Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma

Background: The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC4 synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A(-444)C) in the gene might be associated with asthma severity and aspirin intolerance. Objective: We sought to screen the LTC4 synthase gene for polymorphisms and to determine whether there is an association between these polymorphisms and asthma severity or aspirin sensitivity in a large, well-phenotyped population and to determine whether this polymorphism is functionally relevant. Methods: The coding regions of the LTC4 synthase gene were screened for polymorphisms and the A(-444)C polymorphism was analyzed in a large Australian white adult population of mild (n = 282), moderate (n = 236), and severe asthmatic subjects (n = 86) and nonasthmatic subjects (n = 458), as well as in aspirin-intolerant asthmatic subjects (n = 67). The functional activity of the promoter polymorphism was investigated by transient transfection of HL-60 cells with a promoter construct. Results: A new polymorphism was identified in intron 1 of the gene (IVS1-10c>a) but was not associated with asthma. Association studies showed that the A(-444)C polymorphism was weakly associated with asthma per se, but there was no association between the C-444 allele and chronic asthma severity or aspirin intolerance. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity in C-444 allele frequencies within different clinical subgroups. In vitro functional studies showed no significant differences in transcription efficiency between constructs containing the A(-444) allele or the C-444 allele. Conclusions: Our data confirm that, independent of transcriptional activity, the C-444 allele in the LTC4 synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance.

The incidence of corpora amylacea (CA) in the optic nerve of patients with Alzheimer's disease

Corpora amylacea (CA) are spherical or ovoid bodies 50-50 microns in diameter. They have been described in normal elderly brain as well as in a number of neurodegenerative disorders. In this study, the incidence of CA in the optic nerves of Alzheimer's disease (AD) patients was compared with normal elderly controls. Samples of optic nerves (MRC Brain Bank, Institute of Psychiatry) were taken from 12 AD patients (age range 69-94 years) and 18 controls (43-82 years). Optic nerves were fixed in 2% buffered glutaraldehyde, post-fixed in osmium tetroxide, embedded in epoxy resin and then sectioned to a thickness of 2 microns. Sections were stained with toluidine blue. CA were present in all of the optic nerves examined. In addition, a number of similarly stained but more irregularly shaped bodies were present. Fewer CA were found in the optic nerves of AD patients compared with controls. By contrast, the number or irregularly shaped bodies was increased in AD. In AD, there may be a preferential decline in the large diameter fibres which may mediate the M-cell pathway. Hence, the decline in the incidence of CA in AD may be associated with a reduction in these fibres. It is also possible that the irregualrly shaped bodies are a degeneration product of the CA.

Self-association of calcium-binding protein S100A4 and metastasis

Elevated levels of the calcium-binding protein S100A4 promote metastasis and in carcinoma cells are associated with reduced survival of cancer patients. S100A4 interacts with target proteins that affect a number of activities associated with metastatic cells. However, it is not known how many of these interactions are required for S100A4-promoted metastasis, thus hampering the design of specific inhibitors of S100A4-induced metastasis. Intracellular S100A4 exists as a homodimer through previously identified, well conserved, predominantly hydrophobic key contacts between the subunits. Here it is shown that mutating just one key residue, phenylalanine 72, to alanine is sufficient to reduce the metastasis-promoting activity of S100A4 to 50% that of the wild type protein, and just 2 or 3 specific mutations reduces the metastasis-promoting activity of S100A4 to less than 20% that of the wild type protein. These mutations inhibit the self-association of S100A4 in vivo and reduce markedly the affinity of S100A4 for at least two of its protein targets, a recombinant fragment of non-muscle myosin heavy chain isoform A, and p53. Inhibition of the self-association of S100 proteins might be a novel means of inhibiting their metastasis-promoting activities.

Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting. © 2014 American Heart Association, Inc.

Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality:a systematic review

Objectives: to determine the effect of drugs with anti-cholinergic properties on relevant health outcomes.Design: electronic published and unpublished literature/trial registries were systematically reviewed. Studies evaluating medications with anti-cholinergic activity on cognitive function, delirium, physical function or mortality were eligible.Results: forty-six studies including 60,944 participants were included. Seventy-seven percent of included studies evaluating cognitive function (n = 33) reported a significant decline in cognitive ability with increasing anti-cholinergic load (P < 0.05). Four of five included studies reported no association with delirium and increasing anti-cholinergic drug load (P > 0.05). Five of the eight included studies reported a decline in physical function in users of anti-cholinergics (P < 0.05). Three of nine studies evaluating mortality reported that the use of drugs with anti-cholinergic properties was associated with a trend towards increased mortality, but this was not statistically significant. The methodological quality of the evidence-base ranged from poor to very good.Conclusion: medicines with anti-cholinergic properties have a significant adverse effect on cognitive and physical function, but limited evidence exists for delirium or mortality outcomes. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.

Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults

Objectives: To assess the association between the use of medications with anticholinergic activity and the subsequent risk of injurious falls in older adults. Design: Prospective, population-based study using data from The Irish Longitudinal Study on Ageing. Setting: Irish population. Participants: Community-dwelling men and women without dementia aged 65 and older (N = 2,696). Measurements: Self-reported injurious falls reported once approximately 2 years after baseline interview. Self-reported regular medication use at baseline interview. Pharmacy dispensing records from the Irish Health Service Executive Primary Care Reimbursement Service in a subset (n = 1,553). Results: Nine percent of men and 17% of women reported injurious falls. In men, the use of medications with definite anticholinergic activity was associated with greater risk of subsequent injurious falls (adjusted relative risk (aRR) = 2.55, 95% confidence interval (CI) = 1.33-4.88), but the risk of having any fall and the number of falls reported were not significantly greater. Greater anticholinergic burden was associated with greater injurious falls risk. No associations were observed for women. Findings were similar using pharmacy dispensing records. The aRR for medications with definite anticholinergic activity dispensed in the month before baseline and subsequent injurious falls in men was 2.53 (95% CI = 1.15-5.54). Conclusion: The regular use of medications with anticholinergic activity is associated with subsequent injurious falls in older men, although falls were self-reported after a 2-year recall and so may have been underreported. Further research is required to validate this finding in men and to consider the effect of duration and dose of anticholinergic medications.

A tudásérték meghatározása minőségügyi szempontból, hálózatelemzési módszerekkel (The knowledge value in terms of quality with network analysis methods)

A minőségügy egyik kulcsfeladata, hogy azonosítsa az értékteremtés szempontjából kritikus tényezőket, meghatározza ezek értékét, valamint intézkedjen negatív hatásuk megelőzése és csökkentése érdekében. Az értékteremtés sok esetben folyamatokon keresztül történik, amelyek tevékenységekből, elvégzendő feladatokból állnak. Ezekhez megfelelő munkatársak kellenek, akiknek az egyik legfontosabb jellemzője az általuk birtokolt tudás. Mindezek alapján a feladat-tudás-erőforrás kapcsolatrendszer ismerete és kezelése minőségügyi feladat is. A komplex rendszerek elemzésével foglalkozó hálózatkutatás eszközt biztosíthat ehhez, ezért indokolt a minőségügyi területen történő alkalmazhatóságának vizsgálata. Az alkalmazási lehetőségek rendszerezése érdekében a szerzők kategorizálták a minőségügyi hálózatokat az élek (kapcsolatok) és a csúcsok (hálózati pontok) típusai alapján. Ezt követően definiálták a multimodális (több különböző csúcstípusból álló) tudáshálózatot, amely a feladatokból, az erőforrásokból, a tudáselemekből és a közöttük lévő kapcsolatokból épül fel. A hálózat segítségével kategóriákba sorolták a tudáselemeket, valamint a fokszámok alapján meghatározták értéküket. A multimodális hálózatból képzett tudáselem-hálózatban megadták az összefüggő csoportok jelentését, majd megfogalmaztak egy összefüggést a tudáselem-elvesztés kockázatának meghatározására. _______ The aims of quality management are to identify those factors that have significant influence on value production, qualify or quantify them, and make preventive and corrective actions in order to reduce their negative effects. The core elements of value production are processes and tasks, along with workforce having the necessary knowledge to work. For that reason the task-resource-knowledge structure is pertinent to quality management. Network science provides methods to analyze complex systems; therefore it seems reasonable to study the use of tools of network analysis in association with quality management issues. First of all the authors categorized quality networks according to the types of nodes (vertices) and links (edges or arcs). Focusing on knowledge management, they defined the multimodal knowledge network, consisting of tasks, resources, knowledge items and their interconnections. Based on their degree, network nodes can be categorized and their value can be quantified. Derived from the multimodal network knowledge-item network is to be created, where the meaning of cohesive subgroups is defined. Eventually they proposed a formula for determining the risk of knowledge loss.

