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Introduction The 'Long COVID' syndrome, where symptoms persist beyond the acute illness with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19), is anecdotally described However, a comprehensive report of clinical, radiological, functional and psychological recovery from COVID-19 is currently lacking We present a detailed radiological, patient-reported and physiological characterisation of patients attending face-to-face assessment following hospitalisation with COVID-19 pneumonia Methods Prospective single-centre observational cohort study at an inner-city South London teaching hospital All patients admitted with severe COVID-19 pneumonia (admission duration-48 hours, oxygen requirement-40% or critical care admission) were invited to attend Post-COVID Clinic 6-8 weeks following hospital discharge Primary outcome: Radiological resolution of COVID-19 pneumonitis Secondary outcomes: Demographics and anthropometrics, inpatient clinical course, patient-reported and physiological outcomes at follow-up (symptoms, functional disability, mental health screening, 4-metre gait speed (4MGS), 1-minute sit-to-stand (STS) test) Results 119 consecutive patients attended clinic between 3rd June and 2nd July 2020, at median (IQR) 61 (51-67) days post discharge Baseline characteristics are presented in table 1 Despite apparent radiographic resolution of lung infiltrates in the majority (RALE score

Introduction Non-invasive ventilation can be an effective treatment for acute hypercapnic respiratory failure, but national audits have consistently demonstrated poorer clinical outcomes than expected. Several potential factors have been identified as being associated with poor outcome. This study was conducted to assess the impact of factors on the clinical outcomes of patients commenced on acute NIV at a central London teaching hospital. Methods A case record review was carried out for all patients treated with acute NIV for hypercapnic respiratory failure in a 12-month period. Patients already being treated with home ventilation were excluded. Clinical outcomes assessed were: NIV success (as defined by BTS criteria) and in-hospital mortality. Lateness of NIV initiation ( 24 hrs), location of instigation (ED vs non-ED), background of COPD (presence vs absence), presence of consolidation (presence vs absence) and initial pH ( 7.26) were recorded and their relationships with the clinical outcomes assessed. Results 141 Acute NIV episodes were identified, of which 75 had complete records available for analysis (mean±SD age 69±10 years, 56% female). Mean±SD initial pH was 7.22±0.08, pCO2 10.8±2.4 kPa and HCO3- 31.2±6.0 mEq.L-1. Overall NIV success rate was 72% and in-hospital mortality 22.7% (vs 34.6% nationally). 69% were admitted to ICU. 12% were intubated (vs 5% nationally). pH Conclusions In this single centre study, NIV success and in-hospital mortality of patients treated with acute NIV compared favourably with national data. pH

We used thematic analysis to investigate factors affecting decision making about gastrostomy and noninvasive ventilation (NIV) by people with Amyotrophic Lateral Sclerosis (ALS) from the viewpoint of the health care professionals (HCPs) supporting them. We conducted 20 in-depth interviews with 19 HCPs nominated by people with ALS who had made a decision to accept or decline NIV or gastrostomy. We found the main themes influencing decision making were patient-centric, caregiver-related or related to HCPs’ own beliefs, perspectives, and actions. HCPs felt patients should be, and were, in control of decision making, although caregivers and HCPs played a role. The patient’s evaluation of quality of life, the desirability of prolonging life, and acceptance of the disease and its progression by both patient and caregiver were the most important factors identified by HCPs. HCPs should be aware of the importance of multiprofessional discussions, and the potential influences (identified above) that might require discussion with patients and caregivers.

Our objective was to identify factors associated with acceptance of non-invasive ventilation (NIV) and gastrostomy in an exploratory population-based study. Seventy-eight people with ALS at least six months post-diagnosis, and 50 caregivers, were recruited from the South-East ALS Register. Baseline physical, cognitive and psychological measures were obtained. Three-monthly follow-ups monitored whether patients had accepted or refused NIV or gastrostomy. Following an intervention decision, post-decision interviews repeated baseline measures and included further intervention-specific questionnaires. Results showed that 32 people with ALS made at least one intervention decision and of these 10 decided about both NIV and gastrostomy. While illness factors predicted those needing to make an intervention decision, cognitive and education status, and level of executive dysfunction were associated with decision-making and acceptance or refusal of interventions. Patients' understanding of their illness, their early approach to considering interventions and carer-related factors were also associated with treatment decisions. In conclusion, our findings highlight the complexity of decision-making and provide a platform for designing further studies. Cognitive and psychosocial factors may assume a greater role in palliative care decisions for people with ALS than has been explicitly recognized. Future work must clarify how to ensure patients are not inadvertently being denied suitable interventions.

Rationale: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking. Objectives: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator-free survival, up to 3 years. Methods: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter. Measurements and Main Results: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilationfree survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation. Conclusions: The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value.

