NREM sleep hypersomnia and reduced sleep/wake continuity in a neuroendocrine mouse model of anxiety/depression based on chronic corticosterone administration.

Sleep/wake disorders are frequently associated with anxiety and depression and to elevated levels of cortisol. Even though these alterations are increasingly sought in animal models, no study has investigated the specific effects of chronic corticosterone (CORT) administration on sleep. We characterized sleep/wake disorders in a neuroendocrine mouse model of anxiety/depression, based on chronic CORT administration in the drinking water (35 µg/ml for 4 weeks, "CORT model"). The CORT model was markedly affected during the dark phase by non-rapid eye movement sleep (NREM) increase without consistent alteration of rapid eye movement (REM) sleep. Total sleep duration (SD) and sleep efficiency (SE) increased concomitantly during both the 24h and the dark phase, due to the increase in the number of NREM sleep episodes without a change in their mean duration. Conversely, the total duration of wake decreased due to a decrease in the mean duration of wake episodes despite an increase in their number. These results reflect hypersomnia by intrusion of NREM sleep during the active period as well as a decrease in sleep/wake continuity. In addition, NREM sleep was lighter, with an increased electroencephalogram (EEG) theta activity. With regard to REM sleep, the number and the duration of episodes decreased, specifically during the first part of the light period. REM and NREM sleep changes correlated respectively with the anxiety and the anxiety/depressive-like phenotypes, supporting the notion that studying sleep could be of predictive value for altered emotional behavior. The chronic CORT model in mice that displays hallmark characteristics of anxiety and depression provides an insight into understanding the changes in overall sleep architecture that occur under pathological conditions.

Correlation between improvement in functional signs and plethysmographic parameters during venoactive treatment (Cyclo 3 Fort).

AIM: The aim of this study was to compare the change in functional signs of venous insufficiency and venous refilling time measured by mercury strain-gauge plethysmography under the effects of the combination of Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort). METHODS: An open-label clinical trial conducted in 65 women presenting with CEAP class C2s and C3s assessment criteria. At D0 and D28, functional signs were measured on a visual analog scale (VAS), venous refilling time by mercury strain-gauge plethysmography and venous reflux by echo-Doppler method. RESULTS: Under treatment, venous refilling time increased from 11.7±4 s to 13.8±4.4 s with Δ of 26% (P<0.0001) and the percentage of patients showing improvement of functional symptoms ≥30% was significantly correlated (P=0.04) with the percentage of patients presenting an improvement in venous refilling time ≥10%. CONCLUSION: Improvement in subjective functional signs under treatment with Cyclo 3 Fort was correlated with objective plethysmographic parameter improvement. There-fore, this study contributes to objectively document the benefit of prescribing this venoactive drug to active women with CEAP class C2s to C3s.

The European Sleep Apnoea Database (ESADA): report from 22 European sleep laboratories.

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h(-1)) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m(-2)) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h(-1), p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

[Why and how to diagnose sleep respiratory disorders?]. / Pourquoi et comment diagnostiquer les troubles respiratoires du sommeil?

Gas exchange abnormalities occur firstly during sleep in restrictive and obstructive chronic respiratory failure. Nocturnal hypoxemia is often a revealing feature of a sleep-related hypoventilation/hypoxemia syndrome in patients who will have later a diurnal hypoxemia. On the other hand, sleep may induce breathing abnormalities in individuals without lung diseases, like in obstructive sleep apnea syndrome (OSAS). In OSAS, repeated closure and/or narrowing of the pharynx during sleep increases the inspiratory effort and induces sleep fragmentation. Intermittent hypoxemia is another consequence of the obstructive events in OSAS. Besides its direct consequences on sleep, OSAS is also associated with an increased risk of cardiovascular morbi-mortality. Reduced daytime alertness and cognitive functions are usually present in patients with sleep-disordered breathing. These features are believed to be related to both sleep fragmentation and nocturnal hypoxia/hypercapnia. Sleep-related hypoventilation/hypoxemia and pharyngeal obstructive events may occur together in patients with respiratory insufficiency, especially in obese and/or chronic obstructive pulmonary disease (COPD) subjects. A correct qualitative and quantitative assessment of sleep-disordered breathing may only be performed by recording specific physiological signals during sleep.

[Role of a health network dedicated to patient care for sleep disorders]. / Rôle d'un réseau de santé dans la prise en charge des troubles du sommeil.

The Réseau Morphée is a health network funded by the Regional Health Commission (Mission Régionale de Santé d'Ile-de-France). Its mission is to improve the management of sleep disorders via actions for the public, patients and health professionals. For patients suffering from sleep apnea, the network improves access to care and organises education and support groups for patients treated by Continuous Positive Airway Pressure (CPAP) in order to improve compliance. Health professionals can optimise patient care using an Internet based computerised consultation system which automatically incorporates sleep recording and CPAP reports. The expertise of the Morphée medical team is on hand at all times to help in the management of complex patients and expert advice from other members of the network is shared during regular patient management meetings. The réseau Morphée is certified as a continuing medical education (FMC) and clinical practice accreditation (EPP) organisation and so active members can validate both their FMC and EPP.

