bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting drug‐induced QT prolongation and torsades de pointes
Authors: Roden Dan M. 
Published: December 2015

AbstractDrugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia (‘torsades de pointes’). This syndrome of drug‐induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (IKr) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarizations thought to trigger torsades de pointes. This review describes the evidence in support of this construct, and describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.
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TRPM7 kinase activity regulates murine mast cell degranulation
Authors: Zierler Susanna , Sumoza‐Toledo Adriana , Suzuki Sayuri , Dúill Fionán Ó , Ryazanova Lillia V. , Penner Reinhold , Ryazanov Alexey G. , Fleig Andrea 
Published: December 2015

Key points
The Mg2+ and Ca2+ conducting transient receptor potential melastatin 7 (TRPM7) channel–enzyme (chanzyme) has been implicated in immune cell function.
Mice heterozygous for a TRPM7 kinase deletion are hyperallergic, while mice with a single point mutation at amino acid 1648, silencing kinase activity, are not.
As mast cell mediators trigger allergic reactions, we here determine the function of TRPM7 in mast cell degranulation and histamine release.
Our data establish that TRPM7 kinase activity regulates mast cell degranulation and release of histamine independently of TRPM7 channel function.
Our findings suggest a regulatory role of TRPM7 kinase activity on intracellular Ca2+ and extracellular Mg2+ sensitivity of mast cell degranulation.
AbstractTransient receptor potential melastatin 7 (TRPM7) is a divalent ion channel with a C‐terminally located α‐kinase. Mice heterozygous for a TRPM7 kinase deletion (TRPM7+/∆K) are hypomagnesaemic and hyperallergic. In contrast, mice carrying a single point mutation at amino acid 1648, which silences TRPM7 kinase activity (TRPM7KR), are not hyperallergic and are resistant to systemic magnesium (Mg2+) deprivation. Since allergic reactions are triggered by mast cell‐mediated histamine release, we investigated the function of TRPM7 on mast cell degranulation and histamine release using wild‐type (TRPM7+/+), TRPM7+/∆K and TRPM7KR mice. We found that degranulation and histamine release proceeded independently of TRPM7 channel function. Furthermore, extracellular Mg2+ assured unperturbed IgE‐DNP‐dependent exocytosis, independently of TRPM7. However, impairment of TRPM7 kinase function suppressed IgE‐DNP‐dependent exocytosis, slowed the cellular degranulation rate, and diminished the sensitivity to intracellular calcium (Ca2+) in G protein‐induced exocytosis. In addition, G protein‐coupled receptor (GPCR) stimulation revealed strong suppression of histamine release, whereas removal of extracellular Mg2+ caused the phenotype to revert. We conclude that the TRPM7 kinase activity regulates murine mast cell degranulation by changing its sensitivity to intracellular Ca2+ and affecting granular mobility and/or histamine contents.
Treatment of cam-type femoroacetabular impingement
Authors: Fiorentino Gennaro , Fontanarosa Alberto , Cepparulo Riccardo , Guardoli Alberto , Berni Luca , Coviello Gianluca , Guardoli Aldo 
Published: December 2015

Purpose: the aim of this study was to evaluate preliminary clinical and radiographic results of arthroscopic treatment of cam-type femoroacetabular impingement (FAI).
Methods: thirty-eight patients underwent hip arthroscopy for cam-type FAI between 2009 and 2012. Preoperative assessment was based on clinical examination, modified Harris Hip Score (mHHS) and radiographic examination with anteroposterior pelvis, frogleg and Lequesne views. The patients’ clinical conditions at follow-up were assessed using the mHHS administered as a telephone survey. Radiographic outcome measurements evaluated pre and postoperatively were the alpha angle and femoral head-neck offset.
Results: the patients were clinically evaluated at a mean follow-up of 36 months. Radiographic follow-up was performed at an average of 12.7 months. Thirty of the 38 patients (79%) were satisfied with the results of the arthroscopic procedure. A total of nine patients subsequently underwent a total hip replacement. All 30 patients who declared themselves satisfied recorded an mHHS increase; in particular, the mHHS increased from a mean of 52.9 preoperatively (range: 27.5-82.5) to a mean of 85.6 postoperatively (range: 45.1-100.1). Three significant differences between the two groups of patients (satisfied and not satisfied) were recorded: mean age, alpha angle and BMI were all significantly greater in the patients who were not satisfied with the treatment.
Conclusions: a crucial aspect in order to obtain good clinical outcomes of arthroscopic treatment of camtype impingement is correct selection of patients who are likely to benefit from this kind of surgery. Hip arthroscopy should be avoided in patients aged over 50 years with risk factors for early osteoarthritis (high BMI and a significantly increased alpha angle).
Level of evidence: Level IV, therapeutic case series.
The Effects of Cold Environments on Double-Poling Performance and Economy in Male Cross-Country Skiers Wearing a Standard Racing Suit
Authors: Wiggen Øystein N. , Heidelberg Cecilie T. , Waagaard Silje H. , Færevik Hilde , Sandbakk Øyvind 
Published: December 2015

