Klotho and smoking--An interplay influencing the skeletal muscle function deficits that occur in COPD.

BACKGROUND: Klotho is an 'anti-ageing' hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies. METHODS: Fat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 'healthy smokers' and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air. RESULTS: Quadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters. CONCLUSIONS: Klotho is expressed in skeletal muscle and levels are reduced by smoking. Despite this, quadriceps Klotho protein expression in those with established disease appears complex as levels were paradoxically elevated in COPD patients with established muscle wasting. Whilst serum Klotho levels were not reduced in smokers or COPD patients and were not associated with quadriceps Klotho protein, they did relate to quadriceps strength.

The prevalence of quadriceps weakness in COPD and the relationship with disease severity.

Quadriceps strength relates to exercise capacity and prognosis in chronic obstructive pulmonary disease (COPD). We wanted to quantify the prevalence of quadriceps weakness in COPD and hypothesised that it would not be restricted to patients with severe airflow obstruction or dyspnoea. Predicted quadriceps strength was calculated using a regression equation (incorporating age, sex, height and fat-free mass), based on measurements from 212 healthy subjects. The prevalence of weakness (defined as observed values 1.645 standardised residuals below predicted) was related to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and Medical Research Council (MRC) dyspnoea score in two cohorts of stable COPD outpatients recruited from the UK (n = 240) and the Netherlands (n = 351). 32% and 33% of UK and Dutch COPD patients had quadriceps weakness. A significant proportion of patients in GOLD stages 1 and 2, or with an MRC dyspnoea score of 1 or 2, had quadriceps weakness (28 and 26%, respectively). These values rose to 38% in GOLD stage 4, and 43% in patients with an MRC Score of 4 or 5. Quadriceps weakness was demonstrable in one-third of COPD patients attending hospital respiratory outpatient services. Quadriceps weakness exists in the absence of severe airflow obstruction or breathlessness.

Diaphragm electromyograms recorded from multiple surface electrodes following magnetic stimulation.

The diaphragm compound-muscle action potential (CMAPdi), elicited by unilateral magnetic stimulation (UMS) of the phrenic nerve can be recorded using surface electrodes. However, there is no consensus on the best positioning of surface electrodes and there are no data on the reproducibility of the signal. Using 36 surface electrode pairs, in five healthy subjects, the CMAPdi elicited by UMS and electrical stimulation (ES) were compared and 12 pairs were identified as providing acceptable signals. The latency and amplitude were measured for each CMAPdi, following UMS at 60-100% of maximal stimulator output, in 12 healthy subjects, on two occasions. Latencies obtained using UMS and ES ranged between 6.1-7.33 and 6.25-7.17 ms, respectively. Optimum CMAPdi were not recorded from the same electrode pair in all subjects, or for both hemidiaphragms in each subject. However, the optimal recording site for a particular individual remained unchanged on subsequent testing. When recorded from the optimal site, latencies and amplitudes of CMAPdi elicited on the two occasions were not significantly different. The current study suggests that the use of multiple chest wall electrodes can identify an optimal electrode pair, from which it is possible to obtain reproducible compound-muscle action potential signals.

Abdominal muscle and quadriceps strength in chronic obstructive pulmonary disease.

BACKGROUND: Quadriceps muscle weakness is common in chronic obstructive pulmonary disease (COPD) but is not observed in a small hand muscle (adductor pollicis). Although this could be explained by reduced activity in the quadriceps, the observation could also be explained by anatomical location of the muscle or fibre type composition. However, the abdominal muscles are of a similar anatomical and fibre type distribution to the quadriceps, although they remain active in COPD. Cough gastric pressure is a recently described technique that assesses abdominal muscle (and hence expiratory muscle) strength more accurately than traditional techniques. A study was undertaken to test the hypothesis that more severe weakness exists in the quadriceps than in the abdominal muscles of patients with COPD compared with healthy elderly controls. METHODS: Maximum cough gastric pressure and quadriceps isometric strength were measured in 43 patients with stable COPD and 25 healthy elderly volunteers matched for anthropometric variables. RESULTS: Despite a significant reduction in mean quadriceps strength (29.9 kg v 41.2 kg; 95% CI -17.9 to -4.6; p = 0.001), cough gastric pressure was preserved in patients with COPD (227.3 cm H(2)O v 204.8 cm H(2)O; 95% CI -5.4 to 50.6; p = 0.11). CONCLUSIONS: Abdominal muscle strength is preserved in stable COPD outpatients in the presence of quadriceps weakness. This suggests that anatomical location and fibre type cannot explain quadriceps weakness in COPD. By inference, we conclude that disuse and consequent deconditioning are important factors in the development of quadriceps muscle weakness in COPD patients, or that activity protects the abdominal muscles from possible systemic myopathic processes.

