Syncope in the Pediatric Patient: A Case Report

The diagnosis and management of a child presenting with acute loss of consciousness accompanied by involuntary motor activity poses a diagnostic challenge to pediatric primary care providers. Syncope accompanied by convulsions is often benign, but rarely it may reflect significant neurologic or cardiac pathologies. Recent studies have reported a rate of misdiagnosed epilepsy varying between 19% and 67%, with syncope being the most common problem misdiagnosed as epilepsy in children (Mariani, Mastrangelo, Iannetti, Papetti, & Ursitti, 2011).

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Watch Me Grow: A Well-Child Examination Protocol to Improve Preventive Care in Dominican Children

Morbidity and mortality rates among Dominican children are a serious health concern worsened by a lack of preventive care that hinders early identification and avoidance of illnesses. The purpose of this study was to improve health outcomes in Dominican children by implementing a well-child examination (WCE) protocol entitled "Watch Me Grow."

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Adolescent Infertility: A Case Report

Reproductive health for teens has primarily focused on preventing or delaying pregnancies (and sexually transmitted infections [STIs]) rather than treating infertility. There continues to be millions of teen pregnancies per year (Martin, Hamilton, Osterman, Curtin, & Mathews, 2015), many intended by females and/or their partners, especially in developing countries where adolescent parenting is commonplace to the cultural norms (Haimov-Kochman, Imbar, Farchat, Bdolah, & Hurwitz, 2008). In the United States, there is evidence in media reports (e.g., the Massachusetts pregnancy pact [Kingsbury, 2008] and the reality TV program Teen Mom) and in the medical literature that some adolescents consider pregnancy desirable.

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Sleep Evaluation in the Assessment of Pediatric Attention Deficit Disorders

Examining the impact of appropriate sleep evaluation on diagnosis of attention deficit disorders can improve the standard of care in pediatrics. This quality improvement project examined current practice and subsequent implementation of a validated standardized sleep evaluation tool in the assessment of children with symptoms of attention deficit.

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The Na+/H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

Key points summary

Exogenous NHE1 expression stimulated collective migration of epithelial cell sheets Stimulation with epidermal growth factor (EGF), a key morphogen, primarily increased migration of the front row of cells, whereas NHE1 increased that of submarginal cell rows, and the two stimuli were additive Accordingly, NHE1 localized not only to the leading edges of leader cells, but also in cryptic lamellipodia in submarginal cell rows NHE1 expression disrupted the morphology of epithelial cell sheets and 3D cysts

Abstract

Collective cell migration plays essential roles in embryonic development, in normal epithelial repair processes, and in many diseases including cancer. The Na⁺/H⁺ Exchanger 1 (NHE1, SLC9A1) is an important regulator of motility in many cells and has been widely studied for its roles in cancer, yet its possible role in collective migration of normal epithelial cells has remained unresolved. Here, we show that NHE1 expression in MDCK‐II kidney epithelial cells accelerated collective cell migration. NHE1 localized to the leading edges of leader cells, as well as to cryptic lamellipodia in submarginal cell rows. Epidermal growth factor (EGF), a kidney morphogen, increased displacement of the front row of collectively migrating cells and reduced the number of migration fingers. NHE1 expression increased number of migration fingers and increased displacement of submarginal cell rows, resulting in additive effects of NHE1 and EGF. Finally, NHE1 expression resulted in disorganized development of MDCK‐II cell cysts. Thus, NHE1 contributes to collective migration and epithelial morphogenesis, suggesting roles for the transporter in embryonic and early postnatal development.

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Sleep disordered breathing in children disrupts the maturation of autonomic control of heart rate and its association with cerebral oxygenation

Key Point Summary

Sleep disordered breathing (SDB) affects 4 ‐ 11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control. The relationship between heart rate variability (HRV; a measure of autonomic control), and age found in non‐snoring control children was absent during sleep in children with SDB. Age significantly predicted increasing cerebral oxygenation during wake in non‐snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation. Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep. SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non‐snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow.

Abstract

Background

The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3‐12 y) with SDB and non‐snoring controls.

Methods

Children (SDB, n = 117; controls, n = 42; 3–12 y) underwent overnight polysomnography. Total (TP), low (LF) and high frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters.

Results

During wake, age had a positive association with LF power reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep.

Conclusion

SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non‐snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes.

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Challenges and advances in atomistic simulations of potassium and sodium Ion channel gating and permeation

Abstract

Ion channels are implicated in many essential physiological events such as electrical signal propagation and cellular communication. The advent of K⁺ and Na⁺ ion channel structure determination has facilitated numerous investigations of molecular determinants of their behavior. At the same time, rapid development of computer hardware and molecular simulation methodologies has made computational studies of large biological molecules in all‐atom representation tractable. The concurrent evolution of experimental structural biology with biomolecular computer modeling has yielded mechanistic details of fundamental processes unavailable through experiments alone, such as ion conduction and ion channel gating. The following is a short survey of the atomistic computational investigations of K⁺ and Na⁺ ion channels, focusing on KcsA and several voltage‐gated channels from the K_V and Na_V families, that have garnered many successes and engendered several long‐standing controversies regarding the nature of their structure‐function relationship. We review the latest advancements and challenges facing the field of molecular modeling and simulation regarding the structural and energetic determinants of ion channel function and their agreement with experimental observations.