Purpose:To investigate differences in double-poling (DP) endurance performance, economy, and peak oxygen uptake (V̇O2peak) at low (–15°C) and moderate (6°C) ambient temperatures (TA) in cross-country skiers wearing standard racing suits.Methods:Thirteen well-trained male cross-country skiers performed a standardized warm-up followed by a 5-min submaximal test (Sub1), a 20-min self-paced performance test, a 2nd 5-min submaximal test (Sub2), and an incremental test to exhaustion while DP on an ergometer at either low or moderate TA, randomized on 2 different days. Skin and rectal temperatures, as well as power output and respiratory variables, were measured continuously during all tests.Results:Skin and rectal temperatures were more reduced at low TA than moderate TA (both P < .05). There was a 5% (P < .05) lower average power output during the 20-min performance test at low TA than at moderate TA, which primarily occurred in the first 8 min of the test (P < .05). Although DP economy decreased from Sub1 to Sub2 for both TAs (both P < .01), a 3.7% (P < .01) larger decrease in DP economy from Sub1 to Sub2 emerged for the low TA. Across the sample, V̇O2peak was independent of TA.Conclusions:These results demonstrate a lower body temperature and reduced performance for cross-country skiers when DP at low than at moderate TA while wearing standard cross-country-skiing racing suits. Lower DP performance at the low TA was mainly due to lower power production during the first part of the test and coincided with reduced DP economy.
Effect of Intensive Training on Mood With No Effect on Brain-Derived Neurotrophic Factor
Authors: Piacentini Maria Francesca , Witard Oliver C. , Tonoli Cajsa , Jackman Sarah R. , Turner James E. , Kies Arie K. , Jeukendrup Asker E. , Tipton Kevin D. , Meeusen Romain 
Published: December 2015

Context:Monitoring mood state is a useful tool for avoiding nonfunctional overreaching. Brain-derived neurotrophic factor (BDNF) is implicated in stress-related mood disorders.Purpose:To investigate the impact of intensified training-induced mood disturbance on plasma BDNF concentrations at rest and in response to exercise.Methods: Eight cyclists performed 1 wk of normal (NT), 1 wk of intensified (INT), and 1 wk of recovery (REC) training. Fasted blood samples were collected before and after exercise on day 7 of each training week and analyzed for plasma BDNF and cortisol concentrations. A 24-item Profile of Mood State questionnaire was administered on day 7 of each training week, and global mood score (GMS) was calculated.Results:Time-trial performance was impaired during INT (P = .01) and REC (P = .02) compared with NT. Basal plasma cortisol (NT = 153 ± 16 ng/mL, INT = 130 ± 11 ng/mL, REC = 150 ± 14 ng/ml) and BDNF (NT = 484 ± 122 pg/mL, INT = 488 ± 122 pg/mL, REC = 383 ± 56 pg/mL) concentrations were similar between training conditions. Likewise, similar exercise-induced increases in cortisol and BDNF concentrations were observed between training conditions. GMS was 32% greater during INT vs NT (P < .001).Conclusions: Consistent with a state of functional overreaching (FOR), impairments in performance and mood state with INT were restored after 1 wk of REC. These results support evidence for mood changes before plasma BDNF concentrations as a biochemical marker of FOR and that cortisol is not a useful marker for predicting FOR.
Correlation Between Ankle-Dorsiflexion and Hip-Flexion Range of Motion and the Functional Movement Screen Hurdle-Step Score
Authors: Janicki Jacob J. , Switzler Craig L. , Hayes Bradley T. , Hicks-Little Charlie A. 
Published: December 2015

