Specific and Nonuniform Brain States during Cold Perception in Mice.

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.

Sensory interventions to relieve dyspnoea in critically ill mechanically ventilated patients.

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 cmH2O (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.

Increasing Sweep Gas Flow Reduces Respiratory Drive and Dyspnea in Nonintubated Venoarterial Extracorporeal Membrane Oxygenation Patients: A Pilot Study.

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.

Dyspnoea relief as an inherent benefit of high flow nasal cannula therapy: A laboratory randomized trial in healthy humans.

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 FiO2 of 100% (HFNT100) or 21% (HFNT21). The sensory (S-VAS) and affective (A-VAS) components of dyspnoea, transcutaneous CO2 pressure (PtcCO2 ), pulse-oximetry oxygen saturation (SpO2 ), 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 PtcCO2 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.

Interventions Relieving Dyspnea in Intubated Patients Show Responsiveness of the Mechanical Ventilation-Respiratory Distress Observation Scale.

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).

Moderate-to-severe obstructive sleep apnea syndrome is associated with altered tongue motion during wakefulness.

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.

Tau-PET imaging predicts cognitive decline and brain atrophy progression in early Alzheimer's disease.

OBJECTIVES: To explore whether regional tau binding measured at baseline is associated with the rapidity of Alzheimer's disease (AD) progression over 2 years, as assessed by the decline in specified cognitive domains, and the progression of regional brain atrophy, in comparison with amyloid-positron emission tomography (PET), MRI and cerebrospinal fluid (CSF) biomarkers. METHODS: Thirty-six patients with AD (positive CSF biomarkers and amyloid-PET) and 15 controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging, and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in patients with AD. RESULTS: Baseline tau-PET was strongly associated with the subsequent cognitive decline in regions that are usually associated with each cognitive domain. No significant relationship was observed between the cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarkers. Baseline tau tracer binding in the superior temporal gyrus was associated with subsequent atrophy in an inferomedial temporal volume of interest, as was the voxelwise tau tracer binding with subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices. CONCLUSIONS: These results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, which provides important insights into the interaction between tau burden and neurodegeneration, and is of the utmost importance to develop new prognostic markers that will help improve the design of therapeutic trials.

Reliability of B-mode ultrasound and shear wave elastography in evaluating sacral bone and soft tissue characteristics in young adults with clinical feasibility in elderly.

BACKGROUND: Physiologic aging is associated with loss of mobility, sarcopenia, skin atrophy and loss of elasticity. These factors contribute, in the elderly, to the occurrence of a pressure ulcer (PU). Brightness mode ultrasound (US) and shear wave elastography (SWE) have been proposed as a patient-specific, bedside, and predictive tool for PU. However, reliability and clinical feasibility in application to the sacral region have not been clearly established. METHOD: The current study aimed to propose a simple bedside protocol combining US and SWE. The protocol was first tested on a group of 19 healthy young subjects by two operators. The measurements were repeated three times. Eight parameters were evaluated at the medial sacral crest. Intraclass Correlation Coefficient (ICC) was used for reliability assessment and the modified Bland Altman plot analysis for agreement assessment. The protocol was then evaluated for clinical feasibility on a healthy older group of 11 subjects with a mean age of 65 ± 2.4 yrs. FINDINGS: ICC showed poor to good reliability except for skin SWE and hypodermis thickness with an ICC (reported as: mean (95%CI)) of 0.78 (0.50-0.91) and 0.98 (0.95-0.99) respectively. No significant differences were observed between the young and older group except for the muscle Shear Wave Speed (SWS) (respectively 2.11 ± 0.27 m/s vs 1.70 ± 0.17 m/s). INTERPRETATION: This is the first protocol combining US and SWE that can be proposed on a large scale in nursing homes. Reliability, however, was unsatisfactory for most parameters despite efforts to standardize the protocol and measurement definitions. Further studies are needed to improve reliability.

Abnormal Activity of Neck Inspiratory Muscles during Sleep as a Prognostic Indicator in Chronic Obstructive Pulmonary Disease.

