether missing. Here, we combine experimental measures of conditional cooperation and survey measures on costly monitoring among 49 forest user groups in Ethiopia with measures of natural forest commons outcomes to show that (i) groups vary in conditional cooperator share, (ii) groups with larger conditional cooperator share are more successful in forest commons management, and (iii) costly monitoring is a key instrument with which conditional cooperators enforce cooperation. Our findings are consistent with models of gene-culture coevolution on human cooperation and provide external validity to laboratory experiments on social dilemmas.


The Application of Non-Invasive Apoptosis Detection Sensor (NIADS) on Histone Deacetylation Inhibitor (HDACi)-Induced Breast Cancer Cell Death.
Breast cancer is the most common malignancy in women and the second leading cause of cancer death in women. Triple negative breast cancer (TNBC) subtype is a breast cancer subset without ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2) expression, limiting treatment options and presenting a poorer survival rate. Thus, we investigated whether histone deacetylation inhibitor (HDACi) could be used as potential anti-cancer therapy on breast cancer cells. In this study, we found TNBC and HER2-enriched breast cancers are extremely sensitive to Panobinostat, Belinostat of HDACi via experiments of cell viability assay, apoptotic marker identification and flow cytometry measurement. On the other hand, we developed a bioluminescence-based live cell non-invasive apoptosis detection sensor (NIADS) detection system to evaluate the quantitative and kinetic analyses of apoptotic cell death by HDAC treatment on breast cancer cells. In addition, the use of HDACi may also contribute a synergic anti-cancer effect with co-treatment of chemotherapeutic agent such as doxorubicin on TNBC cells (MDA-MB-231), but not in breast normal epithelia cells (MCF-10A), providing therapeutic benefits against breast tumor in the clinic.


Genetic identification of yeast 18S rRNA residues required for efficient recruitment of initiator tRNA(Met) and AUG selection.
High-resolution structures of bacterial 70S ribosomes have provided atomic details about mRNA and tRNA binding to the decoding center during elongation, but such information is lacking for preinitiation complexes (PICs). We identified residues in yeast 18S rRNA critical in vivo for recruiting methionyl tRNA(i)(Met) to 40S subunits during initiation by isolating mutations that derepress GCN4 mRNA translation. Several such Gcd(-) mutations alter the A928:U1389 base pair in helix 28 (h28) and allow PICs to scan through the start codons of upstream ORFs that normally repress GCN4 translation. The A928U substitution also impairs TC binding to PICs in a reconstituted system in vitro. Mutation of the bulge G926 in h28 and certain other residues corresponding to direct contacts with the P-site codon or tRNA in bacterial 70S complexes confer Gcd(-) phenotypes that (like A928 substitutions) are suppressed by overexpressing tRNA(i)(Met). Hence, the nonconserved 928:1389 base pair in h28, plus conserved 18S rRNA residues corresponding to P-site contacts in bacterial ribosomes, are critical for efficient Met-tRNA(i)(Met) binding and AUG selection in eukaryotes.


Validity of thermography for measuring burn wound healing potential.
Accurate assessment of burn wound depth and the associated healing potential is vital in determining the need for surgical treatment in burns. Infrared thermography measures the temperature of the burn wound noninvasively, thereby providing indirect information on its blood flow. Previous research demonstrated that a small, low-priced, handheld thermal imager has an excellent reliability, but a moderate validity for measuring burn wound healing potential. A new and more sensitive version of this convenient device has become available. The aim of this study was to evaluate the validity of thermography for measuring burn wound healing potential, compared to Laser Doppler Imaging (LDI) as a reference standard. Thermal images and LDI scans were obtained from burn wounds between 2 and 5 days postburn. Temperature differences between burned and nonburned skin (ΔT) were calculated. To evaluate validity, ΔT values were compared to the healing potential categories assessed by LDI. Two receiver operating characteristic curves were created and two ΔT cutoff values were calculated to illustrate the ability to discriminate between burn wounds that heal in a time period of less than 14 days, between 14 and 21 days, and more than 21 days. Between June and October 2018, 43 burn wounds in 32 patients were measured. ΔT cutoff values of 0.6°C (sensitivity 68%, specificity 95%) and -2.3°C (sensitivity 30%, specificity 95%) were calculated to discriminate between burn wounds that heal in <14 and ≥14 days, and burn wound that heal in ≤21 and >21 days, respectively. This study shows a good validity of the feasible thermal imager for the assessment of burn wound healing potential. Therefore, we consider it a promising technique to be used for triage in local hospitals and general practices, and as a valuable addition to clinical evaluation in burn centers.


