Biomedical subjects

M Green

Publications and source records attributed to M Green.

At least 253 records · Page 14Linked to original sources

PubMed1996

The regulatory domain of human heat shock factor 1 is sufficient to sense heat stress.

Heat shock factor (HSF) activates transcription in response to cellular stress. Human HSF1 has a central regulatory domain which can repress the activity of its activation domains at the control temperature and render them heat shock inducible. To determine whether the regulatory domain works in tandem with specific features of the HSF1 transcriptional activation domains, we first used deletion and point mutagenesis to define these activation domains. One of the activation domains can be reduced to just 20 amino acids. A GAL4 fusion protein containing the HSF 1 regulatory domain and this 20-amino-acid activation domain is repressed at the control temperature but potently activates transcription in response to heat shock. No specific amino acids in this activation domain are required for response to the regulatory domain; in particular, none of the potentially phosphorylated serine and threonine residues are required for heat induction, implying that heat-induced phosphorylation of the transcriptional activation domains is not required for induction. The regulatory domain is able to confer heat responsiveness to an otherwise completely heterologous chimeric activator that contains a portion of the VP16 activation domain, suggesting that the regulatory domain can sense heat in the absence of other portions of HSF1.

Amino Acid Sequence↗

PubMed1996

Clinical assessment of diaphragm strength by cervical magnetic stimulation of the phrenic nerves.

BACKGROUND: Accurate assessment of diaphragm strength can be difficult. Transdiaphragmatic pressure (PDI) measurements during volitional manoeuvres are useful but it may be difficult to ensure maximum patient effort. Magnetic stimulation of the phrenic nerves is easy to perform and the results are reproducible in normal subjects. The purpose of the present study was to evaluate the usefulness of magnetic stimulation of the phrenic nerves in the assessment of diaphragm weakness in patients. METHODS: Sixty-six patients referred for assessment of respiratory muscle strength and 23 normal subjects were studied. Twitch PDI (TwPDI) following magnetic stimulation of the phrenic nerves and sniffPDI were obtained in all individuals. TWPDI following bilateral electrical stimulation of the phrenic nerves was also obtained in eight patients. RESULTS: Mean (SD) TwPdi for the normal subjects was 31 (6) cm H2O and 18 (11) cm H2O for the patients. TwPDI and sniffPDI were correlated (r = 0.77). Seven of the 37 patients (19%) with a reduced sniffPDI had a TwPDI within the normal range whereas two of the 32 patients (6%) with a reduced TwPDI had a normal sniffPDI. TwPDI was similar with magnetic and electrical stimulation. CONCLUSIONS: TwPDI following magnetic stimulation of the phrenic nerves is a clinically useful measurement when assessing diaphragm weakness.

Adult↗

PubMed1996

Effect of maximum ventilation on abdominal muscle relaxation rate.

BACKGROUND: When the demand placed on the respiratory system is increased, the abdominal muscles become vigorously active to achieve expiration and facilitate subsequent inspiration. Abdominal muscle function could limit ventilatory capacity and a method to detect abdominal muscle fatigue would be of value. The maximum relaxation rate (MRR) of skeletal muscle has been used as an early index of the onset of the fatiguing process and precedes failure of force generation. The aim of this study was to measure MRR of abdominal muscles and to investigate whether it slows after maximum isocapnic ventilation (MIV). METHODS: Five normal subjects were studied. Each performed short sharp expiratory efforts against a 3 mm orifice before and immediately after a two minute MIV. Gastric pressure (PGA) was recorded and MRR (% pressure fall/10 ms) for each PGA trace was determined. RESULTS: Before MIV the mean (SD) maximum PGA MRR for the five subjects was 7.1 (0.8)% peak pressure fall/10 ms. Following MIV mean PGA MRR was decreased by 30% (range 25-35%), returning to control values within 5-10 minutes. CONCLUSIONS: The MRR of the abdominal muscles, measured from PGA, is numerically similar to that described for the diaphragm and other skeletal muscles. After two minutes of maximal isocapnic ventilation abdominal muscle MRR slows, indicating that these muscles are sufficiently heavily loaded to initiate the fatiguing process.

Abdominal Muscles↗

PubMed1996

Abdominal muscle fatigue after maximal ventilation in humans.

