bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation
Authors: Campbell Courtney M. , Campbell Jonathan D. , Thompson Christopher H. , Galimberti Eleonora Savio , Darbar Dawood , Vanoye Carlos G. , George Alfred L.
Published: September 2013

Background

Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition.

Methods and Results

Wild-type (WT) KCNQ1 or the familial atrial fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (
I
Ks
) and investigation of pharmacological effects of the
I
Ks
selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-
I
Ks
) that exhibited greater sensitivity to HMR-1556 than WT-
I
Ks
. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function atrial fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-
I
Ks
) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-
I
Ks
but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-
I
Ks
to levels that were not significantly different from WT-
I
Ks
and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-
I
Ks
shortened action potential duration compared with WT-
I
Ks
. Application of HMR-1556 mitigated S140G-
I
Ks
–induced action potential duration shortening and did not alter action potential duration in cells expressing WT-
I
Ks
.

Conclusions

The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.
Taxonomy and distribution of the Afrotropical genus Anchophthalmops Koch, 1956 with a key to species (Coleoptera: Tenebrionidae: Pedinini)
Authors: KAMIŃSKI MARCIN JAN
Published: September 2013

The taxonomic and distributional data concerning the representatives of the genus Anchophthalmops were revised. Lectotypes for Anchophthalmops foveipennis and A. ventralis were designated to fix the taxonomic status of these species. A. neumanni and A. zablockii were described as new species. Maximum entropy modeling was used to test the probability of occurrence of A. menouxi on Madagascar. An identification key is provided to all known species of Anchophthalmops.
Trends in Storm-Triggered Landslides over Southern California
Authors: Ren Diandong , Leslie Lance M. , Lynch Mervyn J.
Published: September 2013

Changes in storm-triggered landslide activity for Southern California in a future warming climate are estimated using an advanced, fully three-dimensional, process-based landslide model, the Scalable and Extensible Geofluid Modeling System for landslides (SEGMENT-Landslide). SEGMENT-Landslide is driven by extreme rainfall projections from the Geophysical Fluid Dynamics Laboratory High Resolution Atmospheric Model (GFDL-HIRAM). Landslide changes are derived from GFDL-HIRAM forcing for two periods: 1) the twentieth century (CNTRL) and 2) the twenty-first century under the moderate Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios A1B enhanced greenhouse gas emissions scenario (EGHG). Here, differences are calculated in landslide frequency and magnitude between the CNTRL and EGHG projections; kernel density estimation (KDE) is used to determine differences in projected landslide locations. This study also reveals that extreme precipitation events in Southern California are strongly correlated with several climate drivers and that GFDL-HIRAM simulates well the southern (relative to Aleutian synoptic systems) storm tracks in El Niño years and the rare (~27-yr recurrence period) hurricane-landfalling events. GFDL-HIRAM therefore can provide satisfactory projections of the geographical distribution, seasonal cycle, and interannual variability of future extreme precipitation events (>50 mm) that have possible landslide consequences for Southern California. Although relatively infrequent, extreme precipitation events contribute most of the annual total precipitation in Southern California. Two findings of this study have major implications for Southern California. First is a possible increase in landslide frequency and areal distribution during the twenty-first century. Second, the KDE reveals three clusters in both the CNTRL and EGHG model mean scarp positions, with a future eastward (inland) shift of ~0.5° and a northward shift of ~1°. These findings suggest that previously stable areas might become susceptible to storm-triggered landslides in the twenty-first century.
Influence of Assimilating Satellite-Derived Atmospheric Motion Vector Observations on Numerical Analyses and Forecasts of Tropical Cyclone Track and Intensity
Authors: Wu Ting-Chi , Liu Hui , Majumdar Sharanya J. , Velden Christopher S. , Anderson Jeffrey L.
Published: September 2013

The influence of assimilating enhanced atmospheric motion vectors (AMVs) on mesoscale analyses and forecasts of tropical cyclones (TC) is investigated. AMVs from the geostationary Multifunctional Transport Satellite (MTSAT) are processed by the Cooperative Institute for Meteorological Satellite Studies (CIMSS, University of Wisconsin–Madison) for the duration of Typhoon Sinlaku (2008), which included a rapid intensification phase and a slow, meandering track. The ensemble Kalman filter and the Weather Research and Forecasting Model are utilized within the Data Assimilation Research Testbed. In addition to conventional observations, three different groups of AMVs are assimilated in parallel experiments: CTL, the same dataset assimilated in the NCEP operational analysis; CIMSS(h), hourly datasets processed by CIMSS; and CIMSS(h+RS), the dataset including AMVs from the rapid-scan mode. With an order of magnitude more AMV data assimilated, the CIMSS(h) analyses exhibit a superior track, intensity, and structure to CTL analyses. The corresponding 3-day ensemble forecasts initialized with CIMSS(h) yield smaller track and intensity errors than those initialized with CTL. During the period when rapid-scan AMVs are available, the CIMSS(h+RS) analyses offer additional modifications to the TC and its environment. In contrast to many members in the ensemble forecasts initialized from the CTL and CIMSS(h) analyses that predict an erroneous landfall in China, the CIMSS(h+RS) members capture recurvature, albeit prematurely. The results demonstrate the promise of assimilating enhanced AMV data into regional TC models. Further studies to identify optimal strategies for assimilating integrated full-resolution multivariate data from satellites are under way.
Predictability Characteristics of Landfalling Cyclones along the North American West Coast
Authors: McMurdie Lynn A. , Ancell Brian
Published: September 2013

