bluuebunny/crossref_metadata_2025_split huggingface dataset:
Symmorphosis and skeletal muscle : in vivo and in vitro measures reveal differing constraints in the exercise‐trained and untrained human
Authors: Gifford Jayson R. , Garten Ryan S. , Nelson Ashley D. , Trinity Joel D. , Layec Gwenael , Witman Melissa A. H. , Weavil Joshua C. , Mangum Tyler , Hart Corey , Etheredge Cory , Jessop Jake , Bledsoe Amber , Morgan David E. , Wray D. Walter , Rossman Matthew J. , Richardson Russell S. 
Published: November 2015

Key points
The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption () such that no single process is limiting or in excess at .
The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance‐trained humans.
Among untrained individuals, is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals, is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity.
AbstractThe concept of symmorphosis postulates a matching of structural capacity to functional demand within a defined physiological system, regardless of endurance exercise training status. Whether this concept applies to oxygen (O2) supply and demand during maximal skeletal muscle O2 consumption () in humans is unclear. Therefore, in vitro skeletal muscle mitochondrial (Mito, mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscle during single leg knee extensor exercise (KE, direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole‐body during cycling (Body, indirect calorimetry) in 10 endurance exercise‐trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O2 supply (KEO2max) exceeded (462 ± 37 ml kg−1 min−1, P < 0.05) and KE matched (340 ± 22 ml kg−1 min−1, P > 0.05) Mito (364 ± 16 ml kg−1 min−1). Conversely, in trained subjects, both KEO2max (557 ± 35 ml kg−1 min−1) and KE (458 ± 24 ml kg−1 min−1) fell far short of Mito (743 ± 35 ml kg−1 min−1, P < 0.05). Although Mito was related to KE (r = 0.69, P < 0.05) and Body (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects, is limited by mitochondrial O2 demand, with evidence of adequate O2 supply, whereas, in trained subjects, an exercise training‐induced mitochondrial reserve results in skeletal muscle being markedly limited by O2 supply. Taken together, these in vivo and in vitro measures reveal clearly differing limitations and excesses at in untrained and trained humans and challenge the concept of symmorphosis as it applies to O2 supply and demand in humans.
Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation
Authors: Fritzen Andreas M. , Madsen Agnete B. , Kleinert Maximilian , Treebak Jonas T. , Lundsgaard Anne‐Marie , Jensen Thomas E. , Richter Erik A. , Wojtaszewski Jørgen , Kiens Bente , Frøsig Christian 
Published: November 2015

Key points
Regulation of autophagy in human muscle in many aspects differs from the majority of previous reports based on studies in cell systems and rodent muscle.
An acute bout of exercise and insulin stimulation reduce human muscle autophagosome content.
An acute bout of exercise regulates autophagy by a local contraction‐induced mechanism.
Exercise training increases the capacity for formation of autophagosomes in human muscle.
AMPK activation during exercise seems insufficient to regulate autophagosome content in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy‐inhibiting effect of insulin.
AbstractStudies in rodent muscle suggest that autophagy is regulated by acute exercise, exercise training and insulin stimulation. However, little is known about the regulation of autophagy in human skeletal muscle. Here we investigate the autophagic response to acute one‐legged exercise, one‐legged exercise training and subsequent insulin stimulation in exercised and non‐exercised human muscle. Acute one‐legged exercise decreased (P<0.01) lipidation of microtubule‐associated protein 1A/1B‐light chain 3 (LC3) (∼50%) and the LC3‐II/LC3‐I ratio (∼60%) indicating that content of autophagosomes decreases with exercise in human muscle. The decrease in LC3‐II/LC3‐I ratio did not correlate with activation of 5′AMP activated protein kinase (AMPK) trimer complexes in human muscle. Consistently, pharmacological AMPK activation with 5‐aminoimidazole‐4‐carboxamide riboside (AICAR) in mouse muscle did not affect the LC3‐II/LC3‐I ratio. Four hours after exercise, insulin further reduced (P<0.01) the LC3‐II/LC3‐I ratio (∼80%) in muscle of the exercised and non‐exercised leg in humans. This coincided with increased Ser‐757 phosphorylation of Unc51 like kinase 1 (ULK1), which is suggested as a mammalian target of rapamycin complex 1 (mTORC1) target. Accordingly, inhibition of mTOR signalling in mouse muscle prevented the ability of insulin to reduce the LC3‐II/LC3‐I ratio. In response to 3 weeks of one‐legged exercise training, the LC3‐II/LC3‐I ratio decreased (P<0.05) in both trained and untrained muscle and this change was largely driven by an increase in LC3‐I content. Taken together, acute exercise and insulin stimulation reduce muscle autophagosome content, while exercise training may increase the capacity for formation of autophagosomes in muscle. Moreover, AMPK activation during exercise may not be sufficient to regulate autophagy in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy‐inhibiting effect of insulin.
Effect of head pitch and roll orientations on magnetically induced vertigo
Authors: Mian Omar S. , Li Yan , Antunes Andre , Glover Paul M. , Day Brian L. 
Published: November 2015