Context:Functional movement screening (FMS) has been gaining popularity in the fields of sports medicine and performance. Currently, limited research has examined whether FMS screening that identifies low FMS scores is attributed primarily to limits in range of motion (ROM).Objective:To compare scores from the FMS hurdle-step movement with ROM measurements for ankle dorsiflexion and hip flexion (HF).Design:Correlational research design.Setting:Sports medicine research laboratory.Participants:20 healthy active male (age 21.2 ± 2.4 y, weight 77.8 ± 10.2 kg, height 180.8 ± 6.8 cm) and 20 healthy active female (21.3 ± 2.0 y, 67.3 ± 8.9 kg, 167.4 ± 6.6 cm) volunteers.Intervention:All 40 participants completed 3 trials of the hurdle-step exercise bilaterally and goniometric ROM measurements for active ankle dorsiflexion and HF.Main Outcome Measures:Correlations were determined between ROM and FMS scores for right and left legs. In addition, mean data were compared between FMS scores, gender, and dominant and nondominant limbs.Results:There were no significant correlations present when all participants were grouped. However, when separated by gender significant correlations were identified. There was a weak correlation with HF and both hurdle-step (HS) and average hurdle-step (AHS) scores on both left (r = .536, P = .015 and r = .512, P = .012) and right (r = .445, P = .049 and r = .565, P = .009) legs for women. For men, there was a poor negative correlation of HF and both HS and AHS on the left leg (r = –.452, P = .045 and r = .451, P = .046).Conclusion:Our findings suggest that although hip and ankle ROMs do not have a strong relationship with FMS hurdle-step scores, they are a contributing factor. More research should be conducted to identify other biomechanical factors that contribute to individual FMS test scores.
Effects of Experimental Anterior Knee Pain on Muscle Activation During Landing and Jumping Performed at Various Intensities
Authors: Park Jihong , Denning W. Matt , Pitt Jordan D. , Francom Devin , Hopkins J. Ty , Seeley Matthew K. 
Published: December 2015

Context:Although knee pain is common, some facets of this pain are unclear. The independent effects (ie, independent from other knee injury or pathology) of knee pain on neural activation of lower-extremity muscles during landing and jumping have not been observed.Objective:To investigate the independent effects of knee pain on lower-extremity muscle (gastrocnemius, vastus medialis, medial hamstrings, gluteus medius, and gluteus maximus) activation amplitude during landing and jumping, performed at 2 different intensities.Design:Laboratory-based, pretest, posttest, repeated-measures design, where all subjects performed both data-collection sessions.Methods:Thirteen able-bodied subjects performed 2 different land and jump tasks (forward and lateral) under 2 different conditions (control and pain), at 2 different intensities (high and low). For the pain condition, experimental knee pain was induced via a hypertonic saline injection into the right infrapatellar fat pad. Functional linear models were used to evaluate the influence of experimental knee pain on muscle-activation amplitude throughout the 2 land and jump tasks.Results:Experimental knee pain independently altered activation for all of the observed muscles during various parts of the 2 different land and jump tasks. These activation alterations were not consistently influenced by task intensity.Conclusion:Experimental knee pain alters activation amplitude of various lower-extremity muscles during landing and jumping. The nature of the alteration varies between muscles, intensities, and phases of the movement (ie, landing and jumping). Generally, experimental knee pain inhibits the gastrocnemius, medial hamstring, and gluteus medius during landing while independently increasing activation of the same muscles during jumping.
Tyneside Neighbourhoods
Authors: Nettle Daniel 
Published: December 2015

Nettle’s book presents the results of five years of comparative ethnographic fieldwork in two different neighbourhoods of the same British city, Newcastle upon Tyne. The neighbourhoods are only a few kilometres apart, yet whilst one is relatively affluent, the other is amongst the most economically deprived in the UK. Tyneside Neighbourhoods uses multiple research methods to explore social relationships and social behaviour, attempting to understand whether the experience of deprivation fosters social solidarity, or undermines it. The book is distinctive in its development of novel quantitative methods for ethnography: systematic social observation, economic games, household surveys, crime statistics, and field experiments. Nettle analyses these findings in the context of the cultural, psychological and economic consequences of economic deprivation, and of the ethical difficulties of representing a deprived community. In so doing the book sheds light on one of the main issues of our time: the roles of culture and of socioeconomic factors in determining patterns of human social behaviour.
Tyneside Neighbourhoods is a must read for scholars, students, individual readers, charities and government departments seeking insight into the social consequences of deprivation and inequality in the West.
Nettle’s book presents the results of five years of comparative ethnographic fieldwork in two different neighbourhoods of the same British city, Newcastle upon Tyne. The neighbourhoods are only a few kilometres apart, yet whilst one is relatively affluent, the other is amongst the most economically deprived in the UK. Tyneside Neighbourhoods uses multiple research methods to explore social relationships and social behaviour, attempting to understand whether the experience of deprivation fosters social solidarity, or undermines it. The book is distinctive in its development of novel quantitative methods for ethnography: systematic social observation, economic games, household surveys, crime statistics, and field experiments. Nettle analyses these findings in the context of the cultural, psychological and economic consequences of economic deprivation, and of the ethical difficulties of representing a deprived community. In so doing the book sheds light on one of the main issues of our time: the roles of culture and of socioeconomic factors in determining patterns of human social behaviour. Tyneside Neighbourhoods is a must read for scholars, students, individual readers, charities and government departments seeking insight into the social consequences of deprivation and inequality in the West.
Structural and Environmental Characteristics of Extratropical Cyclones that Cause Tornado Outbreaks in the Warm Sector: A Composite Study
Authors: Tochimoto Eigo , Niino Hiroshi 
Published: December 2015

