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Spa therapy is recommended to manage symptoms of fibromyalgia, but the physiological mechanisms underlying this improvement have been poorly studied. In an original study, we explored the effect of a 3-week rheumatology spa treatment for fibromyalgia patients on quality of life and with a symptom severity questionnaire. We present here the results of an ancillary study which explored three secondary criteria using objective measurement methods: diurnal actimetry for physical activity analysis, nocturnal actimetry for sleep analysis and heart rate variability. Eighty-three fibromyalgia patients were randomized to participate in an immediate 3-week rheumatological spa therapy, either a start within 6 weeks after inclusion (interventional group, n = 39) or a delayed, start 6 months after inclusion (control group, n = 44). Patients were asked to wear an actimeter (n = 56) to assess diurnal physical activity and sleep quality and a 24-h Holter ECG (n = 60) to assess nocturnal heart rate variability at baseline, 3 months and 6 months after inclusion. Time spent in sedentary and light physical activity was reduced to ∼30 min at 6 months in the interventional group (P = 0.027). Sleep quality and heart rate variability were not improved. Spa therapy made it possible to reduce sedentary activities in patients' daily life for up to 6 months afterwards, concomitant with the improvement in quality of life, pain and fatigue as highlighted in the original Thermalgi study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae., (© 2023 Wiley Periodicals LLC.)

Objectives: In our clinical research center, a 27 multiple-choice and 3 verbatim questions satisfaction questionnaire has been used since 2008 in order to assess the satisfaction of the volunteers participating in our studies. In this work, we aimed at reducing the number of questions of this cumbersome questionnaire while exploring the same dimensions., Materials and Methods: We used k-mean and hierarchical clustering to determine which questions provided the same information or, on the contrary, which questions were able to discriminate a satisfied volunteer from an unsatisfied volunteer., Results: We were able to reduce our satisfaction questionnaire from 30 questions to 6 closed-ended and 2 open-ended questions, which will allow to save volunteers time while increasing their participation rate., Conclusion: This questionnaire could be used in other structures practicing clinical research, as part of their quality process., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Fibromyalgia is a common chronic pain pathology with an incidence of 4.3 per 1,000 person-years. An open, randomized clinical trial of patients with fibromyalgia comparing an immediate vs. delayed 18-day spa therapy in five spa therapy care facilities in France enrolled 220 patients. Randomization was in blocks of four, stratified by center, severity of fibromyalgia and previous spa therapy. Patients continued usual treatment. The main endpoint was the number of patients achieving minimal clinically important difference at 6 months, defined as 14% change in their baseline fibromyalgia impact questionnaire score. The intention-to-treat analysis included 100 and 106 patients in the intervention and control groups, respectively. At 6 months, 45/100 (45.0%) and 30/106 (28.3%) patients in the intervention and control groups, respectively, achieved a minimal clinically important difference (P= .013). There was also a significant improvement in pain, fatigue, and symptom severity (secondary outcomes) in the intervention group but not for generic quality of life (QOL), sleep or physical activity. None of the 33 serious adverse events reported by 25 patients were related to the spa therapy. Our results demonstrate the benefit of spa treatment in patients with fibromyalgia. PERSPECTIVE: A 12-month, open, randomized clinical trial of 220 patients with fibromyalgia compared an immediate versus delayed (ie, after 6 months) 18-day spa therapy. The results showed a clinically significant improvement at 6 months for those who received immediate therapy which was maintained up to 12 months. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02265029., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Insulin resistance (IR), currently called prediabetes (PD), affects more than half of the adult population worldwide. Type 2 diabetes (T2D), which often follows in the absence of treatment, affects more than 475 million people and represents 10-20% of the health budget in industrialized countries. A preventive public health policy is urgently needed in order to stop this constantly progressing epidemic. Indeed, early management of prediabetes does not only strongly reduce its evolution toward T2D but also strongly reduces the appearance of cardiovascular comorbidity as well as that of associated cancers. There is however currently no simple and reliable test available for the diagnosis or screening of prediabetes and it is generally estimated that 20-60% of diabetics are not diagnosed. We therefore developed an ELISA for the quantitative determination of serum Insulin-Regulated AminoPeptidase (IRAP). IRAP is associated with and translocated in a stoechiometric fashion to the plasma membrane together with GLUT4 in response to insulin in skeletal muscle and adipose tissue which are the two major glucose storage sites. Its extracellular domain (IRAPs) is subsequently cleaved and secreted in the blood stream. In T2D, IRAP translocation in response to insulin is strongly decreased. Our patented sandwich ELISA is highly sensitive (≥10.000-fold "normal" fasting concentrations) and specific, robust and very cost-effective. Dispersion of fasting plasma concentration values in a healthy population is very low (101.4 ± 15.9 μg/ml) as compared to those of insulin (21-181 pmol/l) and C-peptide (0.4-1.7 nmol/l). Results of pilot studies indicate a clear correlation between IRAPs levels and insulin sensitivity. We therefore think that plasma IRAPs may be a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for PD and T2D, thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trocmé, Gonnet, Di Tommaso, Samouda, Cracowski, Cracowski, Lambert-Porcheron, Laville, Nobécourt, Gaddhab, Le Lay, Bohn, Poitou, Clément, Al-Mulla, Bitar and Bottari.)

Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC 0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC 0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer., (© 2020, The American College of Clinical Pharmacology.)

Background: Exposure to certain synthetic phenols is of growing concern, in particular among pregnant women, because of their endocrine disrupting nature. Many phenols are still authorized in personal care products (PCP). We aimed to assess if use of PCPs, by pregnant women could influence their urinary concentrations of synthetic phenols., Methods: We used a panel design with intense urine sample collection. Eight women completed a diary with exact time and use of PCPs in three weeks. We measured the concentrations of phenols (four parabens, bisphenol A and S, two dichlorophenols, triclosan, and benzophenone-3) in 178 urine samples, collected during 7 consecutive days at 3 time points during pregnancy. We characterized PCP use as the total number of PCP applications or as a single PCP use (yes/no) in three time windows (0-6, 6 to 12 and 12 to 24h before each urine sample collection). We used adjusted linear and Tobit regressions to assess associations between PCP use and phenol urinary concentrations., Results: The total number of PCP applications was positively associated with ethylparaben, propylparaben and butylparaben concentrations. We observed a peak in urinary concentration of ethylparaben, butylparaben and propylparaben at 2.86, 2.55 and 2.67 h since last PCP use, respectively and twelve different types of PCPs were positively associated with at least one of these parabens. The bisphenol S concentration increased by 12.4% (95%CI: confidence interval: 5.9; 19.3) for each additional PCP application in the 12 to 24 time window and use of specific PCPs such as anti-stretchmarks cream, facial cleanser and shower gel. Associations varied by time window., Conclusion: Our study showed that PCP use was associated with a short-term increase in the urinary concentration of ethylparaben, butylparaben and propylparaben, but not methylparaben. This study also reported a positive association between the use of PCPs and the bisphenol S concentration, a finding that warrants further investigation in cohorts with repeated collection of urine samples and detailed information on PCP use., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The Raynaud's condition score is a 11-point scale severity score used in Raynaud's phenomenon clinical trials since 1998. The Raynaud's condition score diary has been recommended for use in clinical trials assessing efficacy of interventions on scleroderma related Raynaud's phenomenon. However, this score has never been formally validated in French. We thus performed a translation and a linguistic validation of the Raynaud's condition score through a forward/backward translations process followed by an expert review and cognitive patient interviews. The translations led to a French version of the Raynaud's condition score that was linguistically valid, and conceptually equivalent to the original English version. This "Score de Raynaud" will be usable to perform and harmonize clinical trials in French-speaking patients with secondary Raynaud's phenomenon., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative., Objective: To assess the efficacy and safety of on-demand sildenafil in RP., Design: Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360)., Setting: Outpatients at a French university hospital., Participants: Patients with primary or secondary RP., Intervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily., Measurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy., Results: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients., Limitation: The response to sildenafil was substantially heterogeneous among patients., Conclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP., Primary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

Introduction: Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling., Methods: Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of treprostinil (2.56 × 10(-4) M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8 °C, and skin blood flow was recorded continuously using LSCI., Results: During the local cooling, CVC was significantly higher at the treprostinil site than at the placebo site and remained higher 30 minutes after the test., Conclusions: In patients with SSc, digital treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital treprostinil iontophoresis should now be tested in larger scale studies., (© 2016 John Wiley & Sons Ltd.)

