bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain‐of‐function variant
Authors: Millichap John J. , Miceli Francesco , De Maria Michela , Keator Cynthia , Joshi Nishtha , Tran Baouyen , Soldovieri Maria Virginia , Ambrosino Paolo , Shashi Vandana , Mikati Mohamad A. , Cooper Edward C. , Taglialatela Maurizio 
Published: November 2016

SummaryVariants in KCNQ2 encoding for Kv7.2 neuronal K+ channel subunits lead to a spectrum of neonatal‐onset epilepsies, ranging from self‐limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss‐of‐function, whereas few increase channel activity (gain‐of‐function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2‐related epilepsy: infantile spasms without prior neonatal seizures associated with a gain‐of‐function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow‐up (ages 3–11 years), all patients were seizure‐free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain‐of‐function; in neurons, Kv7.2 and Kv7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here
Kinetics of binding of fluorescent ligands to enzymes with engineered access tunnels
Authors: Kaushik Shubhangi , Prokop Zbynek , Damborsky Jiri , Chaloupkova Radka 
Published: November 2016

Molecular recognition mechanisms and kinetics of binding of ligands to buried active sites via access tunnels are not well understood. Fluorescence polarization enables rapid and non‐destructive real‐time quantification of the association between small fluorescent ligands and large biomolecules. In this study, we describe analysis of binding kinetics of fluorescent ligands resembling linear halogenated alkanes to haloalkane dehalogenases. Dehalogenases possess buried active sites connected to the surrounding solvent by access tunnels. Modification of these tunnels by mutagenesis has emerged as a novel strategy to tailor the enzyme properties. We demonstrate that the fluorescence polarization method can sense differences in binding kinetics originating from even single mutations introduced to the tunnels. The results show, strikingly, that the rate constant of the dehalogenase variants varied across seven orders of magnitude, and the type of ligand used strongly affected the binding kinetics of the enzyme. Furthermore, fluorescence polarization could be applied to cell‐free extracts instead of purified proteins, extending the method's application to medium‐throughput screening of enzyme variant libraries generated in directed evolution experiments. The method can also provide in‐depth kinetic information about the rate‐determining step in binding kinetics and reveals the bottlenecks of enzyme accessibility. Assuming availability of appropriate fluorescent ligand, the method could be applied for analysis of accessibility of tunnels and buried active sites of enzymes forming a covalent alkyl–enzyme intermediate during their catalytic cycle, such as α/β‐hydrolases containing > 100 000 protein sequences based on the Pfam database.
Physiological effects of ice‐angling capture and handling on northern pike, Esox lucius
Authors: Louison M. J. , Hasler C. T. , Fenske M. M. , Suski C. D. , Stein J. A. 
Published: November 2016

AbstractUnderstanding how released fish recover following capture is vital information for researchers examining the effects of angling on exploited populations. This information is virtually non‐existent for fish angled through the ice in winter, despite the popularity of ice‐angling in many northern areas. To address this gap, 60 northern pike, Esox lucius L., were angled through the ice from an impoundment in eastern Wisconsin, USA, and subjected to one of ten combinations of handling and recovery duration. Plasma samples were collected and analysed for cortisol, lactate and glucose. The results showed a delayed response in the elevation of plasma variables, and a significant interaction between air exposure and recovery time for plasma lactate. No fish suffered mortality during the period of holding. Collectively, these data suggest that northern pike are physiologically resilient to ice‐angling capture stress as long as air exposure times are kept at 4 min or less.
Hot spots of wheat yield decline with rising temperatures
Authors: Asseng Senthold , Cammarano Davide , Basso Bruno , Chung Uran , Alderman Phillip D. , Sonder Kai , Reynolds Matthew , Lobell David B. 
Published: November 2016

AbstractMany of the irrigated spring wheat regions in the world are also regions with high poverty. The impacts of temperature increase on wheat yield in regions of high poverty are uncertain. A grain yield–temperature response function combined with a quantification of model uncertainty was constructed using a multimodel ensemble from two key irrigated spring wheat areas (India and Sudan) and applied to all irrigated spring wheat regions in the world. Southern Indian and southern Pakistani wheat‐growing regions with large yield reductions from increasing temperatures coincided with high poverty headcounts, indicating these areas as future food security ‘hot spots’. The multimodel simulations produced a linear absolute decline of yields with increasing temperature, with uncertainty varying with reference temperature at a location. As a consequence of the linear absolute yield decline, the relative yield reductions are larger in low‐yielding environments (e.g., high reference temperature areas in southern India, southern Pakistan and all Sudan wheat‐growing regions) and farmers in these regions will be hit hardest by increasing temperatures. However, as absolute yield declines are about the same in low‐ and high‐yielding regions, the contributed deficit to national production caused by increasing temperatures is higher in high‐yielding environments (e.g., northern India) because these environments contribute more to national wheat production. Although Sudan could potentially grow more wheat if irrigation is available, grain yields would be low due to high reference temperatures, with future increases in temperature further limiting production.
Women Living Together Have a Higher Frequency of Menstrual Migraine
Authors: Ferreira Karen S. , Guilherme Gisela , Faria Viviane R. , Borges Larissa M. , Uchiyama Angel A.T. 
Published: November 2016

