The Journal of Physiology最新文献

{"title":"The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accumulation and protein kinase C activity in male rat liver.","authors":"Shailee Jani,&nbsp;Daniel Da Eira,&nbsp;Mateja Stefanovic,&nbsp;Rolando B Ceddia","doi":"10.1113/JP283552","DOIUrl":"https://doi.org/10.1113/JP283552","url":null,"abstract":"<p><p>Obesity-associated insulin resistance plays a major role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramide content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched diet (HFS) or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C-ε activity, but markedly increased liver ceramide content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4 and Il6), and shifted substrate away from de novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. KEY POINTS: The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and non-alcoholic fatty liver disease (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver. The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver. The KD also promoted the production of beneficial very long-chain ceramides instead of potentially harmful long-chain ceramides. Through multiple mechanisms, the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4137-4151"},"PeriodicalIF":5.5,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40619111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variation in HIF-2α attenuates ventilatory sensitivity and carotid body growth in chronic hypoxia in high-altitude deer mice.","authors":"Catherine M Ivy,&nbsp;Jonathan P Velotta,&nbsp;Zachary A Cheviron,&nbsp;Graham R Scott","doi":"10.1113/JP282798","DOIUrl":"https://doi.org/10.1113/JP282798","url":null,"abstract":"<p><p>The gene encoding HIF-2α, Epas1, has experienced a history of natural selection in many high-altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high-altitude variant of Epas1 in North American deer mice (Peromyscus maniculatus) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high- and low-altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of Epas1 alleles (Epas1^H and Epas1^L , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4 weeks at 12 kPa O₂ ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O₂ saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high-altitude Epas1 allele (Epas1^H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1^L/L mice in chronic hypoxia, was not observed in Epas1^H/H mice. Epas1 genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF-2α in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in Epas1 is responsible for evolved changes in the control of breathing and metabolism in high-altitude deer mice. KEY POINTS: High-altitude natives of many species have experienced natural selection on the gene encoding HIF-2α, Epas1, including high-altitude populations of deer mice. HIF-2α regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in Epas1 in high-altitude natives may underlie evolved changes in control of breathing. Deer mice from controlled crosses between high- and low-altitude populations were used to examine the effects of Epas1 genotype on an admixed genomic background. The high-altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology. The results help us better understand the genetic basis for the unique physiological phenotype of high-altitude natives.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4207-4225"},"PeriodicalIF":5.5,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40478565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exertional dyspnoea in patients with mild-to-severe chronic obstructive pulmonary disease: neuromechanical mechanisms.","authors":"Matthew D James,&nbsp;Devin B Phillips,&nbsp;Sandra G Vincent,&nbsp;Sara J Abdallah,&nbsp;Adamo A Donovan,&nbsp;Juan P de-Torres,&nbsp;J Alberto Neder,&nbsp;Benjamin M Smith,&nbsp;Dennis Jensen,&nbsp;Denis E O'Donnell","doi":"10.1113/JP283252","DOIUrl":"https://doi.org/10.1113/JP283252","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In patients with chronic obstructive pulmonary disease (COPD), exertional dyspnoea generally arises when there is imbalance between ventilatory demand and capacity, but the neurophysiological mechanisms are unclear. We therefore determined if disparity between elevated inspiratory neural drive (IND) and tidal volume (V&lt;sub&gt;T&lt;/sub&gt; ) responses (neuromechanical dissociation) impacted dyspnoea intensity and quality during exercise, across the COPD severity spectrum. In this two-centre, cross-sectional observational study, 89 participants with COPD divided into tertiles of FEV&lt;sub&gt;1&lt;/sub&gt; %predicted (Tertile 1 = FEV&lt;sub&gt;1&lt;/sub&gt; = 87 ± 9%, Tertile 2 = 60 ± 9%, Tertile 3 = 32 ± 8%) and 18 non-smoking controls, completed a symptom-limited cardiopulmonary exercise test (CPET) with measurement of IND by diaphragm electromyography (EMGdi (%max)). The association between increasing dyspnoea intensity and EMGdi (%max) during CPET was strong (r = 0.730, P &lt; 0.001) and not different between the four groups who showed marked heterogeneity in pulmonary gas exchange and mechanical abnormalities. Significant inspiratory constraints (tidal volume/inspiratory capacity (V&lt;sub&gt;T&lt;/sub&gt; /IC) ≥ 70%) and onset of neuromechanical dissociation (EMGdi (%max):V&lt;sub&gt;T&lt;/sub&gt; /IC &gt; 0.75) occurred at progressively lower minute ventilation ( &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;mi&gt;E&lt;/mi&gt;&lt;/msub&gt; &lt;annotation&gt;${dot{V}}_{{rm{E}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) from Control to Tertile 3. Lower resting IC meant earlier onset of neuromechanical dissociation, heightened dyspnoea intensity and greater propensity (93% in Tertile 3) to select qualitative descriptors of 'unsatisfied inspiration'. We concluded that, regardless of marked variation in mechanical and pulmonary gas exchange abnormalities in our study sample, exertional dyspnoea intensity was linked to the magnitude of EMGdi (%max). Moreover, onset of critical inspiratory constraints and attendant neuromechanical dissociation amplified dyspnoea intensity at higher exercise intensities. Simple measurements of IC and breathing pattern during CPET provide useful insights into mechanisms of dyspnoea and exercise intolerance in individuals with COPD. KEY POINTS: Dyspnoea during exercise is a common and troublesome symptom reported by patients with chronic obstructive pulmonary disease (COPD) and is linked to an elevated inspiratory neural drive (IND). The precise mechanisms of elevated IND and dyspnoea across the continuum of airflow obstruction severity in COPD remains unclear. The present study sought to determine the mechanisms of elevated IND (by diaphragm EMG, EMGdi (%max)) and dyspnoea during cardiopulmonary exercise testing (CPET) across the continuum of COPD severity. There was a strong association between increasing dyspnoea intensity and EMGdi (%max) during CPET across the COPD continuum despite significant heterogeneity in underlying pulmonary gas exchange and respiratory mechanical impair","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4227-4245"},"PeriodicalIF":5.5,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40541614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kappa opioids inhibit the GABA/glycine terminals of rostral ventromedial medulla projections in the superficial dorsal horn of the spinal cord.","authors":"Yo Otsu,&nbsp;Karin R Aubrey","doi":"10.1113/JP283021","DOIUrl":"https://doi.org/10.1113/JP283021","url":null,"abstract":"<p><p>Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn (SDH) of the spinal cord that are involved in the modulation of nociception, the development of chronic pain and itch, and an important analgesic target for opioids. This projection is primarily inhibitory, but the relative contribution of GABAergic and glycinergic transmission is unknown and there is limited knowledge about the SDH neurons targeted. Additionally, the details of how spinal opioids mediate analgesia remain unclear, and no study has investigated the opioid modulation of this synapse. We address this using ex vivo optogenetic stimulation of RVM fibres in conjunction with whole-cell patch-clamp recordings from the SDH in spinal cord slices. We demonstrate that both GABAergic and glycinergic neurotransmission is employed and show that SDH target neurons have diverse morphological and electrical properties, consistent with both inhibitory and excitatory interneurons. Then, we describe a subtype of SDH neurons that has a glycine-dominant input, indicating that the quality of descending inhibition across cells is not uniform. Finally, we discovered that the kappa-opioid receptor agonist U69593 presynaptically suppressed most RVM-SDH synapses. By contrast, the mu-opioid receptor agonist DAMGO acted both pre- and postsynaptically at a subset of synapses, and the delta-opioid receptor agonist deltorphin II had little effect. These data provide important mechanistic information about a descending control pathway that regulates spinal circuits. This information is necessary to understand how sensory inputs are shaped and develop more reliable and effective alternatives to current opioid analgesics.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4187-4205"},"PeriodicalIF":5.5,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/01/cd/TJP-600-4187.PMC9540474.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40622241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory gene expression during acute high-altitude exposure.","authors":"Kathy Pham,&nbsp;Shyleen Frost,&nbsp;Keval Parikh,&nbsp;Nikhil Puvvula,&nbsp;Britney Oeung,&nbsp;Erica C Heinrich","doi":"10.1113/JP282772","DOIUrl":"https://doi.org/10.1113/JP282772","url":null,"abstract":"<p><p>The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4169-4186"},"PeriodicalIF":5.5,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/50/23/TJP-600-4169.PMC9481729.