bluuebunny/crossref_metadata_2025 huggingface dataset:
Brief Intervention for Daily Marijuana Users Identified by Screening in Primary Care: A Subgroup Analysis of the ASPIRE Randomized Clinical Trial
Authors: Fuster Daniel , Cheng Debbie M. , Wang Na , Bernstein Judith A. , Palfai Tibor P. , Alford Daniel P. , Samet Jeffrey H. , Saitz Richard
Published: October 2015

Background

The use of brief intervention for decreasing frequent marijuana use holds potential, but its efficacy in primary care is not known.

Methods

Objective: To assess the impact of 2 brief interventions on marijuana use among daily/or almost daily marijuana users. Design: Subgroup analysis of a 3-arm randomized clinical trial of 2 brief counseling interventions compared with no brief intervention on daily marijuana use in a primary care setting (ASPIRE). Participants: ASPIRE study participants who both reported 21–30 days of marijuana use during the past month and identified marijuana as their drug of most concern. Interventions: (1) brief negotiated interview (BNI), a 10–15-minute structured interview, and (2) an adaptation of motivational interviewing (MOTIV), a 30–45-minute intervention. Control group participants received only a list of substance use treatment resources. Main measures: The primary outcome was number of days of marijuana use in the past 30 days at the 6-month follow-up. Secondary outcomes were (1) number of days of marijuana use at 6-week follow-up and (2) drug problems (Short Inventory of Problems—Drugs, SIP-D) at 6-week and 6-month follow-ups. Differences between intervention groups were analyzed using negative binomial regression models.

Results

Among the 167 eligible participants, we did not find any significant impact of either of the 2 interventions on past 30 days of marijuana use at 6 months (adjusted incidence rate ratio [aIRR]: 0.95, 95% confidence interval [CI]: 0.75–1.15, P = .82 for BNI vs. control; aIRR: 1.02, 95% CI: 0.85–1.23, P = .82 for MOTIV vs. control). There was no significant impact on drug-related problems at 6-month follow-up (aIRR: 1.12, 95% CI: 0.69–1.82, P = .66 and aIRR: 1.46, 95% CI: 0.89–2.38, P = .27 for BNI vs. control and MOTIV vs. control, respectively). Results were similar at 6 weeks.

Conclusions

Brief intervention has no apparent impact on marijuana use or drug-related problems among primary care patients with frequent marijuana use identified by screening.
Journalists and Substance Use: A Systematic Literature Review
Authors: MacDonald Jasmine B. , Saliba Anthony J. , Hodgins Gene
Published: October 2015

Background: Journalists’ exposure to potentially traumatic events (PTEs), high levels of job stress, and anecdotal reports within the industry seem to suggest that journalists are at greater risk than the general population to experience substance use disorders. The present systematic literature review (SLR) aims to provide a concise, comprehensive, and systematic review of the quantitative literature relating to journalists’ experience of substance use. Methods: The systematic review method adopted within the present study was based on that prescribed by Fink in the 2010 book, Conducting systematic literature reviews: From the internet to paper, 3rd ed., which contains three main elements: sampling the literature, screening the literature, and extracting data. Results: Alcohol consumption is the most widely studied substance in journalist samples and is discussed in relation to quantity, level of risk, and potential alcoholism. The review also considers journalists’ use of substances, including cigarettes, cannabis, and other illicit substances. In particular, comparisons are made between journalistic roles and gender. Conclusions: The research is piecemeal in nature, in that more recent research does not build upon the research that has come before it. Much of what has been reported does not reflect the progress that has taken place in recent years within the alcohol consumption and substance use field in terms of theory, assessment, scale development, practice, and interventions with those who use or are addicted to various substances. This SLR raises a number of methodological and theoretical issues to be explored and addressed in future research.
Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead
Authors: Kikumori Masayuki , Yanagita Ryo C , Tokuda Harukuni , Suenaga Kiyotake , Nagai Hiroshi , Irie Kazuhiro
Published: October 2015

Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.
Relationship between physical activity, physical fitness and multiple metabolic risk in youths from Muzambinho's study
Authors: Barbosa João Paulo Dos Anjos Souza , Basso Luciano , Seabra André , Prista Antonio , Tani Go , Maia José António Ribeiro , Forjaz Cláudia Lúcia De Moraes
Published: October 2015