BackgroundMenstrual migraine is a highly prevalent disorder among adult women, resulting in disability and loss of quality of life. Some studies have reported menstrual cycle synchrony among women living together. No study has reported whether there may also be a higher prevalence of menstrual migraine among these women. Thus, they reported here the prevalence of menstrual migraine in a group of women living together compared with a control group of women living alone, and discussed the possible factors involved.MethodsThe study was conducted on female university students aged 18‐30 years with a diagnosis of migraine according to the criteria of the International Classification of Headache Disorders III, beta appendix criteria. The subjects were divided into a group of women who lived together with two or more other students and a control group of age‐matched students who lived alone, interviewed with a specific questionnaire and assessed for 3 months by means of a paper pain diary. The data evaluated included frequency of headache, presence of menstrual migraine, intensity of headache, medications used including contraceptives, and triggering factors such as diet, sleep deprivation, and stress. The menstrual data and data related to migraine were also investigated in the roommates.ResultsA higher occurrence of menstrual migraine among women living together (9, 50%) compared with women living alone (3, 16.7%) (P = .03) was detected. After binary logistic regression analysis, this finding was not related to the main influencing factors detected, that is, use of a contraceptive, test stress, or sleep deprivation (P = .03, adjusted odds ratio: 7.87; 1.23‐50.36). These women also showed menstrual cycle synchrony with their roommates (8, 44.4%) and the presence of headache crises during the menstruation of their colleagues (11, 61.1%).ConclusionThe present study detected a higher occurrence of menstrual migraine among women who lived together. Since there was no previous description of this topic in the literature, it was believed that the present study could represent a step toward more elaborate investigations of this complex topic.
Development of hepatocellular carcinoma in Japanese patients with biopsy‐proven non‐alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression
Authors: Seko Yuya , Sumida Yoshio , Tanaka Saiyu , Mori Kojiroh , Taketani Hiroyoshi , Ishiba Hiroshi , Hara Tasuku , Okajima Akira , Umemura Atsushi , Nishikawa Taichiro , Yamaguchi Kanji , Moriguchi Michihisa , Kanemasa Kazuyuki , Yasui Kohichiroh , Imai Shunsuke , Shimada Keiji , Itoh Yoshito 
Published: November 2016

AimSome patients with non‐alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin‐like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy‐proven NAFLD.MethodsIn this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long‐term changes in biomarkers.ResultsOf 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow‐up period of 6.1 years, 10 patients (4.2%) with non‐alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow‐up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group.ConclusionsIn Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.
Janus‐Faced Youth Justice Work and the Transformation of Accountability
Authors: ARMITAGE VICI , KELLY LAURA , PHOENIX JO 
Published: November 2016

AbstractThis article revisits claims about the relationship between ‘standardisation’, ‘discretion’ and ‘accountability’ in youth justice made in the wake of the Crime and Disorder Act 1998. We argue that less centralisation and less standardisation have transformed accountability, but this is experienced differently according to the place held in the organisational hierarchy. This recognition demands a more nuanced understanding of ‘practitioner discretion’, which can account for differences between managerial and frontline experiences of what we describe as ‘janus‐faced youth justice work’, and a broad definition of the youth justice field and associated actors.
CHA2DS2VASc score predicts unsuccessful electrical cardioversion in patients with persistent atrial fibrillation
Authors: Mlodawska Elzbieta , Tomaszuk‐Kazberuk Anna , Lopatowska Paulina , Kaminski Marcin , Musial Wlodzimierz J. 
Published: November 2016

