Physiology

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Acetylated microtubules are essential for touch sensation in mice
(University College Cork, 2016) Morley, Shane J.; Heppenstall, Paul; Rae, Mark
The sense of touch depends upon the transformation of mechanical energy into electrical signals by peripheral sensory neurons and associated cells in the skin. This conversion is thought to be mediated by a complex of proteins in which ion channels such as Piezo2 function as mechanotransducers. However, how mechanical energy is transmitted into mechanosensitive ion channel opening, and how cellular components such as the cytoskeleton influence this process, is largely unknown. Here we show that mice lacking the tubulin acetyltransferase, Atat1, in sensory neurons display profound deficits in their ability to detect mechanical touch and pain. In the absence of Atat1, behavioural responses to innocuous and noxious mechanical stimuli are strongly reduced in multiple assays while sensitivity of mice to thermal stimuli is unaltered. In ex vivo skin-nerve preparations, the mechanosensitivity of all low- and high- threshold mechanoreceptor subtypes innervating the skin is substantially decreased in Atat1 conditional knockout mice. In cultured dorsal root ganglion neurons, both slowly- and rapidly- adapting mechanically- activated currents are absent or reduced upon Atat1 deletion with no effect on other neuronal functions. We establish that this broad loss of mechanosensitivity is dependent upon the acetyltransferase activity of Atat1, and that by mimicking α-tubulin acetylation genetically by substituting the lysine amino acid for a structurally similar glutamine, mechanosensitivity can be restored in Atat1- deficient sensory neurons. Finally, we demonstrate that acetylated microtubules localize to a prominent band under the membrane of sensory neuron cell bodies and axons, and in the absence of Atat1 and acetylated α-tubulin, cultured sensory neurons display significant reductions in their membrane elasticity. Our results indicate that the microtubule cytoskeleton is an essential component of the mammalian mechanotransduction complex and that by influencing cellular stiffness, α-tubulin acetylation can tune mechanical sensitivity across the full range of mechanoreceptor subtypes.
Active peer-mentored learning can improve student understanding of physiological concepts in an undergraduate journal club
(American Physiological Society, 2019-07-15) Drumm, Bernard T.; Rae, Mark G.; Ward, Sean M.; National Institute of Diabetes and Digestive and Kidney Diseases
One of the most ubiquitous active learning modalities in the biological sciences at third level is the journal club. Journal club can promote several beneficial learning outcomes for students such as gaining critical reading skills to evaluate the scientific literature, improving scientific literacy, serving as an introduction to new concepts and techniques and improving communication skills. However, it can be difficult for instructors who facilitate journal club to gauge student audiences' understanding of topics being related by presenters. At the University of Nevada, Reno School of Medicine, international life sciences undergraduate students enrolled in our research program undergo a 12-month placement in selected research laboratories within the medical school in order to develop an understanding of basic medical scientific research and physiological concepts. As such, an integral component of this program is participation in regular journal club sessions which we had assumed helped students to develop such an understanding. However as we had never empirically assessed if this was the case or not, the aim of the current study was to determine if student understanding could be improved by complementing the standard journal club with peer-mentored workshop presentations. Data from this case study suggest that by allowing students to undergo peer-mentored learning in conjunction with journal club, student understanding of physiological concepts, as well as student confidence in presenting and communication, increases.
