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1.  Comparison of two methods to report potentially avoidable hospitalizations in France in 2012: a cross-sectional study 
Background
Potentially avoidable hospitalizations represent an indirect measure of access to effective primary care. However many approaches have been proposed to measure them and results may differ considerably. This work aimed at examining the agreement between the Weissman and Ansari approaches in order to measure potentially avoidable hospitalizations in France.
Methods
Based on the 2012 French national hospital discharge database (Programme de Médicalisation des Systèmes d’Information), potentially avoidable hospitalizations were measured using two approaches proposed by Weissman et al. and by Ansari et al. Age- and sex-standardised rates were calculated in each department. The two approaches were compared for diagnosis groups, type of stay, severity, age, sex, and length of stay.
Results
The number and age-standardised rate of potentially avoidable hospitalizations estimated by the Weissman et al. and Ansari et al. approaches were 742,474 (13.3 cases per 1,000 inhabitants) and 510,206 (9.0 cases per 1,000 inhabitants), respectively. There are significant differences by conditions groups, age, length of stay, severity level, and proportion of medical stays between the Weissman and Ansari methods.
Conclusions
Regarding potentially avoidable hospitalizations in France in 2012, the agreement between the Weissman and Ansari approaches is poor. The method used to measure potentially avoidable hospitalizations is critical, and might influence the assessment of accessibility and performance of primary care.
doi:10.1186/s12913-014-0661-7
PMCID: PMC4316643  PMID: 25608760
Diagnosis-related groups; International classification of disease; Potentially avoidable hospitalizations; PMSI; France
2.  Reduced myotube diameter, atrophic signalling and elevated oxidative stress in cultured satellite cells from COPD patients 
The mechanisms leading to skeletal limb muscle dysfunction in chronic obstructive pulmonary disease (COPD) have not been fully elucidated. Exhausted muscle regenerative capacity of satellite cells has been evocated, but the capacity of satellite cells to proliferate and differentiate properly remains unknown. Our objectives were to compare the characteristics of satellite cells derived from COPD patients and healthy individuals, in terms of proliferative and differentiation capacities, morphological phenotype and atrophy/hypertrophy signalling, and oxidative stress status. Therefore, we purified and cultivated satellite cells from progressively frozen vastus lateralis biopsies of eight COPD patients and eight healthy individuals. We examined proliferation parameters, differentiation capacities, myotube diameter, expression of atrophy/hypertrophy markers, oxidative stress damages, antioxidant enzyme expression and cell susceptibility to H2O2 in cultured myoblasts and/or myotubes. Proliferation characteristics and commitment to terminal differentiation were similar in COPD patients and healthy individuals, despite impaired fusion capacities of COPD myotubes. Myotube diameter was smaller in COPD patients (P = 0.015), and was associated with a higher expression of myostatin (myoblasts: P = 0.083; myotubes: P = 0.050) and atrogin-1 (myoblasts: P = 0.050), and a decreased phospho-AKT/AKT ratio (myoblasts: P = 0.022). Protein carbonylation (myoblasts: P = 0.028; myotubes: P = 0.002) and lipid peroxidation (myotubes: P = 0.065) were higher in COPD cells, and COPD myoblasts were significantly more susceptible to oxidative stress. Thus, cultured satellite cells from COPD patients display characteristics of morphology, atrophic signalling and oxidative stress similar to those described in in vivo COPD skeletal limb muscles. We have therefore demonstrated that muscle alteration in COPD can be studied by classical in vitro cellular models.
doi:10.1111/jcmm.12390
PMCID: PMC4288361  PMID: 25339614
COPD; muscle dysfunction; cellular model; atrophy; oxidative stress; satellite cells
3.  Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients 
Diabetes Care  2013;36(6):1454-1461.
OBJECTIVE
To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk.
RESEARCH DESIGN AND METHODS
Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR.
RESULTS
In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.