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Modularity in the intact and spinal cat: methods, issues and questions for the future

Abstract

The paper of Etienne Desrochers and colleagues in the Frigon lab (Desrochers et al., this volume) is an important contribution. They provide a clear demonstration of a synergy organization in the spinal cord of the cat that is closely similar before and after spinal transection, using the methods of Krouchev and colleagues (2006) of 'Direct Component Analysis' (DCA).

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A new coupling of an acid‐base transporter to PKD and cyst formation

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a devastating disease that affects millions of people, and often leads to renal failure, kidney dialysis, and transplantation (Ghata & Cowley Jr, 2017).

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Induced‐in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness

Key Points Summary

Breast cancer 1, early onset gene codes for the DNA repair enzyme, breast cancer type 1 susceptibility protein (BRCA1). The gene is prone to mutations that cause a loss of protein function. BRCA1/Brca1 has recently been found to regulate several cellular pathways beyond DNA repair and is expressed in skeletal muscle. Skeletal muscle specific knockout of Brca1 in mice caused a loss of muscle quality, identifiable by reductions in muscle force production and mitochondrial respiratory capacity. Loss of muscle quality was associated with a shift in muscle phenotype and an accumulation of mitochondrial DNA (mtDNA) mutations. These results demonstrate that BRCA1 is necessary for skeletal muscle function and that increased mtDNA mutations may represent a potential underlying mechanism.

Abstract

Recent evidence suggests that the breast cancer 1, early onset gene (BRCA1) influences numerous peripheral tissues, including skeletal muscle. The purpose of this study was to determine if induced‐loss of the breast cancer type 1 susceptibility protein (Brca1) alters skeletal muscle function. We induced genetic ablation of exon 11 in the Brca1 gene specifically in skeletal muscle of adult mice to generate skeletal muscle‐specific Brca1 homozygote knockout (Brca1KO^smi) mice. Brca1KO^smi exhibited kyphosis and decreased maximal isometric force in limb muscles when compared to age‐matched wildtype (WT) mice. Brca1KO^smi skeletal muscle shifted toward an oxidative muscle fiber type and, in parallel, increased myofiber size and reduced capillary numbers. Surprisingly, myofiber bundle mitochondrial respiration was reduced while contraction‐induced lactate production was elevated in Brca1KO^smi muscle. Brca1KO^smi mice accumulated mtDNA mutations and exhibited an altered mitochondrial morphology characterized by distorted and enlarged mitochondria, and which were more susceptible to swelling. In summary, skeletal muscle‐specific loss of Brca1 leads to a myopathy and mitochondriopathy characterized by reductions in skeletal muscle quality and a consequent kyphosis. Given the substantial impact of BRCA1 mutations on cancer development risk in humans, a parallel loss of BRCA1 function in patient skeletal muscle cells would potentially result in implications for human health.

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Simulation of P2X‐mediated calcium signaling in microglia

Key Points Summary

• A computational model of P2X channel activation in microglia was developed that includes downfield Ca2+ dependent signaling pathways. • This model provides quantitative insights into how diverse signaling pathways in microglia converge to control microglial function.

Abstract

Microglia function is orchestrated through highly‐coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adeno‐ sine triphosphate (ATP), transient increases in intracellular Ca2+ driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis. While steps comprising the pathways bridging purinergic receptor activation with transcriptional responses have been probed in great detail, a quantitative model for how these steps collectively control cytokine production has not been established. Here we developed a minimal computational model that quantitatively links extracellular stimulation of two prominent ionotropic purinergic receptors, P2 × 4 and P2 × 7, with the graded production of a gene product, namely the tumor necrosis factor α (TNFα) cytokine. In addition to Ca2+ handling mechanisms common to eukaryotic cells, our model includes microglia‐specific processes including ATP‐dependent P2 × 4 and P2 × 7 activation, activation of nuclear factor of activated T‐cells (NFAT) transcription factors, and TNFα production. Parameters for this model were optimized to reproduce published data for these processes, where available. With this model, we determined the propensity for TNFα production in microglia, subject to a wide range of ATP exposure amplitudes, frequencies and durations that the cells could encounter in vivo. Furthermore, we have investigated the extent to which modulation of the signal transduction pathways influence TNFα production. Our results suggest that pulsatile stimulation of P2 × 4 via micromolar ATP may be sufficient to promote TNFα production, whereas high amplitude ATP exposure is necessary for production via P2 × 7. Further, under conditions that increase P2 × 4 expression, for instance the activation by pathogen associated molecular factors, P2 × 4‐associated TNFα production is greatly enhanced. Given that Ca2+ homeostasis in microglia is profoundly important to its function, this computational model provides a quantitative framework to explore hypotheses pertaining to microglial physiology.

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Metabolic remodeling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice

Key points

Hearts from type 2 diabetic animals display perturbations in excitation‐contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β‐adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in presence of palmitate, there is a metabolic remodeling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic re‐direction leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to design novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients.

Abstract

Type‐2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose are central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose rescuing β‐adrenergic‐stimulated cardiac excitation‐contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodeling associated with cardiac function in diabetic db/db mice subjected to stress given by β‐adrenergic stimulation with isoproterenol and high‐glucose compared to their nondiabetic controls (+/+, WT) under euglycemic conditions. When perfused with Palm, T2DM hearts exhibit improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodeling as demonstrated by metabolomics‐fluxomics combined with bioinformatics and computational modeling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids, and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2‐fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β‐oxidation and decreased glucose uptake, leading to flux‐redirection away from redox‐consuming pathways (e.g., polyol) while maintaining the flux through redox‐generating pathways together with glucose‐FA "shared fueling" of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycemia and increased workload.