Rationale: In patients with chronic obstructive pulmonary disease (COPD), increased activity of neck inspiratory muscles has been reported as a compensatory response to hyperinflation-related diaphragmatic dysfunction. The persistence of this activity during sleep could attenuate sleep-related hypoventilation and also negatively impact sleep and clinical outcomes.Objectives: To assess the persistence of neck-muscle activity during sleep in patients with COPD recovering from severe exacerbations (i.e., requiring hospitalization) and its impact on sleep quality and recurrence of exacerbations.Methods: Video polysomnography with neck-muscle EMG was performed in patients with COPD who were recovering from a severe exacerbation. The follow-up period lasted 6 months to record the next severe exacerbation.Measurements and Main Results: Twenty-nine patients were included in the study (median [25th-75th percentile] age, 71 [64-72] yr; 55% male; body mass index, 24 [21-29]; FEV1% predicted, 37 [29-45]; and BODE [body mass index, airflow obstruction, dyspnea, and exercise] index, 6 [5-7]). Twenty-six of these patients exhibited sleep-related neck-muscle activity, which was intermittent (limited to stage 3 sleep) in 17 and permanent throughout sleep in 9. α-Delta EEG activity during stage 3 sleep was observed in 87% of the patients. Compared with patients with no or intermittent neck-muscle activity, those with permanent neck-muscle activity showed more disrupted sleep, had experienced more exacerbations in the previous year, and suffered their next severe exacerbation earlier.Conclusions: Sleep-related neck-muscle activity occurs frequently in patients with COPD who are recovering from a severe exacerbation and seems to negatively affect sleep quality and prognosis; therefore, identification of this activity might improve COPD management after a severe exacerbation.

Ultrafast ultrasound coupled with cervical magnetic stimulation for non-invasive and non-volitional assessment of diaphragm contractility.

KEY POINTS: Twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation of the phrenic nerves is a fully non-volitional method for assessing diaphragm contractility in humans, yet it requires invasive procedures such as oesophageal and gastric catheter balloons.  Ultrafast ultrasound enables a very high frame rate allowing the capture of transient events, such as muscle contraction elicited by nerve stimulation (twitch). Whether indices derived from ultrafast ultrasound can be used as an alternative to the invasive measurement of twitch transdiaphragmatic pressure is unknown.  Our findings demonstrate that maximal diaphragm tissue velocity assessed using ultrafast ultrasound following cervical magnetic stimulation is reliable, sensitive to change in cervical magnetic stimulation intensity, and correlates to twitch transdiaphragmatic pressure.  This approach provides a novel fully non-invasive and non-volitional tool for the assessment of diaphragm contractility in humans. ABSTRACT: Measuring twitch transdiaphragmatic pressure (Pdi,tw ) elicited by cervical magnetic stimulation (CMS) is considered as a reference method for the standardized evaluation of diaphragm function. Yet, the measurement of Pdi requires invasive oesophageal and gastric catheter-balloons. Ultrafast ultrasound is a non-invasive imaging technique enabling frame rates high enough to capture transient events such as evoked muscle contractions. This study investigated relationships between indices derived from ultrafast ultrasound and Pdi,tw , and how these indices might be used to estimate Pdi,tw . CMS was performed in 13 healthy volunteers from 30% to 100% of maximal stimulator intensity in units of 10% in a randomized order. Pdi,tw was measured and the right hemidiaphragm was imaged using a custom ultrafast ultrasound sequence with 1 kHz framerate. Maximal diaphragm axial velocity (Vdi ,max ) and diaphragm thickening fraction (TFdi,tw ) were computed. Intra-session reliability was assessed. Repeated-measures correlation (R) and Spearman correlation coefficients (ρ) were used to assess relationships between variables. Intra-session reliability was strong for Pdi,tw and Vdi,max and moderate for TFdi,tw . Vdi,max correlated with Pdi,tw in all subjects (0.64 < ρ < 1.00, R = 0.75; all P < 0.05). TFdi,tw correlated with Pdi,tw in eight subjects only (0.85 < ρ < 0.93, R = 0.69; all P < 0.05). Coupling ultrafast ultrasound and CMS shows promise for the non-invasive and fully non-volitional assessment of diaphragm contractility. This approach opens up the prospect of both diagnosis and follow-up of diaphragm contractility in clinical populations.

Evening sock marks as an adjunct to the clinical prediction of obstructive sleep apnea.

STUDY OBJECTIVES: Fluid overload shifting from the legs to the upper airway during sleep promotes obstructive sleep apnea (OSA) and interventions targeting fluid attenuate OSA. Fluid shift has been previously measured by bioelectrical impedance, a complex and time-consuming technique not applicable in the daily clinical settings. The aim of this study is to evaluate the presence of clinically detectable fluid overload and shift and its association with OSA. METHODS: Patients undergoing sleep study for suspected OSA were asked to report the presence of 11 signs/symptoms associated to excessive accumulation of fluid in different parts of the body at different times of the day. RESULTS: Among 392 patients (male: 53%, median [interquartile range] age: 56 years [1], body mass index, BMI: 29 kg/m2 [2]) included in the study, 135 (34%) had moderate-to-severe OSA (apnea hypopnea index, AHI ≥ 15). Daytime fluid accumulation and nocturnal fluid shift, clinically detectable by patient-reported "evening sock marks," "heavy legs during the day," and "morning stuffed nose," were prevalent in the entire population (46%, 43%, and 33%, respectively). In multivariate analysis, evening sock marks was an independent correlate of having an AHI ≥ 15, together with male sex, older age, and self-reported snoring and apneas. CONCLUSIONS: Clinically detectable fluid overload and shift are prevalent in patients addressed for suspected OSA, and evening sock marks, a marker for leg swelling, is an independent correlate of moderate-to-severe OSA. This sign might contribute to OSA diagnosis and identification of patients likely to be treated by interventions targeting fluid overload and shift.