Studies of air pollution effects during pregnancy generally only consider exposure in the outdoor air at the home address. We aimed to compare exposure models differing in their ability to account for the spatial resolution of pollutants, space-time activity and indoor air pollution levels. We recruited 40 pregnant women in the Grenoble urban area, France, who carried a Global Positioning System (GPS) during up to 3 weeks; in a subgroup, indoor measurements of fine particles (PM2.5) were conducted at home (n=9) and personal exposure to nitrogen dioxide (NO2) was assessed using passive air samplers (n=10). Outdoor concentrations of NO2, and PM2.5 were estimated from a dispersion model with a fine spatial resolution. Women spent on average 16 h per day at home. Considering only outdoor levels, for estimates at the home address, the correlation between the estimate using the nearest background air monitoring station and the estimate from the dispersion model was high (r=0.93) for PM2.5 and moderate (r=0.67) for NO2. The model incorporating clean GPS data was less correlated with the estimate relying on raw GPS data (r=0.77) than the model ignoring space-time activity (r=0.93). PM2.5 outdoor levels were not to moderately correlated with estimates from the model incorporating indoor measurements and space-time activity (r=-0.10 to 0.47), while NO2 personal levels were not correlated with outdoor levels (r=-0.42 to 0.03). In this urban area, accounting for space-time activity little influenced exposure estimates; in a subgroup of subjects (n=9), incorporating indoor pollution levels seemed to strongly modify them., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Peripherally inserted central catheters (PICC) are more and more used for intravenous antibiotic infusions in cystic fibrosis (CF) patients in the Grenoble area (France). The aim of this study was to assess the use of this technique in this indication., Methods: 1. Retrospective evaluation of 102 consecutive PICC insertions over 3years and the incidence of adverse events during the therapy. 2. Prospective evaluation of 12 patient's satisfaction and their nurses over a 3-month period. 3. Comparative analysis of single domiciliary treatment costs using PICC versus peripheral catheter (PC)., Results: 102 PICC insertions were attempted in 31 patients. Seven failures and 7 complications occurred during the treatment requiring removal of the PICC, i.e. an overall success rate of 86.2% (88/102). Pain during PICC introduction was 4.2/10 (visual analogical scale). Mean satisfaction levels during therapy were 9.3/10 for patients and 8.7/10 for nurses. Compared with PC, all the patients said that PICC was "more comfortable". Differential costs of treatment with PC and with PICC at home were estimated at 57.15€ and 590.16€ respectively., Conclusion: PICC is an alternative to CP for intravenous antibiotherapy in CF patients, providing better safety and comfort. PICC use should be promoted in this indication., (Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynaud's phenomenon (PRP) and healthy controls., Methods: Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand., Results: Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction)., Conclusions: We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynaud's phenomenon secondary to SSc., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

Background: We investigated the effect of neuromuscular electrical stimulation (NMES) training prior to endurance training in patients with cystic fibrosis (CF) and severe pulmonary obstruction., Methods: Fourteen patients with CF (FEV(1) = 35% ± 11% predicted) were prospectively randomized to either a 6-week NMES training program (n = 7) or a 6-week control period (n = 7) both followed by ergocycle (ERGO) training (8 weeks) (NMES + ERGO and control + ERGO groups). Measurements were pulmonary function, mid-thigh circumference, quadriceps strength, 6-min walk distance, maximal exercise capacity on a cycloergometer, plasma biomarkers, insulin resistance (homeostasis model assessment indexes), and quality of life (CF questionnaire for adults and teenagers > 14 years of age [CFQ14 + ], Baseline Dyspnea Index-Transition Dyspnea Index)., Results: NMES + ERGO training greatly improved mid-thigh circumference ( + 2.6 ± 0.9 cm vs - 0.4 ± 1.4 cm), quadriceps strength ( + 6 ± 5 kg vs - 2 ± 2 kg), and BMI ( + 0.6 ± 0.6 kg/m(2) vs - 0.5 ± 0.7 kg/m(2) ) compared with control + ERGO training ( P < .05). No differences between groups were found in exercise-induced changes in 6-min walk distance and maximal exercise capacity. However, dyspnea after the 6-minute walk test, the fasting glucose/insulin ratio (calculated as an index of insulin resistance), and physical function and health perception domains of the CFQ14 + improved after NMES + ERGO training compared with control + ERGO training ( P < .05). Significant correlations were found between changes in mid-thigh circumference and muscle strength, ventilation requirements during exercise, insulin sensibility, and the physical function section of CFQ14 + ( P < .05)., Conclusions: NMES training performed prior to endurance training is useful for strengthening peripheral muscles, which in turn may augment gains in body weight and quality of life, further reductions in ventilation requirements during exercise, and retard insulin resistance in patients with CF with severe pulmonary obstruction.

