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Variations in chromosome 21 gene-expression in Down syndrome were analyzed in lymphoblastoid cells derived from patients and control individuals. It is concluded that alternative transcripts belonging to the same gene are similarly regulated in Down syndrome but sense and antisense transcripts are not.

To understand the aetiology and the phenotypic severity of Down syndrome, we searched for transcriptional signatures in a substructure of the brain (cerebellum) during post-natal development in a segmental trisomy 16 model, the Ts1Cje mouse. The goal of this study was to investigate the effects of trisomy on changes in gene expression across development time. The primary gene-dosage effect on triplicated genes (∼1.5) was observed at birth [post-natal day 0 (P0)], at P15 and P30. About 5% of the non-triplicated genes were significantly differentially expressed between trisomic and control cerebellum, while 25% of the transcriptome was modified during post-natal development of the cerebellum. Indeed, only 165, 171 and 115 genes were dysregulated in trisomic cerebellum at P0, P15 and P30, respectively. Surprisingly, there were only three genes dysregulated in development and in trisomic animals in a similar or opposite direction. These three genes ( Dscr1, Son and Hmg14) were, quite unexpectedly, triplicated in the Ts1Cje model and should be candidate genes for understanding the aetiology of the phenotype observed in the cerebellum. [ABSTRACT FROM AUTHOR]

Question: Dyspnoea persisting despite treatments of underlying causes requires symptomatic approaches. Medical hypnosis could provide relief without the untoward effects of pharmacological approaches. We addressed this question through experimentally induced dyspnoea in healthy humans (inspiratory threshold loading (excessive inspiratory effort) and carbon dioxide stimulation (air hunger))., Material and Methods: 20 volunteers (10 women, aged 21-40 years) were studied on four separate days. The order of the visits was randomised in two steps: firstly, the "inspiratory threshold loading first" versus "carbon dioxide first" group (n=10 in each group); secondly, the "medical hypnosis first" versus "visual distraction first" subgroup (n=5 in each subgroup). Each visit comprised three 5-min periods (reference, intervention, washout) during which participants used visual analogue scales (VAS) to rate the sensory and affective dimensions of dyspnoea, and after which they completed the Multidimensional Dyspnea Profile., Results: Medical hypnosis reduced both dimensions of dyspnoea significantly more than visual distraction (inspiratory threshold loading: sensory reduction after 5 min 34% of full VAS versus 8% (p=0.0042), affective reduction 17.6% versus 2.4% (p=0.044); carbon dioxide: sensory reduction after 5 min 36.9% versus 3% (p=0.0015), affective reduction 29.1% versus 8.7% (p=0.0023)). The Multidimensional Dyspnea Profile showed more marked sensory effects during inspiratory threshold loading and more marked affective effects during carbon dioxide stimulation., Answer to the Question: Medical hypnosis was more effective than visual distraction at attenuating the sensory and affective dimensions of experimentally induced dyspnoea. This provides a strong rationale for clinical studies of hypnosis in persistent dyspnoea patients., Competing Interests: Conflict of interest: C. Morélot-Panzini reports grants from Fondation du Souffle and lecture honoraria from Chiesi, outside the submitted work.Conflict of interest: L. Serresse reports lecture honoraria from Chiesi and travel support from SOS Oxygene, outside the submitted work.Conflict of interest: T. Similowski reports consulting fees from AstraZeneca, Chiesi, KPL Consulting, Lungpacer Inc. and OSO-AI; lecture honoraria from Chiesi and Vitalaire; stock or stock options from AUSTRAL Dx and HEPHAI; and the following patents: WO2008006963A3, WO2012004534A1, WO2013164462A1; outside the submitted work.Conflict of interest: The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Data on assessment and management of dyspnea in patients on venoarterial extracorporeal membrane oxygenation (ECMO) for cardiogenic shock are lacking. The hypothesis was that increasing sweep gas flow through the venoarterial extracorporeal membrane oxygenator may decrease dyspnea in nonintubated venoarterial ECMO patients exhibiting clinically significant dyspnea, with a parallel reduction in respiratory drive., Methods: Nonintubated, spontaneously breathing, supine patients on venoarterial ECMO for cardiogenic shock who presented with a dyspnea visual analog scale (VAS) score of greater than or equal to 40/100 mm were included. Sweep gas flow was increased up to +6 l/min by three steps of +2 l/min each. Dyspnea was