bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discontinued stimulation of cardiomyocytes provides protection against hypothermia–rewarming‐induced disruption of excitation–contraction coupling
Authors: Han Young Soo , Schaible Niccole , Tveita Torkjel , Sieck Gary 
Published: March 2018

New Findings
What is the central question of this study?
Will discontinued stimulation of isolated cardiomyocytes (asystole) during hypothermia mitigate hypothermia–rewarming‐induced cytosolic Ca2+ overload?

What is the main finding and its importance?
Mimicking asystole or hypothermic cardiac arrest by discontinued stimulation of cardiomyocytes during hypothermia resulted in normal contractile function after rewarming. This result suggests that asystole during severe hypothermia provides protection from hypothermia–rewarming‐induced contractile dysfunction in cardiomyocytes.

AbstractAfter exposure of spontaneously beating hearts or electrically stimulated isolated cardiomyocytes to hypothermia–rewarming (H/R), cardiac dysfunction or alteration in excitation–contraction coupling, respectively, is a consequence. In contrast, hypothermic cardiac arrest, as routinely applied during cardiac surgery, will not impose any hazard to cardiac function after rewarming. We hypothesize that by maintaining asystole during H/R, cardiomyocytes will avoid Ca2+ overload attributable to the transient stimulation‐evoked elevation of [Ca2+]i and thus, H/R‐induced elevation of phosphorylated cardiac troponin I and reduced Ca2+ sensitivity after rewarming. To test this hypothesis, the aim of the study was to determine whether discontinued electrical stimulation (to imitate hypothermic cardiac arrest) versus stimulation during 3 h of H/R prevents disruption of excitation–contraction coupling in our established cardiomyocyte H/R model. Cytosolic Ca2+ and the contractile response (sarcomere length shortening) were measured using an IonOptix system, and the dynamic assessment of Ca2+ sensitivity of contraction was conducted using a phase‐loop plot. Cardiomyocytes were divided into three groups. Group 1 (time‐matched control) was continuously stimulated at 0.5 Hz for 3 h at 35°C. Group 2 was continuously stimulated during H/R at 0.5 Hz, whereas in group 3 stimulation was discontinued during H/R and thus the cells remained quiescent until the resumption of stimulation after rewarming. The results demonstrate that discontinued stimulation of cardiomyocytes during H/R, imitating hypothermic cardiac arrest during cardiac surgery, provides protection against H/R‐induced disruption of excitation–contraction coupling. We suggest that protective effects are caused by preventing the protein kinase A‐induced elevation of phosphorylated cardiac troponin I, which is a key mechanism to reduce myofilament Ca2+ sensitivity of contraction.
Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity
Authors: Hart Corey R. , Layec Gwenael , Trinity Joel D. , Kwon Oh Sung , Zhao Jia , Reese Van R. , Gifford Jayson R. , Richardson Russell S. 
Published: March 2018

New Findings
What is the central question of this study?
What is the degree to which skeletal muscle mitochondria‐derived reactive oxygen species (ROS) production is linked to impaired skeletal muscle function in patients with early‐stage peripheral arterial disease (PAD) and what is the impact on mitochondrial respiratory capacity?

What is the main finding and its importance?
This is the first study to document increased mitochondria‐derived reactive oxygen species production associated with elevated intramuscular oxidative stress, despite preserved mitochondrial respiratory function, in patients with PAD. Furthermore, systemic inflammation, mitochondria‐derived ROS production and skeletal muscle oxidative stress were strongly correlated to disease severity, as indicated by ankle‐brachial index, in patients with PAD.