Several mediators contribute to postocclusive reactive hyperemia (PORH) of the skin, including sensory nerves and endothelium-derived hyperpolarizing factors. The main objective of our study was to investigate the specific contribution of epoxyeicosatrienoic acids in human skin PORH. Eight healthy volunteers were enrolled in two placebo-controlled experiments. In the first experiment we studied the separate and combined effects of 6.5 mM fluconazole, infused through microdialysis fibers, and lidocaine/prilocaine cream on skin PORH following 5 min arterial occlusion. In the second experiment we studied the separate and combined effects of 6.5 mM fluconazole and 10 mM N(G)-monomethyl-l-arginine (l-NMMA). Skin blood flux was recorded using two-dimensional laser speckle contrast imaging. Maximal cutaneous vascular conductance (CVC(max)) was obtained following 29 mM sodium nitroprusside perfusion. The PORH peak at the placebo site averaged 66 ± 11%CVC(max). Compared with the placebo site, the peak was significantly lower at the fluconazole (47 ± 10%CVC(max); P < 0.001), lidocaine (29 ± 10%CVC(max); P < 0.001), and fluconazole + lidocaine (30 ± 10%CVC(max); P < 0.001) sites. The effect of fluconazole on the area under the curve was more pronounced. In the second experiment, the PORH peak was significantly lower at the fluconazole site, but not at the l-NMMA or combination site, compared with the placebo site. In addition to sensory nerves cytochrome epoxygenase metabolites, putatively epoxyeicosatrienoic acids, play a major role in healthy skin PORH, their role being more important in the time course rather than the peak.

Objectives: The aim of the study was to evaluate sleep quality and nocturnal gas exchange in patients with cystic fibrosis (CF) and to assess if sleep quality and daytime lung function could predict nocturnal hypoxaemia or hypercapnia., Study Design: Daytime sleepiness and objective sleep quality were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and actigraphy in 25 children and 55 young adults (mean age 24±10 years, forced expiratory volume in 1 s (FEV(1)) 41±11% predicted). Nocturnal gas exchange was assessed by pulse oximetry (SpO(2)) and transcutaneous carbon dioxide (PtcCO(2)) recordings. Eleven patients underwent simultaneous polysomnography (PSG)., Results: PSQI was 6.3±3.4 with 51% of the patients having a score >5 corresponding to significant sleep complaints. On actigraphy, sleep efficiency was impaired at 79±11% with a fragmentation index at 41±18. Mean nocturnal SpO(2) was 93±3% with 18% of the patients exhibiting >10% of night time spent with a value below 90%. Mean PtcCO(2) was 44±6 mm Hg with 47% of the patients exhibiting >10% of night time with a value >45 mm Hg. Daytime arterial blood gases correlated with nocturnal gas exchange. FEV(1) was the only lung function parameter that correlated with nocturnal SpO(2) (p<0.01). Compared with PSG, SpO(2) and PtcCO(2) accurately identified rapid eye movement sleep hypoventilation., Conclusions: Patients with CF exhibit poor sleep quality that does not predict nocturnal gas exchange. Nocturnal hypoxaemia and hypercapnia can be identified by simple tools.

Objectives: Within the past decade, biochemical markers have emerged as attractive tools to assess pulmonary arterial hypertension (PAH) prognosis, being noninvasive and easily repeatable.The objective of this study was to determine whether biomarkers measured at initial diagnostic right-sided heart catheterization predict 3-year all-cause mortality for incident cases of PAH independently of clinical and hemodynamic parameters., Methods: Patients with incident PAH were enrolled between December 2003 and April 2006 in six centers from the French Network on Pulmonary Hypertension and followed for 3 years.Venous blood samples were taken during right-sided heart catheterization, and analyses were centralized., Results: Among 110 enrolled patients, 11 underwent lung or heart/lung transplantation, and 27 died during follow-up. The Kaplan-Meier estimates of survival were 91%, 78%, and 75% at 1, 2, and 3 years, respectively. Plasma big endothelin-1 (hazard ratio [HR] per 1-SD increase, 1.48; 95% CI,1.14-1.92), serum troponin T . 0.01 mg/L (HR, 2.35; 95% CI, 1.05-5.29), and urinary F 2 -isoprostanes(15-F2t -isoprostane) (HR per 1-SD increase, 1.76; 95% CI, 1.31-2.36) were associated with increased unadjusted hazard of death. In multivariate analysis adjusting for patient characteristics, the level of urinary F 2 -isoprostanes was the only biomarker that remained independently associated with increased hazard of death (HR per 1-SD increase, 1.82; 95% CI, 1.28-2.60)., Conclusions: This study shows that levels of urinary F 2 -isoprostane, a biomarker of lipid peroxidation,quantified at initial diagnostic right-sided heart catheterization are independently associated with mortality in a cohort of patients with incident PAH.