CONCLUSIONS
A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.
doi:10.2337/dc12-1652
PMCID: PMC3661802  PMID: 23275372
4.  Effects of Intermittent Training on Anaerobic Performance and MCT Transporters in Athletes 
PLoS ONE  2014;9(5):e95092.
This study examined the effects of intermittent hypoxic training (IHT) on skeletal muscle monocarboxylate lactate transporter (MCT) expression and anaerobic performance in trained athletes. Cyclists were assigned to two interventions, either normoxic (N; n = 8; 150 mmHg PIO2) or hypoxic (H; n = 10; ∼3000 m, 100 mmHg PIO2) over a three week training (5×1 h-1h30.week−1) period. Prior to and after training, an incremental exercise test to exhaustion (EXT) was performed in normoxia together with a 2 min time trial (TT). Biopsy samples from the vastus lateralis were analyzed for MCT1 and MCT4 using immuno-blotting techniques. The peak power output (PPO) increased (p<0.05) after training (7.2% and 6.6% for N and H, respectively), but VO2max showed no significant change. The average power output in the TT improved significantly (7.3% and 6.4% for N and H, respectively). No differences were found in MCT1 and MCT4 protein content, before and after the training in either the N or H group. These results indicate there are no additional benefits of IHT when compared to similar normoxic training. Hence, the addition of the hypoxic stimulus on anaerobic performance or MCT expression after a three-week training period is ineffective.
doi:10.1371/journal.pone.0095092
PMCID: PMC4010422  PMID: 24797797
5.  Sequential Exercise in Triathletes: Variations in GH and Water Loss 
PLoS ONE  2014;9(4):e96145.
Growth hormone (GH) may stimulate water loss during exercise by activating sweating. This study investigated GH secretion and water loss during sequential cycling and running, taking postural changes into account. The two exercise segments had similar durations and were performed at the same relative intensity to determine their respective contributions to water loss and the plasma volume variation noted in such trials. Eight elite triathletes first performed an incremental cycle test to assess maximal oxygen consumption. Then, the triathletes performed one of two trials in randomized order: constant submaximal cycling followed by treadmill running (C1-R2) or an inversed succession of running followed by cycling (R1-C2). Each segment of both trials was performed for 20 minutes at ∼75% of maximal oxygen consumption. The second trial, reversing the segment order of the first trial, took place two weeks later. During cycling, the triathletes used their own bicycles equipped with a profiled handlebar. Blood sampling (for GH concentrations, plasma viscosity and plasma volume variation) was conducted at rest and after each segment while water loss was estimated from the post- and pre-measures. GH increases were significantly lower in R2 than C2 (72.2±50.1 vs. 164.0±157 ng.ml−1.min−1, respectively; P<0.05). Water loss was significantly lower after C1-R2 than R1-C2 (1105±163 and 1235±153 ml, respectively; P<0.05). Plasma volume variation was significantly negative in C1 and R1 (−6.15±2.0 and −3.16±5.0%, respectively; P<0.05), not significant in C2, and significantly positive for seven subjects in R2 (4.05±3.1%). We concluded that the lower GH increases in R2 may have contributed to the smaller reduction in plasma volume by reducing sweating. Moreover, this lower GH response could be explained by the postural change during the transition from cycling to running. We recommend to pay particular attention to their hydration status during R1 which could limit a potential dehydration during C2.
doi:10.1371/journal.pone.0096145
PMCID: PMC3999104  PMID: 24763386
6.  Relationship between CT air trapping criteria and lung function in small airway impairment quantification 
Background
Small airways are regarded as the elective anatomic site of obstruction in most chronic airway diseases. Expiratory computed tomography (CT) is increasingly used to assess obstruction at this level but there is no consensus regarding the best quantification method. We aimed to evaluate software-assisted CT quantification of air trapping for assessing small airway obstruction and determine which CT criteria better predict small airway obstruction on single breath nitrogen test (SBNT).