BackgroundAtrial fibrillation (AF) is the most common arrhythmia occurring in 2% of the population. It is known that AF increases morbidity and limits quality of life. The CHA2DS2VASc score (congestive heart failure/left ventricular dysfunction, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65–74 and sex category (female)) is widely used to assess thrombotic complications. The CHA2DS2VASc score was not used until now in predicting the effectiveness of electrical cardioversion.AimTo assess the value of CHA2DS2VASc score in predicting unsuccessful electrical cardioversion.MethodsWe analysed 258 consecutive patients with persistent AF who underwent electrical cardioversion between January 2012 and April 2016 in a Cardiology University Centre in Poland.ResultsOut of 3500 hospitalised patients with AF, 258 (mean age 64 ± 11 years, 64% men) underwent electrical cardioversion. The CHA2DS2VASc score in analysed population (258 patients) was 2.5 ± 1.7 (range 0–8), and the HAS‐BLED (hypertension, abnormal liver or renal function, stroke, bleeding, labile international normalised ratio, elderly, drugs or alcohol) was 1 ± 0.9 (range 0–4). Electrical cardioversion was unsuccessful in 12%. Factors associated with unsuccessful cardioversion were age (P = 0.0005), history of ischaemic stroke (P = 0.04), male gender (P = 0.01) and CHA2DS2VASc score (P = 0.002). The CHA2DS2VASc score in patients who had unsuccessful cardioversion was higher compared to patients who had successful cardioversion – 3.5 versus 2.4 (P = 0.001). In the logistic regression model, if the CHA2DS2VASc score increases by 1, the odds of unsuccessful cardioversion increase by 39% (odds ratio (OR) 1.39; confidence interval (CI): 1.12–1.71; P = 0.002). The odds of unsuccessful cardioversion are three times higher in patients with a CHA2DS2VASc score ≥ 2 than in patients with a CHA2DS2VASc score of 0 or 1 (OR 3.06; CI: 1.03–9.09; P = 0.044).ConclusionThe CHA2DS2VASc score routinely used in thromboembolic risk assessment may be a simple, easy and reliable scoring system that can be used to predict unsuccessful electrical cardioversion.
The Unintended Consequences of the Frequency of PCAOB Inspection
Authors: Tanyi Paul , Litt Barri 
Published: November 2016

AbstractAfter more than 50 years of self‐regulation of the US auditing profession, the Sarbanes‐Oxley Act of 2002 (SOX) created the Public Company Accounting Oversight Board (PCAOB) as a quasi‐governmental entity with statutory authority to inspect accounting firms that audit public clients. The frequency of this inspection is annual or triennial, based upon the number of public clients the firm audits. We examine the effects of these two levels of inspection frequency on financial reporting quality and audit fees for clients of small and midsize public accounting firms. Our findings provide evidence of significantly higher audit quality and audit fees for clients of annually inspected firms relative to clients of triennially inspected firms. These findings are robust to auditor‐client alignment analyses, propensity score matching, time‐series analyses, examination of firms that have changed from triennial to annual inspection, and particular examination of firms with inspection deficiencies. Overall, our study suggests that the two‐tier frequency system of PCAOB inspection may have also resulted in two‐tier audit quality and audit fee systems for small and midsize public accounting firms, with more frequent inspection leading to more rigorous and informed auditor decisions. We discuss the implications of our results for the Board and the profession at large.
Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer
Authors: Chen Xu , Gu Peng , Xie Ruihui , Han Jinli , Liu Hao , Wang Bo , Xie Weibin , Xie Weijie , Zhong Guangzheng , Chen Changhao , Xie Shujie , Jiang Ning , Lin Tianxin , Huang Jian 
Published: November 2016

AbstractHeterogeneous nuclear ribonucleoprotein K (hnRNPK) is an essential RNA‐ and DNA‐binding protein that regulates diverse biological events, especially DNA transcription. hnRNPK overexpression is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of hnRNPK in bladder cancer are unclear. We investigated hnRNPK expression by immunohistochemistry in 188 patients with bladder cancer, and found that hnRNPK expression levels were significantly increased in bladder cancer tissues and that high‐hnRNPK expression was closely correlated with poor prognosis. Loss‐ and gain‐of‐function assays demonstrated that hnRNPK promoted proliferation, anti‐apoptosis, and chemoresistance in bladder cancer cells in vitro, and hnRNPK knockdown suppressed tumorigenicity in vivo. Mechanistically, hnRNPK regulated various functions in bladder cancer by directly mediating cyclin D1, G0/G1 switch 2 (G0S2), XIAP‐associated factor 1, and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) transcription. In conclusion, we discovered that hnRNPK plays an important role in bladder cancer, suggesting that it is a potential prognostic marker and a promising target for treating bladder cancer.
Antithrombotic medications in dialysis patients: a double‐edged sword
Authors: Vlachopanos Georgios , Ghalli Farid Girgis 
Published: November 2016