Negative associations between physical activity (PA), physical fitness and multiple metabolic risk factors (MMRF) in youths from populations with low PA are reported. The persistence of this association in moderately‐to highly active populations is not, however, well established. The aim of the present study was to investigate this association in a Brazilian city with high frequency of active youths. We assessed 122 subjects (9.9 ± 1.3 years) from Muzambinho city. Body mass index, waist circumference, glycaemia, cholesterolaemia, systolic and diastolic blood pressures were measured. Maximal handgrip strength and one‐mile walk/run test were used. Leisure time PA was assessed by interview. Poisson regression was used in the analysis. The model explained 11% of the total variance. Only relative muscular strength and one‐mile walk/run were statistically significant (p < .05). Those who needed more time to cover the one‐mile walk/run test had an increased in metabolic risk of 11%, and those with greater strength reduced the risk by about 82%. In conclusion, children and youths from an active population who need less time to cover the one‐mile walk/run test or who had greater muscular strength showed a reduced metabolic risk. These results suggest that even in children and youths with high leisure time PA, a greater aerobic fitness and strength might help to further reduce their MMRF.
Observations of 6.7 GHz methanol masers with East-Asian VLBI Network. II. Internal proper motion measurement in G006.79−00.25
Authors: Sugiyama Koichiro , Fujisawa Kenta , Hachisuka Kazuya , Yonekura Yoshinori , Motogi Kazuhito , Sawada-Satoh Satoko , Matsumoto Naoko , Hirano Daiki , Hayashi Kyonosuke , Kobayashi Hideyuki , Kawaguchi Noriyuki , Shibata Katsunori M. , Honma Mareki , Hirota Tomoya , Murata Yasuhiro , Doi Akihiro , Ogawa Hideo , Kimura Kimihiro , Niinuma Kotaro , Chen Xi , Xia Bo , Li Bin , Sorai Kazuo , Momose Munetake , Saito Yu , Takaba Hiroshi , Omodaka Toshihiro , Kim Kee-Tae , Shen Zhiqiang
Published: October 2015

We detected internal proper motions of the methanol maser features at 6.7 GHz in a high-mass star-forming region G006.79−00.25 with the East-Asian VLBI Network. The spatial distribution of the maser features shows an elliptical morphology. The internal proper motions of 17 methanol maser features relative to the barycenter of the features were measured. The amplitude of the internal motions ranged from 1.30 to 10.25 km s−1. Most of the internal proper motions of the maser features seem to point counterclockwise along the elliptical morphology of the maser features. We applied the disk model, which includes both rotating and expanding components, to the observed positions, l.o.s. velocities, and proper motions. The derived rotation, expansion, and systemic velocities are $+3^{+2}_{-2}$, $+6^{+2}_{-2}$, and $+21^{+2}_{-2}\:$km s−1, respectively, at the radius of 1260 au on the disk with a position angle of the semi-major axis of − 140° and an inclination of 60°. The derived rotating motion suggests that the methanol maser emissions showing the elliptical spatial morphology possibly trace the rotating disk. The derived expanding motion might be caused by the magnetic-centrifugal wind on the disk, which was estimated on the basis of the typical magnetic field strength at emitting zones of a methanol maser.
Absence of left atrial stunning after cardioversion of recent-onset atrial fibrillation in patients at low-stroke risk
Authors: Antonielli Emanuele , Pizzuti Alfredo , Dogliani Sarah , Stasi Michele , Bassignana Antonia , Doronzo Baldassarre
Published: October 2015

Objective

The aim of the present study was to evaluate the presence and degree of spontaneous echo contrast (SEC) in the left atrium and of left atrial appendage (LAA) contractility before and after cardioversion (CV) in patients with recent-onset atrial fibrillation (AF).

Methods

Our study included 56 patients divided into two groups: group 1, comprising 32 clinically stable patients who were admitted to the Emergency Department with less than or equal to 48 h duration AF, and who underwent transoesophageal echocardiography (TEE)-guided CV; and the control group (group 2), comprising 24 patients admitted to the Cardiological Department for elective TEE-guided CV of greater than 48 h AF. All patients underwent repeat TEE within 1 h after successful CV.

Results

Patients with recent-onset AF (group 1) showed no thrombogenic milieu at baseline without any evidence of atrial stunning after successful CV. SEC mean grade (0–3 grading) was 0.09±0.3 versus 0.12±0.4 after CV (P=0.98), and LAA flow velocity was 60.7±19.4 versus 56.7±20.5 cm/s after CV (P=0.07). Group 2 patients showed a significantly higher degree of SEC compared with those in group 1 (0.09±0.3 vs. 0.66±0.7, P=0.0093) and significantly lower LAA flow velocities (60.7±19.4 vs. 32.5±12.4, P<0.0001), with significant worsening after successful CV (SEC degree: 0.66±0.9 vs. 1.37±0.9, P=0.0093; LAA flow velocity: 32.5±12.4 vs. 20.4±12.7 cm/s, P<0.0001).