Methods
Eighty-nine healthy volunteers age from 60 to 90 years old, underwent spirometrically-gated inspiratory (I) and expiratory (E) CT and pulmonary function tests (PFTs) using SBNT, performed on the same day. Air trapping was estimated using dedicated software measuring on inspiratory and expiratory CT low attenuation area (LAA) lung proportion and mean lung density (MLD). CT indexes were compared to SBNT results using the Spearman correlation coefficient and hierarchical dendrogram analysis. In addition, receiver operating characteristic (ROC) curve analysis was performed to determine the optimal CT air-trapping criterion.
Results
43 of 89 subjects (48,3%) had dN2 value above the threshold defining small airway obstruction (i.e. 2.5% N2/l). Expiratory to inspiratory MLD ratio (r = 0.40) and LAA for the range −850 -1024 HU (r = 0.29) and for the range −850 -910 HU (r = 0.37) were positively correlated with SBNT results. E/I MLD was the most suitable criterion for its expression. Expiratory to inspiratory MLD ratio (E/I MLD) showed the highest AUC value (0.733) for small airway obstruction assessment.
Conclusion
Among all CT criteria, all correlating with small airway obstruction on SBNT, E/I MLD was the most suitable criterion for its expression in asymptomatic subjects with mild small airway obstruction
Trial registration
Registered at Clinicaltrials.gov, identifier: NCT01230879.
doi:10.1186/1471-2466-14-29
PMCID: PMC4015710  PMID: 24581147
Air trapping; Bronchiole; Single breath nitrogen test; Biomarker; Software-assisted CT quantification
7.  Determining a Clinically Relevant Strategy for Bone Tissue Engineering: An “All-in-One” Study in Nude Mice 
PLoS ONE  2013;8(12):e81599.
Purpose
Autologous bone grafting (BG) remains the standard reconstruction strategy for large craniofacial defects. Calcium phosphate (CaP) biomaterials, such as biphasic calcium phosphate (BCP), do not yield consistent results when used alone and must then be combined with cells through bone tissue engineering (BTE). In this context, total bone marrow (TBM) and bone marrow-derived mesenchymal stem cells (MSC) are the primary sources of cellular material used with biomaterials. However, several other BTE strategies exist, including the use of growth factors, various scaffolds, and MSC isolated from different tissues. Thus, clinicians might be unsure as to which method offers patients the most benefit. For this reason, the aim of this study was to compare eight clinically relevant BTE methods in an “all-in-one” study.
Methods
We used a transgenic rat strain expressing green fluorescent protein (GFP), from which BG, TBM, and MSC were harvested. Progenitor cells were then mixed with CaP materials and implanted subcutaneously into nude mice. After eight weeks, bone formation was evaluated by histology and scanning electron microscopy, and GFP-expressing cells were tracked with photon fluorescence microscopy.
Results/Conclusions
Bone formation was observed in only four groups. These included CaP materials mixed with BG or TBM, in which abundant de novo bone was formed, and BCP mixed with committed cells grown in two- and three-dimensions, which yielded limited bone formation. Fluorescence microscopy revealed that only the TBM and BG groups were positive for GFP expressing-cells, suggesting that these donor cells were still present in the host and contributed to the formation of bone. Since the TBM-based procedure does not require bone harvest or cell culture techniques, but provides abundant de novo bone formation, we recommend consideration of this strategy for clinical applications.
doi:10.1371/journal.pone.0081599
PMCID: PMC3862877  PMID: 24349093
8.  Novel perspective: exercise training stimulus triggers the expression of the oncoprotein human double minute-2 in human skeletal muscle 
Physiological Reports  2013;1(2):e00028.
