Nutrition strategies to improve physical capabilities in Duchenne muscular dystrophy.

There is no current cure for Duchenne muscular dystrophy (DMD), and palliative and prophylactic interventions to improve the quality of life of patients remain limited, with the exception of corticosteroids. This article describes 2 potential nutritional interventions for the treatment of DMD, green tea extract (GTE) and the branched-chain amino acid leucine, and their positive effects on physical activity. Both GTE and leucine are suitable for human consumption, are easily tolerated with no side effects, and, with appropriate preclinical data, could be brought forward to clinical trials rapidly.

Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial.

BACKGROUND: Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. METHODS: We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. FINDINGS: All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). INTERPRETATION: Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. FUNDING: Broncus Technologies.

Functional muscle analysis of the Tcap knockout mouse.

Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.

Exercise intensity and duration affect blood soluble HSP72.

Soluble heat shock protein 72 (sHSP72) is suggested to play a role as a signalling molecule in the immune response to exercise. We were interested in whether duration and intensity of endurance running affect the level of inducible sHSP72 in the plasma/serum of endurance athletes. In the first part of the study, the influence of a continuous treadmill run of 60 min (CR) with an intensity of 75 % VO2max, a long treadmill run of 120 min (LR) with an intensity of 60 % VO2max, an extensive interval training program (IT; 10 x 1000 m, ca. 35 min, VO2max 88 %), and a competitive marathon run (MA) within 260 +/- 39 min (VO2max ca. 65 %) on the release of sHSP72 into the peripheral blood was tested. Blood samples were drawn before and directly after exercise, as well as 0.5, 1, 3, 24 h after exercise to determine sHSP72 levels. Secondly, we compared the effects of two exercise bouts with identical duration (23.7 +/- 7 min) but different intensities (Exhaustive exercise (ET) at 80 % VO2max vs. moderate exercise (MT) at 60 % VO2max) on sHSP72 concentration. The sHSP72 levels in plasma/serum were analyzed using an enzyme immunoassay specific for inducible HSP72 (Stressgen,Victoria, Canada). Early, significant increases of sHSP72 were detected immediately after all types of exercise with highest levels after MA. ET induced significantly higher levels of sHSP72 compared with MT. Long-lasting, competitive endurance exercise induced a more pronounced response of sHSP compared with more intensive but shorter exercise. Exercise intensity was also an important influencing factor. A duration- and intensity-dependent role for sHSP72 in the exercise-induced changes of the immune response may be assumed.

Biodistribution and kinetics of nasal carbon-11-triamcinolone acetonide.

UNLABELLED: PET is a technique with a strong potential for use in drug evaluation and development. In particular, the distribution and pharmacokinetics of locally administered drugs may be advantageously explored noninvasively using labeled compounds. This pilot study was performed to demonstrate the effectiveness of PET for drug development and to determine the human biodistribution and kinetics of triamcinolone acetonide, labeled with 11C, formulated and nasally administered as Nasacort AQ nasal inhalant. METHODS: Carbon-11-labeled triamcinolone acetonide was formulated as the commercial product, and PET scans of the heads of four volunteers were performed in a vertical orientation. Region-of-interest analysis with MRI coregistration was used to analyze the distribution and kinetics in nasal tissues. RESULTS: Deposition of the majority of the dose on target tissues was immediate. Penetration into sinuses was observed. There was moderate redistribution and slow migration of the drug through nasal passages to the throat. Significant amounts of the drug remained in target regions for several hours. CONCLUSION: PET is an effective means to determine local drug distribution and kinetics.

Resolution of recurrent atelectasis in spinal cord injury patients with administration of recombinant human DNase.

Atelectasis occurs frequently in patients with spinal cord injury (SCI). Impaired cough leads to ineffective clearance of secretions. If the secretions cannot be cleared and become thick and purulent, atelectasis may occur. Recombinant human DNase (rhDNase) has been shown to decrease purulent sputum viscosity in vitro. We report two SCI patients with respiratory failure due to recurrent atelectasis from purulent secretions in whom conventional treatment methods had failed. Administration of rhDNase resulted in successful resolution of atelectasis. These results suggest the need for a controlled clinical trial.

Arterial oxygenation time after an FIO2 increase in mechanically ventilated patients.

The time for arterial PO2 to reach equilibrium after a 0.2 increase in the fraction of inspired oxygen (FIO2) was studied, using arterial blood gases measured at 1, 2, 3, 4, 5, 7, 9, and 11 min in 30 stable, mechanically ventilated medical intensive care unit (ICU) patients. Eight patients also underwent a 0.4 increase in FIO2. Each patient's rise in PO2 over time [PO2(t)] was fit to the following exponential equation: PO2(t) = PO2i + (PO2f-PO2i) (1-e-kt), where t refers to time, PO2i and PO2f refer to the initial and final equilibrated PO2. The time constant k and PO2f were determined by a nonlinear curve fitting technique. The 90% oxygenation times (t90%), defined as the time required to reach 90% of the final equilibrated PO2, were calculated. The mean t90% (+/- SD) was 6.0 (+/- 3.4) min for all patients (range 1.7 to 14.3 min); 7.1 +/- 2.1 min for 18 patients with chronic obstructive pulmonary disease (COPD) and 4.4 +/- 2.0 min for 12 patients without COPD (p < 0.05). In the subgroup of patients undergoing both an FIO2 increase of 0.2 and 0.4, there was no significant difference in the mean t90%'s for the two FIO2 changes (7.7 versus 7.7 min). We conclude that after a 0.2 or 0.4 increase of FIO3, a 15-min equilibration time period is adequate for 90% of the increase in PO2 to occur, in stable, mechanically ventilated medical ICU patients.

Allocation of systemic glucose output to cerebral utilization as a function of fetal canine growth.

To determine whether the neonatal canine brain consumes a major proportion of the systemic glucose production, we investigated the cerebral glucose requirement and hepatic glucose production in beagle pups. Sixteen pups received D-[6-3H]-glucose to determine systemic glucose production. Cerebral blood flow was measured by [N-methyl-14C]antipyrine, and the brain uptake index (BUI) of glucose was determined using 2-[14C]deoxy-D-glucose. Glucose production was 49.6 +/- 11.0 mumol.kg-1.min-1. Cerebral blood flow was 0.83 ml.g-1.min-1; cerebral uptake of glucose was 0.60 +/- 0.15 mumol.g-1.min-1. Of the total glucose production 36.6 +/- 7.9% was accounted for by the cerebral uptake of glucose. Brain-to-body weight and brain-to-liver weight ratios were the greatest in the smallest pups, suggesting brain sparing. The effect of growth status on cerebral substrate availability could not be correlated with cerebral uptake of glucose or oxygen or with systemic glucose production. However, the percentage of systemic glucose production allotted to the cerebral cortex increased with increasing body weight (r = 0.50, P less than 0.05). Cerebral glucose entry measured by BUI was demonstrated to be 0.108 +/- 0.014; BUI inversely correlated with canine birth weight (r = -0.832, P less than 0.001). We conclude that the percentage of glucose production utilized by the neonatal canine brain is not proportionately larger in the smaller pups despite a proportionately larger brain. Because the absolute cerebral glucose utilization may be static, we speculate that BUI (glucose entry) may be less of a rate-limiting factor for cerebral glucose entry in the smallest pups.