The predictability of North Pacific cyclones can vary widely, from highly accurate prediction of storm intensity and location to forecast position errors of hundreds of kilometers and central pressure errors of tens of hectopascals. In this study, a Weather Research and Forecasting Model (WRF) ensemble Kalman filter is used to investigate predictability of landfalling cyclones on the west coast of North America over two winter seasons (2008/09 and 2009/10). Predictability is defined as the ensemble spread of cyclone central pressure at the final forecast time (24 h) where large spread means low predictability. Both ensemble spread and ensemble initial-condition sensitivity are examined for a wide variety of cyclones that occurred during the two seasons. Storms that are deepening and track from the southwest exhibit the largest ensemble initial-condition sensitivity and highest ensemble spread compared to decaying storms and storms that track from other directions. Storms that end south of 40°N, typically slow moving storms from the northwest, exhibit higher predictability regardless of whether or not they are deepening or decaying. Cyclones with large ensemble spread and low sensitivity are mature cyclones whose low predictability likely results from large initial-condition spread instead of large perturbation growth. These results highlight particular synoptic situations and cyclone characteristics that are associated with low predictability and can potentially be used to improve forecasts through improved observational coverage.
Open Versus Endovascular Stent Graft Repair of Abdominal Aortic Aneurysms
Authors: Firwana Belal , Ferwana Mazen , Hasan Rim , Alpert Martin A. , Faries Peter , Dangas George , Gluud Christian
Published: September 2013

We performed an analysis to assess the need for conducting additional randomized controlled trials (RCTs) comparing open and endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). Trial sequential analysis (TSA) is a statistical methodology that can calculate the required information size of a meta-analysis and assess the risk of random errors similar to interim analysis in a single optimally powered trial. It helps to decide whether we have obtained sufficient evidence or whether further RCTs are required. For short-term mortality reintervention rates, TSA showed firm evidence that there would be no extra benefit in conducting more RCTs to detect the effectiveness of EVAR versus open repair. For long-term mortality, TSA revealed either inconclusive evidence to support or refute endovascular or open repair; so, further RCTs should be performed to investigate long-term, all-cause mortality after AAA repair.
Assessment of aggressiveness of rectal cancer using 3-T MRI: correlation between the apparent diffusion coefficient as a potential imaging biomarker and histologic prognostic factors
Authors: Akashi Michiaki , Nakahusa Yuji , Yakabe Tomomi , Egashira Yoshiyuki , Koga Yasuo , Sumi Kenji , Noshiro Hirokazu , Irie Hiroyuki , Tokunaga Osamu , Miyazaki Kohji
Published: September 2013

Background

Diffusion-weighted magnetic resonance imaging (DW-MRI) permits non-invasive assessment of tumor characteristics.

Purpose

To assess the value of DW-MRI as a potential non-invasive marker of tumor aggressiveness in rectal cancer by analyzing the relationship between tumoral apparent diffusion coefficient (ADC) values of MRI and histopathologic prognostic parameters that are not affected by preoperative chemoradiation therapy.

Material and Methods

Forty patients with rectal cancer were assessed with primary staging 3-T MRI, including DWI, before undergoing surgical therapy. In all patients, surgery was performed without neoadjuvant therapy. Mean tumor ADC was measured and compared between subgroups based on pretreatment carcinoembryonic antigen (CEA) levels, MRI parameters (e.g. postoperative local recurrence), and histopathologic parameters, including A (invasive distance: A1, T-stage; A2, mesorectal fascia [MRF] status), B (differentiation grade: B1, poorly differentiated; B2, moderately differentiated; B3, well differentiated), C (others: C1, N-stage; C2, lymphangiovascular invasion).

Results

Mean tumor ADCs were different when comparing groups stratified by histologic differentiation grades ( P = 0.0192). There was no significant difference in mean ADCs when stratifying patients according to CEA levels, T-stage, N-stage, MRF status, presence of lymphangiovascular invasion, or the presence of local recurrence.