The discrimination and association of float glass and the quantitative analysis of liquids from aerosols and microdrops using laser induced breakdown spectroscopy

Glass is a common form of trace evidence found at many scenes of crimes in the form of small fragments. These glass fragments can transfer to surrounding objects and/or persons and may provide forensic investigators valuable information to link a suspect to the scene of a crime. Since the elemental composition of different glass sources can be very similar, a highly discriminating technique is required to distinguish between fragments that have originated from different sources. ^ The research presented here demonstrates that Laser Induced Breakdown Spectroscopy (LIBS) is a viable analytical technique for the association and discrimination of glass fragments. The first part of this research describes the optimization of the LIBS experiments including the use of different laser wavelengths to investigate laser-material interaction. The use of a 266 nm excitation laser provided the best analytical figures of merit with minimal damage to the sample. The resulting analytical figures of merit are presented. The second part of this research evaluated the sensitivity of LIBS to associate or discriminate float glass samples originating from the same manufacturing plants and produced at approximately the same time period. Two different sample sets were analyzed ranging in manufacturing dates from days to years apart. Eighteen (18) atomic emission lines corresponding to the elements Sr, K, Fe, Ca, Al, Ba, Na, Mg and Ti, were chosen because of their detection above the method detection limits and for presenting differences between the samples. Ten elemental ratios producing the most discrimination were selected for each set. When all the ratios are combined in a comparison, 99% of the possible pairs were discriminated using the optimized LIBS method generating typical analytical precisions of ∼5% RSD. ^ The final study consisted of the development of a new approach for the use of LIBS as a quantitative analysis of ultra-low volume solution analysis using aerosols and microdrops. Laser induced breakdown spectroscopy demonstrated to be an effective technique for the analysis of as low as 90 pL for microdrop LIBS with 1 pg absolute LOD and 20 µL for aerosol LIBS with an absolute LOD of ∼100 fg.^

The effects of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and relationship with the partner on the quality of life of men with prostate cancer

Prostate cancer, the leading cause of cancer in men, has positive survival rates and constitutes a challenge to men with its side effects. Studies have addressed the bivaritate relationships between prostate cancer treatment side effects masculinity, partner relationship, and quality of life (QOL). However, few studies have highlighted the relationships among prostate cancer treatment side effects (i.e., sexual dysfunction, urinary incontinence), masculinity, and relationship with the partner together on QOL in men. Most studies were conducted with predominately Caucasian sample of men. Miami is a unique multiethnic setting that hosts Cuban, Columbian, Venezuelan, Haitian, other Latin American and Caribbean communities that were not represented in previous literature. The purpose of this study was to examine relative contributions of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and perception of the relationship with the partner on the quality of life in men diagnosed with prostate cancer. Data were collected using self administered questionnaires measuring demographic variables, sexual and urinary functioning (UCLA PCI), masculinity (CMNI), partner relationship (DAS), and QOL (SF-36). A total of 117 partnered heterosexual men diagnosed with prostate cancer were recruited from four urology clinics in Miami, Florida. Men were 67.47 (SD = 8.42) years old and identified themselves to be of Hispanic origin (54.3 %, n = 63). Findings demonstrated that there was a significant moderate negative relationship between urinary and sexual functioning of men. There was a significant strong negative association between men's perceived relationship with partner and masculinity. There was a weak negative relationship between the partner relationship and QOL. Hierarchal multiple regression showed that the partner relationship (β = -.25, t (91) = -2.28, p = .03) significantly contributed overall to QOL. These findings highlight the importance of the relationship satisfaction in the QOL of men with prostate cancer. Nursing interventions to enhance QOL for these men should consider strengthening the relationship and involving the female partner as an active participant.^