Key points
Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole‐body rotation.
The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.
The hypothesis predicts that the perception of whole‐body rotation will depend on head orientation in the field.
Results showed that the direction and magnitude of apparent whole‐body rotation while stationary in a 7 T magnetic field is influenced by head orientation.
The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head‐referenced vestibular signals to Earth‐referenced body motion.
AbstractHigh strength static magnetic fields are known to induce vertigo, believed to be via stimulation of the vestibular system. The leading hypothesis (Lorentz forces) predicts that the induced vertigo should depend on the orientation of the magnetic field relative to the head. In this study we examined the effect of static head pitch (−80 to +40 deg; 12 participants) and roll (−40 to +40 deg; 11 participants) on qualitative and quantitative aspects of vertigo experienced in the dark by healthy humans when exposed to the static uniform magnetic field inside a 7 T MRI scanner. Three participants were additionally examined at 180 deg pitch and roll orientations. The effect of roll orientation on horizontal and vertical nystagmus was also measured and was found to affect only the vertical component. Vertigo was most discomforting when head pitch was around 60 deg extension and was mildest when it was around 20 deg flexion. Quantitative analysis of vertigo focused on the induced perception of horizontal‐plane rotation reported online with the aid of hand‐held switches. Head orientation had effects on both the magnitude and the direction of this perceived rotation. The data suggest sinusoidal relationships between head orientation and perception with spatial periods of 180 deg for pitch and 360 deg for roll, which we explain is consistent with the Lorentz force hypothesis. The effects of head pitch on vertigo and previously reported nystagmus are consistent with both effects being driven by a common vestibular signal. To explain all the observed effects, this common signal requires contributions from multiple semicircular canals.
Attenuated hypothalamic responses to α‐melanocyte stimulating hormone during pregnancy in the rat
Authors: Ladyman S. R. , Augustine R. A. , Scherf E. , Phillipps H. R. , Brown C. H. , Grattan D. R. 
Published: November 2015