AbstractSkeletal muscle mitochondrial dysfunction, which is not fully explained by disease‐related arterial occlusion, has been implicated in the pathophysiology of peripheral arterial disease (PAD). Therefore, this study comprehensively assessed mitochondrial respiratory function in biopsies from the gastrocnemius of 10 patients with PAD (Fontaine Stage II) and 12 healthy controls (HC). Intramuscular and systemic inflammation, mitochondria‐derived reactive oxygen species (ROS) production, and oxidative stress were also assessed to better understand the mechanisms responsible for the proposed PAD‐induced mitochondrial dysfunction. Interestingly, mitochondrial respiratory capacity, assessed as complex I (CI) and complex II (CII)‐driven State 3 respiration, measured separately and in combination (State 3 CI+II), revealed no difference between the patients with PAD and the HC. However, mitochondria‐derived ROS production was significantly elevated in PAD (HC: 1.0 ± 0.9; PAD: 4.3 ± 1.0 AU (mg tissue)−1). Furthermore, patients with PAD exhibited significantly greater concentrations of the pro‐inflammatory markers tumour necrosis factor α in plasma (HC: 0.9 ± 0.4; PAD: 2.0 ± 0.3 pg ml−1) and interleukin 6 in both plasma (HC: 2.3 ± 0.4; PAD: 4.3 ± 0.5 pg ml−1) and muscle (∼75% greater). Intramuscular oxidative stress, assessed by protein carbonyls and 4‐hydroxynonenal, was significantly greater in PAD compared to HC. Ankle brachial index was significantly correlated with intramuscular inflammation, oxidative stress and mitochondria‐derived ROS production. Thus, elevated intramuscular inflammation, oxidative stress and mitochondria‐derived ROS production are likely to contribute to the pathophysiology of the skeletal muscle dysfunction associated with PAD, even in the presence of preserved mitochondrial respiratory function in this population.
Nerve growth factor‐dependent hyperexcitability of capsaicin‐sensitive bladder afferent neurones in mice with spinal cord injury
Authors: Shimizu Takahiro , Majima Tsuyoshi , Suzuki Takahisa , Shimizu Nobutaka , Wada Naoki , Kadekawa Katsumi , Takai Shun , Takaoka Eiichiro , Kwon Joonbeom , Kanai Anthony J. , de Groat William C. , Tyagi Pradeep , Saito Motoaki , Yoshimura Naoki 
Published: March 2018

New Findings
What is the central question of this study?
Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin‐sensitive C‐fibre bladder afferent pathways after spinal cord injury (SCI)?

What is the main finding and its importance?
Neutralization of NGF by anti‐NGF antibody treatment reversed the SCI‐induced increase in the number of action potentials and the reduction in spike thresholds and A‐type K+ current density in mouse capsaicin‐sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin‐sensitive C‐fibre bladder afferent neurones attributable to the reduction in A‐type K+ channel activity in SCI.
AbstractNerve growth factor (NGF) has been implicated as an important mediator in the induction of C‐fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti‐NGF antibody (NGF‐Ab) normalizes the SCI‐induced changes in electrophysiological properties of capsaicin‐sensitive C‐fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF‐Ab (10 μg kg−1 h−1, s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast‐Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6–S1 dorsal root ganglion neurones were prepared. Whole‐cell patch‐clamp recordings were then performed in FB‐labelled neurones. After recording action potentials or voltage‐gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin‐sensitive FB‐labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI‐induced changes were reversed by NGF‐Ab. Densities of slow‐decaying A‐type K+ (KA) and sustained delayed rectifier‐type K+ currents were significantly reduced by SCI. The NGF‐Ab treatment reversed the SCI‐induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin‐sensitive C‐fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF‐targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.
The peripheral chemoreflex: indefatigable guardian of fetal physiological adaptation to labour
Authors: Lear Christopher A. , Wassink Guido , Westgate Jenny A. , Nijhuis Jan G. , Ugwumadu Austin , Galinsky Robert , Bennet Laura , Gunn Alistair J. 
Published: March 2018

AbstractThe fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic–ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5–2 min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour.
image
History‐dependence of muscle slack length following contraction and stretch in the human vastus lateralis
Authors: Stubbs Peter W. , Walsh Lee D. , D'Souza Arkiev , Héroux Martin E. , Bolsterlee Bart , Gandevia Simon C. , Herbert Robert D. 
Published: March 2018

Key points
In reduced muscle preparations, the slack length and passive stiffness of muscle fibres have been shown to be influenced by previous muscle contraction or stretch. In human muscles, such behaviours have been inferred from measures of muscle force, joint stiffness and reflex magnitudes and latencies.
Using ultrasound imaging, we directly observed that isometric contraction of the vastus lateralis muscle at short lengths reduces the slack lengths of the muscle–tendon unit and muscle fascicles. The effect is apparent 60 s after the contraction.
These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles.
AbstractIn reduced muscle preparations, stretch and muscle contraction change the properties of relaxed muscle fibres. In humans, effects of stretch and contraction on properties of relaxed muscles have been inferred from measurements of time taken to develop force, joint stiffness and reflex latencies. The current study used ultrasound imaging to directly observe the effects of stretch and contraction on muscle–tendon slack length and fascicle slack length of the human vastus lateralis muscle in vivo. The muscle was conditioned by (a) strong isometric contractions at long muscle–tendon lengths, (b) strong isometric contractions at short muscle–tendon lengths, (c) weak isometric contractions at long muscle–tendon lengths and (d) slow stretches. One minute after conditioning, ultrasound images were acquired from the relaxed muscle as it was slowly lengthened through its physiological range. The ultrasound image sequences were used to identify muscle–tendon slack angles and fascicle slack lengths. Contraction at short muscle–tendon lengths caused a mean 13.5 degree (95% CI 11.8–15.0 degree) shift in the muscle–tendon slack angle towards shorter muscle–tendon lengths, and a mean 5 mm (95% CI 2–8 mm) reduction in fascicle slack length, compared to the other conditions. A supplementary experiment showed the effect could be demonstrated if the muscle was conditioned by contraction at short lengths but not if the relaxed muscle was held at short lengths, confirming the role of muscle contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles.
Uteroplacental insufficiency temporally exacerbates salt‐induced hypertension associated with a reduced natriuretic response in male rat offspring
Authors: Gallo Linda A. , Walton Sarah L. , Mazzuca Marc Q. , Tare Marianne , Parkington Helena C. , Wlodek Mary E. , Moritz Karen M. 
Published: March 2018