Conclusion

Significant correlations were found between mean ADC values and differentiation grade. ADC may be useful as an imaging biomarker of tumor aggressiveness, but it cannot serve as an independent biomarker of advanced rectal cancer.
Digital breast tomosynthesis versus full-field digital mammography: comparison of the accuracy of lesion measurement and characterization using specimens
Authors: Seo Nieun , Kim Hak Hee , Shin Hee Jung , Cha Joo Hee , Kim Hyunji , Moon Jin Hee , Gong Gyungyub , Ahn Sei-Hyun , Son Byung Ho
Published: September 2013

Background

Digital breast tomosynthesis (DBT) is one of the new techniques being developed to overcome the inherent limitations of mammography caused by superimposed structures in a 2D projection.

Purpose

To compare the diagnostic performances of digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM) for lesion characterization and size measurement using breast specimens.

Material and Methods

Out of 156 women scheduled for surgery, we included in our study 114 women, each of whom had a single, breast lesion. Three breast radiologists independently evaluated the DBT and FFDM performance regarding the breast specimens obtained during surgery. Each reader measured the lesion size, and then categorized the probability of malignancy using the American College of Radiology Breast Imaging Reporting and Data system (BI-RADS). After both reading sessions, the readers selected the preferred modality of either FFDM or DBT in lesion characterization. We also analyzed the radiologists’ evaluation performance in patients with dense versus fatty breasts when using DBT and FFDM.

Results

The imaging findings of 84 cancers and 30 benign lesions, all of which had been pathologically proven, were reviewed. The size evaluation determined by DBT was more accurately correlated with that found by pathology ( P = 0.001 for fatty breasts and <0.001 for dense breasts) than that determined by FFDM. The correlation coefficients of DBT and FFDM to the pathologically determined lesion size were 0.90 and 0.89, respectively ( P < 0.001). Compared with the pathologically determined lesion size, the size determined by both imaging modalities was overestimated. Overall, assessment of the probability of malignancy by DBT and FFDM did not differ significantly ( P = 0.07); however, in dense breast, DBT was more strongly correlated with the pathology determination than FFDM ( P = 0.03).

Conclusion

DBT may be superior to FFDM for determining the preoperative size measurement of breast lesions irregardless of their parenchymal density. Particularly in dense breasts, DBT was more useful for differentiating the lesion malignancy rate.
Sport-Specific Injury Pattern Recorded During Anterior Cruciate Ligament Reconstruction
Authors: Granan Lars-Petter , Inacio Maria C.S. , Maletis Gregory B. , Funahashi Tadashi T. , Engebretsen Lars
Published: September 2013

Background:

Anterior cruciate ligament (ACL) injuries are more commonly seen with certain cutting and pivoting sports. However, injury patterns associated with these sports have not been well described.

Purpose:

(1) To describe the patient demographics and injury pattern at the time of ACL reconstruction (ACLR) by activities that lead to ACL injuries and (2) to estimate the association of activities at the time of injury with the odds of isolated ACL injuries as well as with meniscus, cartilage, and multiligament injuries diagnosed at the time of ACLR.

Study Design:

Cross-sectional study; Level of evidence, 3.

Methods:

This study combined 2 ACLR registry cohorts, from Norway and the United States, from 2004 to 2011. A cohort of 10,958 primary ACLRs was included. The most prevalent sports activities at the time of injury were the following: soccer, skiing, American football, basketball, and team handball. The end points were the concurrent injury patterns at the time of ACLR: isolated ACL, meniscus, cartilage, and multiligament injuries.

Results:

All sports were compared with the most prevalent injury mechanism: soccer. Skiing injuries were 1.13 (95% confidence interval [CI], 1.01-1.27) times more likely to result in isolated ACL tears, 2.05 (95% CI, 1.01-4.16) times more likely to result in posterior cruciate ligament tears, 1.94 (95% CI, 1.51-2.49) times more likely to result in medial collateral ligament (MCL) tears, and 1.73 (95% CI, 1.38-2.17) times more likely to result in multiligament injuries. Athletes playing American football were 2.72 (95% CI, 1.32-5.62) times more likely to have MCL tears. Those injured playing basketball were 1.28 (95% CI, 1.06-1.54) times more likely to have lateral meniscus tears, 1.23 (95% CI, 1.01-1.51) times more likely to have cartilage damage, and 1.38 (95% CI, 1.11-1.72) times more likely to have meniscus and cartilage injuries. Athletes injured playing team handball were less likely to have MCL tears (odds ratio [OR], 0.68; 95% CI, 0.46-0.99) and more likely to have lateral meniscus injuries (OR, 1.27; 95% CI, 1.10-1.48).