Ondansetron and fluoxetine reduce sleep apnea in mice lacking monoamine oxidase A.

Prospective clinical trials addressing the role of serotonin (5-HT) in sleep apnea have indicated that the 5-HT uptake inhibitor fluoxetine is beneficial to some patients with obstructive apnea, whereas the 5-HT(3) receptor antagonist ondansetron seems of little value despite its efficacy in rat and dog models of sleep apnea (central and obstructive). Here, we examined the effect of these drugs in transgenic mice lacking monoamine oxidase A (Tg8), which exhibit approximately 3-fold higher rates of central sleep apnea than their wild-type counterparts (C3H), linked to their enhanced 5-HT levels. Acute ondansetron (2 mg kg(-1), intraperitoneal), acute fluoxetine (16 mg kg(-1)) and 13-day chronic fluoxetine (1 or 16 mg kg(-1)) decreased by approximately 80% the total (spontaneous and post-sigh) apnea index in Tg8 mice during non-rapid eye movement sleep, with no statistically significant effect on apnea in C3H mice. Our study shows that both drugs reduce the frequency of apneic episodes attributable to increased monoamine levels in this model of MAOA deficiency, and suggests that both may be effective in some patients with central sleep apneas.

Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study.

The percentage of compliant continuous positive airway pressure (CPAP)-treated apnoeic patients that continue to experience residual excessive sleepiness (RES) is unknown. RES was defined by an Epworth Sleepiness Scale (ESS) score of >or=11. In total, 502 patients from 37 French sleep centres using CPAP >3 h night(-1) attending their 1-yr follow-up visit were eligible. ESS and polysomnographic data as well as symptoms, quality of life, depression scores and objective CPAP compliance at 1 yr were collected. Overall, 60 patients remained sleepy on CPAP (ESS 14.3+/-2.5) leading to a prevalence rate of RES of 12.0% (95% confidence interval (CI) 9.1-14.8). After having excluded associated restless leg syndrome, major depressive disorder and narcolepsy as confounding causes, the final prevalence rate of RES was 6.0% (95% CI 3.9-8.01). Patients with RES were younger and more sleepy at diagnosis. The relative risk of having RES was 5.3 (95% CI 1.6-22.1), when ESS before treatment was >or=11. Scores of emotional and energy Nottingham Health Profile domains were two times worse in patients with RES. As 230,000 obstructive sleep apnoea patients are currently treated in France by continuous positive airway pressure, more than 13,800 of them might suffer from residual excessive sleepiness.

Evaluation of autoCPAP devices in home treatment of sleep apnea/hypopnea syndrome.

BACKGROUND AND PURPOSE: Quality of life (QOL) and sleepiness for patients with sleep apnea/hypopnea syndrome (SAHS) might improve with continuous positive airway pressure devices working in auto-adjust mode (autoCPAP) by allowing pressure modulations following patient needs. Clinical comparisons between devices driven by different algorithms are needed. METHODS: We compared the clinical effectiveness of fixed pressure CPAP and four different autoCPAP devices by assessing compliance and QOL (36-item short-form health survey [SF-36]). SAHS patients were randomly allocated to five groups. Polysomnography (PSG) was performed to titrate the effective pressure in the constant CPAP group and evaluate residual apnea/hypopnea index (AHI) under autoCPAP. Follow-up consisted of clinical visits at three and six months by homecare technicians who assessed compliance, symptom scores and SF-36 scores. A laboratory-based PSG using the same CPAP/autoCPAP device as at home was performed at six months. RESULTS: Eighty-three patients (mean age 56+/-10 yrs) with mean body mass index (BMI) 30.8+/-5.3 kg/m(2) and severe SAHS (mean AHI: 52.3+/-17.8/h) were included. There were no differences in clinical symptoms or QOL scores, and similar clinical and PSG improvements were seen in all groups. CPAP use was >5 h per night, without any significant difference between groups. CONCLUSIONS: AutoCPAP is equally as effective as fixed CPAP for long-term home treatment in severe SAHS patients.

[Evaluation of a home respiratory polygraphy system in the diagnosis of the obstructive sleep apnea syndrome]. / Evaluation d'un système de polygraphie ventilatoire dans le syndrome d'apnées du sommeil.