Sonia Cortassa has a PhD in Chemical Sciences from the Universidad Nacional de Córdoba, Argentina, country where she held research and teaching positions at Universidad Nacional de Tucumán and Consejo Nacional Investigaciones Científicas y Técnicas (CONICET). In the United States of America, she continued her research at the Johns Hopkins University and, at present, at the Laboratory of Cardiovascular Sciences/National Institute on Aging/NIH. Her field of research is Physiology, Bioenergetics, with expertise in Computational modeling of metabolic networks. She believes that quantitative Systems Biology approaches represent a real opportunity to contribute to the understanding of human body function in health and disease.

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Presidential Address 2011: Autonomic modes of control and health

Abstract

Understanding psychosomatic relations, and their implications for heath, is importantly dependent on our conceptual and measurement models. The historical view of reciprocal control of the autonomic branches is applicable in some contexts, but not others. Control of the autonomic branches can vary reciprocally, independently, and even coactively. Assessment of sympathovagal balance, based on a reciprocal model of regulation of the autonomic branches, may have applications in orthostatic contexts and in insulin resistance in diabetes. However, it does not adequately capture the pattern of autonomic control that is relevant for myocardial infarction (MI; in humans) and experimental cardiac arrest (in mice). A measure of sympathovagal balance (cardiac autonomic balance) was predictive and informative of the autonomic contributions to diabetes but was blind to autonomic contributions to cardiac arrest and its sequelae. However, a metric designed to capture the coactivity dimension of cardiac autonomic regulation (CAR) was predictive of MI and its sequelae. Both human and animal model studies revealed that low CAR (low sympathetic and especially low parasympathetic control) predicted the occurrence of MI and the neuroinflammatory consequences of cardiac arrest. These effects were importantly modulated by social support in both humans and animals, via an apparent oxytocinergic pathway that impacts parasympathetic cardiac control and CAR, and thus neuroinflammation. Results indicate the importance of a physiologically meaningful model of autonomic control in understanding health implications of the modes of autonomic control.

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Latency of skin conductance responses across stimulus modalities

Abstract

Reproducibility and methodological robustness are of major concern in research today, also with respect to autonomic measures. Quantification of skin conductance responses (SCRs), for instance, relies on response characteristics such as response onset (i.e., latency), which were established more than four decades ago by using paper‐pencil methods. Since then, data acquisition has advanced to digital methods, improving sampling rates up to 100,000 samples/second and thereby improving resolution and accuracy. Here, SCR latency as a major characteristic for defining an appropriate response window is revisited by using state‐of‐the‐art equipment. Furthermore, SCR latencies are investigated across different stimulus modalities (tactile, auditory, visual) and with respect to their temporal dynamics over the course of a learning experiment (i.e., fear conditioning). The established response latency criteria were largely confirmed even though results did suggest an even narrower and potential stimulus modality‐specific latency criterion. Exploratory analyses investigating individual differences in SCR latencies provided first evidence for a role of sex and cognitive effects (i.e., contingency awareness) while dispositional negativity as well as other personality traits did not affect SCR latencies. Consequently, SCR latencies might have an informative and discriminative value beyond a solely criterial function for defining response windows. The current findings may help to improve the rigor of using SCRs and suggest that SCR latency as a descriptive measure warrants further investigation.

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Motor Unit Number Index (MUNIX) of hand muscles is a disease biomarker for adult spinal muscular atrophy

5q spinal muscular atrophy (SMA) is a monogenetic, autosomal-recessive, lower motoneuron disease caused by deletion or mutation of SMN1 (survival of motoneuron 1) which results in reduced expression of full-length SMN protein. Although no systematic data exist on treatment effects in adult SMA patients, the antisense-oligonucleotide Nusinersen was recently approved by the FDA and EMA as a disease modifying drug for SMA patients, including adults (Mercuri et al., 2018). As only limited data are available on adult SMA and because adult SMA include clinical stages from slightly to severely affected, reliable determination of disease progression, definition of treatment goals and establishment of suitable disease (progression) biomarkers are needed for a comprehensive high quality health care.

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First reported adult patient with TARP syndrome: A case report

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X‐linked syndrome often resulting in pre‐ or post‐natal lethality in affected males. In 2010, RBM10 was identified as the disease‐causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displacement of lacrimal points in the cranial direction, small teeth, and chin dimple, which are the findings that have not previously been associated with TARP syndrome. Our patient was found to carry a hemizygous c.273_283delinsA RBM10 mutation in exon 4, an exon skipped in three of five protein‐coding transcripts, suggesting a possible explanation for our patient surviving to adulthood. Direct sequencing of maternal DNA indicated possible mosaicism, which was confirmed by massive parallel sequencing. One of two sisters were heterozygous for the mutation. Therefore, we recommend sisters of patients with TARP syndrome be carrier tested before family planning regardless of carrier testing results of the mother. Based on our patient and previously reported patients, we suggest TARP syndrome be considered as a possible diagnosis in males with severe or profound intellectual disability combined with septal heart defect, and Robin sequence, micrognathia, or cleft palate.