Magnetic stimulation for the measurement of respiratory and skeletal muscle function.

Respiratory and skeletal muscle function is of interest in many areas of pulmonary and critical care medicine. The capacity of the respiratory muscle pump to respond to the load imposed by disease is the basis of an understanding of ventilatory failure. Over the last four decades, considerable progress has been made in quantifying the capacity of the respiratory muscles, in terms of strength, endurance and fatigue. With the development of magnetic stimulation, it has recently become possible to nonvolitionally assess the respiratory muscles in a clinically acceptable way. This is of particular interest in the investigation of patients receiving critical care, those with neuromuscular disease, and in children where volitional efforts are either not possible or likely to be sub-maximal. Furthermore, the adaptation of these techniques to quantify the strength of peripheral muscles, such as the quadriceps, has allowed the effects of muscle training or rehabilitation, uninfluenced by learning effect, to be assessed. This article focuses on the physiological basis of magnetic nerve stimulation, and reviews how the technique has been applied to measure muscle strength and fatigue, with particular emphasis upon the diaphragm. The translation of magnetic stimulation into a clinical tool is described, and how it may be of diagnostic, prognostic and therapeutic value in several areas of pulmonary medicine. In particular, the use of magnetic stimulation in neuromuscular disease, the intensive care setting, chronic obstructive pulmonary disease and paediatrics will be discussed.

Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease.

Prospective data to support the hypothesis that corticosteroids are a significant cause of muscle weakness in patients with chronic obstructive pulmonary disease (COPD) are lacking. The authors studied respiratory and quadriceps muscle function, using both volitional techniques and magnetic nerve stimulation, as well as measuring metabolic parameters during incremental cycle ergometry, in 25 stable COPD patients. The forced expiratory volume in one second was 37.6 +/- 21.4% predicted, before and after a 2-week course of o.d. prednisolone 30 mg. Quadriceps strength was also assessed in 15 control patients on two occasions. Only two patients met the British Thoracic Society definition of steroid responsiveness. There was no change either in sniff transdiaphragmatic pressure (pre: 96.8 +/- 19.7 cmH2O; post: 98.6 +/- 22.4 cmH2O) or in twitch transdiaphragmatic pressure elicited by bilateral anterolateral magnetic phrenic-nerve stimulation (pre: 16.8 +/- 9.1 cmH2O; post: 17.9 +/- 10 cmH2O). Quadriceps twitch force did not change significantly either in the steroid group (pre: 9.5 +/- 3.1 kg; post: 8.9 +/- 3.7 kg) or in the control patients (pre: 8.1 +/- 2.7 kg; post: 7.9 +/- 2.2 kg). There were no changes in either peak or isotime ventilatory and metabolic parameters during exercise. In conclusion, in stable patients with chronic obstructive pulmonary disease, a 2-week course of 30 mg prednisolone daily does not cause significant skeletal muscle dysfunction or alter metabolic parameters during exercise.

Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD.

BACKGROUND: Some patients with irreversible chronic obstructive pulmonary disease (COPD) experience subjective benefit from long acting bronchodilators without change in forced expiratory volume in 1 second (FEV(1)). Dynamic hyperinflation is an important determinant of exercise induced dyspnoea in COPD. We hypothesised that long acting bronchodilators improve symptoms by reducing dynamic hyperinflation and work of breathing, as measured by respiratory muscle pressure-time products. METHODS: Sixteen patients with "irreversible" COPD (<10% improvement in FEV(1) following a bronchodilator challenge; mean FEV(1) 31.1% predicted) were recruited into a randomised, double blind, placebo controlled, crossover study of salmeterol (50 micro g twice a day). Treatment periods were of 2 weeks duration with a 2 week washout period. Primary outcome measures were end exercise isotime transdiaphragmatic pressure-time product and dynamic hyperinflation as measured by inspiratory capacity. RESULTS: Salmeterol significantly reduced the transdiaphragmatic pressure-time product (294.5 v 348.6 cm H(2)O/s/min; p = 0.03), dynamic hyperinflation (0.22 v 0.33 litres; p = 0.002), and Borg scores during endurance treadmill walk (3.78 v 4.62; p = 0.02). There was no significant change in exercise endurance time. Improvements in isotime Borg score were significantly correlated to changes in tidal volume/oesophageal pressure swings, end expiratory lung volume, and inspiratory capacity, but not pressure-time products. CONCLUSIONS: Despite apparent "non-reversibility" in spirometric parameters, long acting bronchodilators can cause both symptomatic and physiological improvement during exercise in severe COPD.