INTRODUCTION: Recent recommendations advise against the use of portable home respiratory polygraphy systems for the diagnosis of the obstructive sleep apnoea syndrome (OSAS). Nevertheless such systems are widely used, particularly in France. Our aim was to assess the diagnostic value of one of these systems in the diagnosis of OSAS. METHODS: 65 consecutive patients were assessed prospectively, on account of suspicion of OSAS, by home respiratory polygraphy (HRP, Medcare Embletta). HRP confirmed severe OSAS [apnoea/hypopnoea index (AHI)>30/hr] in 8 patients. Those having AHI<30 hr or a failure of HRP (5 patients) were studied by full polysomnography in the sleep laboratory (PSG). RESULTS: In 52 patients the AHI obtained by HRP and analysed manually correlated weakly with that obtained by PSG (n=52; p<0.001; r=0.36). The AHI-PSG was 27.1+/-2.8/hr and the AHI-HRP was 12+/-0.9/hr. The mean difference (HRP-PSG) was 15.1+/-37.5/hr with poor concordance. A better cut off value in terms of efficacy of HRP was an AHI of 10/hr, with sensitivity of 61.4% and a specificity of 100%. CONCLUSION: A negative result by HRP does not exclude OSAS and full PSG is required in patients suspected of having this condition.

Chiari malformation and sleep related breathing disorders.

OBJECTIVE: To estimate the frequency, mechanisms and predictive factors of sleep apnoea syndrome (SAS) in a large group of children and adults with type I (CMI) and II (CMII) Chiari malformation (CM). BACKGROUND: The anatomical and functional integrity of both respiratory circuits and lower cranial nerves controlling the upper airway is necessary for breathing control during sleep. These latter structures may be altered in CM, and a few investigations have reported CM related sleep disordered breathing. METHODS: Forty-six consecutive unrelated patients with CM (40 CMI, six CMII), of which 20 were children (eight males) and 26 were adults (12 males), underwent physical, neurological and oto-rhino-laryngoscopic examination, MRI and polysomnography. RESULTS: SAS was present in 31 (67.4%) of the patients with CM (70% of CMI, 50% of CMII, including mainly children). Sixty per cent of children with CM exhibited SAS, including 35% with obstructive (OSAS) and 25% with central (CSAS) sleep apnoea syndrome. SAS was observed in 73% of CM adults (57.7% OSAS, 15.4% CSAS). Severe SAS was found in 23% of CM adults. Multiple regression analysis revealed that age, type II Chiari and vocal cord paralysis predicted the central apnoea index. CONCLUSION: SAS is highly prevalent in all age groups of patients suffering from CM. CSAS, a rare condition in the general population, was common among the patients with CM in our study. Sleep disordered breathing associated with CM may explain the high frequency of respiratory failures observed during curative surgery of CM. Our results suggest that SAS should be systematically screened for in patients with CM, especially before surgery.

Chemokine receptor expression on allergen-specific T cells in asthma and allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a rare variant of severe asthma resulting from hypersensitivity to Aspergillus fumigatus (Asp f) present in the airways. AIMS OF THE STUDY: We analyzed the expression of a panel of six chemokine receptors (CCR3, CCR4, CCR8, CCR5, CXCR3 and CXCR4) on total blood CD4(+) T cells and Asp f-specific-T cells in ABPA patients. We hypothesized that chemokine receptor pattern on T cells differs between ABPA patients, non-ABPA allergic asthmatics sensitized to Dermatophagoides pteronyssinus (Der p) or Phleum pratense (Phl p) and healthy controls. METHODS: We used the fluorescent dye PKH26, a membrane bound marker, to identify accumulated proliferating (cell-sorted PKH26(low)) CD4(+) T cells in response to allergens (Asp f, Der p, Phl p) or recall antigens (PPD and TT). Chemokine receptor expression was analyzed by flow cytometry on proliferating CD3(+) CD4(+) PKH26(low) cells. RESULTS: Stimulation of CD4(+) T cells with the relevant allergen resulted in different patterns of chemokine receptor expression in ABPA and non-ABPA allergic asthmatics. Upon Asp f exposure, proliferating CD4(+) T cells from ABPA patients down-regulated the expression of CCR4 and CXCR3 while CCR4 and CXCR3 were up-regulated in allergen-specific T cells from non-ABPA allergic asthmatics. Considering each group of patients, the pattern of chemokine receptors expressed on proliferating allergen-specific CD4(+) T cells was similar to that expressed by recall antigen-specific T cells. CONCLUSIONS: The down-regulation of CCR4 and CXCR3 after allergen exposure in Asp f-specific T cells seems to be a characteristic feature of ABPA patients and requires further evaluation.

Outcome of acetylcholinesterase deficiency for neuromuscular functioning.