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Japanese patient with Cole‐carpenter syndrome with compound heterozygous variants of SEC24D

Cole‐Carpenter syndrome is a rare skeletal dysplasia associated with low‐bone mass or an osteogenesis imperfecta (OI)‐like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole‐Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15‐year‐old Japanese boy with short stature of the short‐trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole‐Carpenter syndrome. He had low‐bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole‐Carpenter syndrome type 2.

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Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

We report a 9‐year‐old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio‐based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes.

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Unmasking familial CPX by WES and identification of novel clinical signs

Mutations in the T‐Box transcription factor gene TBX22 are found in X‐linked Cleft Palate with or without Ankyloglossia syndrome (CPX syndrome). In addition to X‐linked inheritance, ankyloglossia, present in the majority of CPX patients, is an important diagnostic marker, but it is frequently missed or unreported, as it is a "minor" feature. Other described anomalies include cleft lip, micro and/or hypodontia, and features of CHARGE syndrome. We conducted whole exome sequencing (WES) on 22 individuals from 17 "a priori" non‐syndromic cleft lip and/or cleft palate (CL/P) families. We filtered the data for heterozygous pathogenic variants within a set of predefined candidate genes. Two canonical splice‐site mutations were found in TBX22. Detailed re‐phenotyping of the two probands and their families unravelled orofacial features previously not associated with the CPX phenotypic spectrum: choanal atresia, Pierre‐Robin sequence, and overgrowths on the posterior edge of the hard palate, on each side of the palatal midline. This study emphasizes the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in "a priori" non‐syndromic clefts.

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A HS6ST2 gene variant associated with X‐linked intellectual disability and severe myopia in two male twins

X‐Linked Intellectual Disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized.

We used Whole Exome Sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G>C (G306R) in the X‐linked Heparan Sulfate 6‐O‐ Sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulphate from adenosine 3'‐phosphate, 5'‐phosphosulphate (PAPS) to the 6^th position of the N‐sulphoglucosamine (GlcNS) residue in Heparan Sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site and its effect was considered "deleterious" by in‐silico tools. An In‐vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here.

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Targeted panel sequencing in adult patients with left ventricular non‐compaction reveals a large genetic heterogeneity

Left ventricular non‐compaction (LVNC) is a cardiomyopathy that may be of genetic origin, however few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias.

Fifty‐two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes.

Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub‐phenotype of cardiomyopathy.

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The magnitude of neuromuscular fatigue is not intensity‐dependent when cycling above critical power but relates to aerobic and anaerobic capacities

New Findings

What is the central question of this study?

Is the magnitude of neuromuscular fatigue dependent upon exercise intensity above critical power (CP) when W′ (the curvature constant of the power‐duration relationship) is depleted?

What is the main finding and its importance?

The magnitude of neuromuscular fatigue is the same following two bouts of supra‐CP cycling (3 vs. 12 min) when controlling for W′ depletion, but is larger for individuals of greater anaerobic capacity following the shorter, and smaller for individuals of greater aerobic capacity following the longer exercise. These findings provide new insight into the mechanisms underpinning exercise above CP.

Abstract

The aim of the present study was to test whether the development of neuromuscular fatigue within the severe intensity domain could be linked to the depletion of the curvature constant (W′) of the power‐duration relationship. Twelve recreationally active men completed tests to determine V̇O_2peak, Critical Power (CP) and W′, followed by two randomly assigned constant‐load supra‐CP trials set to fully deplete W′ in 3 (P‐3) and 12 min (P‐12). Pre‐ to post‐exercise changes in maximal voluntary contraction (MVC), potentiated quadriceps twitch force evoked by single (Q_pot) and paired high‐ (PS100) and low‐frequency (PS10) stimulations and voluntary activation (VA) were determined. Cycling above CP reduced MVC (P‐3: −20 ± 10% vs. P‐12: −15 ± 7%), measures associated with peripheral fatigue (Q_pot: −35 ± 13% vs. −31 ± 14%; PS10: −38 ± 13% vs. −37 ± 17%; PS100: −18 ± 9% vs. −13 ± 8% for P‐3 and P‐12, respectively) and VA (P‐3: −12 ± 3% vs. P‐12: −13 ± 3%) (P < 0.05), with no significant difference between trials (P > 0.05). Changes in MVC and evoked twitch forces were inversely correlated with CP and V̇O_2peak following P‐12, while W′ was significantly correlated with changes in Q_pot and PS10 following P‐3 (P < 0.05). Therefore, the magnitude of neuromuscular fatigue does not depend on exercise intensity when W′ is fully exhausted during severe intensity exercise, yet exploration of inter‐individual variations suggests that mechanisms underpinning exercise tolerance within this domain differ between short‐ vs. long‐duration exercise.

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Evidence of high 18F‐Fluorodeoxyglucose uptake in the subcutaneous adipose tissue of the dorsocervical area in young adults

New Findings

What is the central question of this study?Some studies have performed biopsies of the subcutaneous adipose tissue (SAT) in the abdomen and they failed to find browning markers. Is abdomen the right place to take biopsies?

What is the main finding and its importance?For first time, we observed that the glucose uptake in the SAT is higher in comparison to other SAT parts.