Acute hypoxia-induced diaphragm dysfunction is prevented by antioxidant pre-treatment
(University College Cork, 2016) O'Leary, Andrew J.; O'Halloran, Ken D.; Mackrill, John; Physiology, College of Medicine and Health, University College Cork; Strategic Research Fund, University College Cork
Diaphragm weakness is a strong predictor of poor outcome in patients. Acute hypoxia is a feature of respiratory conditions such as acute respiratory distress syndrome and ventilator-associated lung injury. However, the effects of acute hypoxia on the diaphragm are largely unknown despite the potential clinical relevance. C57BL6/J mice were exposed to 8hr of hypoxia (FiO2 = 0.10) or normoxia. A separate group of mice were administered N-acetyl cysteine (NAC; 200mg/kg, I.P.) immediately prior to acute hypoxia exposure. Ventilation was assessed using whole-body plethysmography. O2 consumption and CO2 production were measured as indices of metabolism. Diaphragm muscle contractile performance was determined ex-vivo. Gene expression was examined at 1, 4, and 8 hrs using qRT-PCR. Protein/phosphoprotein content was assessed using a sandwich immunoassay. Proteasome activity was measured using a spectrophotometric assay. Acute hypoxia decreased diaphragm force and fatigue. Ventilation during acute hypoxia was initially increased during the first 10 minutes, but quickly returned to normoxic levels for the duration of gas exposure. Metabolism was reduced by acute hypoxia, and gene expression driving mitochondrial uncoupling was increased. Acute hypoxia increased atrophic signalling, but not proteasome activity. Acute hypoxia increased hypertrophic and hypoxia protein signalling. NAC pre-treatment prevented the acute hypoxia-induced diaphragm weakness. Diaphragm weakness is reported in mechanically ventilated patients, which is primarily attributed to inactivity of the muscle, although this is controversial. The potential role of hypoxia in the development and/or exacerbation of ICU-related weakness is unclear. These data reveals that acute hypoxia is sufficient to cause diaphragm muscle weakness, likely relates to hypoxic stress. Muscle weakness was prevented by antioxidant supplementation, independent of the hypoxia-induced hypometabolic state. These findings highlight a potentially critical role for hypoxia in diaphragm muscle dysfunction observed in patients with acute respiratory diseases, and the potential benefits of NAC in preventing acute hypoxia-induced diaphragm dysfunction.
Alterations of haemodynamic parameters in spontaneously hypertensive rats by Aristolochia ringens Vahl. (Aristolochiaceae)
(Elsevier Ltd on behalf of the Center for Food and Biomolecules, National Taiwan University, 2017-02) Aigbe, Flora Ruth; Munavvar, Abdul Sattar Zubaid; Rathore, Hassan; Eseyin, Olorunfemi; Pei, Yen Pei; Akhtar, Safia; Chohan, Ashfaq; Jin, Hui; Khoo, Jooli; Tan, Samual; Lazhari, Mohammed; Afzar, Sheryar; Ahmed, Fiaz; Adeyemi, Olufunmilayo Olaide; Johns, Edward J.; University of Lagos, Nigeria
Aristolochia ringens Vahl. (Aristolochiaceae (AR); 馬兜鈴 mǎ dōu líng) is used traditionally in Nigeria for the management of various disorders including oedema. Preliminary investigation revealed its modulatory effect on the cardiovascular system. This study was aimed at investigating the effect of the aqueous root extract of A. ringens (AR) on haemodynamic parameters of spontaneously hypertensive rats (SHRs). The effect of oral subacute (21 days) and intravenous acute exposure of SHRs to the extract were assessed using tail cuff and carotid artery canulation methods respectively. In the latter, the effect of chloroform, butanol and aqueous fractions of AR were also evaluated. The extract significantly reduced systolic and diastolic blood pressures in SHRs, with peak reductions of 20.3% and 26.7% respectively at 50 mg/kg by the 21st day of oral subacute exposure. Upon intravenous exposure, AR (50 mg/kg) reduced systolic and diastolic blood pressure by as much as 53.4 ± 2.2 and 49.2 ± 2.8 mmHg respectively. A dose-dependent reduction in heart rate, significant at 25 and 50 mg/kg was also observed. Hexamethonium (20 mg/kg) and atropine (1 mg/kg) inhibited the extract's reduction of systolic blood pressure, diastolic blood pressure and heart rate significantly. The extract's butanol fraction produced the greatest systolic and diastolic blood pressures reduction of 67.0 ± 3.8 and 68.4 mmHg respectively at 25 mg/kg and heart rate reduction of 40 ± 7 beats per minute at 50 mg/kg. HPLC analysis revealed the presence of 4-hydroxybenzoic acid and quercetin in AR. The extract's alterations of haemodynamic parameters in this study show that it has hypotensive effect on spontaneously hypertensive rats.