Acetylcholinesterase (AChE) plays an essential role in neuromuscular transmission, therefore it is surprising that AChE knockout (KO) mice could live to the adulthood. Neuromuscular functioning in KO and normal (wild type, WT) mice were studied, at different age (1.5-, 4- and 9-month-old). Hindlimb muscle force productions in response to nerve or muscle electric stimulation were recorded in situ and in vitro. Our results show that contrary to WT mice, 1.5-, 4- and 9-month-old KO mice exhibited a decreased in tetanic force during short periods (500 ms) of repetitive nerve stimulations (tetanic fade). Nevertheless submaximal muscle forces in response to single or repetitive nerve stimulation were increased (potentiation) in 1.5-, 4- and 9-month-old KO mice as compared to WT mice (p<0.05). Tetanic fade and potentiation were absent when muscles were directly stimulated, indicating neuromuscular transmission alterations in KO mice. Contrary to younger mice, muscle weight and maximal tetanic force in response to repetitive nerve stimulation were not reduced in 4- and 9-month-old KO mice as compared to WT mice (p>0.05). In conclusion AChE deficit leads to marked neuromuscular alterations in hind limb muscle functioning and a prominent symptom is the lack of resistance to fatigue.

Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.

OBJECTIVE: To compare compliance with and effectiveness of adaptive servoventilation (ASV) versus continuous positive airway pressure (CPAP) in patients with the central sleep apnoea syndrome (CSA) with Cheyne-Stokes respiration (CSR) and with congestive heart failure in terms of the apnoea-hypopnoea index (AHI), quality of life, and left ventricular ejection fraction (LVEF) over six months. METHODS: 25 patients (age 28-80 years, New York Heart Association (NYHA) class II-IV) with stable congestive heart failure and CSA-CSR were randomly assigned to either CPAP or ASV. At inclusion, both groups were comparable for NYHA class, LVEF, medical treatment, body mass index, and CSA-CSR. RESULTS: Both ASV and CPAP decreased the AHI but, noticeably, only ASV completely corrected CSA-CSR, with AHI below 10/h. At three months, compliance was comparable between ASV and CPAP; however, at six months compliance with CPAP was significantly less than with ASV. At six months, the improvement in quality of life was higher with ASV and only ASV induced a significant increase in LVEF. CONCLUSION: These results suggest that patients with CSA-CSR may receive greater benefit from treatment with ASV than with CPAP.

Bench testing of auto-adjusting positive airway pressure devices.

Continuous positive airway pressure devices are routinely used to treat sleep breathing disorders. Automated devices that adjust the therapeutic pressure have recently been proposed. The utility of such devices is still controversial, as rigorous clinical comparisons are difficult to perform as a result of patient and device differences. The current authors studied automated devices in a respiratory model that was able to mimic upper airway mechanics and to interact with pressure adjustment in a closed loop. Five auto-adjusted devices were submitted to this model, in order to determine their ability to detect respiratory events and adjust pressure accordingly. All apnoeas were suppressed, whilst the reaction to repetitive hypopnoeas was dependent on the airflow shape. In some devices, repetitive hypopnoeas were changed to flow limitation. Artificial snoring caused a pressure increase in four devices, and constant mask leak was not systematically compensated. Only one device did not raise pressure in response to central apnoeas with opened upper airways. These findings show that, in some devices, event classification failed and normal airflow was not fully restored, resulting in elevated residual event indices. In conclusion, this model is useful in order to reproducibly compare diagnostic and therapeutic capacities of commercial devices as a first step, before costly clinical studies.

Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice.

To investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control.

[Nasal obstruction and compliance to nasal positive airway pressure]. / Obstruction nasale et compliance à la ventilation nasale à pression positive.

UNLABELLED: Obstructive sleep apnea syndrome is a very common disease. Nasal continuous positive airway pressure is a useful and efficient treatment but compliance depends on several factors including the degree of nasal obstruction. OBJECTIVES: The aim of this study was to evaluate the effects of surgical correction of nasal obstruction on compliance to nasal continuous positive airway pressure in obstructive sleep apnea syndrome. MATERIAL AND METHODS: This retrospective study (from March 1998 to March 2000) included ten patients suffering from a severe obstructive sleep apnea syndrome (apnea-hypopnea index greater than 30 per hour) treated by nasal continuous positive airway pressure for at least three months and presenting an anatomic nasal obstruction limiting the use of nasal continuous positive airway pressure. Surgical procedures included one septoplasty, two inferior turbinectomies and seven septoplasties with turbinectomies. RESULTS: The post-operative polysomnography showed that surgical correction of nasal obstruction had no effect on obstructive sleep apnea syndrome severity (no significative change of apnea hypopnea index after surgery) but allowed the use of lower nasal continuous positive airway pressure levels (7.1 mmHg after surgery versus 10 mmHg before) and improved compliance to treatment (six compliant patients after surgery versus no compliant patient before). These results were compared with those published in the literature. CONCLUSION: An examination of the nose has to be performed before initiating nasal continuous positive airway pressure. If nasal continuous positive airway pressure cannot be tolerated because of nasal obstruction, surgery is required to improve compliance and tolerance to treatment.