Key points
Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide α‐melanocyte stimulating hormone (α‐MSH) are suppressed.
This study investigated hypothalamic responses to α‐MSH during pregnancy, using c‐fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative α‐MSH‐responsive neuronal population that shows a well‐characterised α‐MSH‐induced inhibition of firing.
While icv injection of α‐MSH significantly increased the number of c‐fos‐positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non‐pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic α‐MSH‐induced inhibition of firing that was observed in non‐pregnant animals.
Given the known functions of α‐MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.
AbstractDuring pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide α‐melanocyte stimulating hormone (α‐MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic α‐MSH target neurons, non‐pregnant and pregnant rats were treated with α‐MSH or vehicle and c‐fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known α‐MSH responsive neuronal population, was examined in non‐pregnant and pregnant rats following α‐MSH treatment. Intracerebroventricular injection of α‐MSH significantly increased the number of c‐fos‐positive cells in the paraventricular, arcuate and ventromedial hypothalamic nuclei in non‐pregnant rats, but no significant increase was observed in any of these regions in pregnant rats. In the SON, α‐MSH did induce expression of c‐fos during pregnancy, but this was significantly reduced compared to that observed in the non‐pregnant group. Furthermore, during pregnancy, SON oxytocin neurons did not demonstrate the characteristic α‐MSH‐induced inhibition of firing rate that was observed in non‐pregnant animals. Melanocortin receptor mRNA levels during pregnancy were similar to non‐pregnant animals, suggesting that receptor down‐regulation is unlikely to be a mechanism underlying the attenuated responses to α‐MSH during pregnancy. Given the known functions of α‐MSH in the hypothalamus, the attenuated responses will facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.
Parvovirus B19 myocarditis in children: an observational study
Authors: Vigneswaran Trisha V , Brown Julianne R , Breuer Judith , Burch Michael 
Published: November 2015

BackgroundThe advent of PCR testing for the presence of viral genomes has led to the identification of parvovirus B19 (PVB19) as a causative agent of myocarditis.MethodsThe clinical presentation, course and outcome of children with PVB19 myocarditis was ascertained through a retrospective review. The PVB19 viral genome was detected by PCR from whole blood or endomyocardial biopsy specimens in patients presenting with new onset heart failure.ResultsSeventeen patients presented at a median age of 1.3 years (range: 0.4–15.4 years) in cardiac failure with a mean fractional shortening of 15±3%. Eleven patients required mechanical ventilation and intravenous inotropes and seven required extra-corporeal mechanical oxygenation. Four of the five deaths occurred in patients who had a short prodromal illness of less than 48 hours. All patients with ST segment elevation died (n=4). All non-fulminant cases survived. Event-free survival occurred in 11/17 (65%) patients. Five (29%) patients died and one patient underwent heart transplantation. Complete recovery of cardiac function occurred within a median of 12 months (range: 1–48) in five patients. There was incomplete recovery in five patients and one patient had persistent dilated cardiomyopathy.ConclusionsPVB19 can cause a devastating myocarditis in children. Children with fulminant myocarditis, ST segment changes or a short prodrome have the worst outcome. Transplantation may be considered, but is rarely required in the acute period if mechanical circulatory support is utilised. If the initial presentation is survived, recovery of the myocardium can occur even in those who had fulminant myocarditis.
Consensus statement on the methodology of injury and illness surveillance in FINA (aquatic sports)
Authors: Mountjoy M , Junge A , Alonso J M , Clarsen B , Pluim B M , Shrier I , van den Hoogenband C , Marks S , Gerrard D , Heyns P , Kaneoka K , Dijkstra H P , Khan K M 
Published: November 2015

BackgroundInjury and illness surveillance in the aquatic disciplines has been conducted during the FINA World Championships and Olympic Games. The development of an aquatic-specific injury and illness surveillance system will improve the quality of the data collected and the development of preventive measures. Our ultimate objective is to enhance aquatic athlete health and performance.ObjectiveThe objective was to refine the injury and illness surveillance protocols to develop aquatic-specific definitions of injury and illness; define aquatic-specific injury location and causation; better describe overuse injuries; regard pre-existing and recurrent injuries; more accurately define aquatic athlete exposures and develop a protocol to capture out-of-competition aquatic athlete health parameters.MethodsFINA compiled an Injury and Illness Surveillance Expert Working Group comprised of international experts to review the scientific literature in the field. A consensus meeting was convened to provide an opportunity for debate, following which recommendations were collated.ResultsAquatic-specific injury and illness surveillance protocols covering both the in-competition and out-of-competition time periods were developed. Definitions for all relevant variables were outlined, and documentation forms for athletes and for clinicians were proposed. Recommendations for the implementation of an injury and illness surveillance system for FINA are presented.ConclusionThe FINA consensus authors recommend ongoing in-competition and out-of-competition surveillance to determine injury and illness trends over time. The implementation of the definitions and methodology outlined in this paper will improve the accuracy and value of injury and illness surveillance, and provide important information for injury prevention.
Use of surrogate outcomes in US FDA drug approvals, 2003–2012: a survey
Authors: Yu Tsung , Hsu Yea-Jen , Fain Kevin M , Boyd Cynthia M , Holbrook Janet T , Puhan Milo A 
Published: November 2015