High expression levels of human double minute-2 (Hdm2) are often associated with increased risk of cancer. Hdm2 is well established as an oncoprotein exerting various tumorigenic effects. Conversely, the physiological functions of Hdm2 in nontumor cells and healthy tissues remain largely unknown. We previously demonstrated that exercise training stimulates expression of murine double minute-2 (Mdm2), the murine analog of Hdm2, in rodent skeletal muscle and Mdm2 was required for exercise-induced muscle angiogenesis. Here we showed that exercise training stimulated the expression of Hdm2 protein in human skeletal muscle from +38% to +81%. This robust physiological response was observed in 60–70% of the subjects tested, in both young and senior populations. Similarly, exercise training stimulated the expression of platelet endothelial cell adhesion molecule-1, an indicator of the level of muscle capillarization. Interestingly, a concomitant decrease in the tumor suppressor forkhead box O-1 (FoxO1) transcription factor levels did not occur with training although Mdm2/Hdm2 is known to inhibit FoxO1 expression in diseased skeletal muscle. This could suggest that Hdm2 has different targets when stimulated in a physiological context and that exercise training could be considered therapeutically in the context of cancer in combination with anti-Hdm2 drug therapies in order to preserve Hdm2 physiological functions in healthy tissues.
doi:10.1002/phy2.28
PMCID: PMC3831923  PMID: 24303114
FoxO1; Mdm2; PECAM-1
9.  DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy? 
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress. PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was found expressed in only 1/1000 FSHD myoblasts. We have now shown it was induced upon differentiation and detected in about 1/200 myotube nuclei. The DUX4 and PITX1 proteins presented staining gradients in consecutive myonuclei which suggested a diffusion as known for other muscle nuclear proteins. Both protein half-lifes were regulated by the ubiquitin-proteasome pathway. In addition, we could immunodetect the DUX4 protein in FSHD muscle extracts. As a model, we propose the DUX4 gene is stochastically activated in a small number of FSHD myonuclei. The resulting mRNAs are translated in the cytoplasm around an activated nucleus and the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. The PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4. Together the diffusion and the deregulation cascade would explain how a rare protein could cause the muscle defects observed in FSHD.
doi:10.1111/j.1582-4934.2012.01647.x
PMCID: PMC3823138  PMID: 23206257
FSHD; DUX4; homeodomain; differentiation; myoblasts; PITX1; muscle; nucleus
10.  Increased FAT/CD36 Cycling and Lipid Accumulation in Myotubes Derived from Obese Type 2 Diabetic Patients 
PLoS ONE  2011;6(12):e28981.
Background
Permanent fatty acid translocase (FAT/)CD36 relocation has previously been shown to be related to abnormal lipid accumulation in the skeletal muscle of type 2 diabetic patients, however mechanisms responsible for the regulation of FAT/CD36 expression and localization are not well characterized in human skeletal muscle.
Methodology/Principal Findings
Primary muscle cells derived from obese type 2 diabetic patients (OBT2D) and from healthy subjects (Control) were used to examine the regulation of FAT/CD36. We showed that compared to Control myotubes, FAT/CD36 was continuously cycling between intracellular compartments and the cell surface in OBT2D myotubes, independently of lipid raft association, leading to increased cell surface FAT/CD36 localization and lipid accumulation. Moreover, we showed that FAT/CD36 cycling and lipid accumulation were specific to myotubes and were not observed in reserve cells. However, in Control myotubes, the induction of FAT/CD36 membrane translocation by the activation of (AMP)-activated protein kinase (AMPK) pathway did not increase lipid accumulation. This result can be explained by the fact that pharmacological activation of AMPK leads to increased mitochondrial beta-oxidation in Control cells.
Conclusion/Significance
Lipid accumulation in myotubes derived from obese type 2 diabetic patients arises from abnormal FAT/CD36 cycling while lipid accumulation in Control cells results from an equilibrium between lipid uptake and oxidation. As such, inhibiting FAT/CD36 cycling in the skeletal muscle of obese type 2 diabetic patients should be sufficient to diminish lipid accumulation.
doi:10.1371/journal.pone.0028981
PMCID: PMC3241688  PMID: 22194967
11.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
12.  Monocarboxylate transporters, blood lactate removal after supramaximal exercise, and fatigue indexes in humans 
Journal of Applied Physiology  2004;98(3):804-809.
