APC/CCdh1-Mediated Degradation of the F-Box Protein NIPA Is Regulated by Its Association with Skp1

NIPA (Nuclear Interaction Partner of Alk kinase) is an F-box like protein that targets nuclear Cyclin B1 for degradation. Integrity and therefore activity of the SCFNIPA E3 ligase is regulated by cell-cycle-dependent phosphorylation of NIPA, restricting substrate ubiquitination to interphase. Here we show that phosphorylated NIPA is degraded in late mitosis in an APC/CCdh1-dependent manner. Binding of the unphosphorylated form of NIPA to Skp1 interferes with binding to the APC/C-adaptor protein Cdh1 and therefore protects unphosphorylated NIPA from degradation in interphase. Our data thus define a novel mode of regulating APC/C-mediated ubiquitination

Effect of Anticholinergic Use for the Treatment of Overactive Bladder on Cognitive Function in Postmenopausal Women

Overactive bladder (OAB) is a common condition affecting the elderly. The mainstay of treatment for OAB is medical therapy with anticholinergics. However, adverse events have been reported with this class of drugs including cognitive changes

A falling of the veils: turning points and momentous turning points in leadership and the creation of CSR

This article uses the life stories approach to leadership and leadership development. Using exploratory, qualitative data from a Forbes Global 2000 and FTSE 100 company, we discuss the role of the turning point (TP) as an important antecedent of leadership in corporate social responsibility. We argue that TPs are causally efficacious, linking them to the development of life narratives concerned with an evolving sense of personal identity. Using both a multi-disciplinary perspective and a multi-level focus on CSR leadership, we identify four narrative cases. We propose that they helped to re-define individuals’ sense of self and in some extreme cases completely transformed their self-identity as leaders of CSR. Hence we also distinguish the momentous turning point (MTP) that created a seismic shift in personality, through re-evaluation of the individuals’ personal values. We argue that whilst TPs are developmental experiences that can produce responsible leadership, the MTP changes the individuals’ personal priorities in life to produce responsible leadership that perhaps did not exist previously. Thus we appropriate Maslow’s (1976, p. 77) metaphorical phrase ‘A falling of the veils’ from his discussion of peak and desolation experiences that produce personal growth. Using a multi-disciplinary literature from social theory (Archer, 2012) moral psychology (Narvaez, 2009) and social psychology (Schwartz, 2010), we present a theoretical model that illustrates the psychological process of the (M)TP, thus contributing to the growing literature on the microfoundations of CSR

Describing the profile of diagnostic features in autistic adults using an abbreviated version of the Diagnostic Interview for Social and Communication Disorders (DISCO-Abbreviated)

The rate of diagnosis of autism in adults has increased over recent years; however, the profile of behaviours in these individuals is less understood than the profile seen in those diagnosed in childhood. Better understanding of this profile will be essential to identify and remove potential barriers to diagnosis. Using an abbreviated form of the Diagnostic Interview for Social and Communication Disorders, comparisons were drawn between the profile of a sample of able adults diagnosed in adulthood and the profile of a sample of able children. Results revealed both similarities and differences. A relative strength in non-verbal communication highlighted a potential barrier to diagnosis according to DSM-5 criteria for the adult sample, which may also have prevented them from being diagnosed as children

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals

Training Genetic Counsellors to Deliver an Innovative Therapeutic Intervention: their views and experience of facilitating multi-family discussion groups

Innovations in clinical genetics have increased diagnosis, treatment and prognosis of inherited genetic conditions (IGCs). This has led to an increased number of families seeking genetic testing and / or genetic counselling and increased the clinical load for genetic counsellors (GCs). Keeping pace with biomedical discoveries, interventions are required to support families to understand, communicate and cope with their Inherited Genetic Condition. The Socio-Psychological Research in Genomics (SPRinG) collaborative have developed a new intervention, based on multi-family discussion groups (MFDGs), to support families affected by IGCs and train GCs in its delivery. A potential challenge to implementing the intervention was whether GCs were willing and able to undergo the training to deliver the MFDG. In analysing three multi-perspective interviews with GCs, this paper evaluates the training received. Findings suggests that MFDGs are a potential valuable resource in supporting families to communicate genetic risk information and can enhance family function and emotional well-being. Furthermore, we demonstrate that it is feasible to train GCs in the delivery of the intervention and that it has the potential to be integrated into clinical practice. Its longer term implementation into routine clinical practice however relies on changes in both organisation of clinical genetics services and genetic counsellors' professional development