The management of motor neurone disease (MND) has evolved rapidly over the last two decades. Although still incurable, MND is not untreatable. From an attitude of nihilism, treatments and interventions that prolong survival have been developed. These treatments do not, however, arrest progression or reverse weakness. They raise difficult practical and ethical questions about quality of life, choice, and end of life decisions. Coordinated multidisciplinary care is the cornerstone of management and evidence supporting this approach, and for symptomatic treatment, is growing.1–3 Hospital based, community rehabilitation teams and palliative care teams can work effectively together, shifting emphasis and changing roles as the needs of the individuals affected by MND evolve. In the UK, MND care centres and regional networks of multidisciplinary teams are being established. Similar networks of MND centres exist in many other European countries and in North America. Here, we review current practice in relation to diagnosis, genetic counselling, the relief of common symptoms, multidisciplinary care, the place of gastrostomy and assisted ventilation, the use of riluzole, and end of life issues. View this table: Table 1 Clinical syndromes of MND (ALS—amyotrophic lateral sclerosis) and related disorders (modified from Kato et al , 2003*, with permission) The average delay from onset of symptoms to diagnosis is about 14 months, about one third of expected survival. Occasionally, survival following diagnosis may be less than six months. The patient may already suspect the diagnosis …

Anecdotal observations suggest that low frequency fatigue, as judged by a fall in twitch tension, is more difficult to achieve in the diaphragm than nonrespiratory muscle but this hypothesis has not previously been directly tested. We studied 7 subjects by performing incremental repetitive contraction loading protocols of the diaphragm and quadriceps. We measured twitch transdiaphragmatic pressure (Tw Pdi) and twitch quadriceps tension (Tw Q) during both muscle contraction and relaxation phases during the run. Unpotentiated and potentiated Tw Pdi and Tw Q were measured before and at 20, 40, and 60 minutes after the run. During the run, greater activation of the quadriceps was achieved; for example, at 70% of maximal voluntary effort the interpolated Tw Q was 12.5% of the relaxation phase Tw Q (implying activation of 87.5%) compared with 29.4% (i.e., 70.6% activation) for the diaphragm (p = 0.05). A significantly greater fall in Tw Q than Tw Pdi was observed (unpotentiated Tw Pdi at 20 minutes 94% baseline versus Tw Q 59% baseline, p = 0.007). Low frequency fatigue in humans is more difficult to generate in the diaphragm than in the quadriceps muscle due in part to reduced central activation.

OBJECTIVES—Neuropsychological investigations have shown a degree of cognitive dysfunction in a proportion of non-demented patients with ALS. Respiratory muscle weakness in ALS can lead to nocturnal hypoventilation, resulting in sleep disturbance and daytime somnolence. Sleep deprivation of this type may cause impairments in cognitive function, but this has not been formally evaluated in ALS. METHODS—Cognitive functioning was evaluated in nine patients with ALS with sleep disturbance caused by nocturnal hypoventilation (NIPPV group), and in a comparison group of 10 similar patients without ventilation problems (control group). The NIPPV group then started non-invasive positive pressure ventilation (NIPPV) at night. After about 6 weeks, change in cognitive function was evaluated. RESULTS—Statistically significant improvement in scores on two of the seven cognitive tests was demonstrated in the NIPPV group postventilation, and a trend towards significant improvement was found for two further tests. Scores in the control group did not improve significantly for these four tests, although an improvement was found on one other test. CONCLUSIONS—Nocturnal hypoventilation and sleep disturbance may cause cognitive dysfunction in ALS. These deficits may be partially improved by NIPPV over a 6 week period. This has important implications for investigations of both cognitive dysfunction in non-demented patients with ALS, and the effect of ventilation on quality of life.

To test the hypothesis that diaphragm fatigue leads to an increase in neural respiratory drive, we measured the esophageal diaphragm electromyogram (EMG) during CO2 rebreathing before and after diaphragm fatigue in six normal subjects. The electrode catheter was positioned on the basis of the amplitude and polarity of the diaphragm compound muscle action potential recorded simultaneously from four pairs of electrodes during bilateral anterior magnetic phrenic nerve stimulation (BAMPS) at functional residual capacity. Two minutes of maximum isocapnic voluntary ventilation (MIVV) were performed in six subjects to induce diaphragm fatigue. A maximal voluntary breathing against an inspiratory resistive loading (IRL) was also performed in four subjects. The reduction of transdiaphragmatic pressure elicited by BAMPS was 22% (range 13–27%) after 2 min of MIVV and was similar, 20% (range 13–26%), after IRL. There was a linear relationship between minute ventilation (V˙e) and the root mean square (RMS) of the EMG during CO2 rebreathing before and after fatigue. The mean slope of the linear regression of RMS on V˙e was similar before and after diaphragm fatigue: 2.80 ± 1.31 vs. 3.29 ± 1.40 for MIVV and 1.51 ± 0.31 vs 1.55 ± 0.31 for IRL, respectively. We conclude that the esophageal diaphragm EMG can be used to assess neural drive and that diaphragm fatigue of the intensity observed in this study does not affect respiratory drive.

Measurement of the amplitude of the esophageal diaphragm compound muscle action potential (CMAP) could be useful for the diagnosis and monitoring of neuromuscular disease. However, quantification of the diaphragm CMAP has been hampered by difficulty in positioning the esophageal electrode at the diaphragm's electrically active center and many investigators report arbitrary units rather than voltage. To quantify the esophageal diaphragm CMAP we designed a multipair electrode which we evaluated during unilateral magnetic stimulation. The esophageal catheter consisted of four sequential electrode pairs. Overall the electrode spanned 17 cm and covered the entire electrically active region of the diaphragm. The diaphragm CMAP was simultaneously recorded from the four pairs at distances of 40, 39, 38, and 37 cm from the nose to the proximal electrode pair. Studies were undertaken in 10 normal subjects and 10 patients with diaphragm dysfunction. The amplitude of the CMAP (peak to peak) was defined as the average of five twitches recorded from the optimal pair of electrodes. The amplitude of the diaphragm CMAP elicited by unilateral maximal magnetic stimulation was 1.45 +/- 0.35 mV (mean +/- SD) for the right side and 1.68 +/- 0.47 mV for the left. When measured on different occasions the coefficient of variation (CV) was 8.6%. The amplitude of the CMAP measured from dysfunctional hemidiaphragms was much less than that measured from normal subjects. This study suggests that the diaphragm CMAP can be quantified using an appropriate esophageal electrode.