Conclusion

The absence of thrombogenic milieu and of left atrial stunning after CV in patients with recent-onset AF favours early CV without anticoagulation, at least in patients with a low thromboembolic risk profile. These patients could be discharged earlier from urgent care.
Pre-Procedural Patient Education Reduces Fall Risk in an Outpatient Endoscopy Suite
Authors: Hilscher Moira B. , Niesen Cynthia R. , Tynsky Desiree A. , Kane Sunanda V.
Published: October 2015

The purpose of this article was to determine whether scripted pre-procedural fall risk patient education and nurses' intention to assist patients after receiving sedation improves receptiveness of nursing assistance during recovery and decreases fall risk in an outpatient endoscopy suite. We prospectively identified high fall risk patients using the following criteria: (1) use of an assistive device, (2) fallen two or more times within the last year, (3) sustained an injury in a fall within a year, (4) age greater than 85 years, or (5) nursing judgment of high fall risk. Using a scripted dialogue, nurses educated high-risk patients of their fall risk and the nurses' intent to assist them to and in the bathroom. Documentation of patient education, script use, and assistance was monitored. Over 24 weeks, 892 endoscopy patients were identified as high fall risk; 790 (88.5%) accepted post-procedural assistance. Documentation of assistance significantly increased from 33% to 100%. Patients receiving education and postprocedural assistance increased from 27.9% to 100% at week 24. No patient falls occurred 12 months following implementation among patients identified as high fall risk. Scripted pre-procedural fall risk education increases patient awareness and receptiveness to assistance and can lead to decreased fall rates.
Significant Delay Posed by the Ileocecal Valve in Videocapsule Endoscopy Small Bowel Transit Time
Authors: Rimbaş Mihai , Voiosu Mihail Radu
Published: October 2015

Because the ileocecal valve could theoretically influence the progression of the videocapsule, we aimed to characterize its posed delay in videocapsule passage to the cecum. A retrospective study was conducted of all procedures in which patients experienced in the same day colonoscopy with ileal biopsy and videocapsule endoscopy. In all 11 patients who satisfied the criteria, at least one biopsy-induced ileal mucosal defect could be identified. There was a mean delay in the passage of the videocapsule through the ileocecal valve of more than 43 minutes (range: 9 seconds to 143 minutes). This article draws attention to the physiologic sphincter role of the ileocecal valve, which could significantly delay the progression of the endoscopic videocapsule to the cecum. The fact that the small bowel videocapsules may get hung up at the ileocecal valve for a while (and sometimes for a considerable amount of time) we find interesting, and essentially confirms intuition. This could be important in some circumstances, such as choosing the route for deep enteroscopy or calculation of the Lewis score.
Cell-cell interactions and evolution using evolutionary game theory
Authors: Basanta David
Published: October 2015

Cancers arise from genetic abberations but also consistently display high levels of intra-tumor heterogeneity and evolve according to Darwinian dynamics. This makes evolutionary game theory an ideal tool in which to mathematically capture these cell-cell interactions and in which to investigate how they impact evolutionary dynamics. In this chapter we present some examples of how evolutionary game theory can elucidate cancer evolution.
Heterogeneity of Transcription Factor binding specificity models within and across cell lines
Authors: Sharmin Mahfuza , Corrada Bravo Héctor , Hannenhalli Sridhar
Published: October 2015

Complex gene expression patterns are mediated by binding of transcription factors (TF) to specific genomic loci. Thein vivooccupancy of a TF is, in large part, determined by the TF’s DNA binding interaction partners, motivating genomic context based models of TF occupancy. However, the approaches thus far have assumed a uniform binding model to explain genome wide bound sites for a TF in a cell-type and as such heterogeneity of TF occupancy models, and the extent to which binding rules underlying a TF’s occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble based approach (TRISECT) to identify heterogeneous binding rules of cell-type specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-Seq data in 4-12 cell-types, shows that by explicitly capturing the heterogeneity of binding rules,TRISECTaccurately identifiesin vivoTF occupancy (93%) substantially improving upon previous methods. Importantly, many of the binding rules derived from individual cell-types are shared across cell-types and reveal distinct yet functionally coherent putative target genes in different cell-types. Closer inspection of the predicted cell-type-specific interaction partners provides insights into context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising interaction partners within a cell-type, many of which nevertheless transcend cell-types. Notably, the putative targets of shared binding rules in different cell-types, while distinct, exhibit significant functional coherence.
The evolutionary advantage of heritable phenotypic heterogeneity
Authors: Carja Oana , Plotkin Joshua B.
Published: October 2015