Zone plates with cells apodized by legendre profiles.
By apodizing the cells of a zone plate and changing the opening ratio, it is possible to shape the relative power spectrum of its foci. We describe a novel procedure that leads to an analytical formula for shaping the focus power spectrum by using apodizers expressible as the Legendre series; these act on cells of arbitrary opening ratio. Our general result is used to design zone plates that have missing foci and to discuss a synthesis procedure using apodizers with various opening ratios. Our applications can also be used for shaping the power spectrum of 1-D gratings.


Heparin for the prevention of intraventricular haemorrhage in preterm infants.
Preterm birth remains the major risk factor for the development of intraventricular haemorrhage, an injury that occurs in 25% of very low birth weight infants. Intraventricular haemorrhage is thought to be venous in origin and intrinsic thromboses in the germinal matrix are likely to play a triggering role. Heparin activates antithrombin and promotes the inactivation of thrombin and other target proteinases. The administration of anticoagulants such as heparin may offset the increased risk of developing intraventricular haemorrhage and may also reduce the risk of developing parenchymal venous infarct, a condition known to complicate intraventricular haemorrhage. To assess whether the prophylactic administration of heparin reduces the incidence of germinal matrix-intraventricular haemorrhage in very preterm neonates when compared to placebo, no treatment, or other anticoagulants. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2015), MEDLINE (1996 to 22 November 2015), EMBASE (1980 to 22 November 2015) and CINAHL (1982 to 22 November 2015), applying no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia and New Zealand and Pediatric Academic Societies) from 2000 to 2015. Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing the administration of early, i.e. within the first 24 hours of life, heparin in very preterm infants (gestational age < 32 weeks). For each of the included trials, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, dose of heparin, mode of administration, and duration of therapy, etc.) and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow up). The primary outcomes considered in this review are intraventricular haemorrhage, severe intraventricular haemorrhage and neonatal mortality. Two randomised controlled trials enrolling a total of 155 infants met the inclusion criteria of this review. Both trials compared low-dose heparin to the same solution without heparin in very preterm newborns requiring umbilical catheterisation. No trials were identified that specifically studied the use of heparin in infants at risk of germinal matrix-intraventricular haemorrhage.We found no differences in the rates of intraventricular haemorrhage (typical RR 0.93, 95% CI 0.61 to 1.41; typical RD -0.03, 95% CI -0.17 to 0.12; 2 studies, 155 infants; I² = 57% for RR and I² = 65% for RD), severe intraventricular haemorrhage (typical RR 1.01, 95% CI 0.46 to 2.23; typical RD 0.00, 95% CI -0.11 to 0.11; 2 studies, 155 infants; I² = 0% for RR and I² = 0% for RD) and neonatal mortality (typical RR 0.69, 95% CI 0.28 to 1.67; typical RD -0.04, 95% CI -0.14 to 0.06; 2 studies, 155 infants; I² = 28% for RR and I² = 50% for RD). We judged the quality of the evidence supporting these findings as very low (rates of intraventricular haemorrhage) and low (severe intraventricular haemorrhage and neonatal mortality) mainly because of limitations in the study designs and the imprecision of estimates. We found very few data on other relevant outcomes, such as bronchopulmonary dysplasia, pulmonary haemorrhage and patent ductus arteriosus; and no study assessing long-term outcomes (e.g. neurodevelopmental disability). There is very limited data on the effect of prophylactic administration of heparin on the incidence and severity of IVH in very preterm neonates. Both the identified trials used heparin in the context of maintaining umbilical line patency and not specifically as an agent to prevent germinal matrix-intraventricular haemorrhage. Given the imprecision of our estimates, the results of this systematic review are consistent with either a benefit or a detrimental effect of heparin and do not provide a definitive answer to the review question. Limited evidence is available on other clinically relevant outcomes.