AbstractIn the clinical context of end‐stage renal disease (ESRD), thrombosis and bleeding risks are simultaneously increased and may have devastating consequences. While anticoagulant and antiplatelet drugs are indispensable for the prevention of thromboembolic events, the significantly higher bleeding risk makes their handling extremely complicated. In ESRD, they are frequently administered for a wide array of conditions. For example, atrial fibrillation is quite common in ESRD and warrants the use of anticoagulants like warfarin. Unfractionated heparin and low molecular weight heparins are typically used for clotting prevention in the hemodialysis extracorporeal circuit. The antithrombotics use dilemma has worsened because ESRD patients have been excluded from major clinical trials that defined standard indications, contraindications and optimal management of these medications. That limits our knowledge and results in that the process of decision‐making depends on weaker data. Besides the substantial bleeding risk, warfarin may also increase cardiovascular risk because it is implicated in the pathogenesis of vascular calcifications in ESRD. The present article attempts to offer a comprehensive overview of practical considerations for the use of the most common antithrombotic medications in ESRD linking them, at the same time, to the best available evidence from randomized controlled trials and observational studies.
Probe‐based confocal laser endomicroscopy in the margin delineation of early gastric cancer for endoscopic submucosal dissection
Authors: Park Jun Chul , Park Yehyun , Kim Hyun Ki , Jo Jeong‐Hyeon , Park Chan Hyuk , Kim Eun Hye , Jung Da Hyun , Chung Hyunsoo , Shin Sung Kwan , Lee Sang Kil , Lee Yong Chan 
Published: November 2016

AbstractBackground and AimWe evaluated probe‐based confocal laser endomicroscopy (pCLE) in the margin delineation of early gastric cancer (EGC) for endoscopic submucosal dissection in comparison with white‐light imaging with chromoendoscopy (CE).MethodsWe conducted a prospective, randomized controlled study from November 2013 to October 2014 in a tertiary referral hospital. A total of 101 patients scheduled for endoscopic submucosal dissection due to differentiated EGC were randomized into pCLE and CE groups (pCLE 51, CE 50). Markings were made by electrocautery at the proximal and distal tumor margins, as determined by either pCLE or CE. The distance from the marking to the tumor margin was measured in the resected specimen histopathologically and was compared between the two groups by a linear mixed model.ResultsAmong 104 lesions, 80 lesions with 149 markings (pCLE 68, CE 81) were analyzed after excluding undifferentiated EGCs (n = 8) and unidentifiable markings (n = 13). Although the complete resection rate showed no difference between the groups (94.6% vs 93.2%, P = 1.000), the median distance from the marking to the margin was shorter in the pCLE group (1.3 vs 1.8 mm, P = 0.525) and the proportion of the distance <1 mm was higher (43.9% vs 27.6%, P = 0.023) in the pCLE group. Finally, subgroup analysis with superficial flat lesions (18 lesions, 31 marking dots) showed a significantly decreased distance in the pCLE group (0.5 vs 3.1 mm, P = 0.007).ConclusionsAmong EGCs with superficial flat morphology, in which the accurate evaluation of lateral extent is difficult with CE, pCLE would be useful for more precise margin delineation.
Mild Thyrotoxicosis Leads to Brain Perfusion Changes: An Arterial Spin Labelling Study
Authors: Göbel A. , Heldmann M. , Sartorius A. , Göttlich M. , Dirk A.‐L. , Brabant G. , Münte T. F. 
Published: November 2016

Hypo‐ and hyperthyroidism have effects on brain structure and function, as well as cognitive processes, including memory. However, little is known about the influence of thyroid hormones on brain perfusion and the relationship of such perfusion changes with cognition. The present study aimed to demonstrate the effect of short‐term experimental hyperthyroidism on brain perfusion in healthy volunteers and to assess whether perfusion changes, if present, are related to cognitive performance. It is known that an interaction exists between brain perfusion and cerebral oxygen consumption rate and it is considered that neural activation increases cerebral regional perfusion rate in brain areas associated with memory. Measuring cerebral blood flow may therefore represent a proxy for neural activity. Therefore, arterial spin labelling (ASL) measurements were conducted and later analysed to evaluate brain perfusion in 29 healthy men before and after ingesting thyroid hormones for 8 weeks. Psychological tests concerning memory were performed at the same time‐points and the results were correlated with the imaging results. In the hyperthyroid condition, perfusion was increased in the posterior cerebellum in regions connected with cerebral networks associated with cognitive control and the visual cortex compared to the euthyroid condition. In addition, these perfusion changes were positively correlated with changes of performance in the German version of the Auditory Verbal Learning Task [AVLT, Verbaler Lern‐und‐Merkfähigkeits‐Test (VLMT)]. Cerebellar perfusion and function therefore appears to be modulated by thyroid hormones, likely because the cerebellum hosts a high number of thyroid hormone receptors.