The present study investigated whether muscular monocarboxylate transporter (MCT) 1 and 4 contents are related to the blood lactate removal after supramaximal exercise, fatigue indexes measured during different supramaximal exercises, and muscle oxidative parameters in 15 humans with different training status. Lactate recovery curves were obtained after a 1-min all-out exercise. A bi-exponential time function was then used to determine the velocity constant of the slow phase (γ2), which denoted the blood lactate removal ability. Fatigue indexes were calculated during 1-min all-out (FIAO) and repeated 10-s (FISprint) cycling sprints. Biopsies were taken from the vastus lateralis muscle. MCT1 and MCT4 contents were quantified by Western blots, and maximal muscle oxidative capacity (Vmax) was evaluated with pyruvate + malate and glutamate + malate as substrates. The results showed that the blood lactate removal ability (i.e., γ2)) after a 1-min all-out test was significantly related to MCT1 content (r=0.70, P <0.01) but not to MCT4 (r=0.50, P >0.05). However, greater MCT1 and MCT4 contents were negatively related with a reduction of blood lactate concentration at the end of 1-min all-out exercise (r =− 0.56, and r= −0.61, P < 0.05, respectively). Among skeletal muscle oxidative indexes, we only found a relationship between MCT1 and glutamate + malate Vmax (r = 0.63, P < 0.05). Furthermore, MCT1 content, but not MCT4, was inversely related to FIAO (r =−0.54, P < 0.05) and FISprint (r r =0.58, P <0.05). We concluded that skeletal muscle MCT1 expression was associated with the velocity constant of net blood lactate removal after a 1-min all-out test and with the fatigue indexes. It is proposed that MCT1 expression may be important for blood lactate removal after supramaximal exercise based on the existence of lactate shuttles and, in turn, in favor of a better tolerance to muscle fatigue
doi:10.1152/japplphysiol.01057.2004
PMCID: PMC2976763  PMID: 15531559
Adult; Anaerobic Threshold; physiology; Exercise Test; Humans; Lactic Acid; blood; Male; Monocarboxylic Acid Transporters; metabolism; Muscle Fatigue; physiology; Muscle, Skeletal; physiology; Physical Endurance; physiology; Symporters; metabolism; Lactate kinetics; bi-exponential mathematical model; all-out exercise
13.  Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects 
Facioscapulohumeral dystrophy (FSHD) is a muscular hereditary disease with a prevalence of 1 in 20 000 caused by a partial deletion of a subtelomeric repeat array on chromosome 4q. However, very little is known about the pathogenesis as well as the molecular and biochemical changes linked to the progressive muscle degeneration observed in these patients. Several studies have investigated possible pathophysiological pathways in FSHD myoblasts and mature muscle cells but some of these reports were apparently in contradiction. The discrepancy between these studies may be explained by differences between the sources of myoblasts. Therefore, we decided to thoroughly analyse affected and unaffected muscles from patients with FSHD in terms of vulnerability to oxidative stress, differentiation capacity and morphological abnormalities.
We have established a panel of primary myoblast cell cultures from patients affected with FSHD and matched healthy individuals. Our results show that primary myoblasts are more susceptible to an induced oxidative stress than control myoblasts. Moreover, we demonstrate that both types of FSHD primary myoblasts differentiate into multinucleated myotubes which present morphological abnormalities. Whereas control myoblasts fuse to form branched myotubes with aligned nuclei, FSHD myoblasts fuse to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution.
In conclusion, we postulate that these abnormalities could be responsible for muscle weakness in patients with FSHD and provide an important marker for FSHD myoblasts.
doi:10.1111/j.1582-4934.2008.00368.x
PMCID: PMC2910739  PMID: 18505476
Facioscapulohumeral dystrophy (FSHD); muscle differentiation; myoblasts; oxidative stress; cellular model
14.  TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin 
Journal of Cell Science  2009;122(Pt 7):947-956.