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40536510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic plasticity of medial olivocochlear efferent system: insights and application for neurotology.","authors":"Shaun A Hanycz,&nbsp;Vishaal Sumra,&nbsp;Anshu Kashyap,&nbsp;Anthony Pokhoy","doi":"10.1113/JP283448","DOIUrl":"https://doi.org/10.1113/JP283448","url":null,"abstract":"Shaun A. Hanycz1 , Vishaal Sumra2,3, Anshu Kashyap1 and Anthony Pokhoy4 1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 2Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 4Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3653-3655"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40511676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-related differences in the peripheral vascular response to reflex coactivation: Fun physiology or window of opportunity?","authors":"Jacqueline K Limberg","doi":"10.1113/JP283474","DOIUrl":"https://doi.org/10.1113/JP283474","url":null,"abstract":"The carotid chemoreceptors are the body’s primary oxygen sensors. Located bilaterally at the bifurcation of the common carotid artery, they are well-situated to sense changes in arterial partial pressure of oxygen and elicit necessary reflex responses (e.g. hyperventilation). In addition to their known oxygen-sensing capabilities, the carotid chemoreceptors play an important role in the integrative cardiovascular response to exercise. Indeed, activity of the sympathetic nervous system increases with exercise and at least a portion of sympathetic vasoconstrictor tone can be attributed to the chemoreceptors. The role for the carotid chemoreceptors in the sympathetic response to exercise becomes particularly relevant in the context of clinical conditions such as hypertension, heart failure and perhaps even diabetes. In both pre-clinical models and human patients with heart failure, the contribution of the carotid chemoreceptors to sympathetic vasoconstrictor tone is evident even at rest. Inhibition of chemoreceptor activity can further improve cardiovascular regulation during exercise in heart failure (Collins et al., 2020). The mechanisms by which this may be occurring are many and include interactions between the exercise pressor reflex (i.e. mechanoand metaboreflex) and the carotid chemoreceptors (Edgell & Stickland, 2014). Thus, chemoreceptor activation in the context of exercise may potentiate cardiovascular consequences of such conditions. Notably, the metaboreflex was recently identified to contribute to enhanced peripheral vasoconstriction in patients with heart failure (Barrett-O’Keefe et al., 2018). When considered clinically, exaggerated sympathetically-mediated vasoconstriction in the context of exercise is not limited to the skeletal muscle circulation and has similarly been observed at the level of the kidney. Although this work has been shown to provide comparable results across species (e.g. dogs, humans), less is known regarding the translation of findings across sexes. A lack of understanding of sex-related differences in reflex interactions is primarily a result of the tendency of prior work to include only males or a very small proportion of females. As a result, sex-related differences have only recently been identified and remain poorly described in clinical cohorts. In the most recent issue of The Journal of Physiology, Wan et al. (2022) tested the hypothesis that reflex interactions between the muscle mechanoreflex (passive limb movement) and chemoreflex (hypoxia, hypercapnia) would restrict vascular conductance and blood flow in male but not female adults – attributed to effects of sympathetic activity on the peripheral vasculature. Although not a primary focus, a previous post hoc analysis of a mixed-sex cohort conducted by this group (Wan et al., 2020) found that the leg blood flow response to combined activation of the exercise pressor and chemoreflexes did not differ between male and female participants. However, as note","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3639-3640"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40516471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Something worth waiting for: is delayed cord clamping always beneficial?","authors":"Joshua L Robinson,&nbsp;Jack R T Darby","doi":"10.1113/JP283315","DOIUrl":"https://doi.org/10.1113/JP283315","url":null,"abstract":"The transition of the fetus to newborn life involves a number of physiological changes, specifically to the respiratory and cardiovascular systems. Prior to birth, the fetus receives well-oxygenated blood from the placenta via the umbilical vein, with no gas exchange occurring at the fluid-filled lungs. To ensure that not all the blood entering the right side of the fetal heart is sent towards the lungs as it would be after birth, the fetal circulation includes unique shunts: the foramen ovale (FO) and the ductus arteriosus (DA). The FO exists between the atria and allows well-oxygenated blood entering from the inferior vena cava to be preferentially shunted from the right to the left side of the heart, while the DA ensures the majority of right ventricular cardiac output bypasses the pulmonary circulation to instead join the blood flow within the descending aorta. Consequently, during fetal life only ∼7–8% of combined ventricular cardiac output perfuses the lungs (Rudolph, 1985). At birth, the lungs replace the function of the placenta in oxygenating the blood, and the neonatal circulation changes with closure of the DA and FO. When these circulatory changes do not occur, oxygenated and deoxygenated blood is mixed.ApatentDA leads to poor peripheral perfusion, tachycardia and pulmonary hypertension. As a result, there is much interest in the regulation of these circulatory changes at the time of birth and more specifically how to ensure that they occur in an appropriate timeframe to mitigate and prevent poor neonatal outcomes. Both the cessation