Key points
Low weight at birth increases the risk of developing chronic diseases in adulthood
A diet that is high in salt is known to elevate blood pressure, which is a major risk factor for cardiovascular and kidney diseases
The present study demonstrates that growth restricted male rats have a heightened sensitivity to high dietary salt, in the context of raised systolic blood pressure, reduced urinary sodium excretion and stiffer mesenteric resistance vessels
Other salt‐induced effects, such as kidney hyperfiltration, albuminuria and glomerular damage, were not exacerbated by being born small
The present study demonstrates that male offspring born small have an increased cardiovascular susceptibility to high dietary salt, such that that minimizing salt intake is probably of particular benefit to this at‐risk population
AbstractIntrauterine growth restriction increases the risk of developing chronic diseases in adulthood. Lifestyle factors, such as poor dietary choices, may elevate this risk. We determined whether being born small increases the sensitivity to a dietary salt challenge, in the context of hypertension, kidney disease and arterial stiffness. Bilateral uterine vessel ligation or sham surgery (offspring termed Restricted and Control, respectively) was performed on 18‐day pregnant Wistar Kyoto rats. Male offspring were allocated to receive a diet high in salt (8% sodium chloride) or remain on standard rat chow (0.52% sodium chloride) from 20 to 26 weeks of age for 6 weeks. Systolic blood pressure (tail‐cuff), renal function (24 h urine excretions) and vascular stiffness (pressure myography) were assessed. Restricted males were born 15% lighter than Controls and remained smaller throughout the study. Salt‐induced hypertension was exacerbated in Restricted offspring, reaching a peak systolic pressure of ∼175 mmHg earlier than normal weight counterparts. The natriuretic response to high dietary salt in Restricted animals was less than in Controls and may explain the early rise in arterial pressure. Growth restricted males allocated to a high salt diet also had increased passive arterial stiffness of mesenteric resistance arteries. Other aspects of renal function, including salt‐induced hyperfiltration, albuminuria and glomerular damage, were not exacerbated by uteroplacental insufficiency. The present study demonstrates that male offspring exposed to uteroplacental insufficiency and born small have an increased sensitivity to salt‐induced hypertension and arterial remodelling.
Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart
Authors: Darby Jack R. T. , McMillen I. Caroline , Morrison Janna L. 
Published: March 2018

Key points
This study investigates the impact of decreased fetal plasma glucose concentrations on the developing heart in late gestation, by subjecting pregnant ewes to a 50% global nutrient restriction.
Late gestation undernutrition (LGUN) decreased fetal plasma glucose concentrations whilst maintaining a normoxemic blood gas status.
LGUN increased the mRNA expression of IGF2 and IGF2R. Fetal plasma glucose concentrations, but not fetal blood pressure, were significantly correlated with IGF2 expression and the activation of CAMKII in the fetal right ventricle.
LGUN increased interstitial collagen deposition and altered the protein abundance of phospho‐PLB and phospho‐troponin I, regulators of cardiac contractility and relaxation.
This study shows that a decrease in fetal plasma glucose concentrations may play a role in the development of detrimental changes in the right ventricle in early life, highlighting CAMKII as a potential target for the development of intervention strategies.
AbstractExposure of the fetus to a range of environmental stressors, including maternal undernutrition, is associated with an increased risk of death from cardiovascular disease in adult life. This study aimed to determine the effect of maternal nutrient restriction in late gestation on the molecular mechanisms that regulate cardiac growth and development of the fetal heart. Maternal undernutrition resulted in a decrease in fetal glucose concentrations across late gestation, whilst fetal arterial remained unchanged between the control and late gestation undernutrition (LGUN) groups. There was evidence of an up‐regulation of IGF2/IGF2R signalling through the CAMKII pathway in the fetal right ventricle in the LGUN group, suggesting an increase in hypertrophic signalling. LGUN also resulted in an increased mRNA expression of COL1A, TIMP1 and TIMP3 in the right ventricle of the fetal heart. In addition, there was an inverse relationship between fetal glucose concentrations and COL1A expression. The presence of interstitial fibrosis in the heart of the LGUN group was confirmed through the quantification of picrosirius red‐stained sections of the right ventricle. We have therefore shown that maternal undernutrition in late gestation may drive the onset of myocardial remodelling in the fetal right ventricle and thus has negative implications for right ventricle function and cardiac health in later life.
Predictability of formulae for intraocular lens power calculation according to the age of implantation in paediatric cataract
Authors: Lee Byung Joo , Lee Sang-Mok , Kim Jeong Hun , Yu Young Suk 
Published: March 2018