Decreased respiratory-related postural perturbations at the cervical level under cognitive load.

PURPOSE: In healthy humans, postural and respiratory dynamics are intimately linked and a breathing-related postural perturbation is evident in joint kinematics. A cognitive dual-task paradigm that is known to induce both postural and ventilatory disturbances can be used to modulate this multijoint posturo-ventilatory (PV) interaction, particularly in the cervical spine, which supports the head. The objective of this study was to assess this modulation. METHODS: With the use of optoelectronic sensors, the breathing profile, articular joint motions of the cervical spine, hip, knees and ankles, and centre of pressure (CoP) displacement were measured in 20 healthy subjects (37 years old [29; 49], 10 females) during natural breathing (NB), a cognitive dual task (COG), and eyes-closed and increased-tidal-volume conditions. The PV interaction in the CoP and joint motions were evaluated by calculating the respiratory emergence (REm). RESULTS: Only the COG condition induced a decrease in the cervical REm (NB: 17.2% [7.8; 37.2]; COG: 4.2% [1.8; 10.0] p = 0.0020) concurrent with no changes in the cervical motion. The CoP REm (NB: 6.2% [3.8; 10.3]; COG: 12.9% [5.8; 20.7] p = 0.0696) and breathing frequency (NB: 16.6 min-1 [13.3; 18.7]; COG: 18.6 min-1 [16.3; 19.4] p = 0.0731) tended to increase, while the CoP (p = 0.0072) and lower joint motion displacements (p < 0.05) increased. CONCLUSION: This study shows stable cervical spine motion during a cognitive dual task, as well as increased postural perturbations globally and in other joints. The concurrent reduction in the PV interaction at the cervical spine suggests that this "stabilization strategy" is centrally controlled and is achieved by a reduction in the breathing-related postural perturbations at this level. Whether this strategy is a goal for maintaining balance remains to be studied.

Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures.

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function.

Etiology and prognosis of acute respiratory failure in patients with primary malignant brain tumors admitted to the intensive care unit.

PURPOSE: Acute respiratory failure (ARF) is common and potentially fatal in patients with primary malignant brain tumors (PMBT). However, few data are available regarding its precipitating factors and prognosis. We sought to: (1) compare the causes of ARF and the outcome between patients with PMBT and patients with other peripheral solid tumors (PST), (2) identify the factors influencing ICU survival in PMBT patients. METHODS: Two-center retrospective case-control study from March 1996 to May 2014. Primary central nervous system lymphomas were also included. RESULTS: Eighty-four patients with PMBT and 133 patients with PST were included. Acute infectious pneumonia was more frequent in PMBT than PST patients (77 vs. 36%, p < 0.001). Pulmonary embolism was also more frequent in PMBT patients (13% vs. 5%, p = 0.042), while cardiogenic pulmonary edema and acute-on-chronic respiratory failure were more frequent in PST patients (37 vs. 10%, p < 0.001). Among acute infectious pneumonia, Pneumocystis pneumonia and aspiration pneumonia were more frequent in PMBT patients (19 vs. 2%, p < 0.001 and 19 vs. 8%, p < 0.001, respectively). ICU mortality was similar between PMBT and PST patients (24% vs. 24%, p = 0.966). In multivariate analysis, cancer progression (OR 7.25 95% CI 1.13-46.45, p = 0.034), need for intubation (OR 7.01 95% CI 1.29-38.54, p = 0.022), were independently associated with ICU mortality in PMBT patients. CONCLUSIONS: The cause of ARF in patients with PMBT differs significantly than those with PST and up to 50% may have been prevented. Mortality did not differ between the two groups. These results suggest that PMBT alone is not a relevant criterion for ICU recusal.

Relieving dyspnoea by non-invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis.