The Impact of a Mother's Emotional Strains and Disclosure of Cancer on Her Child's Defensiveness and Adjustment to Cancer.
Defensiveness is one of the strategies that children with cancer use against psychosocial difficulties, yet it remains unclear what factors may impact children's use of defensiveness. The aim of this study was to explore the psychological adjustment, including use of defensive behaviors, in children who may or may not be told about the diagnosis of cancer. A total of 58 children and 51 mothers participated in the study. Children answered questionnaires about defensiveness, anxiety, and depression, whereas mothers completed a questionnaire of anxiety, depression, and stress and a question about disclosure of cancer to child. Significant differences were found in the defensiveness and depression scores between children with full disclosure and those with no disclosure about their cancer. Although children's adjustment has been directly related to that of their mother's adjustment, we did not find this variable to be a predictor of child's adjustment. The child's defensiveness scores were a strong predictor of child's anxiety and eventually for a high risk for depression. Mothers' emotional strains and lack of open disclosure about cancer significantly affect the psychosocial well-being of children. It is essential for nurses to assess the emotional adjustment and defensiveness strategies that children with cancer use. We believe that nurses caring for children with cancer have a professional responsibility to identify and understand defensive behaviors and other characteristics of psychosocial distress and advocate for psychological interventions that will help mothers and their children cope with cancer.


Redistribution of 23 kDa tubulovesicle-associated GTP-binding proteins during parietal cell stimulation.
Small GTP-binding proteins are important regulators of intracellular traffic. The presence of several small GTP-binding proteins was documented in subfractions of rabbit parietal cells. Upon maximal stimulation of the cells with a combination of histamine and forskolin, one 23 kDa GTP-binding band was observed to decrease in a 50,000 g membrane fraction while increasing in 4000 g membranes. The 23 kDa band resolved into one major and two minor species on two-dimensional gels. GTP-binding species of 23 kDa, 24 kDa and 25 kDa were present in purified preparations of tubulovesicles. The three isoelectric species of the 23 kDa proteins observed in parietal cell 50,000 g microsomes were enriched in tubulovesicle preparations. None of the tubulovesicle-associated GTP-binding proteins were substrates for ADP-ribosylation by a preparation of botulinum D toxin. These results indicate that tubulovesicles contain discrete small GTP-binding proteins which redistribute during parietal cell stimulation.


Markers for seedling and adult plant crown rot resistance in four partially resistant bread wheat sources.
QTL identified for seedling and adult plant crown rot resistance in four partially resistant hexaploid wheat sources. PCR-based markers identified for use in marker-assisted selection. Crown rot, caused by Fusarium pseudograminearum, is an important disease of wheat in many wheat-growing regions globally. Complete resistance to infection by F. pseudograminearum has not been observed in a wheat host, but germplasm with partial resistance to this pathogen has been identified. The partially resistant wheat hexaploid germplasm sources 2-49, Sunco, IRN497 and CPI133817 were investigated in both seedling and adult plant field trials to identify markers associated with the resistance which could be used in marker-assisted selection programs. Thirteen different quantitative trait loci (QTL) conditioning crown rot resistance were identified in the four different sources. Some QTL were only observed in seedling trials whereas others appeared to be adult plant specific. For example while the QTL on chromosomes 1AS, 1BS, and 4BS contributed by 2-49 and on 2BS contributed by Sunco were detected in both seedling and field trials, the QTL on 1DL present in 2-49 and the QTL on 3BL in IRN497 were only detected in seedling trials. Genetic correlations between field trials of the same population were strong, as were correlations between seedling trials of the same population. Low to moderate correlations were observed between seedling and field trials. Flanking markers, most of which are less than 10 cM apart, have now been identified for each of the regions associated with crown rot resistance.