Digital skin vasoconstriction on local cooling is exaggerated in primary Raynaud's phenomenon (RP) as compared with controls. A significant part of such vasoconstriction relies on the inhibition of the nitric oxide (NO) pathway. We tested the effect of the phosphodiesterase 5 (PDE5) inhibitor sildenafil, which potentiates the effect of NO, on skin blood flow. We recruited 15 patients with primary RP, performing local cooling without sildenafil (day 1), after a single oral dose of 50 mg (day 2), and after a dose of 100 mg (day 3). Skin blood flow, skin temperature, and arterial pressure were recorded, and data were expressed as cutaneous vascular conductance (CVC). Sildenafil at 100 mg, but not 50 mg, significantly lessened the cooling-induced decrease in CVC. It also increased resting CVC and skin temperature. These data suggest that 100 mg sildenafil improves digital skin perfusion during local cooling in primary RP. The benefit of sildenafil "as required" should be confirmed in a randomized, controlled trial.

Introduction: The French cystic fibrosis (CF) practice recommendations were published at the end of 2002. They advise each patient to be checked up at least once every 3 months in a reference centre for cystic fibrosis., Objective: To describe the activity of the four reference centres in the Rhône-Alpes area and the patients' follow-up., Methods: All patients with cystic fibrosis consulting one of the four CF centres between 1996 and 2005 were retrospectively included. All outpatient visits were recorded and classified according to (i) patient and year; and (ii) month and year. The two series were assessed graphically to determine a transition threshold, that is, the 2 consecutive years between which practices differed the most., Results: A total of 616 patients were included, representing 17 594 outpatient visits. The average number of visits per patient increased from 3.7 in 1996 to 5.0 in 2005, the graphical representation showed a sharp change between 2000 and 2001. Among patients with less than 4 visits in 2000, 88 of them visited a centre 4 times or more in 2001 (44%). The annual number of outpatient visits went from 1035 to 2420. The monthly average number of outpatient visits was 86 in 1996 and 202 in 2005. The graphical representation of activity also showed a sharp change from 2001., Conclusion: We showed that the implementation of guidelines occurred the year before its official publication. We also showed that the growth of this implementation was sharp rather than gradual., (© 2010 Blackwell Publishing Ltd.)

Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=-0.36, P=0.01). Patients in the lowest PAT tertile (<101 ms) had lower FEV1 and worse nocturnal oxygen saturation, and they were more often on the lung transplant waiting list compared to patients in the other tertiles. Kaplan-Meier curves showed a shorter time to lung transplantation in the lowest PAT tertile (P<0.001) but not in patients with sPAP>35 mmHg. By multivariate analysis, FEV(1)and nocturnal desaturation were the main determinants of reduced PAT. A PAT<101 ms reduction is a promising tool for timing of lung transplantation in CF.