Conclusion:

Injury patterns were associated with certain sports. Compared with soccer, American football has a higher likelihood of resulting in multiligament injuries, whereas basketball has a higher likelihood of resulting in cartilage and lateral meniscus injuries. Injury patterns seen at the time of surgery may reflect the forces applied to the knee by the specific sports performed.
Modelling train motion along arbitrary shaped track in transient regimes
Authors: Markova Olga , Kovtun Helena , Maliy Victor
Published: September 2013

A mathematical model to estimate the dynamic coefficients of a moving freight train is given; an approach is used in which some train vehicles are represented by simplified calculation schemes and other vehicles are represented in detail by taking into account their design and the features of the transported cargo. The train motion along track of different shapes and in various operational modes (with constant and variable speeds) is modelled. Some simulation results are presented.
Leader Behaviors as Mediators of the Leader Characteristics - Follower Satisfaction Relationship
Authors: Blickle Gerhard , Kane-Frieder Rachel E. , Oerder Katharina , Wihler Andreas , von Below Ariane , Schütte Nora , Matanovic Anja , Mudlagk Daniel , Kokudeva Tatyana , Ferris Gerald R.
Published: September 2013

This study examined two potential mediators through which leaders transmit their position power into an effectiveness outcome. Drawing upon recent work integrating trait, situational, and behavioral theories of leadership effectiveness, we hypothesized and tested a model specifying that the interactive effects of leader position power and leader political skill on follower satisfaction would be mediated by followers’ perceptions of leaders’ initiating structure and consideration behaviors. Specifically, this model indicates that leaders who are both in powerful positions and politically skilled are perceived to initiate more structure and demonstrate more consideration for their followers than their nonpolitically skilled counterparts, which, in turn, positively impacts followers’ satisfaction (i.e., an indication of subjective leadership effectiveness). Utilizing 190 leaders and 476 followers, we found support for the hypothesized model. Contributions to various literatures, strengths, limitations, and practical implications are discussed.
Cognitive functions in multiple sclerosis: impact of gray matter integrity
Authors: Llufriu Sara , Martinez-Heras Eloy , Fortea Juan , Blanco Yolanda , Berenguer Joan , Gabilondo Iñigo , Ibarretxe-Bilbao Naroa , Falcon Carles , Sepulveda Maria , Sola-Valls Nuria , Bargallo Nuria , Graus Francesc , Villoslada Pablo , Saiz Albert
Published: September 2013

Objectives:

Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions.

Methods:

Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores.

Results:

Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36–51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance.

Conclusion:

GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.
Social movements, competing rationalities and trigger events: The complexity of Chinese popular mobilizations
Authors: Bruun Ole
Published: September 2013

This article addresses popular mobilizations in repressive regimes, with China as a case in point. It argues that such mobilizations are very different from those in democratic societies and may not be captured in the single-stranded rationalism promoted by much social movement theory. Without access to political representation and stable outlets for social criticism, mobilizations are likely to be set off by ‘trigger events’, just as their growth occurs through distinct phase shifts. A range of Chinese mobilizations over the last several years are introduced. They tend to show that people initially are driven by simple causes rather than ‘ideology’, and often with an ingrained conflict of beliefs. Yet, due to regime reprisal, it may be a short step from addressing a small local issue to challenging the political system as a whole. With reference to complexity theory it is shown that emergent new forms of organized resistance will never follow a linear and predictable development but will be contextually embedded and continually exchanging with that particular cultural and political environment. Thus, when we see the sudden growth of movements which step over the threshold into open discontent and public resistance, the outcome for both the movement itself and the system as a whole is inherently unpredictable.
Freedom and oppression
Authors: Grant Claire
Published: September 2013

Oppression is commonly deemed a problem of freedom. How though should we conceptualise the freedom-restricting nature of oppression? This paper aims to show that the unfreedom in oppression may be understood in terms of individual negative liberty. The controversial concept of collective unfreedom is not needed. Non-cooperation among the oppressed generates constraints on individual freedom. This non-cooperation is ultimately attributable to the exercise of social power by oppressors. It is in this sense that the resultant states of individual unfreedom are due relations of oppression.
“Walrasian Fixed Supply Conjecture” Versus “Contest-Nash” Solutions to Sports League Models
Authors: Madden Paul
Published: September 2013

Winfree and Fort (WF) recently suggested an approach to modeling basic two-team sports leagues, which requires Nash equilibrium solutions to games where investments in (not levels of) talent are the strategic variables. I comment (a) it is crucial that talent investments are the strategic variables, reworking arguments from my earlier article; (b) with nuanced but important differences from Stefan Szymanski’s conclusions regarding WF, Walrasian fixed supply conjecture solutions and the invariance principle are unlikely to emerge from this approach but Contest-Nash solutions can; (d) the long-running debate alluded to in the title of this article may have run its course.
Ivacaftor treatment of cystic fibrosis patients with the G551D mutation: a review of the evidence
Authors: Kotha Kavitha , Clancy John P.
Published: September 2013

