S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer.

Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. Cancer Res; 77(3); 1-10. ©2016 AACR

Burden of visceral leishmaniasis in villages of eastern gedaref state, Sudan: an exhaustive cross-sectional survey.

Since December 2009, Médecins Sans Frontières has diagnosed and treated patients with visceral leishmaniasis (VL) in Tabarak Allah Hospital, eastern Gedaref State, one of the main endemic foci of VL in Sudan. A survey was conducted to estimate the VL incidence in villages around Tabarak Allah

Prevalence of Group A beta-haemolytic Streptococcus isolated from children with acute pharyngotonsillitis in Aden, Yemen.

OBJECTIVES: To estimate the prevalence of Group A beta-haemolytic streptococcus (GAS) and non-GAS infections among children with acute pharyngotonsillitis in Aden, Yemen, to evaluate the value of a rapid diagnostic test and the McIsaac score for patient management in this setting and to determine the occurrence of emm genotypes among a subset of GAS isolated from children with acute pharyngotonsillitis and a history of acute rheumatic fever (ARF) or rheumatic heart disease (RHD). METHODS: Group A beta-haemolytic streptococcus infections in school-aged children with acute pharyngotonsillitis in Aden, Yemen, were diagnosed by a rapid GAS antigen detection test (RADT) and/or GAS culture from a throat swab. The RADT value and the McIsaac screening score for patient management were evaluated. The emm genotype of a subset of GAS isolates was determined. RESULTS: Group A beta-haemolytic streptococcus pharyngotonsillitis was diagnosed in 287/691 (41.5%; 95% CI 37.8-45.3) children. Group B, Group C and Group G beta-haemolytic streptococci were isolated from 4.3% children. The RADT had a sensitivity of 238/258 (92.2%) and specificity of 404/423 (95.5%) against GAS culture. A McIsaac score of ≥4 had a sensitivity of 93% and a specificity of 82% for confirmed GAS infection. The emm genotypes in 21 GAS isolates from children with pharyngitis and a history of ARF and confirmed RHD were emm87 (11), emm12 (6), emm28 (3) and emm5 (1). CONCLUSION: This study demonstrates a very high prevalence of GAS infections in Yemeni children and the value of the RADT and the McIsaac score in this setting. More extensive emm genotyping is necessary to understand the local epidemiology of circulating strains

The impact of Stieltjes' work on continued fractions and orthogonal polynomials

Stieltjes' work on continued fractions and the orthogonal polynomials related to continued fraction expansions is summarized and an attempt is made to describe the influence of Stieltjes' ideas and work in research done after his death, with an emphasis on the theory of orthogonal polynomials

The Global Longitudinal Study of Osteoporosis in Women (GLOW): rationale and study design

SUMMARY: The Global Longitudinal study of Osteoporosis in Women (GLOW) is a prospective cohort study involving 723 physicians and 60,393 women subjects >or=55 years. The data will provide insights into the management of fracture risk in older women over 5 years, patient experience with prevention and treatment, and distribution of risk among older women on an international basis. INTRODUCTION: Data from cohort studies describing the distribution of osteoporosis-related fractures and risk factors are not directly comparable and do not compare regional differences in patterns of patient management and fracture outcomes. METHODS: The GLOW is a prospective, multinational, observational cohort study. Practices typical of each region were identified through primary care networks organized for administrative, research, or educational purposes. Noninstitutionalized patients visiting each practice within the previous 2 years were eligible. Self-administered questionnaires were mailed, with 2:1 oversampling of women >or=65 years. Follow-up questionnaires will be sent at 12-month intervals for 5 years. RESULTS: A total of 723 physicians at 17 sites in ten countries agreed to participate. Baseline surveys were mailed (October 2006 to February 2008) to 140,416 subjects. After the exclusion of 3,265 women who were ineligible or had died, 60,393 agreed to participate. CONCLUSIONS: GLOW will provide contemporary information on patterns of management of fracture risk in older women over a 5-year period. The collection of data in a similar manner in ten countries will permit comparisons of patient experience with prevention and treatment and provide insights into the distribution of risk among older women on an international basis

Megameatus intact prepuce variety of hypospadias: tips for repair using the modified glanular approximation procedure

Background/purpose Megameatus and intact prepuce (MIP) is an unusual, anterior hypospadias variant. Cosmetic remodeling is usually carried out to avoid disturbing the child’s psychological state. Several approaches are used for MIP repair. The purpose of this study was to present a single institution’s experience with the modified glanular approximation procedure (GAP) in the treatment of the MIP variant of hypospadias and the tips needed to obtain the best outcome.Patients and methods Seventeen patients with MIP were repaired between May 2004 and May 2009 by the modified GAP technique. The technique was used to achieve a conical glans with a vertical slit, tip-cited meatus, and a straight urine stream. Patient/parent satisfaction was assessed by a subjective score that ranged between 0 and 3 and complications were reported.Results All patients were repaired using the modified GAP technique. The age of the patients ranged from 6 months to 28 years. Four patients were circumcised with a history of intact prepuce. An intermediate layer was added in seven patients. Excision of a part of the redundant urethral plate was carried out in six cases. Disruption of the repair occurred in one patient as a result of wound infection. Excellent cosmetic results were achieved in 14 patients (10 with a subjective score of 3 and four with a subjective score of 2). Two patients expressed an acceptable score of 1 and one patient was dissatisfied with a subjective score of 0.Conclusion Good cosmetic results, such as achievement of a straight urine stream and patient satisfaction, can be achieved using the modified GAP procedure. The steps should be tailored to individual cases.Keywords: hypospadias, megameatus, modified glanular approximation procedur