Development of a US trust measure to assess and monitor parental confidence in the vaccine system.
To develop a Vaccine Confidence Index (VCI) that is capable of detecting variations in parental confidence towards childhood immunizations centered on trust and concern issues that impact vaccine confidence. We used a web-based national poll of 893 parents of children <7 years in 2016 to assess the measures created for the Emory VCI (EVCI). EVCI measures were developed using constructs related to vaccine confidence identified by the U.S. National Vaccine Advisory Committee (i.e., "Information Environment", "Trust", "Healthcare Provider", "Attitudes and Beliefs", and "Social Norms"). Reliability for EVCI was assessed using Cronbach's alpha. Using the variables related to each of the constructs, we calculated an overall EVCI score that was then assessed against self-reported childhood vaccine receipt using chi-square and the Cochrane-Armitage trend tests. Respondents' EVCI scores could range from 0 to 24, and the full range of values was observed in this sample (Mean = 17.5 (SD 4.8)). EVCI scores were significantly different (p ≤ 0.006 for all comparisons) between parents who indicated their child(ren) received routinely recommended vaccines compared with parents who indicated they had delayed or declined recommended immunizations. There was also a significant, consistent association between higher EVCI scores and greater reported vaccine receipt. We developed EVCI to reliably measure parental vaccine confidence, with individuals' scores linked to parental vaccine-related attitudes, intentions, and behaviors. As such, EVCI may be a useful tool for future monitoring of both population and individual confidence in childhood immunization.


Green tea catechins improve human forearm endothelial dysfunction and have antiatherosclerotic effects in smokers.
Because green tea reduces cardiovascular and cerebrovascular risk, the purpose of this study aimed to elucidate the effect of green tea catechins (GTC) on endothelial dysfunction in smokers. The 30 healthy male smokers were divided into 3 groups and given green tea beverages containing 0 mg (control group), 80 mg (medium-dose group) or 580 mg (high-dose group) of GTC daily for 2 weeks. Endothelial-dependent and- independent vasodilatation was investigated by measuring the forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside using venous occlusion strain-gauge plethysmography. The FBF response to acetylcholine significantly increased at 2 h and 1 and 2 weeks after GTC intake in the high-dose group, but no increase was observed in the other groups. FBF responses to sodium nitroprusside did not alter in any group at any time point. A significant increase in plasma nitric oxide and a decrease in asymmetrical dimethylarginine, malondealdehyde and 4-hydroxynonenal, C-reactive protein, monocyte chemotactic protein-1, and soluble CD40 ligand levels were detected after chronic consumption of high-dose GTC. GTC have antiatherosclerotic effects on dysfunctional vessels in smokers through increasing the level of nitric oxide and reducing oxidative stress.


Surgical treatment of multiple sporadic colorectal carcinoma.
Many aspects of the surgical management of multiple sporadic colorectal cancer syndrome, either synchronous and metachronous, remain to be cleared, in particular the prognostic influence of the extent of surgical resection. A retrospective review was performed of patients diagnosed with multiple colorectal cancer from 1982 to May 2010. Clinical and pathologic data were collected and reviewed. Survival analysis was performed. We identified 23 patients with multiple sporadic colorectal cancers, of which 8 had synchronous (SC) and 15 metachronous cancers (MC). Of the MC patients, 2 (13%) had the second cancer within 2 years, 4 (27%) in the time period of 2-5 years and 9 (60%) after 5 years. Twenty-one patients underwent multiple segmental resections; 2 patients underwent subtotal colectomy. The 5-year overall survival rate of SC and MC patients was 100% and 87% (p<0.001) respectively. The 5-year overall survival rate of multiple segmental resection patients and subtotal colectomy was 94% and 75% (p=0.655) respectively. Either synchronous and metachronous MSCRC patients showed good prognosis independently from to the extent of resection. Our results support a less aggressive biological behaviour allowing a more conservative management. Multiple segmental colorectal resections seem appropriate from an oncologic point of view in MSCRC patients.