Cystic fibrosis (CF) is a recessive disorder caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. CFTR protein is a chloride and bicarbonate channel that is critical for normal epithelial ion transport and hydration of epithelial surfaces. Current CF care is supportive, but recent breakthroughs have occurred with the advent of novel therapeutic strategies that assist the function of mutant CFTR proteins. The development and key clinical trial results of ivacaftor, a small molecule that targets gating defects in disease-causing CFTR mutations including G551D CFTR, are summarized in this review. The G551D mutation is reasonably common in the CF patient population and produces a CFTR protein that localizes normally to the plasma membrane, but fails to open in response to cellular cues. Ivacaftor treatment produces dramatic improvements in lung function, weight, lung disease stability, patient-reported outcomes, and CFTR biomarkers in patients with CF harboring the G551D CFTR mutation compared with placebo controls and patients with two copies of the common F508del CFTR mutation. The unprecedented success of ivacaftor treatment for the G551D CF patient population has generated excitement in the CF care community regarding the expansion of its use to other CF patient populations with primary or secondary gating defects.
Human papillomavirus vaccination in adolescence
Authors: Russell Michelle , Raheja Vinita , Jaiyesimi Rotimi
Published: September 2013

Cervical cancer is the third most common female cancer worldwide. It remains the highest ranking preventable cancer affecting women in developing countries. Cervical cancer is caused by sexual transmission of human papillomavirus (HPV). It is estimated that more than 80% of sexually active women will be infected with HPV in their lifetime, usually in their mid to late teens, 20s and early 30s. Persistence of high-risk oncogenic subtypes can lead to the development of precancerous change (cervical intraepithelial neoplasia (CIN)), which can ultimately lead to cervical cancer. Progression from CIN to cancer is slow in most cases, and it is believed that progression from CIN 3 to cancer at 10, 20 and 30 years is 16%, 25% and 31.3%, respectively. The cervical screening programme has been successful in reducing the incidence of cervical cancer by recognising early precancerous changes and treating them. A promising advance in women’s health has been the development of a vaccine targeting high-risk oncogenic subtypes 16 and 18, which are responsible for 70% of all cervical cancers. Two HPV vaccines are available: Merck & Co.’s Gardasil® and GlaxoSmithKline’s Cervarix®. The aim of this programme is to provide three doses prior to sexual debut with the hope that it will reduce the rates of cervical cancer in the future. Women who are already sexually active can still be vaccinated, but, the vaccine has been shown to be less effective in them. Uptake remains a challenge for public health, and efforts should focus on educating parents about the association between HPV and cervical cancer. Routine vaccination of young men is a debatable issue and has been found to be less cost-effective, as the burden of disease such as anal and penile cancers in males is less than cervical cancers in women. Current evidence suggests that the HPV vaccination programme should focus on increasing and maintaining high coverage of vaccination in girls. There may, however, be some benefit in vaccinating young men in areas where the uptake of vaccination in women in less than 70%. A school-based vaccination programme has been shown to be effective, with an uptake rate in England of 76% for 2009/2010, but this has implications for the role of school nurses in the delivery of other services. This article explores the health benefits of the HPV vaccine, the impact of attitudes, cost-effectiveness and the involvement of school nurses in programme delivery.
Changes in Drop-Jump Landing Biomechanics During Prolonged Intermittent Exercise
Authors: Schmitz Randy J. , Cone John C. , Tritsch Amanda J. , Pye Michele L. , Montgomery Melissa M. , Henson Robert A. , Shultz Sandra J.
Published: September 2013

Background:

As injury rates rise in the later stages of sporting activities, a better understanding of lower extremity biomechanics in the later phases of gamelike situations may improve training and injury prevention programs.

Hypothesis:

Lower extremity biomechanics of a drop-jump task (extracted from a principal components analysis) would reveal factors associated with risk of anterior cruciate ligament injury during a 90-minute individualized intermittent exercise protocol (IEP) and for 1 hour following the IEP.

Study Design:

Controlled laboratory study.

Level of Evidence:

Level 4.

Methods:

Fifty-nine athletes (29 women, 30 men) completed 3 sessions. The first session assessed fitness for an IEP designed to simulate the demands of a soccer match. An experimental session assessed drop-jump biomechanics, after a dynamic warm-up, every 15 minutes during the 90-minute IEP, and for 1 hour following the IEP. A control session with no exercise assessed drop-jump performance at the same intervals.

Results:

Two biomechanical factors early in the first half (hip flexion at initial contact and hip loading; ankle loading and knee shear force) decreased at the end of the IEP and into the 60-minute recovery period, while a third factor (knee loading) decreased only during the recovery period ( P ≤ 0.05).

Conclusion:

The individualized sport-specific IEP may have more subtle effects on landing biomechanics when compared with short-term, exhaustive fatigue protocols.

Clinical Relevance:

Potentially injurious landing biomechanics may not occur until the later stages of soccer activity.
Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports
Authors: Kogut Christopher , Crouse Ericka Breden , Vieweg W. Victor R. , Hasnain Mehrul , Baranchuk Adrian , Digby Geneviève C. , Koneru Jayanthi N. , Fernandez Antony , Deshmukh Anand , Hancox Jules C. , Pandurangi Ananda K.
Published: September 2013

Objective:

In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP?

Method:

We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP.

Results:

A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose.