Phenotypic plasticity is an evolutionary driving force in diverse biological processes, including the adaptive immune system, the development of neoplasms, and the bacterial acquisition of drug resistance. It is essential, therefore, to understand the evolutionary advantage of an allele that confers cells the ability to express a range of phenotypes. Of particular importance is to understand how this advantage of phenotypic plasticity depends on the degree of heritability of non-genetically encoded phenotypes between generations, which can induce irreversible evolutionary changes in the population. Here, we study the fate of a new mutation that allows the expression of multiple phenotypic states, introduced into a finite population otherwise composed of individuals who can express only a single phenotype. We analyze the fixation probability of such an allele as a function of the strength of inter-generational phenotypic heritability, called memory, the variance of expressible phenotypes, the rate of environmental changes, and the population size. We find that the fate of a phenotypically plastic allele depends fundamentally on the environmental regime. In a constant environment, the fixation probability of a plastic allele always increases with the degree of phenotypic memory. In periodically fluctuating environments, by contrast, there is an optimum phenotypic memory that maximizes the probability of the plastic allele’s fixation. This same optimum value of phenotypic memory also maximizes geometric mean fitness, in steady state. We interpret these results in the context of previous studies in an infinite-population framework. We also discuss the implications of our results for the design of therapies that can overcome resistance, in a variety of diseases.
Distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer
Authors: Sharmin Mahfuza , Corrada Bravo Héctor , Hannenhalli Sridhar
Published: October 2015

Background.Large mega base-pair genomic regions show robust alterations in DNA methylation levels in multiple cancers, a vast majority of which are hypo-methylated in cancers. These regions are generally bounded by CpG islands, overlap withLamin Associated DomainsandLarge organized chromatin lysine modifications,and are associated with stochastic variability in gene expression. Given the size and consistency ofhypo-methylated blocks (HMB)across cancer types, their immediate causes are likely to be encoded in the genomic region near HMB boundaries, in terms of specific genomic or epigenomic signatures. However, a detailed characterization of the HMB boundaries has not been reported.

Method.Here, we focused on ~13k HMBs, encompassing approximately half the genome, identified in colon cancer. We analyzed a number of distinguishing features at the HMB boundaries including transcription factor (TF) binding motifs, various epigenomic marks, and chromatin structural features.

Result.We found that the classical promoter epigenomic mark – H3K4me3, is highly enriched at HMB boundaries, as are CTCF bound sites. HMB boundaries harbor distinct combinations of TF motifs. Our Random Forest model based on TF motifs can accurately distinguish boundaries not only from regions inside and outside HMBs, but surprisingly, from active promoters as well. Interestingly, the distinguishing TFs and their interacting proteins are involved in chromatin modification. Finally, HMB boundaries significantly coincide with the boundaries ofTopologically Associating Domainsof the chromatin.

Conclusion.Our analyses suggest that the overall architecture of HMBs is guided by pre-existing chromatin architecture, and are associated with aberrant activity of promoter-like sequences at the boundary.
Characterization of inner membrane protein YciB in Escherichia coli: YciB interacts with cell elongation and division proteins
Authors: Li Gaochi , Badaluddin Noor Afiza , Kitakawa Madoka
Published: October 2015

The function of inner membrane protein YciB in Escherichia coli has not been identified. In this study, the membrane topology of the protein that contains five transmembrane domains was clarified. YciB was found to interact with various proteins involved in cell elongation and cell division using a bacterial two‐hybrid system. It was also found that the deletion mutant of yciB is susceptible to the low osmolarity. These observations together with previous reports indicate that YciB is involved in synthesis of the cell envelope by interacting with cell elongation and cell division complexes.
The Demise of Tax Credits
Authors: Clegg Daniel
Published: October 2015

Introduced in the late 1990s, tax credits grew under successive Labour governments to become a cornerstone of UK social policy. Distinguished from traditional welfare policies by their target group and their mode of administration, and with goals that appeared capable of commanding support across the ideological spectrum, tax credits until recently seemed to hold the key to tackling poverty in a politically popular manner. But since 2010 the tax credit system has been systematically dismantled, initially qualitatively and latterly also quantitatively. This paper discusses the multiple factors that help to explain the rapid fall from grace in the UK of this liberal approach to supporting the incomes of poor working households.
Purification of two bacteriocins produced by Enterococcus faecalis DBFIQ E24 strain isolated from raw bovine milk
Authors: Manzo Ricardo M. , Cardoso María de las Mercedes , Tonarelli Georgina G. , Simonetta Arturo C.
Published: October 2015

Enterococcus faecalis DBFIQ E24 was formerly characterised as a producer of antibacterial and antifungal substances. This strain is vancomycin sensitive, nonhaemolytic and gelatinase negative. SDS‐PAGE revealed the presence of an active band located between 1060 and 3500 Da. After the application of a three‐step purification procedure, two antimicrobial peptides were isolated. One of them is mostly active against Bacillus cereus with a molecular mass of 1364 Da, and the other one with a molecular mass of 1686 Da is mainly active against Escherichia coli. These results confirm the technological potential of E. faecalis DBFIQ E24 strain as a GRAS food biopreservative.
Can electors combat corruption? Institutional arrangements and citizen behaviour
Authors: XEZONAKIS GEORGIOS , KOSMIDIS SPYROS , DAHLBERG STEFAN
Published: October 2015