Abstract

Newborns have subcutaneous brown adipose tissue (BAT) in the dorsocervical area, and it is thought that these depots gradually disappear with age. Here, we study that young adults have high 18F‐Flurodeoxyglucose (¹⁸F‐FDG) uptake in the subcutaneous adipose tissue (SAT) of the dorsocervical area. A total of 133 young adults (age 22 ± 2 years; BMI: 25 ± 5 kg/m²) were included in the present study. We performed a shivering threshold test for every participant. Later, we performed 2 hours of personalized cold exposure, just before performing a positron emission tomography/computed tomography scan. We show that 23 out of 133 participants had ¹⁸F‐FDG uptake in the dorsocervical area that achieved the criteria to be considered BAT mainly in women (96%, n = 22 out of 23). In the whole sample, the glucose uptake in the SAT of the dorsocervical area positively correlated with BAT volume and activity located in the supraclavicular area. We showed that the ¹⁸F‐FDG uptake of the SAT of the dorsocervical area in humans is different in comparison to other SAT area. Future studies are warranted to confirm the brown signature of this tissue.

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Plasma asymmetric dimethylarginine concentrations are not related to differences in maximal oxygen uptake in endurance trained and untrained men

New Findings

What is the central question of this study?

Asymmetric dimethylarginine (ADMA) is related to exercise capacity in patients with cardiovascular diseases. However, no studies have investigated whether there are associations of plasma ADMA concentrations with oxygen (O₂) delivery and subsequently exercise capacity in healthy subjects without potentially confounding influence of inflammation and oxidative stress.

What is the main finding and its importance?

Plasma ADMA concentrations are not related to exercise capacity in healthy subjects, while O₂ delivery in the working skeletal muscle during maximal graded‐exercise test is not associated with any of L‐arginine analogs. These findings demonstrate that ADMA alone does not play a crucial role in local muscle perfusion and in maintaining exercise capacity.

Abstract

Purpose

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis that could limit oxygen (O₂) delivery in the working skeletal muscles by altering endothelium‐dependent vasodilation. Exercise capacity is associated with plasma ADMA concentrations in patients with cardiovascular diseases, but this issue has still not been investigated in healthy subjects. We aimed to determine whether plasma ADMA concentrations were negatively associated with exercise capacity in young healthy male subjects.

Methods

Ten men with maximal oxygen uptake (V̇O_2max) > 65 mL kg⁻¹ min⁻¹ were included in the high exercise capacity group (HI‐FIT), and ten men with V̇O_2max < 45 mL·kg⁻¹·min⁻¹ were included in the low exercise capacity group (LO‐FIT). Plasma ADMA and other L‐arginine analogs concentrations were measured before and after a maximal graded‐exercise test by liquid chromatography–tandem mass spectrometry. Microvascular O₂ delivery during exercise was estimated through the pattern from the sigmoid model of muscle deoxygenation in the vastus lateralis measured by near infrared spectroscopy (NIRS).

Results

V̇O_2max was 60% higher in the HI‐FIT group (median: 70.2; IQR: 68.0–71.9) than in the LO‐FIT group (median: 43.8; IQR: 34.8–45.3). Plasma ADMA concentrations did not differ between the LO‐FIT and HI‐FIT groups before (0.50 ± 0.06 vs. 0.54 ± 0.07 μmol·L⁻¹, respectively) and after maximal incremental exercise test (0.49 ± 0.08 vs. 0.55 ± 0.03 μmol·L⁻¹, respectively). There was no significant association of plasma ADMA concentrations with the pattern of local muscle deoxygenation and exercise capacity.

Conclusion

Exercise capacity and microvascular O₂ delivery are not related to plasma ADMA concentrations in young healthy male subjects. Our findings show that ADMA does not play a crucial role in local muscle perfusion and in maintaining exercise capacity without pathological conditions.

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Impairment of rat esophageal muscle contractility associated with experimental non‐erosive esophageal mucosal damage

New Findings

What is the central question of this study?

Is the responsiveness of isolated segments of the rat esophagus to contractile or relaxant stimuli susceptible to acute luminal exposure of the esophagus to an acid solution that contains pepsin and bile salt?

What is the main finding and its importance?

The study reveals that luminal acidity is an important factor that disrupts barrier function in the esophagus to allow the diffusion of noxious agents, such as bile acid, that alter the contractile status of the esophageal body, even in the absence of inflammation.

Abstract

The present study investigated whether the experimental simulation of duodeno‐gastro‐esophageal reflux alters the contractile responsiveness of rat esophageal strips. Following 30 min of luminal exposure to a solution at acid pH that contained pepsin and taurodeoxycholic acid (TDCA), isolated strips of the rat esophagus and gastroesophageal junction were subjected to contractile or relaxing stimuli. Acid challenge decreased the responsiveness of esophagus strips to contractile stimulation, especially in esophageal preparations that were mounted following the circular orientation of the muscularis externa layer. The contractility of longitudinal preparations of the rat esophagus appeared less susceptible to the deleterious effects of acid challenge. In contrast, the responsiveness of ring‐like preparations from the gastroesophageal junction to contractile stimulation was unaltered by acid challenge. TDCA decreased the responsiveness of circular esophageal preparations to KCl, an effect that was exacerbated by luminal acidity. Contrarily, whereas the relaxant ability of the rat esophagus did not change, acid challenge increased the relaxant efficacy of sodium nitroprusside and isoproterenol in strips of the gastroesophageal junction. A significant decrease in transepithelial electrical resistance (TEER) was seen when the esophageal mucosa was challenged at pH 1 but not at pH 4. Treatment with alginate blunted the deleterious effects of acid challenge on TEER and the responsiveness of esophageal preparations to KCl. The present findings support the notion that luminal acidity is an important factor that disrupts barrier function in the esophagus to allow the diffusion of noxious agents, such as bile acid, that alter the contractile status of the esophagus.