Conclusion:

Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an ‘extreme outlier’. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.
Indolent T-cell lymphoproliferative disease of the gastrointestinal tract
Authors: Perry Anamarija M. , Warnke Roger A. , Hu Qinglong , Gaulard Philippe , Copie-Bergman Christiane , Alkan Serhan , Wang Huan-You , Cheng Jason X. , Bacon Chris M. , Delabie Jan , Ranheim Erik , Kucuk Can , Hu XiaoZhou , Weisenburger Dennis D. , Jaffe Elaine S. , Chan Wing C.
Published: September 2013

Key Points

Ten cases of an indolent T-cell lymphoproliferative disease of the gastrointestinal tract are reported. It is important to recognize this condition because it can be mistaken for aggressive T-cell lymphoma, which may lead to unnecessary therapy.
RNA-seq analyses of gene expression in the microsclerotia of Verticillium dahliae
Authors: Duressa Dechassa , Anchieta Amy , Chen Dongquan , Klimes Anna , Garcia-Pedrajas Maria D , Dobinson Katherine F , Klosterman Steven J
Published: September 2013

Background

The soilborne fungus, Verticillium dahliae, causes Verticillium wilt disease in plants. Verticillium wilt is difficult to control since V. dahliae is capable of persisting in the soil for 10 to 15 years as melanized microsclerotia, rendering crop rotation strategies for disease control ineffective. Microsclerotia of V. dahliae overwinter and germinate to produce infectious hyphae that give rise to primary infections. Consequently, microsclerotia formation, maintenance, and germination are critically important processes in the disease cycle of V. dahliae.

Results

To shed additional light on the molecular processes that contribute to microsclerotia biogenesis and melanin synthesis in V. dahliae, three replicate RNA-seq libraries were prepared from 10 day-old microsclerotia (MS)-producing cultures of V. dahliae, strain VdLs.17 (average = 52.23 million reads), and those not producing microsclerotia (NoMS, average = 50.58 million reads). Analyses of these libraries for differential gene expression revealed over 200 differentially expressed genes, including up-regulation of melanogenesis-associated genes tetrahydroxynaphthalene reductase (344-fold increase) and scytalone dehydratase (231-fold increase), and additional genes located in a 48.8 kilobase melanin biosynthetic gene cluster of strain VdLs.17. Nearly 50% of the genes identified as differentially expressed in the MS library encode hypothetical proteins. Additional comparative analyses of gene expression in V. dahliae, under growth conditions that promote or preclude microsclerotial development, were conducted using a microarray approach with RNA derived from V. dahliae strain Dvd-T5, and from the amicrosclerotial vdh1 strain. Differential expression of selected genes observed by RNA-seq or microarray analysis was confirmed using RT-qPCR or Northern hybridizations.

Conclusion

Collectively, the data acquired from these investigations provide additional insight into gene expression and molecular processes that occur during MS biogenesis and maturation in V. dahliae. The identified gene products could therefore potentially represent new targets for disease control through prevention of survival structure development.
The effect of intravenous iron on postoperative transfusion requirements in hip fracture patients: study protocol for a randomized controlled trial
Authors: Rowlands Martin , Forward Daren P , Sahota Opinder , Moppett Iain K
Published: September 2013

Background

Anaemia following hip fracture is common. Approximately 30 to 45% of patients have haemoglobin concentrations below population norms on admission, and around 10% are severely anaemic. Anaemia on admission, and in the postoperative period, is associated with poor outcomes with regard to mobility, postoperative mortality and readmission. There is currently no clear consensus on the optimal method of managing perioperative anaemia in this group of frail patients with frequent comorbidity. Liberal red cell transfusion in the postoperative period does not appear to improve outcome, whereas tranexamic acid appears to reduce transfusion rate at the expense of increased cardiovascular morbidity. There are encouraging results from one centre with the use of agents to stimulate red cell production, including intravenous iron and erythropoietin. UK practice differs significantly from these patients and these studies, and it is not clear whether these promising results will translate to the UK population.

Methods/Design

This is a single-centre randomized controlled parallel group trial, in a British university hospital.Randomization is achieved using a website and computer-generated concealed tables. Participants are 80 patients 70 years or over with acute hip fracture undergoing operative repair. The intervention group receive three daily infusions of 200 mg iron sucrose, starting within 24 hours of admission. The control group receive standard hospital care at the discretion of the clinical team. Red cell transfusions for each group are given in accordance with standard clinical triggers. The primary outcome is an increase in mean reticulocyte count in the intervention group at day 7. Secondary outcome measures include haemoglobin concentrations, early and late transfusion rates, infectious and cardiovascular complications, mobility and 30-day mortality.

Discussion

This is a pilot study to demonstrate haematopoietic efficacy of intravenous iron in this setting. Hence, we have chosen to measure change in reticulocyte count rather than the more clinically relevant differences in haemoglobin concentration or transfusion rate. If our results are positive, the study will provide the necessary information for development of a full-scale trial of intravenous iron.