BACKGROUND—Diaphragm function can be assessed by electromyography of the diaphragm during electrical phrenic nerve stimulation (ES). Whether phrenic nerve conduction time (PNCT) and diaphragm electrical activity can be reliably measured from chest wall electrodes with ES is uncertain. METHODS—The diaphragm compound muscle action potential (CMAP) was recorded using an oesophageal electrode and lower chest wall electrodes during ES in six normal subjects. Two patients with bilateral diaphragm paralysis were also studied. Stimulations were deliberately given in a manner designed to avoid or incur co-activation of the brachial plexus. RESULTS—For the oesophageal electrode the PNCT was similar with both stimulation techniques with mean (SE) values of 7.1 (0.2) and 6.8 (0.2) ms, respectively (pooled left and right values). However, for surface electrodes the PNCT was substantially shorter when the brachial plexus was activated (4.4 (0.1) ms) than when it was not (7.4 (0.2) ms) (mean difference 3.0 ms, 95% CI 2.7 to 3.4, p

Motor neurone disease (MND) is a devastating and progressive neurological disorder in which degeneration of motor neurones results in weakness and wasting of the dependent muscles. The prevalence of MND is approximately five per 100 000 and approximately 30% of patients have primary bulbar symptoms.1 Half of the patients die within 36 months of experiencing the first symptom. Presentation with ventilatory failure is recognised but uncommon,2 occurring in less than 5% of cases3; however, abnormalities of respiratory muscle function are frequently detectable.4 5 As the condition progresses respiratory muscle strength diminishes4 6; indeed, the rate of change in respiratory function is the only measurable parameter which predicts survival.1 When the load placed on the respiratory muscle pump exceeds the capacity of the respiratory muscles, then the patient is at risk of ventilatory failure. Initially abnormalities may be present only in sleep7 or on exercise8 but, frequently, established ventilatory failure ensues. Ventilatory failure is usually manifest by dyspnoea which may be worse on lying flat (if diaphragm weakness is prominent) or sitting upright (if expiratory muscle weakness predominates). More commonly there is generalised weakness and then there are no clear cut postural symptoms. Direct questioning may elicit symptoms suggestive of disordered sleep architecture—for example, daytime somnolence, difficulty concentrating, or “respiratory” nightmares—or carbon dioxide retention—for example, morning headache. Examination may show paradoxical abdominal motion during respiration. This indicates substantial diaphragm weakness9 combined with preservation of enough upper thoracic musculature to generate sufficient negative intrathoracic pressure to cause inward abdominal motion. In more advanced disease paradoxical motion may be difficult to elicit and the patient may simply appear tachypnoeic without useful rib cage movement. In established MND patients may also complain of choking symptoms; most commonly this represents swallowing difficulties. However, if unrelated …

The purpose of the study was to compare electrical stimulation (ES) and cervical magnetic stimulation (CMS) of the phrenic nerves for the measurement of the diaphragm compound muscle action potential (CMAP) and phrenic nerve conduction time. A specially designed esophageal catheter with three pairs of electrodes was used, with control of electrode positioning in 10 normal subjects. Pair A and pair B were close to the diaphragm ( pair A lower than pair B); pair C was positioned 10 cm above the diaphragm to detect the electromyogram from extradiaphragmatic muscles. Electromyograms were also recorded from upper and lower chest wall surface electrodes. The shape of the CMAP measured with CMS (CMS-CMAP) usually differed from that of the CMAP measured with ES (ES-CMAP). Moreover, the latency of the CMS-CMAP from pair B (5.3 ± 0.4 ms) was significantly shorter than that from pair A (7.1 ± 0.7 ms). The amplitude of the CMS-CMAP (1.00 ± 0.15 mV) was much higher than that of ES-CMAP (0.26 ± 0.15 mV) when recorded from pair C. Good-quality CMS-CMAPs could be recorded in some subjects from an electrode positioned very low in the esophagus. The differences between ES-CMAP and CMS-CMAP recorded either from esophageal or chest wall electrodes make CMS unreliable for the measurement of phrenic nerve conduction time.

Few data exist concerning expiratory muscle function in amyotrophic lateral sclerosis (ALS). We studied 26 patients with ALS (16 with respiratory symptoms and 10 without) and measured the maximal static expiratory mouth pressure (MEP), the gastric pressure during a maximal cough (Cough Pga), and the gastric pressure after magnetic stimulation of the lower thoracic nerve roots (Tw Pga). These measurements were related to the ability to generate transient supramaximal flow during a cough (cough spikes), to arterialized capillary blood gases, and to inspiratory muscle strength. Vocal cord motion was examined endoscopically in 11 of the 16 symptomatic patients. Expiratory muscle weakness was related to inability to generate cough spikes with a threshold effect such that spikes were absent for Cough Pga < 50 cm H2O (p = 0.009) or Tw Pga < 7 cm H2O (p = 0.006) and was usually associated with inspiratory muscle weakness. However, in multivariate analysis, PaCO2 was only significantly associated with the maximal sniff esophageal pressure (p = 0.02). Symptomatic patients had significantly lower inspiratory muscle strength, whereas, of the expiratory muscle tests, only Tw Pga was significantly lower (p = 0.0009) in symptomatic patients. Abnormal vocal cord motion was observed in two of the 11 patients examined. We conclude that abdominal muscle weakness in ALS, when substantial, results in an inability to generate transient supramaximal flow during a cough. However, the primary determinant of both ventilatory failure and respiratory symptoms seems to be inspiratory muscle weakness.