Abdominal muscles are the principal muscles of active expiration. To investigate the possibility of abdominal muscle low-frequency fatigue after maximal ventilation in humans, we stimulated the nerve roots supplying the abdominal muscles. We used a magnetic stimulator (Magstim 200) powering a 90-mm circular coil and studied six normal subjects. To assess the optimum level of stimulation and posture, we stimulated at each intervertebral level between T7 and L1 in the prone, supine, and seated positions. At T10, we used increasing power outputs to assess the pressure-power relationship. Care was taken to avoid muscle potentiation. Twitch gastric pressure (Pga) was recorded with a balloon-tipped catheter. Mean (+/-SD) baseline twitch Pga measured with the subjects in the prone position at T10 was 23.5 +/- 5.4 cmH2O. Within-occasion mean twitch Pga coefficient of variation was 4.6 +/- 1.1%. Twitch Pga was measured with the subjects in the prone position with stimulation over T10 before and after 2 min of maximal isocapnic ventilation (MIV). Twenty minutes after MIV, mean twitch Pga fell by 17 +/- 9.1% (P = 0.03) and remained low 90 min after MIV. We conclude that after maximal ventilation in humans there is a reduction of twitch Pga and, therefore, of low-frequency fatigue in abdominal muscles.

Abdominal Muscles↗

PubMed1996

Exhaustive exercise slows inspiratory muscle relaxation rate in chronic obstructive pulmonary disease.

The excessive load placed on inspiratory muscles when patients with COPD exercise could lead to fatigue and contribute to exercise limitation. Slowing of maximal relaxation rate (MRR) of skeletal muscle is an early index of the fatiguing process. We investigated whether inspiratory muscle MRR slows when patients with COPD walk to exhaustion. We studied nine well-trained and motivated patients with stable severe COPD (mean FEV1: 0.7 L, 28% predicted). Each subject performed sniff maneuvers before and after walking on a treadmill until they were forced to stop because of dyspnea. Esophageal (Pes), gastric, and transdiaphragmatic pressures were measured using balloon-tipped catheters. MRR was calculated as the percent Pes drop/10 ms. In the first minute after exercise there was a mean decrease of Pes MRR of 42% (range, 21 to 65%) (p < 0.01), which returned to baseline within 3 to 5 min. The fall in MRR indicates that the inspiratory muscles of patients with COPD walking to exhaustion are sufficiently heavily loaded to initiate the fatiguing process.

Aged↗

PubMed1996

Bilateral magnetic stimulation of the phrenic nerves from an anterolateral approach.

We investigated whether bilateral magnetic stimulation of the phrenic nerves from an anterolateral approach (BAMPS) could combine the reproducibility and ease of use of cervical magnetic stimulation (CMS) with the specificity of bilateral electrical stimulation (BES) and whether it could be used in supine subjects. We placed two double 43-mm coils over the phrenic nerves in the neck. BAMPS produced supramaximal phrenic stimulation by electromyogram (EMG) assessment in six of seven subjects. There was no significant difference in the twitch gastric pressure/twitch esophageal pressure ratio (twitch Pgas/Pes) between BAMPS (1.2) and BES (1.3). Both differed from CMS (0.9, p < 0.001). The effect of a change in posture on twitch transdiaphragmatic pressure (TwPdi) and Pgas/Pes ratio was the same for BAMPS and BES. In normal subjects and patients BAMPS correlated significantly with BES (r = 0.97), maximal sniffs (r = 0.85), and CMS (r = 0.92). The mean difference between BAMPS and BES was 0.3 cm H2O (SD = 2.3). Two-minute maximal isocapnic ventilation produced a 19% fall in TwPdi elicited by BAMPS. BAMPS is easy, well tolerated and can be used in the supine subject. TwPdi and partitioning of Pes and Pgas were very close for BAMPS and BES, suggesting similar specificity for the diaphragm.

Case-Control Studies↗

PubMed1996

Inspiratory pressure support reduces slowing of inspiratory muscle relaxation rate during exhaustive treadmill walking in severe COPD.

When patients with COPD walk to a state of intolerable dyspnea, there is excessive inspiratory muscle loading, as evidenced by slowing of the maximum relaxation rate of the inspiratory muscles, measured from esophageal pressure during a sniff (Sn Pes MRR). In this setting, inspiratory pressure support (IPS) delivered via an orofacial mask increases walking distance and reduces dyspnea, but the mechanism by which this benefit is achieved remains unclear. In this study we compared Sn Pes MRR after equidistant treadmill walking in six men with severe COPD (mean FEV1: 0.6 L, 22% predicted). After the free walk there was a mean slowing of Sn Pes MRR of 41% (p < 0.03). After the IPS-assisted walks, the slowing of Sn Pes MRR was 20% of baseline; this was significantly less than after the free walk (p < 0.05). Four subjects performed shorter walks; after free walks of one third and two thirds of maximum distance, the mean slowing of Sn Pes MRR was 23% and 28%, respectively. We conclude that when patients with COPD walk to exhaustion, IPS reduces slowing of inspiratory muscle MRR, and that this represents a considerable unloading of the inspiratory muscles. The magnitude of the reduction is approximately the same as reducing the distance walked by two thirds.