An exploration into the effects of high altitude exposure on the neurovascular coupling response
(University College Cork, 2022) Leacy, Jack K.; O'Halloran, Ken; Day, Trevor A.; University College Cork; Mount Royal University; Natural Sciences and Engineering Research Council of Canada
Introduction The neural infrastructure within cerebral tissue is both elaborate and metabolically volatile. Owing to limitations in energy substrate storage capacity, the neural nexus relies upon continuous perfusion for the delivery of essential nutrients. Vital substrates which are transported within the blood help to support energy-dependent metabolic processes throughout the central nervous system at a global and regional level. Despite constituting ≈2% of total body mass, the brain receives a disproportionate ≈20% of total cardiac output. The physiological phenomenon which describes the intimate link between local neuronal activity and regional cerebral blood flow is termed neurovascular coupling (NVC). This phenomenon has been observed across all cerebral structures wherein dynamic changes in local metabolic activity are met with a concomitant increase in local perfusion of the active tissue. A vast body of work has assessed the translational implications of NVC for neurophysiological function and behavioural outcomes across several pathologies (aging, neurodegenerative disease, autoimmune disorders, trauma and metabolic disorders). Thesis Aims Herein, we sought to characterise the effects of high altitude (HA) exposure on NVC in healthy human volunteers encompassing different ascent paradigms (chapters 3 and 4). HA exposure is a pernicious multimodal stressor among habitual lowlanders, which necessitates an integrative physiological acclimatisation to sustain homeostasis and overall health and function. This environmental stressor has pronounced effects on other components of cerebral blood flow control. Prior to this thesis there was a dearth of literature regarding the effects of HA exposure on NVC. In addition, we conducted a complementary laboratory-based investigation which examined the degree of variance within the NVC response attributable to either age and/or sex (chapter 2). This comprehensive study was essential with respect to appreciating the interaction between participant demographics (age, sex) and NVC. Demographic heterogeneity is an inherent component of many HA research expedition. We therefore determined that it was of paramount importance to ascertain the magnitude to which heterogeneity influences our primary physiological measures. Methods Transcranial Doppler ultrasound (TCD) was employed to provide non-invasive measures of cerebral blood velocity. NVC was indexed as the change in posterior cerebral artery velocity (PCAv) during intermittent visual stimulation (30s on/off; 6Hz) in all experiments. This technique is widely used within the literature, as visual stimulation mediates an increase in metabolic activity of the visual cortex, a neural territory perfused by the PCA. Healthy human volunteers were recruited for studies described in chapter 2 (n=125, 41 male), 3 (n=10, 4 male) and 4 (n=12, 7 male). Arterial blood draws were sampled from the radial artery during HA expeditions (chapter 3 and 4), providing and index of ventilatory and acid-base acclimatisation status within each participant. Ascent profiles differed between chapters 3 and 4 relevant to the experimental question. Key results and conclusions Collectively, our results demonstrate that approximately 0-6.1% of the variance across several NVC metrics are attributable to either age and/or sex (chapter 2). Moreover, the magnitude of the haemodynamic response across several NVC metrics was remarkably intact following incremental and acute ascent to 4240m and 3800m respectively (chapters 3 and 4 respectively). Taken in conjunction, this thesis reveals that: (1) Neither age nor sex greatly affect the magnitude of the NVC response in healthy human volunteers (21-66yrs old) and (2) NVC response magnitude remains remarkably intact across multiple HA exposure paradigms in habitual lowlanders.
The art of facilitation: a delicate hormonal balance!
(John Wiley & Sons Ltd., 2021-07-23) McDonald, Fiona B.