Background: Noninvasive ventilation (NIV) reduces mortality and improves some aspects of quality of life (QoL) in ALS. However, concerns remain that progressive disability may negate these benefits and unnecessarily burden caregivers. Methods: Thirty-nine patients requiring NIV were offered treatment. Twenty-six were established on NIV, but 13 declined or could not tolerate NIV. Fifteen patients without respiratory muscle weakness (RMW) but with similar ALS severity and age were studied in parallel. Caregivers of 21 NIV, 7 untreated, and 10 patients without RMW participated. Patients and caregivers had detailed QoL measurements for 12 months. NIV patients underwent cognitive testing before and after treatment. Results: RMW correlated with lower QoL. The median survival of untreated patients (18 days; 95% CI 11 to 25 days) was shorter than for NIV patients (298 days; 95% CI 192 to 404 days) and non-RMW patients (370 days; 95% CI 278 to 462 days; log rank test [2 df ] = 81, p = 0.00001). A wide range of QoL measures improved within 1 month of starting NIV, and improvements were maintained for 12 months. QoL of non-RMW patients declined as RMW progressed. Caregivers of NIV and non-RMW patients showed similar increases in burden, but NIV patient caregivers developed a deterioration in the Short Form-36 Vitality score. No improvements were found on measures of learning and recall in the NIV patients. Conclusions: Respiratory muscle weakness has a greater impact on quality of life (QoL) than overall ALS severity. Noninvasive ventilation (NIV) improves QoL despite ALS progression. NIV has no impact on most aspects of caregiver QoL and does not significantly increase caregiver burden or stress.

Cough flows and pressures were measured during cough augmentation in healthy subjects and patients with bulbar and nonbulbar amyotrophic lateral sclerosis. Manual assistance increased flow 11% in bulbar (p < 0.01) and 13% in nonbulbar (p < 0.001) patients. Mechanical insufflation-exsufflation increased flow 17% in healthy subjects (p < 0.05), 26% (p < 0.001) in bulbar, and 28% (p < 0.001) in nonbulbar patients. The greatest improvements were in patients with the weakest coughs. Patient group and level of weakness influenced the effect of augmentation.

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.

Although ventilatory failure is the most common cause of death in amyotrophic lateral sclerosis (ALS) and measurement of respiratory muscle strength (RMS) has been shown to have prognostic value, no single test of strength can predict the presence of hypercapnia reliably. RMS was measured in 81 ALS patients to evaluate the relationship between tests of RMS and the presence of ventilatory failure, defined as a carbon dioxide tension > or = 6 kPa. We studied the predictive value of vital capacity (VC), static inspiratory and expiratory mouth pressures (MIP, MEP), maximal sniff oesophageal (sniff P(oes)), transdiaphragmatic (sniff P(di)) and nasal (SNP) pressure, cough gastric (cough P(gas)) pressure and transdiaphragmatic pressure after bilateral cervical magnetic phrenic nerve stimulation (CMS P(di)) to identify the risk of ventilatory failure in the whole group and in subgroups of patients with and without significant bulbar involvement. For patients without significant bulbar involvement, sniff P(di) had greatest predictive power [odds ratio (OR) 57] with specificity, sensitivity and positive and negative predictive values (PPV, NPV) of 87, 90, 74 and 95%, respectively Of the less invasive tests, per cent predicted SNP had greater overall predictive power (OR 25, specificity 85%, sensitivity 81%) than per cent predicted VC (9, 89%, 53%) and per cent predicted MIP (6, 83%, 55%). No test had significant predictive power for the presence of hypercapnia when used to measure RMS in a subgroup of patients with significant bulbar weakness. Thirty-five patients underwent polysomnography. CMS P(di), sniff P(di) and per cent predicted SNP were significantly correlated with the apnoea/hypopnoea index (AHI) (P = 0.035, 0.042 and 0.026, respectively). The correlations between AHI and per cent predicted MIP and VC were less strong (both non-significant). In ALS patients without significant bulbar involvement, novel tests of RMS have greater predictive power than conventional tests to predict hypercapnia. In particular, the non-invasive SNP is more sensitive than VC and MIP, suggesting that it could usefully be included in tests of respiratory muscle strength in ALS and will be helpful in assessing the risk of ventilatory failure. In patients with significant bulbar involvement, tests of respiratory muscle strength do not predict hypercapnia. Sleep-disordered breathing is correlated with RMS and the novel tests of RMS having the strongest relationship with the degree of sleep disturbance.

Expiratory muscle strength is a determinant of cough function. Mouth pressures during a maximal static expiratory effort (PE,max) are dependent on patient motivation and technique and low values are therefore difficult to interpret. This study hypothesized that a short, sharp and maximal expiration through a narrow aperture, a “whistle”, might provide a complementary test of expiratory muscle strength.To obtain a maximal whistle, subjects (27 healthy volunteers and 10 patients with amyotrophic lateral sclerosis) were asked to perform a short, sharp blow as hard as possible, from total lung capacity, through a reversed paediatric inhaler whistle, connected to a flange-type mouthpiece.In both healthy subjects and patients, whistle mouth pressure (Pmo,W) was closely related to the pressure measured in the oesophagus and stomach during the same manoeuvre. In healthy subjects,Pmo,WandPE,maxcorrelated with wide limits of agreement, althoughPmo,Wvalues were significantly higher thanPE,max(131±31 cmH2Oversus101±27 cmH2O, pPmo,WandPE,maxvalues were strongly related (r=0.937, pPmo,Wrepeated measurements were respectively 0.88 and 7.0%. HoweverPmo,WandPE,maxwere always smaller than the gastric pressure generated by a maximal cough.It is concluded that mouth whistle pressure, a noninvasive, reproducible and simple test, provides a reliable measure of expiratory muscle strength in healthy subjects that is acceptable to patients and can be used in a complementary fashion to maximal static expiratory effort.

Motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive degenerative neuromuscular disease against which the only licensed drug, Riluzole (Rilutek; Sanofi-Aventis, Paris, France), is only partially effective. When respiratory muscle weakness is sufficiently severe, type-II respiratory failure occurs. Several data suggest that noninvasive ventilation (NIV) improves quality of life and, at least in nonbulbar patients, extends life 1–3. The timing of initiation of NIV requires considerable clinical skill. As the therapy involves hospital attendance, whether or not the patient is admitted 4, it erodes the limited amount of “quality time” the patient has remaining. If administered too early the burdens of the treatment ( i.e. the need to use a mask, its associated complications and increased carer dependence) may outweigh the perceived benefits, in that symptoms of sleep-disordered breathing (SDB) may initially be mild. Evidence from Duchene muscular dystrophy suggests that if used too early, negative initial experience may deter patients from using the therapy when they are more symptomatic and/or in ventilatory failure 5. However, if administered too late the patient may experience unplanned deterioration, which carries the risk of either intubation or poorly managed end-of-life care 6. The most appropriate method of screening for respiratory failure in these patients with a high pre-test probability remains unclear. The ideal test would be noninvasive, simple to perform and simple to interpret allowing …

The purpose of this study was to establish a sensitive and reliable method of diagnosing diaphragm paralysis by recording the diaphragm compound muscle action potential (CMAP) using a multipair oesophageal electrode and unilateral magnetic phrenic nerve stimulation. An oesophageal electrode catheter was designed containing six coils (1 cm wide and 3 cm apart), creating an array of four sequential electrode pairs. The oesophageal catheter was taped at the nose with the proximal electrode pair 40 cm from the nares. Eight patients with unilateral (n=5) or bilateral (n=3) diaphragm paralysis were studied. Five to seven phrenic nerve stimulations were performed at 80% of maximum magnetic stimulator output and the CMAPs were recorded simultaneously from the four pairs of electrodes. In the five patients with unilateral diaphragm paralysis, the CMAP amplitudes and latencies were 1.16+/-0.29 mV and 7.6+/-1.5 ms for functioning sides. No diaphragm CMAP could be detected when stimulating nonfunctioning phrenic nerves. This study shows that diaphragm paralysis can be reliably diagnosed by unilateral magnetic stimulation combined with a multipaired oesophageal electrode.

The purpose of this study was to establish the phrenic nerve conduction time (PNCT) for magnetic stimulation and further assess the relatively new technique of anterior unilateral magnetic stimulation (UMS) of the phrenic nerves in evaluating the diaphragm electromyogram (EMG). An oesophageal electrode was used to record the diaphragm compound muscle action potential (CMAP) elicited by supramaximal percutaneous electrical phrenic nerve stimulation (ES) and UMS from eight normal subjects. The oesophageal electrode used for recording the CMAP was positioned at the level of the hiatus and 3 cm below. The diaphragm CMAP was also recorded from chest wall surface electrodes in five subjects. All of the phrenic nerves could be maximally stimulated with UMS. A clear plateau of the amplitude of the CMAP was achieved for the right and left phrenic nerves. The mean amplitudes of the CMAP recorded from the oesophageal electrode were, for the right side, 0.74+/-0.29 mV (mean+SD) for ES and 0.76+/-0.30 mV for UMS with maximal power output, and for the left side 0.88+/-0.33 mV for ES and 0.80+/-0.24 mV for UMS. PNCT measured by the oesophageal electrode with ES and UMS with maximal output were, for the right side, 7.0+/-0.8 ms and 6.9+/-0.8 ms, respectively, and for the left side 7.8+/-1.2 ms and 7.7+/-1.3 ms, respectively. However, the CMAP recorded from chest wall surface electrodes with UMS was unsuitable for the measurement of PNCT. The results suggest that unilateral magnetic stimulation of the phrenic nerves combined with an oesophageal electrode can be used to assess diaphragmatic electrical activity and measure the phrenic nerve conduction time.

Exertional dyspnoea is commonly an early feature in respiratory disease; however, neurological disease may limit mobility and, as a consequence, preclude this symptom. Diagnosis of respiratory dysfunction resulting from neurological disease may therefore require a higher index of clinical suspicion or the application of specific tests; this exercise is worthwhile if it allows advance detection and discussion and (where appropriate) treatment, of impending overt respiratory dysfunction. Specific symptoms and appropriate tests will be discussed in the text and have also been reviewed in detail elsewhere.1 However, it should be recalled that, at the most basic level, the function of the respiratory muscle pump is to produce inspiratory airflow, which is related to the ability to generate a subatmospheric pressure within the thorax. Thus, although access to detailed investigation of respiratory muscle is not universal, we encourage measurement of both the lying and standing vital capacity2 and static mouth/nasal pressures,3 4 which can be done either in the neurological clinic or in any standard lung function laboratory. This review deals with acute neuromuscular respiratory disease (including those aspects of respiratory muscle function relevant to intensive care), chronic neuromuscular respiratory disease, sleep related disorders, respiratory consequences of neurological disease, and finally with neurological features of respiratory disease. The presentation of acute ventilatory failure due to neurological disease may be genuinely acute or may simply result from any of the causes of chronic respiratory neuromuscular dysfunction, which are discussed below, passing undiagnosed. Patients who present with acute ventilatory failure and no diagnosis usually receive treatment in the form of mechanical ventilation before a diagnosis is reached. The cause may be disease of the nerves, the neuromuscular junction, or muscle5; however, most data relating to the assessment of such patients have been obtained from the study of patients with …