The impact of Cochrane Systematic Reviews : a mixed method evaluation of outputs from Cochrane Review Groups supported by the UK National Institute for Health Research

© 2014 Bunn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: There has been a growing emphasis on evidence-informed decision making in health care. Systematic reviews, such as those produced by the Cochrane Collaboration, have been a key component of this movement. The UK National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs). The aim of this study was to identify the impacts of Cochrane reviews published by NIHR funded CRGs during the years 2007-11. Methods: We sent questionnaires to CRGs and review authors, interviewed guideline developers and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane reviews. We used a framework with four categories (knowledge production, research targeting, informing policy development, and impact on practice/services). Results: A total of 1502 new and updated reviews were produced by the 20 NIHR funded CRGs between 2007-11. The clearest impacts were on policy with a total of 483 systematic reviews cited in 247 sets of guidance; 62 were international, 175 national (87 from the UK) and 10 local. Review authors and CRGs provided some examples of impact on practice or services, for example safer use of medication, the identification of new effective drugs or treatments and potential economic benefits through the reduction in the use of unproven or unnecessary procedures. However, such impacts are difficult to objectively document and the majority of reviewers were unsure if their review had produced specific impacts. Qualitative data suggested that Cochrane reviews often play an instrumental role in informing guidance although a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and guideline developers were barriers to their use. Conclusions: Health and economic impacts of research are generally difficult to measure. We found that to be the case with this evaluation. Impacts on knowledge production and clinical guidance were easier to identify and substantiate than those on clinical practice. Questions remain about how we define and measure impact and more work is needed to develop suitable methods for impact analysis.Peer reviewe

G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo

Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential

Morphological and molecular evaluation of some Egyptian pomegranate cultivars

Six Egyptian pomegranate (Punica granatum L.) cultivars were characterized by fruit characteristics (physical and chemical) and two molecular markers; Inter simple sequence repeat (ISSR) and amplified fragment length polymorphism (AFLP). Genetic diversity of the pomegranate genotypes was evaluated. Physical fruit traits were determined (weight, volume and diameter), calyx [diameter, length (mm) and Carpels number], fruit firmness (Newton), peel as (weight and thickness), arils weight (g), volume of juice (ml), seeds [fresh and dry weight (g)], and color parameter of (fruit skin, internal peel, arils, juice and seeds). The chemical traits such as soluble solids contents (SSC), vitamin C content, anthocyanin content, pH, and titratable acidity (TA) were assessed and wide variations were observed in each of these traits among the studied cultivars. The genetic variability and relationships among six Egyptian pomegranate cultivars were tested using ISSR and AFLP analyses. The level of polymorphism across cultivars was 53 and 90.7% as revealed by ISSR and AFLP, respectively. ISSR and AFLP revealed different genetic similarities among the six pomegranate cultivars. Each analysis differs not only in its underlying principle, but also in their in-formativeness with regard to the type and amount of polymorphism detected. Genetic similarity matrices estimated from ISSR and AFLP data, showed similarity coefficients to range from 0.77 to 0.94 and 0.33 to 0.73, respectively. ISSR and AFLP characterized the six pomegranate cultivars by a large number of unique markers being 23 and 46 unique markers, respectively. The fruit weight ranged between 479.4 to 185 g of ʻNab El Gamalʼ and ʻAssuityʼ, the firmness was 79.98 of ʻNab El Gamalʼ and 71.84 Newton of ʻManfaloutyʼ cv. The fruit peel thickness varied from 0.6 mm ʻArabyʼ, ʻHegazyʼ and ʻWardiʼ to 0.3 mm ʻAssuityʼ. The arils weight ranged from 87.5 to 275 g of ʻAssuityʼ and ʻNab El Gamalʼ cvs. The percentage net of arils weight/ fruit weight was the highest (59.34% of ʻManfaloutyʼ cv). The juice volume ranged from 62.41 to 71.81 ml/100 g arils for ʻ Wardiʼ and ʻNab El Gamalʼ cvs. The SSC content ranged between 16.01 ʻHegazyʼ and 12.55% ʻAssuityʼ. V.C. content ranged from 3.21 to 14 mg. vitamin/100 ml juice of ʻNab El Gamalʼ and ʻAssuityʼ. The anthocyanin content ranged from 1.47 to 10.03 for ʻArabyʼ and ʻHegazyʼ. The pH values varied from 3.3 (Wardi) to 2.9 (Araby). The Egyptain cultivars of pomegranate have a wide variation in the morphological and chemical characteristics for many uses of fresh fruit and of industry purpose.Keywords: Morphological and chemical fruits characterization, pomegranate, inter simple sequence repeat (ISSR), DNA markers, amplified fragment length polymorphism (AFLP)African Journal of Biotechnology, Vol. 13(2), pp. 226-237, 8 January, 201