of blood flow from the placenta and the start of respiration are stimuli to cause these cardiovascular changes in the newborn. Recently, studies have begun to explore the impact of the relative timing of these two stimuli on neonatal physiology. Historically, the cord is clamped immediately (ICC) after delivery, and the newborn subsequently begins breathing. However, current clinical practice is shifting to delay the clamping of the cord until after ventilation has begun (DCC) and potentially allow an easier switch from blood oxygenation at the placenta to oxygenation in the lungs. This could be more effective in preterm babies with a more immature cardiopulmonary circuitry. Practice guidelines developed by the International Liaison Committee on Resuscitation (ILCOR) recommend at least 30 s delay before cord clamping postpartum in preterm newborns (&lt;34+0 weeks gestational age) not requiring immediate resuscitation (Costa-Nobre et al., 2021). This recommendation is due to improved clinical outcomes with DCC, including improved cardiovascular transition, reduced risks of intraventricular haemorrhage and necrotising enterocolitis, and higher haemoglobin and haematocrit. Additionally, DCC in preterm infants reduces mortality, with the number needed to benefit of 20 (Fogarty et al., 2018). Importantly, there is no recommendation for DCC when infants need immediate resuscitation. This Journal Club focuses on a ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3641-3642"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40587879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sticking your neck out for science.","authors":"Rachel E Szeghy,&nbsp;Nina L Stute","doi":"10.1113/JP283306","DOIUrl":"https://doi.org/10.1113/JP283306","url":null,"abstract":"all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3651-3652"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40604458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High altitude vascular dysfunction: can we 'C' our way to a remedy?","authors":"Erik R Swenson","doi":"10.1113/JP282578","DOIUrl":"https://doi.org/10.1113/JP282578","url":null,"abstract":"Acute and chronic high altitude hypoxaemia evoke a variety of adaptive and maladaptive cardiovascular changes, including increased cardiac output, mild hypertension and vascular dysfunction, which may set the stage for stroke, myocardial injury and thrombosis. Sympathetic nervous system (SNS) activation acting directly on vascular smooth muscle and the vascular endothelium is thought to underlie the development of vascular dysfunction, but exactly how is not fully understood. The dysfunction is not at the smooth muscle level, but at the endothelium, and may involve increased oxidative stress as found in cardiovascular diseases at low altitude (Frei, 1999). Earlier work by Lewis et al. (2014) found an association of impaired vascular function and increased oxidative stress in both short term visitors and long term residents at high altitude (Lewis et al. 2014). In this issue of The Journal of Physiology, Stone et al. (2022) present convincing evidence supporting oxidative stress as a basis for the peripheral vascular dysfunction developing when healthy individuals ascend to high altitude. This vascular dysfunction resides at the endothelial cell, as studied by changes in flow-mediated dilatation (FMD). FMD is dependent on the vascular endothelium since the response to infused vasodilators acting directly on vascular smooth muscle, such as sodium nitroprusside (SNP), is not affected. In contrast, when drugs acting on the endothelium are administered, such as the vasodilator acetylcholine that generates nitric oxide (NO) formation, increases in stimulated blood flow are diminished when vascular dysfunction is present. A further finding supporting the role of the endothelium is that when α-adrenergic blockers are co-infused, even their effect to partially reverse vascular dysfunction is not altered when SNP is given. Stone and colleagues directly focused on oxidative stress, i.e. the formation of oxygen radicals with hypoxia. The various forms of oxygen radicals have myriad effects on cell signalling and vasoactive mediator balance. Importantly, NO is an endothelial cell-derived vasodilator that can be rapidly oxidized to non-vasodilating compounds by reactive oxygen species (ROS). To test the hypothesis that ROS generation underlies high altitude vascular dysfunction, as it does in many cardiovascular diseases (Frei, 1999), they took healthy people to 4300 m in the Peruvian Andean city of Cerro de Pasco and studied them over 3 weeks. They compared measurements of blood flow changes by the strain gauge venous occlusion plethysmography technique (which incorporates both macroand microvascular responses) at near sea level (344 m, Kelowna, British Columbia) and then, after flying to Lima and driving for 4–6 h, at Cerro de Pasco. Between 4 and 6 days after arrival, the subjects were restudied, at which time the average increase in blood pressure was 7%. The basic protocol involved placement of an antecubital arterial catheter for infusions of various amo","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1271-1272"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39637577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}