Online Education, Accrediting Standards, and Student Success: An Examination of the Relationship Between the Southern Association of Colleges and Schools Commission on Colleges Standards for Online Education and Student Success

Prior to 2000, there were less than 1.6 million students enrolled in at least one online course. By fall 2010, student enrollment in online distance education showed a phenomenal 283% increase to 6.1 million. Two years later, this number had grown to 7.1 million. In light of this significant growth and skepticism about quality, there have been calls for greater oversight of this format of educational delivery. Accrediting bodies tasked with this oversight have developed guidelines and standards for online education. There is a lack of empirical studies that examine the relationship between accrediting standards and student success. The purpose of this study was to examine the relationship between the presence of Southern Association of Colleges and Schools Commission on College (SACSCOC) standards for online education in online courses, (a) student support services and (b) curriculum and instruction, and student success. An original 24-item survey with an overall reliability coefficient of .94 was administered to students (N=464) at Florida International University, enrolled in 24 university-wide undergraduate online courses during fall 2014, who rated the presence of these standards in their online courses. The general linear model was utilized to analyze the data. The results of the study indicated that the two standards, student support services and curriculum and instruction were both significantly and positively correlated with student success but with small R2 and strengths of association less than .35 and .20 respectively. Mixed results were produced from Chi-square tests for differences in student success between higher and lower rated online courses when controlling for various covariates such as discipline, gender, race/ethnicity, GPA, age, and number of online courses previously taken. A multiple linear regression analysis revealed that the curriculum and instruction standard was the only variable that accounted for a significant amount of unique variance in student success. Another regression test revealed that no significant interaction effect exists between the two SACSCOC standards and GPA in predicting student success. The results of this study are useful for administrators, faculty, and researchers who are interested in accreditation standards for online education and how these standards relate to student success.

Spatial association of mud volcano and sandstone intrusions, Boyadag anticline, western Turkmenistan

Acknowledgements The Authors are indebted with Dr. Barbara Cerasetti, scientific coordinator of the Italian Archaeological Program in Turkmenistan (Dipartimento di Storia, Culture, Civiltà – Università di Bologna – Ministero per gli Affari Esteri – MAE), for the logistical help before and during the field activities in Turkmenistan. Our thanks to the administration of the National Institute of Deserts, Flora and Fauna, to the Turkmenistan Government and to Dr Aman Nigarov for the fruitful assistance in the field. We thank Prof. Marco Antonellini for the discussions on sandstone intrusions. The authors are indebted to the reviewers J. Peakall, P. Imbert, A. Hurst and an anonymous reviewer for the very helpful comments to the manuscript. Funding was provided by Prof. G. Gabbianelli for the field survey and by PRIN 2009 grants to Prof. Rossella Capozzi.

Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1

The HIV-1 genome contains several genes coding for auxiliary proteins, including the small Vpr protein. Vpr affects the integrity of the nuclear envelope and participates in the nuclear translocation of the preintegration complex containing the viral DNA. Here, we show by photobleaching experiments performed on living cells expressing a Vpr-green fluorescent protein fusion that the protein shuttles between the nucleus and the cytoplasm, but a significant fraction is concentrated at the nuclear envelope, supporting the hypothesis that Vpr interacts with components of the nuclear pore complex. An interaction between HIV-1 Vpr and the human nucleoporin CG1 (hCG1) was revealed in the yeast two-hybrid system, and then confirmed both in vitro and in transfected cells. This interaction does not involve the FG repeat domain of hCG1 but rather the N-terminal region of the protein. Using a nuclear import assay based on digitonin-permeabilized cells, we demonstrate that hCG1 participates in the docking of Vpr at the nuclear envelope. This association of Vpr with a component of the nuclear pore complex may contribute to the disruption of the nuclear envelope and to the nuclear import of the viral DNA.