Studies interested in the cross‐national levels of corruption have concluded that specific institutional characteristics drive the aggregate variation. In countries with high institutional clarity and plurality electoral systems, corruption tends to be lower since increased voter monitoring and clarity of responsibility incentivise politicians to deliver virtuous policies. However, the underlying accountability mechanism has never been tested at the individual level. It is still unclear whether (1) voters do place voting weights on corruption, and (2) whether these weights vary in response to aggregate institutional characteristics. In this article, survey data from 23 democracies is used to put the accountability micro‐mechanism to this test. While there is some evidence that voters do vote on the basis of corruption, the moderating effect of institutional characteristics is not as strong as previously thought.
Molecular Structural Characteristics of Polysaccharide Fractions from Canarium album (Lour.) Raeusch and Their Antioxidant Activities
Authors: Zeng Hongliang , Miao Song , Zheng Baodong , Lin Shan , Jian Yeye , Chen Shen , Zhang Yi
Published: October 2015

The objective of this study was to investigate the multiple relations between the preliminary molecular structural characteristics and antioxidant activities of polysaccharides from Canarium album (Lour.) Raeusch (CPS). Three polysaccharide fractions, CPS1, CPS2, and CPS3, were isolated from CPS by column chromatography. CPS1 and CPS3 were mainly composed of neutral polysaccharides linked by α‐ and β‐glycosidic linkages while CPS2 was pectin polysaccharides mainly linked by β‐glycosidic linkages. According to the SEC‐MALLS‐RI system, the molecular weight of CPS1 was greater compared to CPS2 and CPS3, and the molecular weight and radius of CPS did not display positive correlation. The chain conformation analysis indicated CPS1 and CPS2 were typical highly branched polysaccharides while CPS3 existed as a globular shape in aqueous. Furthermore, the antioxidant activity of CPS2 was better than that of CPS3, while that of CPS1 was the weakest. The antioxidant activities of polysaccharide fractions were affected by their monosaccharide composition, glycosidic linkage, molecular weight, and chain conformation. This functional property was a result of a combination of multiple molecular structural factors. CPS2 was the major antioxidant component of CPS and it could be exploited as a valued antioxidant product.
Genomic Resources Notes Accepted 1 June 2015 – 31 July 2015
Authors:   Genomic Resources Development Consortium, Álvarez P. , Arthofer Wolfgang , Coelho Maria M. , Conklin D. , Estonba A. , Grosso Ana R. , Helyar S. J. , Langa J. , Machado Miguel P. , Montes I. , Pinho Joana , Rief Alexander , Schartl Manfred , Schlick‐Steiner Birgit C. , Seeber Julia , Steiner Florian M. , Vilas C.
Published: October 2015

This article documents the public availability of (i) microbiomes in diet and gut of larvae from the dipteran Dilophus febrilis using massive parallel sequencing, (ii) SNP and SSR discovery and characterization in the transcriptome of the Atlantic mackerel (Scomber scombrus, L) and (iii) assembled transcriptome for an endangered, endemic Iberian cyprinid fish (Squalius pyrenaicus).
Are Voters Equal under Proportional Representation?
Authors: Kedar Orit , Harsgor Liran , Sheinerman Raz A.
Published: October 2015

We develop and apply a new conceptual framework and measure for evaluating electoral systems, focusing on (in)equality in parliamentary representation. Our main arena of interest is proportional representation with districts, an electoral system employed by more than halfof democratic states, and we draw on an almost entirely overlooked fact: Electoral regimes vary substantially within countries, with some voters casting their ballot in semi‐majoritarian districts of few representatives and others in large and proportional ones. This within‐country institutional variation, we contend, affects representational (in)equality. Evaluating equality in parliamentary representation, we demonstrate that districted proportional representation often leads to overrepresentation of voters supporting right‐leaning parties. Utilizing district‐level data from 20 Western parliamentary democracies and complementing our within‐country approach with a cross‐country analysis, we further show that where parliaments are elected by large and small districts, representational inequality among voters is greater compared with countries in which parliament is elected by even‐magnitude districts.
Phenotype, genotype and gender identity in a large cohort of patients from India with 5α‐reductase 2 deficiency
Authors: Shabir I. , Khurana M. L. , Joseph A. A. , Eunice M. , Mehta M. , Ammini A. C.
Published: October 2015