Assessment of respiratory motor units in the mdx mouse model of Duchenne muscular dystrophy
(University College Cork, 2021-03-22) Murphy, Kevin H.; O'Halloran, Ken D.; Burns, David
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease characterised by the absence of the structural protein dystrophin. Respiratory failure is the leading cause of premature death in DMD. Although respiratory insufficiency is recognized as a hallmark of DMD, respiratory control is relatively understudied. We hypothesized that enhanced drive in respiratory motor pathways preserves ventilatory capacity compensating for severe respiratory muscle weakness. Male wild-type (n=23) and mdx (n=23) mice were studied. Breathing was examined during normoxia and chemo-challenge with hypercapnic-hypoxia. In urethane (1.7 g/kg i.p.) anaesthetised mice, diaphragm, external intercostal and genioglossus electromyogram (EMG) and motor unit recordings were performed during baseline conditions and in response to chemo-stimulation. Diaphragm muscle function was examined ex vivo. Diaphragm muscle function is severely impaired in young mdx mice. Despite substantial diaphragm muscle weakness, freely-behaving mdx mice can increase ventilation during chemostimulation with hypercapnic-hypoxia. Motor unit recordings revealed an increase in the number of active units for diaphragm and genioglossus muscle. There were no major differences in the firing frequency of motor units in the respiratory muscles. Diaphragm EMG activity was depressed in mdx mice during baseline and maximum chemostimulation, compared to wild-type. In conclusion, severe mechanical disadvantage of the diaphragm is evident across a range of stimulation frequencies, yet there is a preserved capacity to raise ventilation in young mdx mice indicating a significant ventilatory reserve. Motor unit remodelling is evident in the diaphragm of mdx mice, but ultimately diaphragm EMG activity is impaired. The combination of reduced neural activation of the diaphragm and intrinsic weakness reveals major compromise in the neuromuscular function of the diaphragm in mdx mice as early as 8 weeks of age. The novel observations of this study coupled with other work by our group suggest that support from accessory muscles is critical to the support of respiratory performance in mdx mice, which may have relevance to DMD.
Bacterial modulation of visceral sensation: mediators and mechanisms
(American Physiological Society, 2019-07-10) Lomax, Alan E.; Pradhananga, Sabindra; Sessenwein, Jessica L.; O'Malley, Dervla
The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterised impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short chain fatty acids have pro-nociceptive effects in rodents but may be anti-nociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.
The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effect of noradrenaline
(Elsevier, 2014-09-06) Crotty, Tom P.
Perfusion experiments on an isolated, canine lateral saphenous vein segment preparation have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates the segment by diffusion from its microcirculation (vasa vasorum). The effects caused are opposite to those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected – star patterns need darkness, sound patterns, quietness – has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance, for reasons intrinsic or extrinsic to themselves, is believed to be responsible for degenerative and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia.
A beginner's guide to gene editing
(Wiley, 2017-12-28) Harrison, Patrick T.; Hart, Stephen
Genome editing enables precise changes to be made in the genome of living cells. The technique was originally developed in the 1980′s but largely limited to use in mice. The discovery that a targeted double stranded break (DSB) at a unique site in the genome, close to the site to be changed, could substantially increase the efficiency of editing raised the possibility of using the technique in a broader range of animal models and potentially human cells. But the challenge was to identify reagents that could create targeted breaks at a unique genomic location with minimal off-target effects. In 2005, the demonstration that programmable zinc finger nucleases (ZFNs) could perform this task, led to a number of proof-of-concept studies, but a limitation was the ease with which effective ZFNs could be produced. In 2009, the development of TAL-effector nucleases (TALENs) increased the specificity of gene editing and the ease of design and production. However, it wasn't until 2013 and the development of the CRISPR Cas9/guideRNA that gene editing became a research tool that any lab could use.
Bile acids, bioactive signalling molecules in interoceptive gut-to-brain communication
(John Wiley & Sons, Inc., 2022-04-12) Joyce, Susan A.; O'Malley, Dervla; Science Foundation Ireland; Department of Agriculture, Food and the Marine, Ireland
Aside from facilitating solubilisation and absorption of dietary lipids and lipid-soluble vitamins, amphipathic bile acids (BAs) also act as bioactive signalling molecules. A plethora of conjugated or un-conjugated primary and bacterially-modified secondary BA moieties have been identified, with significant divergence between species. These molecules are excreted into the external environment of the intestinal lumen, yet nuclear and membrane receptors that are sensitive to BAs are expressed internally in the liver, intestinal and neural tissues, amongst others. The diversity of BAs and receptors underpins the multitude of distinct bioactive functions attributed to BAs, but also hampers elucidation of the physiological mechanisms underpinning these actions. In this topical review, we have considered the potential of BAs as cross-barrier signalling molecules that contribute to interoceptive pathways informing the central nervous system of environmental changes in the gut lumen. Activation of BAs on FGF19 -secreting enterocytes, enteroendocrine cells coupled to sensory nerves or intestinal immune cells would facilitate indirect signalling, whereas direct activation of BA receptors in the brain are likely to occur primarily under pathophysiological conditions when concentrations of BAs are elevated. Abstract figure legend The figure illustrates the microbial modification of hepatic primary bile acids into secondary bile acids. In addition to facilitating lipid digestion and absorption, bile acids act as bioactive signalling molecules by binding to bile acid receptors expressed on enterocytes, neural afferent-coupled enteroendocrine cells and immune cells.