Non-volitional assessment of skeletal muscle strength in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although quadriceps weakness is well recognised in chronic obstructive pulmonary disease (COPD), the aetiology remains unknown. In disabled patients the quadriceps is a particularly underused muscle and may not reflect skeletal muscle function as a whole. Loss of muscle function is likely to be equally distributed if the underlying pathology is a systemic abnormality. Conversely, if deconditioning and disuse are the principal aetiological factors, weakness would be most marked in the lower limb muscles. METHODS: The non-volitional technique of supramaximal magnetic stimulation was used to assess twitch tensions of the adductor pollicis, quadriceps, and diaphragm muscles (TwAP, TwQ, and TwPdi) in 22 stable non-weight losing COPD patients and 18 elderly controls. RESULTS: Mean (SD) TwQ tension was reduced in the COPD patients (7.1 (2.2) kg v 10.0 (2.7) kg; 95% confidence intervals (CI) -4.4 to -1.4; p<0.001). Neither TwAP nor TwPdi (when corrected for lung volume) differed significantly between patients and controls (mean (SD) TwAP 6.52 (1.90) N for COPD patients and 6.80 (1.99) N for controls (95% CI -1.5 to 0.97, p=0.65; TwPdi 23.0 (5.6) cm H(2)O for COPD patients and 23.5 (5.2) cm H(2)O for controls (95% CI -4.5 to 3.5, p=0.81). CONCLUSIONS: The strength of the adductor pollicis muscle (and the diaphragm) is normal in patients with stable COPD whereas quadriceps strength is substantially reduced. Disuse may be the principal factor in the development of skeletal muscle weakness in COPD, but a systemic process preferentially affecting the proximal muscles cannot be excluded.

Postprandial effects on twitch transdiaphragmatic pressure.

Twitch transdiaphragmatic pressure (Pdi,tw), measured following magnetic stimulation of the phrenic nerves, is used to assess diaphragm strength, contractility and fatigue. Although the effects of posture, lung volume and potentiation on Pdi,tw are well described, it is not known whether the degree of gastric filling affects the measurement. Pdi,tw was recorded in seven healthy volunteers on two occasions with antero-lateral magnetic stimulation of the phrenic nerves. On the first occasion, the subjects had fasted for at least 8 h, whilst on the second occasion, measurements were made after each subject had eaten a substantial meal sufficient to produce a feeling of satiation. Mean postprandial unpotentiated and potentiated Pdi,tw were significantly greater than corresponding fasting Pdi,tw in all seven volunteers (29.8 versus 25.7 cmH2O and 38.9 versus 34.4 cmH2O, respectively). This was due to a significantly increased gastric pressure component (1.10 versus 0.84 and 0.94 versus 0.78, respectively), and reduced abdominal compliance (36 versus 62 mL x cmH2O(-1)). Twitch oesophageal pressure was preserved (15.0 versus 15.4 cmH2O). The postprandial state increases twitch transdiaphragmatic pressure, and this should be taken into account when using twitch transdiaphragmatic pressure to follow-up patients or to assess the effects of interventions on diaphragm contractility.

Reproducibility of twitch and sniff transdiaphragmatic pressures.

Twitch transdiaphragmatic pressure (Tw Pdi) measured with magnetic stimulation of the phrenic nerve is used to follow up patients and to assess the effect of clinical treatments on diaphragm function. However the reproducibility of Tw Pdi on different occasions has been little studied. We investigated 32 normal subjects, measuring Tw Pdi elicited by bilateral magnetic stimulation of the phrenic nerves on two to 14 occasions. Sniff transdiaphragmatic pressure (sniff Pdi) was also measured. The mean value of Tw Pdi and sniff Pdi were 28+/-5 and 134+/-24 cm H(2)O, respectively. The within subjects coefficient of variation was 11% for both Tw Pdi and sniff Pdi. We conclude that there is a variability of Tw Pdi and the variability of Tw Pdi is the same as that of sniff Pdi.