Deficiency of the 5α‐reductase 2 enzyme impairs the conversion of testosterone to dihydrotestosterone (DHT) and differentiation of external genitalia, seminal vesicles and prostate in males. The present study describes the phenotype, genotype and gender identity in a large cohort of patients with 5αRD2. All patients underwent detailed clinical evaluation, hormonal profile, karyotyping and molecular analysis of the SRD5A2 gene. The molecular analysis of the SRD5A2 gene showed the presence of mutant alleles in 24 patients. We found 6 novel mutations IVS(1‐2) T>C, p.A52T, 188‐189insTA, 904‐905ins A, p.A12T and p.E57X in our patients. All patients had ambiguous genitalia and the degrees of under‐virilization ranged from penoscrotal hypospadias and microphallus to clitoromegaly. The position of gonads was variable in patients with same mutation. All the patients with mutations in the SRD5A2 gene had male gender identity. Those reared as female had gender dysphoria and underwent gender reassignment. Though a specific genotype–phenotype correlation could not be established in our patient but confirming the diagnosis of 5αRD2 with assessment of the SRD5A2 gene may help in appropriate gender assignment.
Retrospective analysis of early outcomes after a single‐armed suture technique for microsurgical intussusception vasoepididymostomy
Authors: Zhao L. , Tu X.‐A. , Zhuang J.‐T. , Chen Y. , Wang W.‐W. , Zeng L.‐Y. , Deng C.‐H.
Published: October 2015

Longitudinal intussusception microsurgical vasoepididymostomy (LIVE) increases the patency rate in men with epididymal obstructive azoospermia (EOA). Here, we retrospectively analyzed the early outcomes of our modified single‐armed suture technique for LIVE in men with EOA. From February 2012 to November 2013, 51 men received the modified technique and 39 men provided at least one post‐operative semen sample. The mean age was 31.4 years old for the men and 29.2 years old for their female partners. The mean duration of obstruction was 34.3 months. Patency was noted in 24 (61.5%) men and pregnancy was reported in 15 (38.5%) female partners. Motile spermatozoa in the epididymal fluid were observed intraoperatively in 14 (58.3%) patent men and 3 (20%) non‐patent men, respectively (p < 0.05). In the patent cohort, the mean ages of the pregnant and non‐pregnant female partners were 26.5 and 32.7 years old, respectively (p < 0.05). Our modified technique resulted in favorable patency and pregnancy rates in this study. Sperm motility in epididymal fluid and female partner age were important factors associated with the patency and pregnancy rates.
The measurement properties of the five‐item International Index of Erectile Function (IIEF‐5): a Dutch validation study
Authors: Utomo E. , Blok B. F. , Pastoor H. , Bangma C. H. , Korfage I. J.
Published: October 2015

Erectile dysfunction (ED), affecting men worldwide, is associated with worse mental health. The severity of ED as well as the effect of its treatment can be assessed using valid self‐reported outcome measures. A widely used measure is the International Index of Erectile Function short form (IIEF‐5) which is not yet validated in Dutch. The objective of this study was to translate the IIEF‐5 into Dutch and to investigate its reliability and validity to provide a useful evaluation tool. The IIEF‐5 was translated into Dutch following standardized forward–backward procedures. To conduct this observational study, men with symptoms of ED completed the Dutch IIEF‐5 at inclusion, 1 week later, and 6 months after inclusion. A population‐based sample (reference group) completed the IIEF‐5 once. The quality domains reliability and validity were addressed by testing the measurement properties internal consistency, reliability, measurement error, and content validity. Data of 82 patients and 253 reference group participants were analyzed. Internal consistency was adequate with Cronbach's alpha of 0.94 in both patient and reference group. In patients, the test–retest reliability was adequate with an intra‐class correlation coefficient for agreement of 0.88. A floor effect was present in the patient group (42%), though not in the reference group (3%). There was no ceiling effect in patients (0%), while this was present in the reference group (17%). Analysis of responsiveness was not possible due to the limited number of patients receiving treatment. The Dutch IIEF‐5 is a reliable and valid measure to determine severity of symptoms of ED. This evaluation tool is valuable for clinical use and interpreting results across international clinical studies. The context of a patient's sexual life is, however, indispensable and should be taken into account.
Anti‐Müllerian hormone, a Sertoli cell‐derived marker, is decreased in plasma of male patients in all stages of chronic kidney disease
Authors: Eckersten D. , Giwercman A. , Bruun L. , Christensson A.
Published: October 2015