Bioaccessibility and bioavailability of a marine-derived multimineral, Aquamin-Magnesium
(MDPI AG, 2018) Felice, Valeria D.; O'Gorman, Denise M.; O'Brien, Nora M.; Hyland, Niall P.; Marigot Ltd; Irish Research Council; Science Foundation Ireland
Introduction: Magnesium is an essential mineral involved in a range of key biochemical pathways. Several magnesium supplements are present on the market and their degree of bioavailability differs depending on the form of magnesium salt used. Aquamin-Mg is a natural source of magnesium, containing 72 additional trace minerals derived from the clean waters off the Irish coast. However, the in vitro bioaccessibility and bioavailability of Aquamin-Mg in comparison with other supplement sources of magnesium has yet to be tested. Method: Aquamin-Mg, magnesium chloride (MgCl2) and magnesium oxide (MgO) were subjected to gastrointestinal digestion according to the harmonized INFOGEST in vitro digestion method and in vitro bioavailability tested using the Caco-2 cell model. Magnesium concentration was measured by atomic absorption spectrophotometry (AAS). Results: Magnesium recovery from both Aquamin-Mg and MgCl2 was greater than for MgO. Magnesium from all three sources was transported across the epithelial monolayer with Aquamin-Mg displaying a comparable profile to the more bioavailable MgCl2. Conclusions: Our data support that magnesium derived from a marine-derived multimineral product is bioavailable to a significantly greater degree than MgO and displays a similar profile to the more bioavailable MgCl2 and may offer additional health benefits given its multimineral profile.
Brainstem network pathology and impaired respiratory drive as successive signatures in a rat model of Parkinson's disease
(John Wiley & Sons, Inc., 2018-08-25) Burns, David P.; O'Halloran, Ken D.
Bugs, breathing and blood pressure: the microbiota-gut-brain axis in cardiorespiratory control
(University College Cork, 2019) O'Connor, Karen M.; O'Halloran, Ken D.; Cryan, John; Department of Physiology, University College Cork; Science Foundation Ireland
Dysregulated microbiota-gut-brain axis communication adversely influences neurocontrol systems, consequently affecting brain behaviours. It is plausible that microbiota-gut-brain axis signalling has a role in the control of breathing and cardiovascular function, as networks that govern cardiorespiratory control reside within the brainstem, a region innervated by the vagus nerve, a key signalling pathway of the microbiota-gut-brain axis. Cardiovascular and respiratory diseases are serious, potentially life-threatening conditions with limited treatment options. Thus, improved understanding of the underlying pathophysiology and novel therapeutic approaches are required. We performed an assessment of cardiorespiratory physiology in animal models of modified gut microbiota [antibiotic-treated (ABX) and faecal microbiota transfer (FMT)], and sleep-disordered breathing [chronic intermittent hypoxia (CIH)-exposed guinea-pigs and rats]. We investigated if dietary prebiotic supplementation prevented CIH-induced cardiorespiratory dysfunction in rats. Whole-body plethysmography was used to record ventilation and metabolism in unanaesthetised animals during normoxia and chemostimulation. Under anaesthesia, cardiorespiratory assessments were performed during normoxia, chemosensory stimulation and drug administration. Brainstem neurochemistry was assessed by high-performance liquid chromatography. 16S rRNA and whole-metagenome shotgun sequencing was used to characterise the gut microbiota. ABX and FMT disrupted the gut microbiota, brain neurochemistry and intestinal integrity, blunting chemoreflex control of breathing. Decreased brainstem noradrenaline and altered gut microbiota as well as impaired respiratory and autonomic control were evident in CIH-exposed guinea-pigs. CIH–exposed rats developed cardiorespiratory pathologies and decreased gut Lactobacillus rhamnosus relative abundance. Prebiotic administration increased short-chain fatty acid concentrations, measured by gas chromatography, but Lactobacillus rhamnosus and cardiorespiratory dysfunctions were not restored. Several commensal and pathogenic bacterial species correlated with blood pressure parameters. Our findings add to emerging research exploring microbiota-gut-brain signalling in homeostatic systems, extending investigations to cardiorespiratory control. Our studies draw focus to the potential application of manipulation of the gut microbiota as an adjunctive therapy for cardiorespiratory disease.