Trial registration

Current Controlled Trials ISRCTN76424792; UK Medicines and Healthcare products Regulatory Authority (EuDRACT: 2011-003233-34).
Haploidentical stem cell transplantation in two children with mucopolysaccharidosis VI: clinical and biochemical outcome
Authors: Jester Sandra , Larsson Julia , Eklund Erik A , Papadopoulou Domniki , Månsson Jan-Eric , Békássy Albert N , Turkiewicz Dominik , Toporski Jacek , Øra Ingrid
Published: September 2013

Background

Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive progressive multiorgan disorder due to mutation in the gene encoding the enzyme Arylsulfatase B (ARSB). Dysfunctional ARSB causes lysosomal accumulation of glycosaminoglycans (GAG). Currently, enzyme replacement therapy (ERT) is preferred to hematopoietic stem cell transplantation (SCT) due to the treatment-related risks of the latter. However, ERT constitutes an expensive life-long treatment. Increased experience and safety of SCT-procedures in recent years suggest that SCT should be further explored as a treatment option.

This is the first report on haploidentical SCT in patients with MPS VI. The primary objective was to assess the treatment safety and clinical and biochemical outcome.

Patients and methods

Two siblings diagnosed with MPS VI at 10 months of age and at birth with genotype p.C192R, reported as mild to intermediate phenotype, underwent unrelated umbilical cord blood transplantation pre-symptomatic. Due to graft failure, both patients were urgently re-transplantated with haploidentical SCT with the father as donor. Continuous clinical and biochemical status was monitored and concluded 3.8 and 4.6 years after the haploidentical SCT.

Results

Haploidentical SCT resulted in prompt and sustained engraftment. Complete donor chimerism was achieved in both patients, apart from mixed B cells chimerism in patient 2. ARSB activity in leukocytes post transplant increased from 0.0 to 19.0 μkat/kg protein (patient 1) and from 3.6 to 17.9 μkat/kg protein (patient 2) (ref. 17–40). Total urinary GAG normalized in both patients, although patient 2’s values slightly exceed normal range since 6 months. However, dermatan sulfaturia was substantially normalized since 16 months and 12 months post-SCT, respectively. Height was -1.85 SD and -1.27 SD at follow-up. Patient 1 had impaired visual acuity and discrete hepatomegaly. Patient 2 had elevated intraocular pressure and X-ray revealed steep acetabular angles and slightly flattened lumbar vertebrae.

Conclusion

This study demonstrates that young children with MPS VI tolerate haploidentical SCT. Normalization of enzyme production and dermatan sulfaturia indicates correction of the inborn error of metabolism and coincide with no obvious symptoms of progressive MPS VI up to 4.6 years post-SCT.
Factors influencing the cell adhesion and invasion capacity of Mycoplasma gallisepticum
Authors: Fürnkranz Ursula , Siebert-Gulle Karin , Rosengarten Renate , Szostak Michael P
Published: September 2013

Background

The cell invasiveness of Mycoplasma gallisepticum, the causative agent of respiratory disease in chickens and infectious sinusitis in turkeys, may be a substantial factor in the well-known chronicity of these diseases and in the systemic spread of infection. To date, not much is known about the host factors and mechanisms involved in promotion or obstruction of M. gallisepticum adherence and/or cell invasion.

In the current study, the influence of extracellular matrix (ECM) proteins such as fibronectin, collagen type IV and heparin, as well as plasminogen/plasmin, on the adhesion and cell invasion levels of M. gallisepticum to chicken erythrocytes and HeLa cells was investigated in vitro. Two strains, Rhigh and Rlow, which differ in their adhesion and invasion capacity, were analyzed by applying a modified gentamicin invasion assay. Binding of selected ECM molecules to M. gallisepticum was proven by Western blot analysis.

Results

Collagen type IV, fibronectin, and plasminogen exerted positive effects on adhesion and cell invasion of M. gallisepticum, with varying degrees, depending on the strain used. Especially strain Rhigh, with its highly reduced cell adhesion and invasion capabilities seemed to profit from the addition of plasminogen. Western and dot blot analyses showed that Rhigh as well as Rlow are able to adsorb horse fibronectin and plasminogen present in the growth medium. Depletion of HeLa cell membranes from cholesterol resulted in increased adhesion, but decreased cell invasion.

Conclusion

ECM molecules seem to play a supportive role in the adhesion/cell invasion process of M. gallisepticum. Cholesterol depletion known to affect lipid rafts on the host cell surface had contrary effects on cell adherence and cell invasion of M. gallisepticum.
Comparative analysis of the Trichoderma reeseitranscriptome during growth on the cellulase inducing substrates wheat straw and lactose
Authors: Bischof Robert , Fourtis Lukas , Limbeck Andreas , Gamauf Christian , Seiboth Bernhard , Kubicek Christian P
Published: September 2013

Background

Renewable lignocellulosic biomass is an advantageous resource for the production of second generation biofuels and other biorefinery products. In Middle Europe, wheat straw is one of the most abundant low-cost sources of lignocellulosic biomass. For its efficient use, an efficient mix of cellulases and hemicellulases is required. In this paper, we investigated how cellulase production by T. reesei on wheat straw compares to that on lactose, the only soluble and also cheap inducing carbon source for enzyme production.