Male patients with terminal renal failure are often infertile and exhibit an abnormal sex hormone pattern in plasma. We studied patients in all chronic kidney disease (CKD) stages to determine plasma levels of anti‐Müllerian hormone (AMH), a Sertoli cell‐derived marker, and other sex hormones. Seventy‐eight male patients with CKD stages 1–5 and a median age of 40 years (22–50 years), as well as 20 healthy controls with a median age of 37 years (26–44 years), were enrolled. The CKD patients were evenly distributed; 18 with CKD stages 1–2, 19 with CKD stage 3, 19 with CKD stage 4, and 22 with CKD stage 5. Cystatin C, follicle‐stimulating hormone, luteinizing hormone, prolactin, sex hormone‐binding globulin, testosterone, and AMH levels in plasma were analysed. AMH was analysed using the Ansh Labs UltraSensitive AMH assay. Several changes occurred in plasma levels of sex hormones in male patients with CKD. Plasma AMH levels were lower in CKD stages 1–4 by 30% (p = 0.041) and by 70% (p < 0.001) in CKD stage 5 compared with controls. Plasma luteinizing hormone and prolactin levels were higher and testosterone levels were lower compared with controls. The pathophysiological role of this reduction in AMH is unclear, but can be linked to altered Sertoli cell function.
Women with minor menstrual irregularities have increased risk of preeclampsia and low birthweight in spontaneous pregnancies
Authors: Bonnesen Barbara , Oddgeirsdóttir Hanna L. , Naver Klara Vinsand , Jørgensen Finn Stener , Nilas Lisbeth
Published: October 2015

Introduction

Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case‐control studies.

Material and methods

This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self‐reported and ultrasound examination‐based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self‐reported and ultrasound examination‐based gestational age were compared with women with a deviation of 7 days or less.

Results

Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001).

Conclusion

Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome.
Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond
Authors: Cunningham M. W. , Cox C. J.
Published: October 2015

Antineuronal autoantibodies are associated with the involuntary movement disorder Sydenham chorea (SC) and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) which are characterized by the acute onset of tics and/or obsessive compulsive disorder (OCD). In SC and PANDAS, autoantibodies signal human neuronal cells and activate calcium calmodulin‐dependent protein kinase II (CaMKII). Animal models immunized with group A streptococcal antigens demonstrate autoantibodies against dopamine receptors and concomitantly altered behaviours. Human monoclonal antibodies (mAbs) derived from SC target and signal the dopamine D2L (long) receptor (D2R). Antibodies against D2R were elevated over normal levels in SC and acute‐onset PANDAS with small choreiform movements, but were not elevated over normal levels in PANDAS‐like chronic tics and OCD. The expression of human SC‐derived anti‐D2R autoantibody V gene in B cells and serum of transgenic mice demonstrated that the human autoantibody targets dopaminergic neurones in the basal ganglia and other types of neurones in the cortex. Here, we review current evidence supporting the hypothesis that antineuronal antibodies, specifically against dopamine receptors, follow streptococcal exposures and may target dopamine receptors and alter central dopamine pathways leading to movement and neuropsychiatric disorders.
The last Eurasian ice sheets – a chronological database and time‐slice reconstruction, DATED‐1
Authors: Hughes Anna L. C. , Gyllencreutz Richard , Lohne Øystein S. , Mangerud Jan , Svendsen John Inge
Published: October 2015

We present a new time‐slice reconstruction of the Eurasian ice sheets (British–Irish, Svalbard–Barents–Kara Seas and Scandinavian) documenting the spatial evolution of these interconnected ice sheets every 1000 years from 25 to 10 ka, and at four selected time periods back to 40 ka. The time‐slice maps of ice‐sheet extent are based on a new Geographical Information System (GIS) database, where we have collected published numerical dates constraining the timing of ice‐sheet advance and retreat, and additionally geomorphological and geological evidence contained within the existing literature. We integrate all uncertainty estimates into three ice‐margin lines for each time‐slice; a most‐credible line, derived from our assessment of all available evidence, with bounding maximum and minimum limits allowed by existing data. This approach was motivated by the demands of glaciological, isostatic and climate modelling and to clearly display limitations in knowledge. The timing of advance and retreat were both remarkably spatially variable across the ice‐sheet area. According to our compilation the westernmost limit along the British–Irish and Norwegian continental shelf was reached up to 7000 years earlier (at c. 27–26 ka) than the eastern limit on the Russian Plain (at c. 20–19 ka). The Eurasian ice sheet complex as a whole attained its maximum extent (5.5 Mkm2) and volume (~24 m Sea Level Equivalent) at c. 21 ka. Our continental‐scale approach highlights instances of conflicting evidence and gaps in the ice‐sheet chronology where uncertainties remain large and should be a focus for future research. Largest uncertainties coincide with locations presently below sea level and where contradicting evidence exists. This first version of the database and time‐slices (DATED‐1) has a census date of 1 January 2013 and both are available to download via the Bjerknes Climate Data Centre and PANGAEA (www.bcdc.no; http://doi.pangaea.de/10.1594/PANGAEA.848117).
Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease
Authors: Miners J. Scott , Palmer Jennifer C. , Love Seth
Published: October 2015

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.
Knockdown of the small conductance Ca2+‐activated K+ channels is potently cytotoxic in breast cancer cell lines
Authors: Abdulkareem Zana Azeez , Gee Julia MW , Cox Charles D , Wann Kenneth T
Published: October 2015

Background and Purpose

Small conductance calcium‐activated potassium (KCa2.x) channels have a widely accepted canonical function in regulating cellular excitability. In this study, we address a potential non‐canonical function of KCa2.x channels in breast cancer cell survival, using in vitro models.