assessed with the dyspnea-VAS and the Multidimensional Dyspnea Profile. The respiratory drive was assessed by the electromyographic activity of the alae nasi and parasternal muscles., Results: A total of 21 patients were included in the study. Upon inclusion, median dyspnea-VAS was 50 (interquartile range, 45 to 60) mm, and sweep gas flow was 1.0 l/min (0.5 to 2.0). An increase in sweep gas flow significantly decreased dyspnea-VAS (50 [45 to 60] at baseline vs. 20 [10 to 30] at 6 l/min; P < 0.001). The decrease in dyspnea was greater for the sensory component of dyspnea (-50% [-43 to -75]) than for the affective and emotional components (-17% [-0 to -25] and -12% [-0 to -17]; P < 0.001). An increase in sweep gas flow significantly decreased electromyographic activity of the alae nasi and parasternal muscles (-23% [-36 to -10] and -20 [-41 to -0]; P < 0.001). There was a significant correlation between the sweep gas flow and the dyspnea-VAS (r = -0.91; 95% CI, -0.94 to -0.87), between the respiratory drive and the sensory component of dyspnea (r = 0.29; 95% CI, 0.13 to 0.44) between the respiratory drive and the affective component of dyspnea (r = 0.29; 95% CI, 0.02 to 0.54) and between the sweep gas flow and the alae nasi and parasternal (r = -0.31; 95% CI, -0.44 to -0.22; and r = -0.25; 95% CI, -0.44 to -0.16)., Conclusions: In critically ill patients with venoarterial ECMO, an increase in sweep gas flow through the oxygenation membrane decreases dyspnea, possibly mediated by a decrease in respiratory drive., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

The quest to decode the complex supraspinal mechanisms that integrate cutaneous thermal information in the central system is still ongoing. The dorsal horn of the spinal cord is the first hub that encodes thermal input which is then transmitted to brain regions via the spinothalamic and thalamocortical pathways. So far, our knowledge about the strength of the interplay between the brain regions during thermal processing is limited. To address this question, we imaged the brains of adult awake male mice in resting state using functional ultrasound imaging during plantar exposure to constant and varying temperatures. Our study reveals for the first time the following: (1) a dichotomy in the response of the somatomotor-cingulate cortices and the hypothalamus, which was never described before, due to the lack of appropriate tools to study such regions with both good spatial and temporal resolutions. (2) We infer that cingulate areas may be involved in the affective responses to temperature changes. (3) Colder temperatures (ramped down) reinforce the disconnection between the somatomotor-cingulate and hypothalamus networks. (4) Finally, we also confirm the existence in the mouse brain of a brain mode characterized by low cognitive strength present more frequently at resting neutral temperature. The present study points toward the existence of a common hub between somatomotor and cingulate regions, whereas hypothalamus functions are related to a secondary network., (Copyright © 2024 Koorliyil et al.)

Background: In critically ill patients receiving mechanical ventilation, dyspnoea is frequent, severe and associated with an increased risk of neuropsychological sequelae. We evaluated the efficacy of sensory interventions targeting the brain rather than the respiratory system to relieve dyspnoea in mechanically ventilated patients., Methods: Patients receiving mechanical ventilation for ≥48 h and reporting dyspnoea (unidimensional dyspnoea visual analogue scale (Dyspnoea-VAS)) first underwent increased pressure support and then, in random order, auditory stimulation (relaxing music versus pink noise) and air flux stimulation (facial versus lower limb). Treatment responses were assessed using Dyspnoea-VAS, the Multidimensional Dyspnea Profile and measures of the neural drive to breathe (airway occlusion pressure ( P 0.1 ) and electromyography of inspiratory muscles)., Results: We included 46 patients (tracheotomy or intubation n=37; noninvasive ventilation n=9). Increasing pressure support decreased Dyspnoea-VAS by median 40 mm (p<0.001). Exposure to music decreased Dyspnoea-VAS compared with exposure to pink noise by median 40 mm (p<0.001). Exposure to facial air flux decreased Dyspnoea-VAS compared with limb air flux by median 30 mm (p<0.001). Increasing pressure support, but not music exposure and facial air flux, reduced P 0.1 by median 3.3 cmH 2 O (p<0.001)., Conclusions: In mechanically ventilated patients, sensory interventions can modulate the processing of respiratory signals by the brain irrespective of the intensity of the neural drive to breathe. It should therefore be possible to alleviate dyspnoea without resorting to pharmacological interventions or having to infringe