Results

We have examined and compared the transcriptome of T. reesei growing on wheat straw and lactose as carbon sources under otherwise similar conditions. Gene expression on wheat straw exceeded that on lactose, and 1619 genes were found to be only induced on wheat straw but not on lactose. They comprised 30% of the CAZome, but were also enriched in genes associated with phospholipid metabolism, DNA synthesis and repair, iron homeostatis and autophagy. Two thirds of the CAZome was expressed both on wheat straw as well as on lactose, but 60% of it at least >2-fold higher on the former. Major wheat straw specific genes comprised xylanases, chitinases and mannosidases. Interestingly, the latter two CAZyme families were significantly higher expressed in a strain in which xyr1 encoding the major regulator of cellulase and hemicellulase biosynthesis is non-functional.

Conclusions

Our data reveal several major differences in the transcriptome between wheat straw and lactose which may be related to the higher enzyme formation on the former and their further investigation could lead to the development of methods for increasing enzyme production on lactose.
Metabolism modifications and apoptosis induction after Cellfood™ administration to leukemia cell lines
Authors: Catalani Simona , Carbonaro Valentina , Palma Francesco , Arshakyan Marselina , Galati Rossella , Nuvoli Barbara , Battistelli Serafina , Canestrari Franco , Benedetti Serena
Published: September 2013

Background

Cellfood™ (CF) is a nutritional supplement containing deuterium sulphate, minerals, amino acids, and enzymes, with well documented antioxidant properties. Its organic and inorganic components are extracted from the red algae Lithothamnion calcareum, whose mineral extract has shown growth-inhibitory effect both on in vitro and in vivo models. The purpose of this study was to evaluate the antiproliferative effects of CF on leukemic cells. In fact, according to its capacity to modulate O2 availability and to improve mitochondrial respiratory metabolism, we wondered if CF could affect cancer cell metabolism making cells susceptible to apoptosis.

Methods

Three leukemic cell lines, Jurkat, U937, and K562, were treated with CF 5 μl/ml up to 72 hours. Cell viability, apoptosis (i.e. caspase-3 activity and DNA fragmentation), hypoxia inducible factor 1 alpha (HIF-1α) concentration, glucose transporter 1 (GLUT-1) expression, lactate dehydrogenase (LDH) activity and lactate release in the culture medium were detected and compared with untreated cells.

Results

CF significantly inhibited leukemic cell viability by promoting cell apoptosis, as revealed by caspase-3 activation and DNA laddering. In particular, CF treated cells showed lower HIF-1α levels and lower GLUT-1 expression as compared to untreated cells. At the same time, CF was able to reduce LDH activity and, consequently, the amount of lactate released in the extracellular environment.

Conclusions

We supplied evidence for an antiproliferative effect of CF on leukemia cell lines by inducing cell death through an apoptotic mechanism and by altering cancer cell metabolism through HIF-1α and GLUT-1 regulation. Thanks to its antioxidative and proapoptotic properties, CF might be a good candidate for cancer prevention.
Understanding the physical activity promotion behaviours of podiatrists: a qualitative study
Authors: Crisford Paul , Winzenberg Tania , Venn Alison , Cleland Verity
Published: September 2013

Background

Health professionals are encouraged to play a part in reducing the health risks of physical inactivity. Little is known of the physical activity promotion practice behaviours of podiatrists.

Methods

We performed 20 semi‐structured interviews with purposefully selected podiatrists to explore their physical activity promotion attitudes, beliefs, knowledge and practice. Transcribed interviews were coded using an iterative thematic approach to identify major themes and salient beliefs.

Results

Overall, the participants had a positive attitude to physical activity promotion, considering it a normal part of their role. They saw their role as giving information, encouraging activity and making recommendations, however in practice they were less inclined to follow up on recommendations, monitor activity levels or document the process. Their approach was generally opportunistic, informal and unstructured and the content of assessment and promotion dependent upon the presenting patient's condition. Advice tended to be tailored to the patient's capabilities and interests. They considered there are opportunities to promote physical activity during regular consultations, however, were more likely to do so in patients with chronic diseases such as diabetes. Main barriers to physical activity promotion included unreceptive and unmotivated patients as well as a lack of time, skills and resources.

Conclusions

Physical activity promotion appears feasible in podiatry practice in terms of opportunity and acceptability to practitioners, but there is scope for improvement. Strategies to improve promotion need to consider the major issues, barriers and opportunities as well as provide a more structured approach to physical activity promotion by podiatrists.