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Humans: A homeothermic animal that needs perturbation?

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Smoking during pregnancy increases chemerin expression in neonatal tissue

New Findings

What is the central question of this study?

Is chemerin, an adipokine implicated in obesity, increased in neonates following in utero cigarette smoke exposure.

What is the main finding and its importance?

Chemerin mRNA expression was increased and chemerin DNA methylation was decreased in babies born to mothers who smoked during pregnancy. These data provide a potential mechanism that may be mediating the increased obesity risk in individuals that are born to mothers who smoked during pregnancy.

Abstract

It has been shown that in utero tobacco exposure increases offspring risk for obesity, but the mechanisms responsible for this increased risk are not well understood. Chemerin is an adipokine that regulates adipocyte differentiation. This chemokine is elevated in obese individuals and with smoke exposure, but its levels have not been measured in neonates exposed to cigarette smoke in utero. We examined chemerin gene expression [n = 31 non‐smoker (NS) and 15 smoker (S)] and DNA methylation (n = 28 NS and n = 11 S) in skin collected from babies born to mothers who smoked during pregnancy as compared to non‐smoking controls. Quality RNA and DNA were isolated from foreskin tissue following circumcision, and chemerin gene expression and DNA methylation were assessed. Further, in a second cohort, we utilized primary dermal foreskin fibroblasts as a functional measure of adipogenesis in living cells (n = 11 NS and n = 8 S). Cells were stimulated with an adipogenic cocktail, mRNA was isolated from cells after 14 days, and chemerin gene expression assessed via real‐time PCR. Chemerin mRNA was elevated in both whole tissue (NS: 2409.20 ± 555.28 counts and S: 2966.72 ± 636.84 counts; P < 0.01) and primary fibroblasts (NS: 1.12 ± and S: 2.13 ± ; P = 0.04) collected from infants born to smoking mothers. Chemerin DNA methylation was reduced in whole tissue of offspring born to smokers (NS: 4.18 ± 1.28 and S: 3.07 ± 1.31%; P = 0.02), which may contribute to the increased gene expression. Neonates born to mothers who smoke during pregnancy exhibit distinct changes in chemerin gene expression in response to in utero tobacco smoke exposure which are regulated in part by epigenetic alterations.

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Effect of increased inspiratory muscle work on blood flow to inactive and active limbs during submaximal dynamic exercise

New Findings

What is the central question of this study?

Increased respiratory muscle activation is associated with neural and cardiovascular consequences via the respiratory muscle metaboreflex. Does increased sympathetic vasoconstriction originating from the respiratory musculature elicit a reduction in blood flow to an inactive limb in order to maintain blood flow to an active limb?

What is the main finding and its importance?

Arm blood flow was reduced while leg blood flow was preserved during mild leg exercise with inspiratory resistance. Blood flow to the active limb is maintained via sympathetic control of blood flow redistribution when the respiratory muscle‐induced metaboreflex is activated.

Abstract

The purpose of this study was to elucidate the effect of increasing inspiratory muscle work on blood flow to inactive and active limbs. Healthy young men (n = 10, 20 ± 2 yrs) performed two bilateral dynamic knee‐extension and –flexion exercise tests at 40% peak oxygen uptake for 10 min. The trials consisted of spontaneous breathing for 5 min followed by voluntary hyperventilation either with or without inspiratory resistance for 5 min (40% of maximal inspiratory mouth pressure, inspiratory duty cycle of 50% and a breathing frequency of 40 breaths/min). Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. Blood flow to the brachial artery (inactive limb) and in femoral artery (active limb) were monitored using Doppler ultrasound. MAP during exercise was higher (P < 0.05) with inspiratory resistance (121 ± 7 mmHg) than without resistance (99 ± 5 mmHg). Brachial artery blood flow increased during exercise without inspiratory resistance (120 ± 31 ml/min) as compared with resting level, while it attenuated with inspiratory resistance (65 ± 43 ml/min). Femoral artery blood flow increased at the onset of exercise and was maintained throughout exercise without inspiratory resistance (2576 ± 640 ml/min) and was unchanged when inspiratory resistance was added (2634 ± 659 ml/min) (P > 0.05). These results suggest that sympathetic control of blood redistribution to active limbs is facilitated, in part, by respiratory muscle‐induced metaboreflex.

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Effects of intermittent hyperbaric exposure on endurance and interval exercise performance in well‐trained mice

New Findings

What is the central question of this study?

Intermittent hyperbaric exposure (1.3 ATA with 20.9% O₂) has been shown to facilitate endurance capacity by facilitating oxidative and glycolytic capacities in skeletal muscle. It currently remains unclear whether this strategy enhances endurance performance in well‐trained individuals.

What is the main finding and its importance?

Hyperbaric exposure (1.3 ATA with 20.9% O₂) with endurance training enhanced oxidative and glycolytic capacities and protein levels of mitochondrial transcription factor A, dynamin‐related protein‐1, and heat shock protein 70. Hyperbaric exposure with sprint interval training increased the proportion of type I muscle fibres and promoted capillary growth and muscle fibre hypertrophy. These results may lead to a new strategy for enhancing exercise capacity in well‐trained mice.