AimsTo analyse the predictability of diverse intraocular lens (IOL) power calculation formulae in paediatric patients with congenital cataract.MethodsThe medical records of patients who underwent cataract surgery and posterior chamber IOL implantation (in-the-bag) for congenital cataract before 17 years of age were reviewed retrospectively. Target refractions calculated by Sanders-Retzlaff-Kraff (SRK)/II, SRK/T and Hoffer-Q formulae were compared with the actual refraction. Patients were subgroup according to the age at IOL implantation (age group 0–24 months, 25–60 months, 61–120 months, 121–203 months), and we compared mean prediction error (PE) and mean absolute error (AE) for each formula. Corrected AE was obtained by linear regression analysis.ResultsTotally 481 eyes were included in the final analysis. Both SRK/II and SRK/T yielded the lowest mean AE in the age group 0–24 months and SRK/II yielded the lowest mean AE in the age group 25–60 months. For every formula, the mean PE was positive during the first five years of age, which converged to zero according to age as IOL implantation increases. The tendency for immediate postoperative overcorrection in younger patients (<6 years) could be improved by corrected formulae based on the linear regression equation.ConclusionsPatients with congenital cataract who underwent IOL implantation within 5 years of age showed higher AE than the older ones did. Among the three formulae evaluated, SRK/II consistently provided the best predictive result in these patients. For patients aged >10 years, all three formulae showed favourable predictive abilities.
Evolution of epilepsy prevalence and incidence in a Tanzanian area endemic for onchocerciasis and the potential impact of community-directed treatment with ivermectin: a cross-sectional study and comparison over 28 years
Authors: Greter Helena , Mmbando Bruno , Makunde Williams , Mnacho Mohamed , Matuja William , Kakorozya Advocatus , Suykerbuyk Patrick , Colebunders Robert 
Published: March 2018

IntroductionWorldwide, there are an estimated 50 million people affected by epilepsy. Its aetiology is manifold, and parasitic infections play an important role, specifically onchocerciasis. In onchocerciasis endemic areas, a distinctive form of epilepsy has been described as nodding syndrome, affecting children and causing nodding seizures, mental retardation and debilitating physical development. Onchocerciasis control programmes using community-directed treatment with ivermectin (CDTI) are implemented in endemic countries. This study is designed to contribute to a better understanding of the linkage between the onset of epilepsy, onchocerciasis and CDTI. Comparing the epidemiological data on epilepsy and onchocerciasis from pre-CDTI and 20 years after its introduction will allow identifying a potential impact of ivermectin on the onset of epilepsy.Methods and analysisThe study will be conducted in the Mahenge highlands in Tanzania. Study site selection is based on an in-depth study on epilepsy in that area dating from 1989. CDTI was introduced in 1997. By a door-to-door approach, the population will be screened for epilepsy using a validated questionnaire. Suspected cases will be invited for a neurological examination for case verification. Onchocerciasis prevalence will be assessed by a rapid epidemiological assessment. As an indicator for ongoing transmission, children younger than 10 years of age will be tested for Ov16 antibodies. Ivermectin use will be assessed at household level. Epilepsy data will be analysed in comparison with the 1989 data to reveal pre-CDTI and post-CDTI prevalence and incidence.Ethics and disseminationThe protocol has received ethical approval from the ethics committees of the University of Antwerp, Belgium, and of the National Institut of Medical Research, Dar es Salaam, Tanzania. The findings will be published in peer-reviewed journals, and presented to the health authorities in Tanzania, at national, regional and village level.