Summary
The contractile activity of striated muscle depends on myofibrils that are highly ordered macromolecular complexes. The protein components of myofibrils are well characterized, but it remains largely unclear how signaling at the molecular level within the sarcomere and the control of assembly are coordinated. We show that the Rho GTPase TC10 appears during differentiation of human primary skeletal myoblasts and it is active in differentiated myotubes. We identify obscurin, a sarcomere-associated protein, as a specific activator of TC10. Indeed, TC10 binds directly to obscurin via its predicted RhoGEF motif. Importantly, we demonstrate that obscurin is a specific activator of TC10 but not the Rho GTPases Rac and Cdc42. Finally, we show that inhibition of TC10 activity by expression of a dominant-negative mutant or its knockdown by expression of specific shRNA block myofibril assembly. Our findings reveal a novel signaling pathway in human skeletal muscle that involves obscurin and the Rho GTPase TC10 and implicate this pathway in new sarcomere formation.
doi:10.1242/jcs.040121
PMCID: PMC2904472  PMID: 19258391
Cell Differentiation; Cells, Cultured; Enzyme Activation; Guanine Nucleotide Exchange Factors; chemistry; metabolism; Humans; Muscle Fibers, Skeletal; cytology; enzymology; Muscle Proteins; chemistry; metabolism; Myofibrils; enzymology; Organogenesis; Phosphorylation; Protein Binding; Protein Structure, Tertiary; RNA, Small Interfering; metabolism; Sarcomeres; enzymology; metabolism; p21-Activated Kinases; metabolism; rho GTP-Binding Proteins; antagonists & inhibitors; metabolism; Myofibrillogenesis; Rho GTPase; Obscurin
15.  Alteration of the piglet diaphragm contractility in vivo and its recovery after acute hypercapnia 
Anesthesiology  2008;108(4):651-658.
Background
The effects of hypercapnic acidosis on the diaphragm and its recovery to normocapnia have been poorly evaluated. We studied diaphragmatic contractility facing acute variations of PaCO2 and evaluated the contractile function at 60 min after normocapnia recovery.
Methods
Thirteen piglets weighing 15–20 kg were anesthetized, ventilated and separated into two groups: a control group (n= 5) evaluated in normocapnia (time-control experiments) and a hypercapnia group (n= 8) in which animals were acutely and shortly exposed to five consecutive ranges of PaCO2 (40, 50, 70, 90 and 110 mmHg). Then CO2 insufflation was stopped. Diaphragmatic contractility was assessed by measuring transdiaphragmatic pressure (Pdi) variations obtained after bilateral transjugulary phrenic pacing at increased frequencies (20–120 Hz). For each level of PaCO2, pressure-frequency curves were obtained in vivo by phrenic nerve pacing.
Results
In the hypercapnia group, mean (±SD) Pdi significantly decreased from 41 ± 3 to 29 ± 3 cmH2O (P<0.05) between the first (40 mmHg) and the fifth stages of capnia (116 mmHg) at the frequency of 100 Hz stimulation. The observed alteration of the contractile force was proportional to the level of PaCO2 (r2= 0.61, P<0.01). Normocapnia recuperation allowed a partial recovery of the diaphragmatic contractile force (80% of the baseline value) at 60 min after CO2 insufflation interruption.
Conclusion
A short exposure to respiratory acidosis decreased diaphragmatic contractility proportionally to the degree of hypercapnia and this alteration was only partially reversed at 60 min following exposure.
doi:10.1097/ALN.0b013e31816725a6
PMCID: PMC2789322  PMID: 18362597
Acute Disease; Animals; Animals, Newborn; Diaphragm; physiology; Hypercapnia; physiopathology; Muscle Contraction; physiology; Recovery of Function; physiology; Swine
16.  Effect of beta-dystroglycan processing on utrophin/Dp116 anchorage in normal and mdx mouse Schwann cell membrane 
Neuroscience  2006;141(2):607-620.