BACKGROUND: Dyspnoea is a threatening sensation of respiratory discomfort that presents many similarities with pain. Experimental dyspnoea in healthy subjects induces analgesia. This 'dyspnoea-pain counter-irritation' could, in reverse, imply that relieving dyspnoea in patients with chronic respiratory diseases would lower their pain thresholds. METHODS: We first determined pressure pain thresholds in 25 healthy volunteers (22-31 years; 13 men; handheld algometer), during unloaded breathing (BASELINE) and during inspiratory threshold loading (ITL). Two levels of loading were used, adjusted to induce dyspnoea self-rated at 60% or 80% of a 10 cm visual analogue scale (ITL6 and ITL8). 18 patients with chronic respiratory failure due to amyotrophic lateral sclerosis (ALS) were then studied during unassisted breathing and after 30 and 60 min of non-invasive ventilation-NIV30 and NIV60-(same dyspnoea evaluation). RESULTS: In healthy volunteers, pressure pain thresholds increased significantly in the deltoid during ITL6 (p<0.05) and ITL8 (p<0.05) and in the trapezius during ITL8 (p<0.05), validating the use of pressure pain thresholds to study dyspnoea-pain counter-irritation. In patients with ALS, the pressure pain thresholds measured in the deltoid during unassisted breathing decreased by a median of 24.5%-33.0% of baseline during NIV30 and NIV60 (p<0.05). CONCLUSION: Relieving dyspnoea by NIV in patients with ALS having respiratory failure is associated with decreased pressure pain thresholds. Clinical implications have yet to be determined, but this observation suggests that patients with ALS could become more susceptible to pain after the institution of NIV, hence the need for reinforced attention towards potentially painful diagnostic and therapeutic interventions.

Sampling method development and optimization in view of human hand odor analysis by thermal desorption coupled with gas chromatography and mass spectrometry.

Forensic profiling of human odor is challenging and would be useful to support information provided by dogs in courts of justice. Analyses of volatile compounds constitutive of human odor are commonly performed with gas chromatography coupled with mass spectrometry. All developed methods and sampling prototypes have to be easy to use in the field by crime scene investigators. This paper will focus on techniques for human hand odor sampling prior to analysis by a thermodesorption device coupled with gas chromatography and mass spectrometry. Thermodesorption and gas chromatography methods were developed using a sorbent phase spiked with a mixture of 80 compounds representative of human hand odor. Then, the crucial sampling step was performed indirectly with a homemade device based on air suction and trapping on a sorbent. This indirect sampling device was evaluated with the same synthetic mixture for optimization. An innovative polymer sorbent called Sorb-Star® was compared to classic Tenax TA® packed tubes. Sorb-Star® provided similar recovery to Tenax TA® packed tubes and a smaller pooled coefficient of variation (6 vs 13%). Thus, it appeared to be fully suited to the indirect sampling of human hand odor. The developed methods were successfully applied to real samples, the ultimate aim being the comparison of a suspect's sample to a sample collected from a crime scene.

Ceramides and sphingomyelinases in senile plaques.

The senile plaque is a hallmark lesion of Alzheimer disease (AD). We compared, without a priori, the lipidome of the senile plaques and of the adjacent plaque-free neuropil. The analysis by liquid chromatography coupled with electrospray ionization mass spectrometry revealed that laser microdissected senile plaques were enriched in saturated ceramides Cer(d18:1/18:0) and Cer(d18:1/20:0) by 33 and 78% respectively with respect to the surrounding neuropil. This accumulation of ceramides was not explained by their affinity for Aß deposits: no interaction between ceramide-liposomes and Aß fibrils was observed in vitro by surface plasmon resonance and fluorescent ceramide-liposomes showed no affinity for the senile plaques in AD brain tissue. Accumulation of ceramides could be, at least partially, the result of a local production by acid and neutral sphingomyelinases that we found to be present in the corona of the senile plaques.

Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes.

Enlarged early endosomes have been observed in neurons and fibroblasts in Down syndrome (DS). These endosome abnormalities have been implicated in the early development of Alzheimer's disease (AD) pathology in these subjects. Here, we show the presence of enlarged endosomes in blood mononuclear cells and lymphoblastoid cell lines (LCLs) from individuals with DS using immunofluorescence and confocal microscopy. Genotype-phenotype correlations in LCLs carrying partial trisomies 21 revealed that triplication of a 2.56 Mb locus in 21q22.11 is associated with the endosomal abnormalities. This locus contains the gene encoding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1), a key regulator of the signalling phospholipid phosphatidylinositol-4,5-biphosphate that has been shown to regulate clathrin-mediated endocytosis. We found that SYNJ1 transcripts are increased in LCLs from individuals with DS and that overexpression of SYNJ1 in a neuroblastoma cell line as well as in transgenic mice leads to enlarged endosomes. Moreover, the proportion of enlarged endosomes in fibroblasts from an individual with DS was reduced after silencing SYNJ1 expression with RNA interference. In LCLs carrying amyloid precursor protein (APP) microduplications causing autosomal dominant early-onset AD, enlarged endosomes were absent, suggesting that APP overexpression alone is not involved in the modification of early endosomes in this cell type. These findings provide new insights into the contribution of SYNJ1 overexpression to the endosomal changes observed in DS and suggest an attractive new target for rescuing endocytic dysfunction and lipid metabolism in DS and in AD.