Objective: Laser speckle contrast imaging (LSCI) can be used to assess real-time responses of skin microcirculation to pharmacological interventions. The main objective of this study was to determine whether intradermal or subdermal microdialysis fiber insertion, coupled with skin flux recording using LSCI, can be used to assess baseline cutaneous flux and the post-occlusive reactive hyperemic response. The microdialysis sites were compared to control area without microdialysis fibers., Methods: One dermal and two subdermal microdialysis fibers were randomly inserted in the right forearm skin of six healthy volunteers. We performed consecutively tests of post-occlusive hyperemia, infusion of 29 mM sodium nitroprusside (SNP), local thermal hyperemia at 43°C and a second 29 mM SNP infusion at the end of the experiment., Results: Two hours after fiber insertion, cutaneous vascular conductances (CVC) at the subdermal fiber sites were not different from their respective control regions of interest, while at the dermal site CVC remained higher (0.48+/-0.15 versus 0.37+/-0.1 PU.mm Hg(-1), P=0.003). The peak CVC and area under the curve observed during post-occlusive reactive hyperemia were similar at all fiber sites and their respective controls. We observed a similar increase in CVC using 29 mM SNP infusion, 40 min local heating at 43°C, and their combination. Finally, physiological and pharmacological responses of the subdermal sites were reproducible in terms of amplitude, whether expressed as raw CVC or as % CVCmax., Conclusions: We showed that studying skin microvascular physiological or pharmacological responses using inserted subdermal microdialysis fibers coupled with LSCI is feasible and reproducible, and provides two-dimensional information. This technique will be useful for future mechanistic studies of skin microcirculation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In France patients with cystic fibrosis benefit from a multidisciplinary follow-up in Cystic Fibrosis Centres. In this follow-up, despite the numerous therapeutic benefits of exercise in this disease, little emphasis is placed on the promotion of physical activity. The aim of this article is to improve this aspect of management, giving advice from a working group of experts, based on the medical literature and clinical experience. These proposals include quantification of physical activity, evaluation of exercise, training and rehabilitation programs and finally, modification of behaviour to include physical activity in the overall cystic fibrosis treatment strategy. It is intended to set up multicentre studies to evaluate the impact of these proposals., (Copyright 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Current guidelines for referring cystic fibrosis (CF) patients for lung transplantation, based on resting parameters, are insufficient to predict 3-year mortality. The aim of this study was to determine the prognostic value of cardiopulmonary exercise testing (CPET) in adult CF patients., Methods: A multicenter retrospective study on 3-year outcomes was made on 51 adult CF patients who underwent CPET with blood gas analysis. Demographic data, resting pulmonary function and CPET parameters were collected to perform a univariate survival analysis by Kaplan-Meier curves and log-rank tests. To estimate prognosis, a multivariate logistic regression analysis was performed., Results: The survival log-rank analysis indicated that lower FEV(1), lower body mass index (BMI), diabetes mellitus, lower work rate and higher alveolar-arterial gradient for oxygen (P[A-a]O(2)) at peak exercise were associated with a significantly higher risk of death. The logistic regression analysis showed that BMI (<19.8) and P(A-a)O(2) peak (>43 mmHg) were independently associated with a lower chance of survival., Conclusion: CPET with blood gas analysis may have a prognostic value in adult CF patients. Further larger prospective clinical studies are warranted to confirm these preliminary results., (Copyright 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The present multicenter, randomized crossover study compared the safety and efficacy of continuous infusion with those of short infusions of ceftazidime in patients with cystic fibrosis. Patients with chronic Pseudomonas aeruginosa colonization received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The primary endpoint was the variation in the forced expiratory volume in 1 s (FEV1) during the course of antibiotic treatment. Sixty-nine of the 70 patients enrolled in the study received at least one course of antibiotic treatment. The improvement in FEV1 at the end of therapy was not statistically different between the two treatment procedures (+7.6% after continuous infusion and +5.5% after short infusions) but was better after continuous ceftazidime treatment in patients harboring resistant isolates (P < 0.05). The interval between the course of antibiotic treatments was longer after the continuous infusion than after the short infusion of ceftazidime (P = 0.04). The mean serum ceftazidime concentration during the continuous infusion was 56.2 +/- 23.2 microg/ml; the mean peak and trough concentrations during the short infusions were 216.3 +/- 71.5 and 12.1 +/- 8.7 microg/ml, respectively. The susceptibility profiles of the P. aeruginosa isolates remained unchanged and were similar for both regimens. Quality-of-life scores were similar whatever the treatment procedure, but 82% of the patients preferred the continuous-infusion regimen. Adverse events were not significantly different between the two regimens. In conclusion, the continuous infusion of ceftazidime did not increase its toxicity and appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harboring resistant isolates of P. aeruginosa.

Lung transplantation (LT) is a recognized procedure for selected patients with end-stage respiratory failure. We performed 123 LT, including 32 single lung, 84 double lung, and 7 heart-lung transplantations in 48 patients with chronic obstructive pulmonary disease (COPD), 13 patients with pulmonary hypertension (PH), 33 with cystic fibrosis (CF), and 29 with interstitial lung disease (ILD) between July 1990 and January 2008. Survival was compared for periods before and after December 2001. The mean age of patients was 44.4 years (range 16-66.5 years); 84 (69%) were men. Before LT, 1 second forced expiratory volume was 28.7% +/- 18.1% and PaCO(2) = 6.3 kPa. Fifty-five patients were on noninvasive ventilation. Cold ischemia time was 320 +/- 91 minutes. Cardiopulmonary bypass (CPB) was used in 77 patients (64%). There were 18 early surgical reinterventions, 8 extracorporeal membrane oxygenations, and 38 bronchial stent insertions among 206 at-risk bronchial sutures. Crude survivals were 69%, 58%, 41%, and 18% at 1, 2, 5, and 10 years, respectively. Comparing before (n = 70 with 15 CF) vs after December 2001 (n = 53 with 17 CF), survivals were 63% vs 78%, 51% vs 71%, and 33% vs 60% at 1, 2, and 5 years, respectively (P = .01) and for CF patients, 52% vs 100%, 52% vs 94%, and 25% vs 94% at 1, 2, and 5 years, respectively (P = .005). There was significant improvement in survival before and after 2001 in 123 LT and particularly among CF patients. Improvement in survival after LT may be related to the sum of numerous changes in our practice since December 2001, including the use of pulmonary rehabilitation pre-LT, extracellular pneumoplegia, statins, macrolides for chronic rejection, monitoring of Epstein-Barr blood load, changes in maintenance immunosuppressants, as well as position movement up the coordinator nurse and learning curve.