Abstract
The structural and environmental characteristics of extratropical cyclones that cause tornado outbreaks [outbreak cyclones (OCs)] and that do not [nonoutbreak cyclones (NOCs)] are examined using the Japanese 55-year Reanalysis dataset (JRA-55). Composite analyses show differences between OCs and NOCs: for OCs, storm relative environmental helicity (SREH) and convective available potential energy (CAPE) are notably larger, and the areas in which these parameters have significant values are wider in the warm sector than they are for NOCs. The larger CAPE in OCs is due to larger amounts of low-level water vapor, while the greater SREH is due to stronger low-level southerly wind.
The composite analyses for environmental fields defined by 20-day means suggest that environmental meridional flows have the potential to advect large amounts of warm and moist air northward, creating atmospheric instability in the troposphere that contributes to the occurrence of a tornado outbreak. A piecewise potential vorticity (PV) diagnosis shows that low- to midlevel PV anomalies are the main contributor to the difference in the low-level winds between OCs and NOCs, whereas upper-level PV anomalies make only a minor contribution.
An examination of the structures of the extratropical cyclones and the upper-level jet stream suggests that the difference in the low-level winds between OCs and NOCs is due to differences in the structure of the jet stream. The OCs develop when the jet stream displays larger anticyclonic shear. This causes a more meridionally elongated structure of OCs, resulting in stronger low-level winds in the southeastern quadrant of the cyclones.
Topographic and Boundary Influences on the 22 May 2014 Duanesburg, New York, Tornadic Supercell
Authors: Tang Brian , Vaughan Matthew , Lazear Ross , Corbosiero Kristen , Bosart Lance , Wasula Thomas , Lee Ian , Lipton Kevin 
Published: December 2015

Abstract
The 22 May 2014 Duanesburg, New York, supercell produced an enhanced Fujita scale category 3 (EF3) tornado and 10-cm-diameter hail. The synoptic setup for the event was ambiguous compared to other documented cases of Northeast tornadoes. Mesoscale inhomogeneities due to terrain and baroclinic boundaries played a key role in the evolution and severity of the storm. The storm initiated at the intersection of an outflow boundary and a north–south-oriented baroclinic boundary. The mesocyclone was able to sustain itself as a result of sufficiently large amounts of low-level streamwise vorticity near the boundary despite subcritical values of 0–6-km vertical wind shear. Differential heating across the north–south-oriented boundary strengthened the pressure gradient across it. Strengthening ageostrophic flow across the boundary induced greater upslope flow along the southeastern slope of the Adirondack Mountains and induced terrain channeling up the Mohawk River valley. The channeling led to a maximum in moisture flux convergence and instability in the Mohawk valley. As the supercell moved into the Mohawk valley, radar and lightning data indicated a rapid intensification of the storm. Cold temperatures aloft due to the presence of an elevated mixed layer (EML) coincided with the surface instability to yield a local environment in the Mohawk valley favorable for extremely large hail. As the storm crossed the boundary, large values of 0–1-km wind shear, streamwise vorticity, and low lifting condensation levels combined to create a local environment favorable for tornadogenesis.
APLP1 as a cerebrospinal fluid biomarker for γ-secretase modulator treatment
Authors: Sjödin Simon , Andersson Kerstin K. A. , Mercken Marc , Zetterberg Henrik , Borghys Herman , Blennow Kaj , Portelius Erik 
Published: December 2015

Abstract
Introduction
Alzheimer’s disease brains are characterized by extracellular plaques containing the aggregated amyloid β42 (Aβ42) peptide and intraneuronal tangles containing hyperphosphorylated tau. Aβ42 is produced by sequential processing of the amyloid precursor protein (APP) by β-secretase followed by γ-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of Aβ42. However, treatments inhibiting γ-secretase have proven disappointing due to off-target effects. To circumvent these effects, γ-secretase modulators (GSMs) have been developed, which rather than inhibiting γ-secretase shift its preference into producing less aggregation-prone shorter Aβ peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for γ-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs.

Methods
An in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing.

Results
We have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1β17, 1β18 and 1β28 accompanied with a decrease of 1β25 and 1β27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection.

Conclusion
We show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on γ-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.