Expression and prognostic value of circulating angiogenic cytokines in pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The utility of circulating angiogenic cytokines (CAC) as biomarkers in pancreatic cancer has not been clarified yet. We investigated the expression and prognostic associations of seven CAC in patients with pancreatic cancer.</p> <p>Methods</p> <p>Serum samples were collected preoperatively in patients undergoing surgery for localized pancreatic cancer (n = 74), metastatic pancreatic cancer (n = 24) or chronic pancreatitis (n = 20) and in healthy controls (n = 48). Quantitative enzyme-linked immunosorbent assays and multiplex protein arrays were used to determine circulating levels of VEGF, VEGFR-1, PlGF, PDGF-AA, PDGF-BB, Ang-1 and EGF. Multivariate analyses on cancer-specific survival were performed with a Cox proportional hazards model.</p> <p>Results</p> <p>VEGF (p < 0.0001), PDGF-AA (p < 0.0001), Ang-1 (p = 0.002) and EGF (p < 0.0001) were differentially expressed in patients with pancreatic cancer compared to healthy controls. The presence of lymph node metastases was associated with increased levels of all CAC except for PlGF, whereas there were only minor associations of CAC with other clinicopathologic variables. The multivariate model including the entire angiogenic panel revealed high levels of circulating PDGF-AA (hazard ratio 4.58; 95% confidence interval 1.43 - 14.69) as predictor of poor cancer-specific survival, whereas high levels of PDGF-BB (0.15; 0.15 - 0.88), Ang-1 (0.30; 0.10 - 0.93) and VEGF (0.24; 0.09 - 0.57) were associated with a favorable prognosis.</p> <p>Conclusion</p> <p>Circulating levels of certain angiogenic cytokines correlate with patients' prognosis after resection for pancreatic cancer, if a panel of several CAC is considered simultaneously. These data should be considered in future studies evaluating angiogenic factors as prognostic biomarkers and therapeutic targets in patients with pancreatic cancer.</p

Validation of the conceptual research utilization scale: an application of the standards for educational and psychological testing in healthcare

<p>Abstract</p> <p>Background</p> <p>There is a lack of acceptable, reliable, and valid survey instruments to measure conceptual research utilization (CRU). In this study, we investigated the psychometric properties of a newly developed scale (the CRU Scale).</p> <p>Methods</p> <p>We used the <it>Standards for Educational and Psychological Testing </it>as a validation framework to assess four sources of validity evidence: content, response processes, internal structure, and relations to other variables. A panel of nine international research utilization experts performed a formal content validity assessment. To determine response process validity, we conducted a series of one-on-one scale administration sessions with 10 healthcare aides. Internal structure and relations to other variables validity was examined using CRU Scale response data from a sample of 707 healthcare aides working in 30 urban Canadian nursing homes. Principal components analysis and confirmatory factor analyses were conducted to determine internal structure. Relations to other variables were examined using: (1) bivariate correlations; (2) change in mean values of CRU with increasing levels of other kinds of research utilization; and (3) multivariate linear regression.</p> <p>Results</p> <p>Content validity index scores for the five items ranged from 0.55 to 1.00. The principal components analysis predicted a 5-item 1-factor model. This was inconsistent with the findings from the confirmatory factor analysis, which showed best fit for a 4-item 1-factor model. Bivariate associations between CRU and other kinds of research utilization were statistically significant (p < 0.01) for the latent CRU scale score and all five CRU items. The CRU scale score was also shown to be significant predictor of overall research utilization in multivariate linear regression.</p> <p>Conclusions</p> <p>The CRU scale showed acceptable initial psychometric properties with respect to responses from healthcare aides in nursing homes. Based on our validity, reliability, and acceptability analyses, we recommend using a reduced (four-item) version of the CRU scale to yield sound assessments of CRU by healthcare aides. Refinement to the wording of one item is also needed. Planned future research will include: latent scale scoring, identification of variables that predict and are outcomes to conceptual research use, and longitudinal work to determine CRU Scale sensitivity to change.</p

Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial)

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl

Clinical laboratory reference values amongst children aged 4 weeks to 17 months in Kilifi, Kenya: A cross sectional observational study

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to <6 months, 6 months to less than <12 months, and 12 months to 17 months for the haematological parameters; and 4 weeks to 17 months for the biochemical parameters. There were no gender differences for all haematological and biochemical parameters in all age groups. Hb, MCV and platelets 95% reference ranges in infants largely overlapped with those from United States or Europe, except for the lower limit for Hb, Hct and platelets (lower); and upper limit for platelets (higher) and haematocrit(lower). Community norms for common haematological and biochemical parameters differ from developed countries. This reaffirms the need in clinical trials for locally derived reference values to detect deviation from what is usual in typical children in low and middle income countries