Objective This study set out to investigate the relationship between mood and physical and psychological factors in amyotrophic lateral sclerosis (ALS). Method As part of a longitudinal study investigating decision-making in ALS, 69 ALS patients, recruited from the South East ALS register, were assessed at baseline on measures of mood (Beck Depression Inventory Fast Screen), purpose in life (Purpose in Life Scale) and illness perceptions (Brief Illness Perceptions Questionnaire). Demographic and illness characteristics were also recorded. Hierarchical multiple regression was used to determine the extent to which psychological variables (purpose in life; and illness perceptions—consisting of perceived consequences of illness, personal control, identity, concern and emotions) predicted mood, after accounting for the effects of demographic (age, years of education) and illness characteristics (symptom severity, measured by ALSFRS-R). Results 42.0% of patients exceeded the recommended clinical cut-off score on the BDI-Fast Screen, suggestive of depression, although most of these (34.8% of the total sample) fell in the mild range. Multiple regression showed that psychological variables (purpose in life and illness perceptions) explained an additional 42% (adjusted R 2 =0.406) of the variance in mood, over and above that explained by demographic and illness characteristics, which only explained a total of 7% of the variance. In the final model, purpose in life was the only statistically significant predictor of mood among ALS patients. Conclusion Purpose in life, based on the work of Frankl (1959), refers to the degree to which a person experiences a sense of meaning in life and includes, for example, having goals to strive for and relationships to maintain (Hedberg et al , 2011; White, 2004). Frankl (1958) suggested that a lack of purpose in life can weaken the will to confront life situations, producing an “existential vacuum” and resulting in depression and anxiety (Hedberg et al , 2011). Current results suggest that purpose in life may play a more significant role in influencing mood among ALS patients than the beliefs about their illness or the severity of their physical symptoms. Findings, therefore, emphasise the importance of understanding psychological factors leading to risk of mental health problems in this population, and ultimately their relation to prognosis and treatment choices. Funding This study is funded by the MNDA, UK.

Many human tumors of epithelial origin contain cells overexpressing the epidermal growth factor (EGF) receptor, and there is convincing evidence that cancer cell growth is correlated with the loss of the normal regulation of the EGF receptor signal transduction pathway. Some cancers are clearly dependent on activation of the EGF receptor for their proliferation. Recently, a class of compounds, tyrphostins, which inhibit the protein tyrosine kinase activity of the growth factor receptor, have been described. In this report, we have examined the antiproliferative effects of potent new tyrphostins on a well-characterized human squamous cell carcinoma in vitro and in vivo. We found that two of these compounds (RG-13022 and RG-14620) suppressed not only EGF-stimulated cancer cell proliferation in vitro but also tumor growth in nude mice. RG-13022 also increased the life span of these tumor-bearing nude mice. When administered to tumor-bearing nude mice together with monoclonal antibodies to the EGF receptor at a suboptimal dose which had no effect alone, inhibition of tumor growth was markedly enhanced. These data suggest that tyrphostins have potential as anticancer agents.

Previous studies have shown conflicting results on the effect of lung volume on the diaphragm compound muscle action potential (CMAP). Consequently, the ability to quantify the oesophageal diaphragm electromyography (EMG) has been questioned. If lung volume changes have little effect on the diaphragm CMAP the accurate measurement of voluntary EMG, as an index of respiratory drive, may be possible. Furthermore, the measurement of CMAP could provide useful clinical information when evaluating patients with neuromuscular disease. To reassess the effect of lung volume on the oesophageal diaphragm CMAP, six normal subjects were studied using an oesophageal catheter incorporating seven electrodes (number one being proximal and seven distal) that were 1 cm in length and 1 cm apart. Electrode number three was positioned at the centre of the electrically active region of the diaphragm (EARdi) at functional residual capacity (FRC). The diaphragm CMAP elicited by bilateral magnetic stimulation of the phrenic nerves was simultaneously recorded from four electrode pairs. Pair one was created from electrodes one and three, pair two from electrodes two and four, pair three from electrodes three and five, and pair four from electrodes five and seven. Phrenic nerve stimulation was at residual volume (RV), FRC, FRC+1.0 L, FRC+2.0 L, and total lung capacity (TLC). The CMAP recorded from pair one was least influenced by changes in lung volume and the amplitude was 2.41+/-0.39 (mean+/-SD), 2.60+/-0.27, 2.64+/-0.29, and 2.71+/-0.45 mV at RV, FRC, FRC+1.0 L and FRC+2.0 L, respectively. At TLC the CMAP was more variable. The CMAP amplitude recorded from pair two increased with increasing lung volume and at FRC+2.0 L was 3.7 times larger than that at FRC. Pair four usually recorded substantially smaller CMAPs at all lung volumes. This study shows that the diaphragm compound muscle action potential recorded from an oesophageal electrode just above the diaphragm is relatively stable over the lung volume range residual volume to functional residual capacity+2.0 L.

