The effects of mild hypoxaemia on hypoglossal motoneurone activity in neonates

Introduction: Apneic episodes and consequent hypoxaemia are common features of breathing in high- risk neonates. Apneas of central origin (no respiratory effort) usually terminate with an obstructive component due to collapse of the upper airway. The genioglossus muscle, the main protruder muscle of the tongue, plays a crucial role in maintaining upper airway patency by opposing the negative intra-airway pressure generated during contraction of the diaphragm and by preventing the tongue blocking the oropharyngeal opening. In adults, the respiratory-related activity of the hypoglossal nerve (the motoneurone of the genioglossus) increases during hypoxaemia in order to maintain upper airway patency. However, in neonates it has been shown that the genioglossus muscle during hypoxia is age-related and this increased activity is not sustained. In neonates, little is known about how the hypoglossal motoneurones respond to hypoxaemia and the role of hypoglossal motoneurones during hypoxia in the maintenance of upper airway patency. Aim: The aim of this study was to determine the effects of hypoxaemia on hypoglossal motoneurones in neonates. Methods: Extracellular and intracellular recordings were made from hypoglossal motoneurones in vagotomized and vagi-intact neonatal kittens during normoxia and hypoxia. Results: The results showed: (1) the majority of hypoglossal motoneurones either decreased their discharge frequency or had only a transient increase during hypoxia. (2) During intracellular recordings, the membrane potential showed a sustained depolarisation during hypoxaemia in most cases and respiratory-related rhythmic EPSP activity was reduced in amplitude. The membrane impedance of these motoneurones increased and the excitability was reduced. (3) During upper airway stimulation, the amplitude of the laryngeal-evoked potentials was reduced during hypoxia. Conclusions: My results demonstrate that, in neonates, hypoglossal motoneurone activity is inhibited during hypoxia and the hypoglossal-upper airway reflexes are also inhibited. The probable consequence of such inhibition, for the newborn human infant, would be the failure of the maintenance of upper airway patency, thus leading to obstructive apnea. The mechanisms mediating the inhibition of hypoglossal motoneurones during hypoxia remain to be determined

A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations

Archivo correspondiente a la versión FREE en la web de la revistaA single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.This work was supported by the following grants: J.M. was funded by GEN-FER from the Spanish Society of Rheumatol- ogy, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucı́a, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain and by Fondo Europeo de Desarrollo Regional (FEDER). T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. and T.R.D.J.R. were sponsored by the Orphan Disease Program grant from the Euro- pean League Against Rheumatism (EULAR). B.P.C.K. is sup- ported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). T.W. was granted by DFG WI 1031/6.1 and DFG KFO 250 TP03. N.O. was funded by PI-0590-2010, Con- sejerı́a de Salud, Junta de Andalucı́a, Spain. The USA studies were supported by NIH/NIAMS Scleroderma Registry and DNA Repository (N01-AR-0-2251), NIH/NIAMS-RO1- AR055258 and NIH/NIAMS Center of Research Translation in Scleroderma (1P50AR054144) and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111)

Dilation of the oropharynx via selective stimulation of the hypoglossal nerve

Obstructive sleep apnea (OSA) is caused by the retraction of the tongue to occlude the upper airway (UAW). Electrical stimulation of the tongue protrudor and retractor muscle has been demonstrated as an effective technique to alleviate UAW obstructions and is considered to be a potential treatment for OSA. Recent studies have shown that selective stimulation of the hypoglossal nerve (HG) to activate tongue muscles using a single implantable device presents an attractive approach for treating OSA. In this study, the functional outcome of selective hypoglossal nerve stimulation with a multi-contact peripheral nerve electrode was studied by imaging the airway in anesthetized beagles. A pulse train of varying amplitude was applied through each one of the tripolar contact sets of the nerve electrode while the pharyngeal images were acquired via a video grabber into a computer. For the open mouth positions, the tongue activation patterns were also viewed and videotaped with a digital camcorder through the mouth. The percent dilation of the pharyngeal opening for each contact was calculated. The images show that stimulations delivered through the electrode contacts placed around the HG nerve trunk can generate several different activation patterns of the tongue muscles. Some of these patterns translate into a substantial increase in the oropharyngeal size, while others do not have any effect on the pharynx. The activation patterns vary as a function of the head position and the lower jaw. These results suggest that selective nerve stimulation can be a useful technique to maximize the effects of HG nerve stimulation in removing the obstructions in sleep apnea patients

The effects of mild hypoxia on hypoglossal motoneurones in neonates

The patency of the upper airway is dependent on the activity of the genioglossus muscle, the main protrusor muscle of the tongue. The force generated by this muscle opposes the negative intraluminal pressure produced by the contraction of the diaphragm during inspiration. Recent studies suggest that there is an immaturity in genioglossus muscle control in neonates and obstructive apnoea may occur when the activity of this muscle is reduced or absent without a corresponding decrease in the activity of the diaphragm. However, little is known of the processes mediating and influencing the activity of the hypoglossal nerve, the motor nerve of the genioglossus muscle, at this stage in development. In newborn babies, central apnoea (when there is no inspiratory effort) is usually followed by obstructive apnoea (when although there is inspiratory effort there is no inspiratory flow). It is therefore possible that hypoxia which develops during central apnoea, inhibits the activity of the genioglossus muscle and as a consequence the airway becomes obstructed. The aim of this study was therefore to determine whether hypoglossal motoneurones are inhibited during hypoxia in neonates. This study has investigated the effect of mild levels of hypoxaemia (PaO2 47.2 ± 3.8mmHg) on the activity of hypoglossal motoneurones in anaesthetized neonatal kittens (27 days old). The results showed that the majority of hypoglossal motoneurones increased in discharge frequency during hypoxia but for a substantial proportion the increase was only transient. Furthermore, some motoneurones showed a decrease in discharge frequency. Intracellular recordings showed that during similar levels of hypoxia, although a large proportion of the motoneurones were depolarized, at least some of these repolarized despite the continuing hypoxia. In addition, some hypoglossal motoneurones were hyperpolarized. This is the clearest evidence that inhibitory mechanisms, in addition to excitatory mechanisms, mediate the effects of hypoxia on hypoglossal output in neonates. Furthermore, the results suggest that hypoxia has an effect on the hypoglossal motoneurones independently of, or in addition to, its effect through respiratory rhythm. In some preliminary studies, the transmembrane input resistance increased during the hyperpolarization in response to hypoxia. One possibility is that the inhibition is mediated by the removal of an excitatory input. If the inhibition found in this study occurs in human babies it may be a compounding factor in apnoeas of the newborn

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