Background: No guidelines are available for noninvasive ventilation (NIV) for cystic fibrosis (CF)., Objective: To survey and evaluate the use of NIV for CF in France., Methods: We surveyed the coordinator physicians of every accredited CF center in France., Results: The respondents represented 36 centers (15 pediatric centers, 13 adult centers, and 8 centers that see both pediatric and adult patients), which had a total of 4,416 patients with CF at the time of the study, 168 (3.8%) of whom were using NIV. NIV was being used more often in the adults centers (7.6% of these patients) than in the pediatric centers (1.2% of these patients) or adult-and-pediatric centers (4.1% of these patients) (P= .01). All the respondent centers use NIV as first-line treatment for severe hypercapnic respiratory exacerbation and for stable diurnal hypercapnia, especially when associated with sleep disturbance. Bi-level pressure-targeted ventilation is the preferred ventilation mode. Settings are adjusted based on arterial blood gas values, noninvasive evaluation of patient-ventilator synchrony, patient comfort, and sometimes a sleep study. The surveyed centers reported a number of expected benefits from NIV, but few of those benefits have been proven. Problems with NIV are common and limit its use., Conclusions: We found a relative homogeneity in these French centers' stated indications for and use of NIV, which highlights their numerous expectations about the benefits of NIV, which contrasts with the few validated benefits. Studies of the benefits of NIV are needed.

Patients with cystic fibrosis (CF) experience repeated infectious respiratory exacerbations leading to a continuous decline in lung function. The exacerbations are treated in hospital or at home. Our aim was to compare the clinical outcome for patients undergoing intravenous antibiotic treatment either in hospital or at home. A retrospective 10-year study was performed in four regional CF Centers. The outcome measures were percentage changes in forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC) and weight for age z-score (WZS). FEV(1), FVC, and WZS changes were calculated for the entire study period and for each course. A total of 1,164 courses were analyzed. For each course, the mean improvement in FEV(1) and FVC was significantly higher when performed in hospital than when performed at home (P < 0.05). FEV(1) and FVC values were 10.2%, 9.5% respectively in the hospital group and 7.3%, 6.8% in the home group. A total of 153 patients were analyzed (51 inpatients matched to 102 patients treated at home). The two groups had no significant differences in any outcome variable at baseline. The mean variation per year in FEV(1) was greater in the hospital group versus the home group (-0.4% vs. -1.8%; P = 0.03). The mean variation per year in WZS was greater in the hospital group versus the home group (P < 0.01). Clinical outcome, as defined by spirometric parameters and body weight, was better after a course of treatment in hospital than after a home treatment. This benefit was maintained throughout of the study period., ((c) 2008 Wiley-Liss, Inc.)

Current Situation: Pulmonary arterial hypertension (PAH) is a serious disease. Its prognostic is based on the functional status quantified by the NYHA class and the 6-min walking test, and the hemodynamic data. The algorithms of treatment are solely based on the hemodynamic data and the functional status. The main objective is to test whether basal concentrations of isoprostanes, Big endotheline 1, ADMA, high sensitivity CRP, NT-Pro-BNP and cardiac troponin T are a 3-year prognostic factor in PAH using a combined criterion: death from any cause and pulmonary or cardiopulmonary transplantation., Materials and Methods: This is a multicenter, prospective, prognostic, single blinded study (plasma and urinary samples being blinded). The study started in november 2003, running for 2 years, with a 3 year follow-up for each patient. The main inclusion criterion is PAH. The data analysis will use a multivariable Cox model, taking into account the functional and hemodynamic parameters., Expected Results: This study will determine whether any of the biomarkers tested provides additional prognostic information in PAH in addition to the functional and hemodynamic parameters.

Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of isoprostaglandin F(2alpha) type III (iPF(2alpha)-III), an F(2)-isoprostane, in patients with pulmonary hypertension (PHT) in comparison with healthy controls. The secondary objective was to test whether baseline iPF(2alpha)-III levels correlate to the reversibility of pulmonary hypertension in response to inhaled NO challenge. Urinary iPF(2alpha)-III levels were measured by gas chromatography-mass spectrometry in 25 patients with PHT, 14 of whom were investigated for response to inhaled NO challenge. Urinary iPF(2alpha)-III levels in PHT patients (225 +/- 27 pmol/mmol creatinine) were 2.3 times as high as in controls (97 +/- 7 pmol/mmol creatinine, p < 0.001). The mean pulmonary arterial pressure variation and the pulmonary vascular resistance variation in response to inhaled NO were correlated to basal iPF(2alpha)-III levels. This study shows that oxidative stress is increased in patients with pulmonary hypertension. Furthermore, iPF(2alpha)-III levels inversely correlate to pulmonary vasoreactivity. These observations are consistent with the hypothesis that free radical generation is involved in PHT pathogenesis.