THE fifteenth-century Scots poem The Thre Prestis of PeblisI is a composite of three linked tales, involving no less than seven narrative elements. The first, the basic narrative framework, concerns the carousing of the priests and their decision to rival one another in story-telling. The tale of Master John, 'of pe thre questionis', is a straightforward account of a king's attempt to discover the cause of the failings of his three Estates, and of the replies of their three spokesmen. Master Archibald's tale, the second of the sequence, is a good deal more complex, echoing in its tripartite structure the pattern of the poem as a whole: the link in this case is the character of Fictus, the wise fool, who exposes the vices of a king through three incidents. These are the story of a wounded man who rebukes the king for brushing flies away from his wounds, that of a murderer who when pardoned repeats his crime, and that of the impersonation by the queen of the king's chosen mistress. The tale of the third priest, Sir William, while it repeats the tripartite structure which is the basis of The Thre Prestis, resembles Master John's tale in having only a single narrative line, the story of a man compelled to undertake a journey and attempting to find a friend to accompany him. The poem thus combines a wide variety of narrative motifs, evidently drawn from a variety of sources. In the past, there has been a certain amount of critical interest in the poet's sources for these stories, not only out of editorial tidiness but also because the study of sources helps to define the cultural background within which the poem must be placed. T. D. Robb, its most recent editor, for example, finds parallels for the over-all linking device in both the Middle Scots Buke of the Sewyn Sagis (itself the representative of a widespread European tradition) and Chaucer's Canterbury Tales, and further suggests that the source for the tale of the wounded man and the flies is probably one of the exempla in the Gesta Romanorum. He gives no source for the second episode of Master Archibald's tale, that of the pardoned murderer, but the episode of the wife who impersonates her husband's mistress is linked by Robb with the story of Giletta di Nerbona in Boccaccio's II Decamerone. He stops short of positively envisaging an Italian-reading poet, however

The response of human endothelial cell migration to various extracellular matrix components and growth factors has been assessed. Human endothelial cells demonstrate increased chemotaxis and chemokinesis when placed in a modified Boyden chamber with endothelial cell growth factor (ECGF) used at a concentration of 10(-9) M. Anti-ECGF antibody inhibits the chemotactic response. Heparin (10(-8) to 10(-10) M) was also chemotactic and was shown to potentiate the chemotactic activity of ECGF. Although laminin, fibronectin, the polypeptide (epidermal, fibroblast, and nerve) growth factors, and collagen types I, II, III, IV, and V demonstrate a chemotactic response, these activities were one third to one half less than observed with ECGF. These data suggest that ECGF and heparin may play a significant role as response modifiers of human endothelial cell migration which may be relevant to tumor metastasis, wound healing, and atherogenesis.

The foundation of the University of St Andrews by Bishop Henry Wardlaw in the latter part of 1410, formally recognized in a charter of 28 February 1412 and in a bull by Benedict XIII of 28 August 1413, had a profound effect upon the educational and cultural life of Scotland. Hitherto, Scottish students had generally travelled to the Continent to obtain a university degree, and it is evident that they did so in considerable numbers, the great majority to Paris, but others to Orleans, Avignon, and in a few cases to the universities of Italy.1 That St Andrews was in effect a daughter-university of Paris is manifest: Wardlaw himself was an Arts graduate of Paris who had moved on to study civil law at Orleans and canon law at Avignon, while Laurence of Lindores, who dominated the new university in its early years, studied and taught at Paris from about 1390 until about 1407.2 This latter date is undoubtedly significant, for it was after the assassination of the duke of Orleans in that year and its consequent civil disturbances that, according to a later generation of Paris nominalists, the leading nominalist teachers left the city, and it is certain that Lindores himself was a follower of the via moderna? It was Lindores' influence, probably, which was decisive in obtaining the proscription of the doctrina Alberti at St Andrews from February 1418 in favour of that of Buridan, a ban which lasted until shortly after his death in 1437, while his authority was no doubt reinforced—morally, at least—by his position as inquisitor hereticepravitatis in regno Scocie.

A malignant nerve sheath tumour arising within a thoracic ganglioneuroma is described. This is only the seventh such case described in the literature and the first at this site. The previously documented cases are reviewed.

Cultured NIH-3T3 cells devoid of endogenous epidermal growth factor (EGF) receptors were transfected with cDNA expression constructs encoding either normal human EGF receptor or a receptor mutated in vitro at Lys-721, a residue that is thought to function as part of the ATP-binding site of the kinase domain. Unlike the wild-type EGF-receptor expressed in these cells, which exhibited EGF-dependent protein tyrosine kinase activity, the mutant receptor lacked protein tyrosine kinase activity and was unable to undergo autophosphorylation and to phosphorylate exogenous substrates. Despite this deficiency, the mutant receptor was normally expressed on the cell surface, and it exhibited both high- and low-affinity binding sites. The addition of EGF to cells expressing wild-type receptors caused the stimulation of various responses, including enhanced expression of proto-oncogenes c-fos and c-myc, morphological changes, and stimulation of DNA synthesis. However, in cells expressing mutant receptors, EGF was unable to stimulate these responses, suggesting that the tyrosine kinase activity is essential for EGF receptor signal transduction.

Polymorphonuclear neutrophils (PMN) traverse basement membrane to reach sites of infection. We have studied the role of laminin, a specific basement membrane component, in this process using three assay systems. In the Boyden chamber, laminin was found to stimulate chemotaxis of neutrophils while fibronectin did not. Co-incubation of cells with antibody to laminin blocked this chemotaxis, while antibody to fibronectin was without effect. In the human amnion system, neutrophils were shown to penetrate through the tissue when the peptide chemoattractant f-Met-Leu-Phe was placed on the opposing side. Antibody to laminin, but not to fibronectin, blocked this penetration. In an attachment assay system, laminin, but not fibronectin, was found to increase dispase-treated neutrophil attachment to type IV (basement membrane) collagen-coated plastic and to a plastic substrate itself. Electrophoretic analysis of PMN extract indicated the presence of laminin, and indirect immunofluorescence suggested that laminin is localized on the surface of the neutrophils. These data suggest that PMN can bind laminin on their cell surfaces, use laminin to attach to basement (type IV) membrane collagen, and migrate toward a gradient of laminin. These properties may be important for the passage of neutrophils from the circulation to sites of infection.