ObjectiveTo evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and how the rationale for using treatment effects on surrogates as predictors of treatment effects on patient-centred outcomes is discussed.Study design and settingWe used the Drugs@FDA website to identify drug approvals produced from 2003 to 2012 by the FDA. We focused on four diseases (chronic obstructive pulmonary disease (COPD), type 1 or 2 diabetes, glaucoma and osteoporosis) for which surrogates are commonly used in trials. We reviewed the drug labels and medical reviews to provide empirical evidence on how surrogate outcomes are handled by the FDA.ResultsOf 1043 approvals screened, 58 (6%) were for the four diseases of interest. Most drugs for COPD (7/9, 78%), diabetes (26/26, 100%) and glaucoma (9/9, 100%) were approved based on surrogates while for osteoporosis, most drugs (10/14, 71%) were also approved for patient-centred outcomes (fractures). The rationale for using surrogates was discussed in 11 of the 43 (26%) drug approvals based on surrogates. In these drug approvals, we found drug approvals for diabetes are more likely than the other examined conditions to contain a discussion of trial evidence demonstrating that treatment effects on surrogate outcomes predict treatment effects on patient-centred outcomes.ConclusionsOur results suggest that the FDA did not use a consistent approach to address surrogates in assessing the benefits and harms of drugs for COPD, type 1 or 2 diabetes, glaucoma and osteoporosis. For evaluating new drugs, patient-centred outcomes should be chosen whenever possible. If the use of surrogate outcomes is necessary, then a consistent approach is important to review the evidence for surrogacy and consider surrogate's usage in the treatment and population under study.
Determinants of access to chronic illness care: a mixed-methods evaluation of a national multifaceted chronic disease package for Indigenous Australians
Authors: Bailie Jodie , Schierhout Gill , Laycock Alison , Kelaher Margaret , Percival Nikki , O'Donoghue Lynette , McNeair Tracy , Bailie Ross 
Published: November 2015

ObjectivesIndigenous Australians have a disproportionately high burden of chronic illness, and relatively poor access to healthcare. This paper examines how a national multicomponent programme aimed at improving prevention and management of chronic disease among Australian Indigenous people addressed various dimensions of access.DesignData from a place-based, mixed-methods formative evaluation were analysed against a framework that defines supply and demand-side dimensions to access. The evaluation included 24 geographically bounded ‘sentinel sites’ that included a range of primary care service organisations. It drew on administrative data on service utilisation, focus group and interview data on community members’ and service providers’ perceptions of chronic illness care between 2010 and 2013.SettingUrban, regional and remote areas of Australia that have relatively large Indigenous populations.Participants670 community members participated in focus groups; 374 practitioners and representatives of regional primary care support organisations participated in in-depth interviews.ResultsThe programme largely addressed supply-side dimensions of access with less focus or impact on demand-side dimensions. Application of the access framework highlighted the complex inter-relationships between dimensions of access. Key ongoing challenges are achieving population coverage through a national programme, reaching high-need groups and ensuring provision of ongoing care.ConclusionsStrategies to improve access to chronic illness care for this population need to be tailored to local circumstances and address the range of dimensions of access on both the demand and supply sides. These findings highlight the importance of flexibility in national programme guidelines to support locally determined strategies.
The burden of stroke in the Netherlands: estimating quality of life and costs for 1 year poststroke
Authors: van Eeden M , van Heugten C , van Mastrigt G A P G , van Mierlo M , Visser-Meily J M A , Evers S M A A 
Published: November 2015