the constraints of mechanical ventilation lung protection strategies by increasing ventilatory support., Competing Interests: Conflict of interest: M. Decavèle reports personal fees from Isis Medical, outside the submitted work. M. Dres reports grants and personal fees from Lungpacer Inc., outside the submitted work. T. Similowski reports personal fees from ADEP Assistance, AstraZeneca France, Boehringer Ingelheim France, Chiesi France, GSK France, Lungpacer Inc., Novartis France and Teva France, outside the submitted work; and in addition has a patent for a brain–ventilator interface licensed, and patents for a protection device for intubation and a noncontact thoracic movement imaging system pending. A. Demoule reports personal fees from Medtronic, Baxter, Hamilton and Getinge, grants and personal fees from Philips and Respinor, personal fees and nonfinancial support from Fisher & Paykel, grants from the French Ministry of Health, and grants and nonfinancial support from Lungpacer, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background and Objective: Persistent dyspnoea is a public health issue for which the therapeutic arsenal is limited. This study tested high-flow nasal cannula therapy (HFNT) as a means to alleviate experimental dyspnoea., Methods: Thirty-two healthy subjects underwent an experimental dyspnoea induced by thoracoabdominal elastic loading. HFNT was administered with alternately FiO 2 of 100% (HFNT100) or 21% (HFNT21). The sensory (S-VAS) and affective (A-VAS) components of dyspnoea, transcutaneous CO 2 pressure (PtcCO 2 ), pulse-oximetry oxygen saturation (SpO 2 ), heart rate, respiratory rate and skin galvanometry were monitored continuously. Three experimental sessions of 8 min were conducted: the first session consisted in familiarization with the experimental dyspnoea and the next two sessions tested the effects of HFNT100 and HFNT21 alternatively in a randomized order., Results: HFNT21 and HFNT100 significantly reduced dyspnoea, respectively of ∆A-VAS = 0.80 cm [-0.02-1.5]; p = 0.007 and ∆A-VAS = 1.00 cm [0.08-1.75]; p < 0.0001; ∆S-VAS = 0.70 cm [-0.15-1.98]), p < 0.0001 and ∆S-VAS = 0.70 cm [0.08-1.95]), p = 0.0002) with no significant difference between HFNT21 and HFNT100. HFNT did not significantly alter the respiratory rate or the heart rate, reduced PtcCO 2 only on room air and GSR under both experimental conditions., Conclusion: HFNT was associated with a statistically significant reduction in the intensity of the sensory and affective components of dyspnoea, independent of oxygen addition. This relief of laboratory dyspnoea could result from a reduction of afferent-reafferent mismatch., (© 2023 Asian Pacific Society of Respirology.)

Rationale: Breathing difficulties are highly stressful. In critically ill patients, they are associated with an increased risk of posttraumatic manifestations. Dyspnea, the corresponding symptom, cannot be directly assessed in noncommunicative patients. This difficulty can be circumvented using observation scales such as the mechanical ventilation-respiratory distress observation scale (MV-RDOS). Objective: To investigate the performance and responsiveness of the MV-RDOS to infer dyspnea in noncommunicative intubated patients. Methods: Communicative and noncommunicative patients exhibiting breathing difficulties under mechanical ventilation were prospectively included and assessed using a dyspnea visual analog scale, MV-RDOS, EMG activity of alae nasi and parasternal intercostals, and EEG signatures of respiratory-related cortical activation (preinspiratory potentials). Inspiratory-muscle EMG and preinspiratory cortical activities are surrogates of dyspnea. Assessments were conducted at baseline, after adjustment of ventilator settings, and, in some cases, after morphine administration. Measurements and Main Results: Fifty patients (age, 67 [(interquartile interval [IQR]), 61-76] yr; Simplified Acute Physiology Score II, 52 [IQR, 35-62]) were included, 25 of whom were noncommunicative. Relief occurred in 25 (50%) patients after ventilator adjustments and in 21 additional patients after morphine administration. In noncommunicative patients, MV-RDOS score decreased from 5.5 (IQR, 4.2-6.6) at baseline to 4.2 (IQR, 2.1-4.7; P  < 0.001) after ventilator adjustments and 2.5 (IQR, 2.1-4.2; P  = 0.024) after morphine administration. MV-RDOS and alae nasi/parasternal EMG activities were positively correlated (ρ = 0.41 and 0.37, respectively). MV-RDOS scores were higher in patients with EEG preinspiratory potentials (4.9 [IQR, 4.2-6.3] vs. 4.0 [IQR, 2.1-4.9]; P  = 0.002). Conclusions: The MV-RDOS seems able to detect and monitor respiratory symptoms reasonably well in noncommunicative intubated patients. Clinical trial registered with www.clinicaltrials.gov (NCT02801838).