ET in the fourth of his Eclogues, 'The Towre of Vertue and Honoure' (I513-14) is unique among the works of Alexander Barclay. It represents his only sustained attempt at formal, courtly allegory, if we agree with the consensus of modern critical opinion and reject the ascription to him of 'The Castell of Laboure'.' The 'Towre' is an occasional poem, concerned with the death in battle of Sir Edward Howard, the son of Thomas Howard, duke of Norfolk, who was soon to become Barclay's patron. Such formal poems are not unusual in the later Middle Ages, and the 'Towre' has received little critical comment. Dr. Beatrice White, editing Barclay's eclogues in 1928, suggested that the inspiration for this poem may have been Jean Lemaire's Temple d'Honneur et de Vertus (I503), but acknowledged that 'Barclay has taken but little detail from Lemaire's "Temple"'.2 Beyond indicating the likely influence of Lemaire, Dr. White gave little attention to the 'Towre', and did not suggest in what way the poem made its avowed 'claim to originality'. It is the intention in this article to explore Barclay's purpose in writing 'The Towre of Vertue and Honoure', stressing the poet's independence of all the probable sources, and then to examine the place of Barclay's poem in the development of English elegy.

In untreated obstructive sleep apnea syndrome (OSAS) inspiratory efforts are made against an occluded airway and diaphragm fatigue might therefore complicate OSAS. To test this hypothesis we measured twitch transdiaphragmatic pressure (Tw Pdi) in response to bilateral cervical magnetic stimulation of the phrenic nerve roots in nine patients with OSAS before and one month after successful therapy with nasal continuous positive airways pressure (nCPAP). The mean Tw Pdi before therapy was 23.2cm H2O and after therapy was 22.8cm H2O (P=0.59); the mean change after initiation of nCPAP was 0.4cm H2O with 95% confidence intervals of −1.3cm H2O and +2.1cm H2O. We conclude that low frequency diaphragm fatigue does not complicate untreated OSAS.

Acidic fibroblast growth factor (aFGF), a polypeptide with a mol. wt of approximately 16,000, is a potent mitogen for a variety of cells and shares 55% amino acid sequence identity with basic FGF. The recent isolation of three new oncogenes which share 35-45% amino acid sequence similarity with the FGFs suggests that the coding sequences for the FGFs themselves may be oncogenic under certain circumstances. To test this hypothesis, we cotransfected 3T3 NR6 cells with factors expressing the aFGF coding sequence and the bacterial neomycin gene. The aFGF produced by cotransfected cells was found only in the cellular homogenate and not in medium conditioned by the cells. Cells expressing aFGF grew to 10 times the density of control cells at saturation and were multilayered and disorganized, similar to transformed cells. The cotransfected cells do not grow in soft agar, but show enhanced soft agar growth relative to controls in the presence of added aFGF and heparin. The aFGF-producing cells formed small, non-progressive tumors when injected subcutaneously into nude mice. Our data suggest that expression of aFGF in NR6 cells results in enhanced growth, and that several traits characteristic of the transformed phenotype are partially expressed.

Mutants of the human KB carcinoma cell line resistant to a cytotoxic conjugate of epidermal growth factor (EGF) and Pseudomonas exotoxin (PE) were selected. EGF-PE and the drug verapamil, which enhanced EGF-PE cytotoxicity, were used in the selection process. These mutants also showed some cross-resistance to PE. All of the EGF-PE resistant variants displayed lower levels of 125I-EGF binding, 20-50% of parental KB levels, without altered affinity for EGF and grew at a slower rate than the parental cell line KB-3-1. These results indicate that EGF-PE resistant KB cells have a complex phenotype which includes a reduction in the number of EGF receptors and reduced sensitivity to unconjugated PE. Resistance to toxin-conjugates, although pleiotropic, is specific and does not lead to resistance to multiple other anticancer drugs, nor are independently selected multidrug resistant KB lines resistant to PE. These results argue that protocols for cancer treatment could effectively use specifically designed cytotoxic toxin conjugates as an adjunct to conventional chemotherapy.

The DNA-binding site of a previously characterized non-histone chromosomal protein antigen(s) from HeLa cells was investigated for its species specificity. Treatment with large amounts of micrococcal nuclease abolishes immunoactivity, which can then be recovered by the subsequent addition of human or HeLa DNA to reconstitute the immune complex. Neither rat nor calif DNA exhibits this property, but DNA from monkey cells gives considerable activity. The antigen is not, however, detectable in monkey chromatin.

Reports were made on combined ventilation-perfusion lung scans by three observers on three occasions and by another observer once. Reproducibility for each observer varied between 80 and 88%. There was complete agreement about the areas of scans reported as abnormal. Agreement between observers on whether or not the abnormality represented a pulmonary embolus averaged 77%. There was 86% agreement with the final clinical diagnosis. Our results show that reporting of ventilation perfusion lung scans by eye is reproducible. They support the claims that, under routine clinical conditions, the technique is 91% to 95% accurate for pulmonary emboli.