Abstract

The present study was designed to clarify the mechanisms by which hyperbaric exposure (1.3 atmospheres absolute with 20.9% O₂) improves endurance and interval exercise capacities in highly‐trained mice. Male mice in the training group were housed in a cage with a wheel activity device for 7 weeks from 5 weeks old. Voluntary running markedly increased maximal endurance capacity by 6.4‐fold. Trained mice were then subjected to either endurance treadmill training (20–32.5 m min⁻¹) or sprint interval training (5 sec‐run/10 sec‐rest, 30–42.5 m min⁻¹) with (HypET or HypSIT, respectively) and without (ET or SIT, respectively) 1‐h hyperbaric exposure for 4 weeks. Maximal endurance capacity was significantly increased by HypET and HypSIT, while maximal interval capacity was significantly enhanced by HypSIT. Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha expression levels were markedly increased after HypET and HypSIT. Activity levels of 3‐hydroxyacyl‐CoA‐dehydrogenase, citrate synthase, and phosphofructokinase in the red gastrocnemius muscle were increased more by HypET than by ET. Protein levels of mitochondrial transcription factor A, dynamin‐related protein‐1, and heat shock protein 70 increased more by HypET than by ET. The proportion of type I fibres in the soleus muscle was remarkably increased by HypSIT. Capillary‐to‐fibre ratio values in the white gastrocnemius were increased more by HypSIT than by SIT. These results suggest that hyperbaric exposure has beneficial effects for endurance and interval training to improve exercise capacity in highly‐trained mice.

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Evidence for protein kinase involvement in the 5‐HT‐ [Ca2+]i ‐ pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

New Findings

What is the central question of this study?

The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O₂ and CO₂/H⁺ homeostasis. Recent studies suggest that 5‐HT, released from CB receptor cells, can stimulate adjacent glial‐like type II cells, leading to a rise in intracellular Ca²⁺ ([ΔCa²⁺_i]) and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. The aim of this study was to elucidate the role of protein kinases in the 5‐HT‐[Ca²⁺]_i‐Panx‐1 signalling pathway.

What is the main finding and its importance?

Src family kinase (SKF) and PKA, acting downstream from [ΔCa²⁺_i], played central roles in 5‐HT‐mediated Panx‐1 channel activation. This provides new insight into mechanisms regulating CB excitation, especially in pathophysiological conditions.

Abstract

Chemoreceptor (type I) cells of the rodent carotid body (CB) synthesize and release several neurotransmitters/neuromodulators including 5‐hydroxytryptamine (5‐HT), implicated in enhanced CB excitation following exposure to chronic intermittent hypoxia, e.g. sleep apnea. However, recent studies suggest that 5‐HT can robustly stimulate adjacent glial‐like type II cells via ketanserin‐sensitive 5‐HT2 receptors, leading to intracellular Ca²⁺ elevation [ΔCa²⁺_i] and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. Using dissociated rat CB cultures, we investigated the role of protein kinases in the intracellular signalling pathways in type II cells. In isolated type II cells, 5‐HT activated a Panx‐1‐like inward current (I_5‐HT) that was reversibly inhibited by the Src family kinase (SFK) inhibitor PP2 (1 μM), but not by its inactive analog PP3 (1 μM). Moreover, I_5‐HT was reversibly inhibited (> 90%) by H‐89 (1 μM), a PKA blocker, whereas the PKC blocker GF109203X (2 μM) was largely ineffective. By contrast, the P2Y2R agonist UTP (100 μM) activated Panx‐1‐like currents that were reversibly inhibited (∼60%) by either H‐89 or GF109203X. Using fura‐2 spectrofluorimetry, the 5‐HT‐induced [ΔCa²⁺_i] was unaffected by PP2, H‐89, and GF109293X, suggesting the kinases acted downstream of the Ca²⁺ rise. Because intracellular Ca²⁺ chelation was previously shown to block receptor‐mediated, Panx‐1 current activation in type II cells, these data suggest that CB neuromodulators use overlapping, but not necessarily identical, signalling pathways to activate Panx‐1 channels and release of ATP, a CB excitatory neurotransmitter. In conclusion, these studies provide new mechanistic insight into 5‐HT signalling in the CB that has pathophysiological relevance.

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The Molecular Origins and Pathophysiological Consequences of Micronuclei: New Insights into an Age-old Problem

Publication date: Available online 23 November 2018

Source: Mutation Research/Reviews in Mutation Research

Author(s): Xihan Guo, Juan Ni, Ziqing Liang, Jinglun Xue, Michael F. Fenech, Xu Wang

ABSTRACT

Micronuclei (MN), the small nucleus-like bodies separated from the primary nucleus, can exist in cells with numerical and/or structural chromosomal aberrations in apparently normal tissues and more so in tumors in humans. While MN have been observed for over 100 years, they were merely and constantly considered as passive indicators of chromosome instability (CIN) for a long time. Relatively little is known about the molecular origins and biological consequences of MN. Rapid technological advances are helping to close these gaps. Very recent studies provide exciting evidence that MN act as key platforms for chromothripsis and innate immune response, suggesting that MN could affect cellular functions by both genetic and nongenetic means. These previously unappreciated findings have reawakened widespread interests in MN. In this review, the diverse mechanisms leading to MN generation and the complex fate profiles of MN are discussed, together with the evidence for their contribution to CIN, inflammation, senescence and cell death. Moreover, we put this knowledge together into a speculative perspective on how MN may be responsible for cancer development and how their presence may influence the choice of treatment. We suggest that the heterogenous responses to MN may function physiological to ensure the arrestment, elimination and immune clearance of damaged cells, but pathologically, may enable the survival and oncogenic transformation of cells bearing CIN. These insights not only underscore the complexity of MN biology, but also raise a host of new questions and provide fertile ground for future research.