In the peripheral nervous system, utrophin and the short dystrophin isoform (Dp116) are co-localized at the outermost layer of the myelin sheath of nerve fibers; together with the dystroglycan complex. Dp116 is associated with multiple glycoproteins, i.e. sarcoglycans, and α-and β-dystroglycan, which anchor the cytoplasmic protein subcomplex to the extracellular basal lamina. In peripheral nerve, matrix metalloproteinase (MMP) activity disrupts the dystroglycan complex by cleaving the extracellular domain of β-dystroglycan. MMP creates a 30 kDa fragment of β-dystroglycan, leading to a disruption of the link between the extracellular matrix and the cell membrane. In this study, we investigated the molecular interactions of full length and 30 kDa β-dystroglycan with Dp116 and utrophins in peripheral nerve Schwann cells from normal and mdx mice. Our results showed that Dp116 had greater affinity to the glycosylated form of β-dystroglycan than the 30 kDa form. Interestingly, the short isoform of utrophin (Up71) was highly expressed in mdx Schwann cells compared with normal Schwann cells. In contrast to Dp116, Up71 had greater affinity to the 30 kDa β-dystroglycan. These results are discussed with regard to the participation of the short utrophin isoform and the cleaved form of β-dystroglycan in mdx Schwann cell membrane architecture and their possible role in peripheral nerve physiology.
doi:10.1016/j.neuroscience.2006.04.043
PMCID: PMC1974842  PMID: 16735092
Animals; Blotting, Western; methods; Cell Membrane; drug effects; metabolism; Dystroglycans; metabolism; Dystrophin; metabolism; Immunohistochemistry; methods; Immunoprecipitation; methods; Matrix Metalloproteinase 9; pharmacology; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; metabolism; Models, Biological; Reverse Transcriptase Polymerase Chain Reaction; methods; S100 Proteins; metabolism; Schwann Cells; cytology; drug effects; Sciatic Nerve; cytology; Statistics, Nonparametric; Utrophin; metabolism; Mouse peripheral nerve; Schwann cell; Utrophin short isoform; Dystroglycan; MMP2; MMP9
17.  Ventilation during air breathing and in response to hypercapnia in 5 and 16 month-old mdx and C57 mice 
Previous studies have shown a blunted ventilatory response to hypercapnia in mdx mice older than 7 months. We test the hypothesis that in the mdx mice ventilatory response changes with age, concomitantly with the increased functional impairment of the respiratory muscles. We thus studied the ventilatory response to CO2 in 5 and 16 month-old mdx and C57BL10 mice (n = 8 for each group). Respiratory rate (RR), tidal volume (VT), and minute ventilation (VE) were measured, using whole-body plethysmography, during air breathing and in response to hypercapnia (3, 5 and 8% CO2). The ventilatory protocol was completed by histological analysis of the diaphragm and intercostals muscles. During air breathing, the 16 month-old mdx mice showed higher RR and, during hypercapnia (at 8% CO2 breathing), significantly lower RR (226 ± 26 vs. 270 ± 21 breaths/min) and VE (1.81 ± 0.35 vs. 3.96 ± 0.59 ml min−1 g−1)(P < 0.001) in comparison to C57BL10 controls. On the other hand, 5 month-old C57BL10 and mdx mice did not present any difference in their ventilatory response to air breathing and to hypercapnia. In conclusion, this study shows similar ventilation during air breathing and in response to hypercapnia in the 5 month-old mdx and control mice, in spite of significant pathological structural changes in the respiratory muscles of the mdx mice. However in the 16 month-old mdx mice we observed altered ventilation under air and blunted ventilation response to hypercapnia compared to age-matched control mice. Ventilatory response to hypercapnia thus changes with age in mdx mice, in line with the increased histological damage of their respiratory muscles.
doi:10.1007/s10974-007-9101-1
PMCID: PMC1974787  PMID: 17431804
Age; Duchenne muscular dystrophy; Hypercapnia mdx mouse; Ventilatory response

Results 1-17 (17)