Rationale: Breathing is a cyclic activity that is variable by nature. Breathing variability is modified in mechanically ventilated patients. We aimed to evaluate whether decreased variability on the day of transition from assist-control ventilation to a partial mode of assistance was associated with a poorer outcome., Methods: This was an ancillary study of a multicentre, randomised, controlled trial comparing neurally adjusted ventilatory assist to pressure support ventilation. Flow and the electrical activity of the diaphragm (EAdi) were recorded within 48 h of switching from controlled ventilation to a partial mode of ventilatory assistance. Variability of flow and EAdi-related variables were quantified by the coefficient of variation, the amplitude ratio of the spectrum's first harmonic to its zero-frequency component (H1/DC) and two surrogates of complexity., Main Results: 98 patients ventilated for a median duration of 5 days were included. H1/DC of inspiratory flow and EAdi were lower in survivors than in nonsurvivors, suggesting a higher breathing variability in this population (for flow, 37% versus 45%, p=0.041; for EAdi, 42% versus 52%, p=0.002). By multivariate analysis, H1/DC of inspiratory EAdi was independently associated with day-28 mortality (OR 1.10, p=0.002). H1/DC of inspiratory EAdi was lower in patients with a duration of mechanical ventilation <8 days (41% versus 45%, p=0.022). Noise limit and the largest Lyapunov exponent suggested a lower complexity in patients with a duration of mechanical ventilation <8 days., Conclusion: Higher breathing variability and lower complexity are associated with higher survival and lower duration of mechanical ventilation., Competing Interests: Conflict of interest: T. Similowski reports grants or contracts from Chiesi France and Air Liquide Medical Systems, outside the submitted work; consulting fees from AstraZeneca France, Boerhinger Ingelheim France, Novartis France, TEVA France, Chiesi France, Lungpacer Inc. and ADEP Assistance, outside the submitted work; and payment or honoraria from AstraZeneca France, Boehringer Ingelheim France, Novartis France, TEVA France, Chiesi France, Lungpacer Inc. and ADEP Assistance, outside the submitted work. Conflict of interest: A. Demoule reports grants or contracts from Philips, Fisher & Paykel, French Ministry of Health, Respinor and Lungpacer, outside the submitted work; consulting fees from Lungpacer and Respinor, outside the submitted work; payment or honoraria from Fisher & Paykel, Getinge, Lungpacer, Gilead, Lowenstein and Astra, outside the submitted work; and support for attending meetings and/or travel from Lungpacer, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Purpose: Impairment of genioglossus control is a frequent "non-anatomical" cause of obstructive sleep apnea syndrome (OSAS) in non- or mildly obese patients. Although wake-related compensatory mechanisms prevent the occurrence of obstructive events, the genioglossus control is often impaired during wakefulness. We hypothesized that the lingual motion would be altered during wakefulness in this population in patients with moderate-to-severe OSAS., Methods: We included non- or mildly obese participants with suspected OSAS. They underwent a Bucco-Linguo-Facial Motor Skills assessment using the MBLF ("Motricité Bucco-Linguo-Faciale"), which includes an evaluation of 13 movements of the tongue. This was followed by a night-attended polysomnography. We compared patients with moderate-to-severe OSAS (apnea-hypopnea index (AHI) ≥ 15/h; n = 15) to patients without or with mild OSAS (AHI < 15/h; n = 24)., Results: MBLF total and "tongue" sub-scores were lower in patients with moderate-to-severe OSAS: total z-score - 0.78 [- 1.31; 0.103] versus 0.20 [- 0.26; 0.31], p = 0.0011; "tongue" z-sub-score (- 0.63 [- 1.83; 0.41] versus 0.35 [0.26; 0.48], p = 0.014). There was a significant age-adjusted correlation between the "tongue" sub-score and AHI. The logistic regression model for the prediction of moderate-to-severe OSAS gave area under the curve ratio of 88.2% for MBLF score plus age., Conclusions: Myofunctional activity of the tongue is impaired during wakefulness in non- or mildly obese patients with moderate-to-severe OSAS. This study supports the lingual myofunctional assessment using the MBLF in screening of moderate-to-severe OSAS. This simple tool could help clinicians to select patients with suspected moderate-to-severe OSAS for polysomnography., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)