Caesarean delivery and subsequent pregnancy interval: a systematic review and meta-analysis
(BioMed Central Ltd., 2013-08-27) O'Neill, Sinéad M.; Kearney, Patricia M.; Kenny, Louise C.; Henriksen, Tine B.; Lutomski, Jennifer E.; Greene, Richard A.; Khashan, Ali S.; Health Research Board
Background: Caesarean delivery has increased worldwide, however, the effects on fertility are largely unknown. This systematic review aims to compare subsequent sub-fertility (time to next pregnancy or birth) among women with a Caesarean delivery to women with a vaginal delivery. Methods: Systematic review of the literature including seven databases: CINAHL; the Cochrane Library; Embase; Medline; PubMed; SCOPUS and Web of Knowledge (1945 - October 2012), using detailed search-strategies and reference list cross-checking. Cohort, case–control and cross-sectional studies were included. Two assessors reviewed titles, abstracts, and full articles using standardised data abstraction forms and assessed study quality. Results: 11 articles were eligible for inclusion in the systematic review, of these five articles which adjusted for confounders were combined in a meta-analysis, totalling 750,407 women using fixed-effect models. Previous Caesarean delivery was associated with an increased risk of sub-fertility [pooled odds ratio (OR) 0.90; 95% CI 0.86, 0.93]. Subgroup analyses by parity [primiparous women: OR 0.91; 95% CI 0.87, 0.96; not limited to primiparous women: OR 0.81; 95% CI 0.73, 0.90]; by publication date (pre-2000: OR 0.80, 95% CI 0.68, 0.94; post-2000: OR 0.90, 95% CI 0.86, 0.94); by length of follow-up (<10 years: OR 0.81, 95% CI 0.73, 0.90; >10 years: OR 0.91, 95% CI 0.87, 0.96); by indication for mode of delivery (specified: 0.92, 95% CI 0.88, 0.97; not specified: OR 0.81, 95% CI 0.73, 0.90); by cohort size (<35,000: OR 0.79, 95% CI 0.67, 0.92; >35,000: OR 0.90, 95% CI 0.87, 0.95), by definition of sub-fertility used divided into (birth interval [BI]: OR 0.89, 95% CI 0.84, 0.94; inter-pregnancy interval [IPI]: OR 0.91, 95% CI 0.85, 0.97; and categorical measures: OR 0.81, 95% CI 0.73, 0.90); continuous measures: OR 0.91, 95% CI 0.87, 0.96) were performed. Results of the six studies not included in the meta-analysis (which did not adjust for confounders) are presented individually. Conclusions: The meta-analysis shows an increased waiting time to next pregnancy and risk of sub-fertility among women with a previous Caesarean delivery. However, included studies are limited by poor epidemiological methods such as variations in the definition of time to next pregnancy, lack of confounding adjustment, or details of the indication for Caesarean delivery. Further research of a more robust methodological quality to better explore any underlying causes of sub-fertility and maternal intent to delay childbearing is warranted.
Caffeine therapy for apnoea of prematurity: wake up to the fact that sex matters
(John Wiley & Sons, Inc., 2018-08-02) McDonald, Fiona B.; Dempsey, Eugene M.; O'Halloran, Ken D.