Aged↗

PubMed1996

Diaphragm strength in chronic obstructive pulmonary disease.

The diaphragm is normally the main inspiratory muscle and diaphragm strength in chronic obstructive pulmonary disease (COPD) is therefore of interest. We assessed diaphragm strength in 20 patients with severe stable COPD (mean FEV1 0.61, mean thoracic gas volume [Vtg] 5.31) and seven normal control subjects, measuring both maximal sniff transdiaphragmatic pressure (sniff Pdi(max)) and twitch transdiaphragmatic pressure (Tw Pdi) elicited by cervical magnetic stimulation (CMS) of the phrenic nerve roots at FRC. Acute-on-chronic hyperinflation was examined in four patients. Mean Tw Pdi in patients and control subjects was 18.5 cm H2O and 25.4 cm H2O, respectively (p < 0.01), and mean sniff Pdi was 81.9 cm H2O and 118 cm H2O, respectively (p < 0.001). Reduction in mean intrathoracic pressures was more marked; twitch esophageal pressure (Tw Pes) was -7.3 cm H2O and -16.3 cm H2O, respectively (p < 0.001) and sniff Pes was -67 cm H2O and -97.8 cm H2O (p < 0.001). During acute-on-chronic hyperinflation there was a linear negative correlation of Tw Pdi with increasing lung volume of 3.5 cm H2O/L. The ability of the diaphragm to generate transdiaphragmatic, and particularly a negative intrathoracic, pressure is reduced in COPD and these changes are exaggerated with acute-on-chronic hyperinflation.

Aged↗

PubMed1996

Diaphragm fatigue following maximal ventilation in man.

When highly motivated normal subjects perform maximal isocapnic ventilation, a substantial fall in ventilation is observed during the first minute associated with slowing of the maximum relaxation rate (MRR) of the inspiratory muscles. This suggests that these muscles are excessively loaded, raising the possibility that overt contractile failure of the diaphragm contributes to the fall in ventilation. We therefore investigated the effect of maximal isocapnic ventilation (MIV) on twitch transdiaphragmatic pressure (Pdi,Tw) elicited by cervical magnetic stimulation. We measured Pdi,Tw before and after 2 min MIV in nine normal subjects. Initial mean (SD) ventilation for the nine subjects was 196 (15) L.min-1 falling by 35% at 1 min. Pdi,Tw fell following MIV, at 10 min was reduced by 24%, and remained substantially reduced 90 min after MIV. No change in Pdi,Tw was observed during control studies in which subjects were studied with the same protocol but omitting MIV. We conclude that diaphragmatic contractility is reduced after 2 min maximal isocapnic ventilation and diaphragmatic fatigue may be a limiting factor in maximal ventilation in man.

Adult↗

PubMed1996

ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group.

PURPOSE: Tomudex (ZD1694; Zeneca Ltd, Macclesfield, United Kingdom) appears to have a favorable toxicity profile (defined in phase I studies) and antitumor activity in a broad range of epithelial tumors. We report here the results of a large phase II study of Tomudex in advanced colorectal cancer (CRC). PATIENTS AND METHODS: One hundred seventy-seven patients were entered onto the study between October 1992 and September 1993. Patients were required to have advanced CRC without prior chemotherapy (adjuvant chemotherapy was permissible) and at least one measurable lesion. Tomudex (ZD1694) was administered at a dose of 3 mg/m2 intravenously once every 3 weeks in the absence of toxicity or disease progression. Patients were assessed for objective response, progression, and survival. RESULTS: Of 177 patients entered onto the study, 5% had received prior adjuvant chemotherapy and 83% had liver metastases. Objective responses were seen in 26% of patients (95% confidence interval, 19% to 33%; four complete responses [CRs] and 41 partial responses [PRs]) while median time to progression was 4.2 months and median survival 9.6 months. All sites were audited, and responses were reviewed by an independent panel. Common toxicities included mild reversible transaminitis, nausea and vomiting, and asthenia or flu-like symptoms, and World Health Organization (WHO) grade 3 and 4 leukopenia and diarrhea were seen in 6% and 9.8% of patients, respectively. Stomatitis and alopecia were common. CONCLUSION: In this large multicenter phase II study of patients with advanced CRC, interesting activity was seen (objective response rate, 26%). In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC.

Adult↗

PubMed1996

Telephone nursing in a general medicine ambulatory clinic.

An innovative telephone nursing service was designed to improve care delivery and efficiency in a general medicine clinic. Professional nurses provide general health information and clinical updates and follow intervention guidelines. Patients, physicians, and nurses report high satisfaction and improved patient outcomes.

Aged↗

PubMed1996