Graphical abstract

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Methimazole-induced acute pancreatitis: a case report

Abstract

A 76-year-old Japanese woman was diagnosed with Graves' disease and was administered methimazole (MMI) 10 mg and potassium iodide 50 mg. After 19 days of the drug regime, she developed high-grade fever and nausea and was admitted to our hospital. Blood test results showed elevated pancreatic enzymes and C-reactive protein levels. Abdominal computed tomography showed swollen pancreas, and she was diagnosed with acute pancreatitis. These abnormalities improved after discontinuation of MMI. Five similar cases have been reported, but this is the first case report without abdominal pain. When acute pancreatitis is observed after the initiation of MMI, drug-induced pancreatitis should be considered as the possible etiology.

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Positive verbal feedback about task performance is related with adaptive physiological responses: An experimental study of the effort-reward imbalance stress model

Publication date: Available online 23 November 2018

Source: International Journal of Psychophysiology

Author(s): Richard P. Brooks, Monica T. Jones, Matthew W. Hale, Thorsten Lunau, Nico Dragano, Bradley J. Wright

Abstract

Effort-reward imbalance in the workplace has been related with poor mental and physical health and a variety of negative organisational outcomes including increased rates of absenteeism, presentism, and job turnover, but the model has rarely been assessed using experimental designs. Female participants (N = 90) were randomly assigned to positive verbal feedback and no verbal feedback conditions. Within a simulated office environment, all participants were under time-pressure to successfully complete computer-based tasks in order to gain remuneration. Positive verbal feedback about task performance was provided to improve the aspect of 'esteem reward' (while keeping effort constant) using a mixed within-between subjects design. Psychological, behavioural (task performance), and physiological (heart rate variability, salivary alpha amylase) measures assessed the impact of the positive verbal feedback. Participants receiving the esteem manipulation did not self-report increased rewards, but performed moderately better on the task, and had more adaptive physiological reactivity in the high reward versus the standard condition. Similar to recent research our findings highlight the importance of concurrent assessments of both self-reports and physiological measures of stress, and suggest that positive verbal feedback about work performance can elicit adaptive physiological responses and may also positively influence task efficacy.

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Alpha particle autoradiography for high spatial resolution mapping of radionuclides

Publication date: February 2019

Source: Journal of Environmental Radioactivity, Volume 197

Author(s): Christopher A.G. Kalnins, Nigel A. Spooner, Michael J.P. Clarke, David Ottaway

Abstract

An autoradiographic technique capable of determining the spatial location of radioactive isotopes within materials on the scale of micrometers is demonstrated in low-activity mineral samples, where the concentrations of radionuclides with short half lives is small and below the detection limits of current measurement techniques. The location of certain radionuclide species within samples with complex structures on the micron scale can yield valuable information, however current methods do not have the spatial resolution required for this purpose.

We demonstrate the use of an autoradiographic emulsion to directly image alpha particle events in samples with low radionuclide concentrations, allowing spatial resolution of radionuclide locations on the order of several microns. Exposure over a long time period allows sufficient integration of decay events enabling analysis of samples with low activity but large area, (less than 1×10−4 Bq/mm²). The use of polarising filters to increase contrast between the alpha particle tracks and the substrate during imaging demonstrates the viability of the technique on samples with a complex structure.

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Efficiency of the TOF-Cuff™ for the evaluation of rocuronium-induced neuromuscular block and its reversal with sugammadex: a comparative study vs. acceleromyography

Abstract

Purpose

The aim of this study was to compare TOF-Cuff™ (TOF-C) and TOF-Watch™ (TOF-W) data following rocuronium-induced neuromuscular block and its reversal with sugammadex.

Methods

Twenty elderly patients aged 68–82 years scheduled for surgery under general anesthesia were enrolled in this study. After induction of anesthesia, neuromuscular block resulting from administration of 0.6 mg/kg rocuronium was concurrently evaluated using TOF-C and TOF-W. The onset of neuromuscular block and duration until the first twitch response following post-tetanic count (PTC) and 2 Hz train-of-four (TOF) stimulation reappeared were evaluated. When the response to the TOF stimulus was detected with both monitors, additional doses of rocuronium were administered to maintain the neuromuscular block. After surgery, 2 mg/kg sugammadex was administered when 1–2 TOF twitches were observed with the TOF-W and the time required for facilitated recovery to a TOF ratio of > 0.9 was assessed.

Results

Regression analyses revealed no statistically significant differences in the mean [SD] onset of rocuronium-induced neuromuscular block [127.8 (27.2) s, 123.5 (30.5) s], time to recovery of the first PTC twitch [23.9 (8.0) min, 25.4 (8.6) min], time to recovery of the first twitch with TOF stimulation [37.2 (8.8) min, 38.9 (11.1) min] and time to adequate reversal with sugammadex [139.2 (30.6) s, 151.8 (31.5) s] between TOF-C and TOF-W, respectively. Bland–Altman analyses also showed acceptable ranges of the biases and limits of agreement between the two methods.

Conclusions

TOF-C may be clinically applicable for the evaluation of both the depth of neuromuscular block and restoration of neuromuscular function.

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