Experimental Approach

The expression of all KCa2.x channel isoforms was initially probed using RT‐PCR, Western blotting and microarray analysis in five widely studied breast cancer cell lines. In order to assess the effect of pharmacological blockade and siRNA‐mediated knockdown of KCa2.x channels on these cell lines, we utilized MTS proliferation assays and also followed the corresponding expression of apoptotic markers.

Key Results

All of the breast cancer cell lines, regardless of their lineage or endocrine responsiveness, were highly sensitive to KCa2.x channel blockade. UCL1684 caused cytotoxicity, with LD50 values in the low nanomolar range, in all cell lines. The role of KCa2.x channels was confirmed using pharmacological inhibition and siRNA‐mediated knockdown. This reduced cell viability and also reduced expression of Bcl‐2 but increased expression of active caspase‐7 and caspase‐9. Complementary to these results, a variety of cell lines can be protected from apoptosis induced by staurosporine using the KCa2.x channel activator CyPPA.

Conclusions and Implications

In addition to a well‐established role for KCa2.x channels in migration, blockade of these channels was potently cytotoxic in breast cancer cell lines, pointing to modulation of KCa2.x channels as a potential therapeutic approach to breast cancer.
Novel Peptides from Skins of Amphibians Showed Broad‐Spectrum Antimicrobial Activities
Authors: Wang Ying , Zhang Yue , Lee Wen‐Hui , Yang Xinwang , Zhang Yun
Published: October 2015

Peptide agents are often considered as potential biomaterials for developing new drugs that can overcome the rising resistance of pathogenic micro‐organisms to classic antibiotic treatments. One key source of peptide agents is amphibian skin, as they provide a great deal of naturally occurring antimicrobial peptide (AMP) templates awaiting further exploitation and utilization. In this study, 12 novel AMPs from the skins of 3 ranid frogs, Rana limnocharis, R. exilispinosa, and Amolops afghanus, were identified using a 5′ PCR primer. A total of 11 AMPs exhibited similarities with currently known AMP families, including brevinin‐1, brevinin‐2, esculentin‐1, and nigrocin, besides, one AMP, named as Limnochariin, represented a novel AMP family. All 12 AMPs contain a C‐terminus cyclic motif and most of them show obvious antimicrobial activities against 18 standard and clinically isolated strains of bacteria, including 4 Gram‐positive bacteria, 11 Gram‐negative bacteria, and 3 fungus. These findings provide helpful insight that will be useful in the design of anti‐infective peptide agents.
Intranasal immunization with heat shock protein 60 induces CD4+CD25+GARP+ and type 1 regulatory T cells and inhibits early atherosclerosis
Authors: Zhong Y , Tang H , Wang X , Zeng Q , Liu Y , Zhao Xi , Yu K , Shi H , Zhu R , Mao X
Published: October 2015

Atherosclerosis is an autoimmune inflammatory disease involving both innate and adaptive immune mechanisms. Immune tolerance induction may have therapeutic potential for the suppression of atherosclerosis. Current interest is directed towards mucosal tolerance induction, especially nasal tolerance. Previous studies have shown that heat shock protein 60 (HSP60) is recognized as an important autoantigen in atherosclerosis, and nasal or oral HSP60 can induce tolerance and ameliorate atherosclerosis by inducing several subsets of regulatory T cells (Tregs) such as latency-associated peptide (LAP)+ and forkhead box transcription factor 3 (FoxP3)+ Tregs. However, little is known regarding the detailed mechanisms of nasal tolerance. Here, we again investigated the impact of nasal HSP60 on atherosclerosis and the mechanisms underlying the anti-atherosclerosis responses. We found that nasal HSP60 caused a significant 33·6% reduction in plaque size at the aortic root in the early stages of atherosclerosis (P < 0·001). Notably, a significant increase in activated CD4+CD25+ glycoprotein A repetitions predominant (GARP)+ Tregs, type 1 Tregs (Tr1 cells), and CD4+CD25+FoxP3+ Tregs, as well as a marked decrease in the numbers of type 1 and 17 T helper cells was detected in the spleens and cervical lymph nodes of HSP60-treated mice. Moreover, nasal HSP60 increases the production of transforming growth factor (TGF)-β and interleukin (IL)-10 and decreases the secretion of IFN-γ and IL-17. Interestingly, the atheroprotective role of nasal HSP60 treatment was abrogated partly by the neutralization of IL-10. Our findings show that nasal administration of HSP60 can attenuate atherosclerotic formation by inducing GARP+ Tregs, Tr1 cells and FoxP3+ Tregs, and that these Tregs maintain immune homeostasis by secreting IL-10 and TGF-β.