Calcium signaling in oomycetes: an evolutionary perspective
(Frontiers Media, 2016-04-05) Zheng, Limian; Mackrill, John J.
Oomycetes are a family of eukaryotic microbes that superficially resemble fungi, but which are phylogenetically distinct from them. These organisms cause major global economic losses to agriculture and fisheries, with representative pathogens being Phytophthora infestans, the cause of late potato blight and Saprolegnia diclina, the instigator of “cotton molds” in fish. As in all eukaryotes, cytoplasmic Ca2+ is a key second messenger in oomycetes, regulating life-cycle transitions, controlling motility and chemotaxis and, in excess, leading to cell-death. Despite this, little is known about the molecular mechanisms regulating cytoplasmic Ca2+ concentrations in these organisms. Consequently, this review analyzed the presence of candidate calcium channels encoded within the nine oomycete genomes that are currently available. This revealed key differences between oomycetes and other eukaryotes, in particular the expansion and loss of different channel families, and the presence of a phylum-specific group of proteins, termed the polycystic kidney disease tandem ryanodine receptor domain (PKDRR) channels.
Cannabinoids on the brain
(Hindawi, 2002-03-09) Irving, Andrew J.; Rae, Mark G.; Coutts, Angela A.
Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids) affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS) regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.
Cardiorespiratory hysteresis during incremental high altitude ascent-descent quantifies the magnitude of ventilatory acclimatization
(John Wiley & Sons, Inc. on behalf of the Physiological Society, 2020-05-18) Leacy, Jack K.; Linares, Andrea M.; Zouboules, Shaelynn M.; Rampuri, Zahrah H.; Bird, Jordan D.; Herrington, Brittney A.; Mann, Leah M.; Soriano, Jan E.; Thrall, Scott F.; Kalker, Anne; Brutsaert, Tom D.; O'Halloran, Ken D.; Sherpa, Mingma T.; Day, Trevor A.; University College Cork; Government of Alberta; Natural Sciences and Engineering Research Council of Canada
Maintenance of arterial blood gases is achieved through sophisticated regulation of ventilation, mediated by central and peripheral chemoreflexes. Respiratory chemoreflexes are important during exposure to high altitude due to the competing influence of hypoxia and hypoxic hyperventilation‐mediated hypocapnia on steady‐state ventilatory drive. Inter‐individual variability exists in ventilatory acclimatization to high altitude, potentially affecting the development of acute mountain sickness (AMS). We aimed to quantify ventilatory acclimatization to high altitude by comparing differential ascent and descent values (i.e. hysteresis) in steady‐state cardiorespiratory variables. We hypothesized that (a) the hysteresis area formed by cardiorespiratory variables during ascent and descent would quantify the magnitude of ventilatory acclimatization, and (b) larger hysteresis areas would be associated with lower AMS symptom scores during ascent. In 25 healthy, Diamox‐free trekkers ascending to and descending from 5160 m, cardiorespiratory hysteresis was measured in the pressure of end‐tidal (PET)CO2, peripheral oxygen saturation (SpO2), minute ventilation (V̇E), chemoreceptor stimulus index (SI; PETCO2/SpO2) and the calculated steady‐state chemoreflex drive (SS‐CD; V̇E/SI) using portable devices (capnograph, peripheral pulse oximeter and respirometer, respectively). AMS symptoms were assessed daily using the Lake Louise Questionnaire. We found that (a) ascent‐descent hysteresis was present in all cardiorespiratory variables, (b) SS‐CD is a valid metric for tracking ventilatory acclimatization to high altitude and (c) highest AMS scores during ascent were significantly, moderately and inversely‐correlated to SS‐CD hysteresis magnitude (rs = ‐0.408, P = 0.043). We propose that ascent‐descent hysteresis is a novel and feasible way to quantify ventilatory acclimatization in trekkers during high altitude exposure.
Cardiovascular sequelae of the sleep apnoea syndrome: sex, stress and therapeutic strategies.
(Wiley, 2018-08) O'Halloran, Ken D.
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