Obstructive nonapneic respiratory events (ONAREs, i.e., obstructive hypopneas [OHs] and respiratory effort related arousals [RERAs]) are clinically important as producing sleep fragmentation but are much more difficult to detect and classify than obstructive apneas. We characterized 1,061 ONAREs in 15 unselected patients with moderate sleep apnea-hypopnea syndrome (OSAHS) according to the 1999 American Academy of Sleep Medicine (AASM) Task Force recommendations concerning accurate skills for respiratory measurements (i.e., pneumotachograph and esophageal pressure [Pes]) and definitions of respiratory events. OHs were defined as > or = 50% decrease in flow or < 50% but > or = 30% decrease in flow associated with either a desaturation of > or = 3% or a cortical arousal. RERAs corresponded to a less than 30% decrease in flow associated with an arousal. OHs represented a large majority of the events (79.9%, n = 848). Among the events demonstrating a 30 to 50% reduction in flow (n = 392), the occurrence of a cortical arousal permitted the classification of 246 events as OHs (62.8%). RERAs represented only 5.3% of the events. Finally 14.8% of the events were classified as indeterminate owing to a < 50% and > or = 30% airflow decrease without arousal or desaturation or an airflow decrease less than 30% without arousal. The same level of DeltaPes was observed at the end of OHs and RERAs (21.9 +/- 5.5 versus 18.9 +/- 5.7 cm H(2)O respectively [NS]) whereas the reduction in flow was as expected, higher for OH (57.9 +/- 10.7 versus 21.3 +/- 4.9%). In a population of moderate OSAHS, OH represented the dominant type of ONAREs when RERAs should be considered as specific but relatively rare respiratory events. The occurrence and the recognition of a microarousal represented the key associated factor for classifying respiratory events as hypopneas. The high rate (15%) of unclassified events demonstrated some limitations in the AASM Task Force recommendations for definitions of respiratory events. Similar levels of DeltaPes found at the end of RERAs and OHs, although the reduction in flow was higher for OHs, suggest that different levels of collapsibility can exist throughout the night in a given patient.

Lung function abnormalities in thalassaemia major are various and complex; however, patients still die from cardiac lesions. This study aimed to investigate pulmonary and cardiac involvement at an early stage in thalassaemic patients and study their respective implications at rest and during exercise. Ten patients (five adults and five children) with thalassaemia major were investigated by echocardiography, lung function and exercise testing a few days after transfusion. All have had regular transfusions and chelation with deferoxamine and none had chronic pulmonary disease symptoms. Minor lung function abnormalities were found: two patients had moderate obstructive syndrome and two had a decreased carbon monoxide transfer factor. Hypoxaemia was never found at rest and no desaturation was observed at the end of exercise. Echocardiographic abnormalities were also moderate. Peak oxygen consumption (V'O2) was decreased in three adults and was lower in adults than children (means 27.7+/-4.6 and 41.1+/-4.8 mL.kg(-1).min(-2) respectively). The V'O2/cardiac frequency slope was lower in adults than children (0.25+/-0.06 versus 0.42+/-0.10 mL.kg(-1).min(-2)), whereas end-exercise breathing reserve was >40% maximal voluntary ventilation for all patients. In conclusion, none of the patients had ventilatory limitations but older patients had cardiac limitations assessed by the relationship between oxygen consumption and cardiac frequency. Exercise testing may detect cardiac impairment in thalassaemia major earlier than investigations at rest.

Deep venous thrombosis (DVT) is a frequent and potentially serious complication in severely burned patients. We report the case of a burned patient (40% of total body surface burned), who had right femoral deep venous thrombosis and severe pulmonary embolism, although a prophylaxis was conducted with low molecular weight heparin, graduated compression stockings and rotating bed. This case shows that DVT early diagnosis and prophylaxis is difficult in severely burned patients. Systematic screening of DVT by duplex scan is possible only for femoral veins, which renders duplex scan more suitable for femoral catheter follow up than for systematic DVT screening. Computed tomography venography seems to be a valuable tool in the diagnosis of proximal thrombosis. Prophylaxis is best achieved with the use of preventive low molecular weight heparins, graduated compression stockings, and early mobilisation when possible. However, the place of low molecular weight heparins at high doses and external pneumatic calf compression needs to be evaluated by prospective studies.