ObjectivesTo assess and explore over 1 year poststroke (1) the societal costs, (2) changes in costs and quality of life (QoL) and (3) the relation between costs and QoL.DesignThe current study is a burden of disease study focusing on the cost-of-illness (in Euros) and QoL (in utilities) after stroke.SettingAdult patients with stroke were recruited from stroke units in hospitals and followed for 1 year.ParticipantsData were collected from 395 patients with stroke.Main outcome measuresCosts and QoL expressed in utilities.MethodsCost categories were identified through a bottom-up method. The Dutch 3-level 5-dimensional EuroQol (EQ-5D-3L) was used to calculate utilities. Non-parametric bootstrapping was applied to test for statistical differences in costs. Subgroup analyses were performed to identify predictors for costs and QoL. Robustness of results was tested via sensitivity analyses.ResultsThe total societal costs for 1 year poststroke were €29 484 (n=352) of which 74% were in the first 6 months. QoL remained stable over time. The discharge location was a significant predictor for cost and QoL; men had a significantly higher QoL than women and younger patients (<65) had significantly more costs than older patients (>65). Ceiling effects appear on all dimension of the EQ-5D-3L. Costs and QoL show a weak correlation (r=−0.29). Sensitivity analyses showed robustness of results.ConclusionsWe found lower patient costs and higher QoL than expected. This may be explained by the good state of health of our study population and by change in the Dutch healthcare system, which has led to considerable shorter hospitalisation poststroke. Future research must question the use of the EQ-5D-3L in a similar population due to ceiling effects.Trial registration numberNTR3051.
Trends from the surveillance of suicidal behaviour by the Belgian Network of Sentinel General Practices over two decades: a retrospective observational study
Authors: Boffin Nicole , Moreels Sarah , Van Casteren Viviane 
Published: November 2015

ObjectivesFirst, we describe trends in characteristics of suicidal events using new (2011–2012) and previous (1993–1995, 2000–2001 and 2007–2008) data reported by the Belgian Network of Sentinel General Practices (SGP); second, we examine patient age-related trends in on-site attendance of sentinel general practitioners (GPs) as first professional caregivers following suicidal behaviour; third, we investigate the accuracy of suicide incidence estimates derived from the SGP data.DesignRetrospective observational study.SettingGeneral practices from the nationwide representative Belgian Network of SGP.Outcome measuresPatient gender and age, suicide methods, whether the patient was new, whether the GP was the first caregiver on-site, and the outcome of the suicidal behaviour (fatal or not) were recorded on standard registration forms. The accuracy of suicide incidence estimates was tested against suicide mortality data.ResultsOver the four time periods, 1671 suicidal events were reported: 275 suicides, 1287 suicide attempts and 109 events of suicidal behaviour of unknown outcome. In 2011–2012, sentinel GPs’ on-site attendance following the suicidal behaviour of patients <65 years had continued to decrease (from 71% in 1993–1995 to 58% in 2000–2001, 39% in 2007–2008 and 25% in 2011–2012). In 2011–2012, it had also decreased steeply in the population ≥65 years (from 70% in 1993–1995, 76% in 2000–2001 and 79% in 2007–2008 to 35% in 2011–2012). No significant differences were found between the SGP-based suicide incidence estimates for 2011–2012 and the available suicide mortality rates for people <65 and ≥65 years.ConclusionsGPs’ on-site attendance as first professional caregivers following suicidal behaviour continues to decline since 2011–2012 also in the population ≥65 years. Unawareness of patients’ suicidal behaviour endangers both care for surviving patients and the completeness of SGP surveillance data. Yet, the incidence of suicide for 2011–2012 was estimated accurately by the SGP.