Diaphragm compound muscle action potential measured with magnetic stimulation and chest wall surface electrodes.

To seek a method to reliably measure phrenic nerve conduction time (PNCT) with magnetic stimulation we investigated two stimulus sites, placing the magnetic coil at the cricoid cartilage (high position) or close to the clavicle (low position). We also compared compound muscle action potential (CMAP) recorded from three different sites: in the sixth to eighth intercostal spaces in the anterior axillary line (Ant-a); in the 8th intercostal space close to the midclavicular line; and with one electrode at the lower sternum and the other at the costal margin. Fourteen normal subjects were studied. The PNCT measured by magnetic stimulation in the high position recorded from (Ant-a) was 7.6+/-0.6 on the left side and 8.4+/-0.7 on the right. The PNCT recorded from all three sites become much shorter when the magnetic coil was moved from the high to the low position. Our results show that PNCT can be accurately measured with magnetic stimulation when care is taken to avoid coactivation of the brachial plexus.

Human T cell leukaemia virus type I associated neuromuscular disease causing respiratory failure.

Polymyositis and inclusion body myositis have rarely been described in association with human T cell leukaemia virus type I (HTLV-I) infection. Most of such patients have coexisting HTLV-I associated myelopathy (HAM). Two patients with HTLV-I infection, myopathy, and respiratory failure are described. The muscle biopsy specimen of the first patient bore the histological features of inclusion body myositis and there was no evidence of concurrent myelopathy. The second patient had HAM, and her muscle biopsy showed non-specific myopathic and neuropathic changes. Both patients developed respiratory muscle weakness over eight years after diagnosis of myopathy, leading to hypercapnic respiratory failure requiring mechanical ventilatory support. Respiratory failure as a complication of HTLV-I associated myopathy has not previously been described.

Nutritional status of children admitted to hospital with different diseases and its relationship to outcome in The Gambia, West Africa.

Admission records from two paediatric units in The Gambia were used to explore the relationship between admission weight and different diseases. In total 13579 hospitalized children were analysed. For comparison, 7399 children were recruited from several surveys of well subjects to provide anthropometric values for healthy Gambian children. Compared to the control children, mean admission weights were lower for malaria (weight for age z-score: -1.602), cerebral malaria (-1.547), transfused malarial anaemia (-1.764), pneumonia (-1.725), meningitis (-1.362), gastro-enteritis (-2.497) and malnutrition (-3.786). Children with bronchiolitis did not have a significantly different weight for age than the controls. Outcome of the hospital admission was recorded and related to the weight on admission. In all disease categories the death rate rose with decreasing admission weight with the exception of bronchiolitis. For all diseases taken together, case fatality was 7.2% for children with a weight for age z-score above -2 Standard Deviations (SD), 9.3% between -2 and -3 SD, 15.6% between -3 and -4 SD and 22.7% for children with weight for age SD z-scores less than -4. Malnourished children are more susceptible to several infectious diseases frequently seen in developing countries and nutritional interventions, as well as standard treatment, may improve outcome.

Dendritic shrinkage and dye-coupling between rat hippocampal CA1 pyramidal cells in the tetanus toxin model of epilepsy.

A small dose of tetanus toxin injected into the rat hippocampus produces a chronic model of temporal lobe epilepsy. We have examined whether morphological changes occur in hippocampal CA1 pyramidal cells in this model by using intracellular injections of biocytin. Eight weeks after the injection of tetanus toxin, significantly more "dye-coupled' cells were found in this group than in the buffer (control) injected group (63% compared with 7%). Half of these coupled cells appeared to be linked at the soma, and the other half by dendrodendritic contacts. Analysis of the dendritic trees revealed that the tetanus toxin group showed a decrease in complexity around the proximal to mid-apical dendritic regions and around the mid- to distal basal dendritic regions. The dye-coupling indicates that electrotonic interaction is induced or strengthened between hippocampal neurones, possibly as a result of the epilepsy-induced dendritic damage.