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Education, Medical, Graduate↗
Biomedical subjects
K B Saunders
Publications and source records attributed to K B Saunders.
Timing of deep breaths during rest and light exercise in man.
1. We used digital filtering techniques and segmental analysis to dissect a series of respiratory variables into three components: (a) outlying values, including deep breaths or sighs; (b) random variation; (c) non-stationary baseline variation. 2. Records of about 30 min breathing were obtained from normal adults at rest and at 50 W exercise. 3. Deep breaths were defined as having a tidal volume greater than 2.5 sd above the mean. 4. We related these deep breaths to preceding trends in tidal volume and end-tidal partial pressure of CO2. 5. At rest, there was no relation between deep breaths and tidal volume, but the deep breaths were significantly clustered around the troughs in end-tidal partial pressure of CO2. 6. At 50 W exercise, there was no relation between deep breaths and end-tidal partial pressure of CO2, but the deep breaths were significantly clustered around tidal volume troughs. 7. Results obtained by pneumography were concordant with those obtained by using a mouthpiece to measure ventilation.
Adult↗
Heparin-mediated release of fibroblast growth factor-like activity into the circulation of rabbits.
Fibroblast growth factors (FGFs) are a family of structurally related proteins that influence the growth and differentiation of a variety of cell types, including the cells of the vascular system. Due to the lack of signal sequence, basic FGF is not actively secreted. However, it has been detected in the extracellular matrix bound, at least in some cases, via heparin-like molecules. Heparin has been shown to displace FGF from cells and matrices in vitro, and we have investigated the possibility that a similar phenomenon might occur in vivo. Heparin was infused intravenously into anesthesized rabbits; plasma samples taken 30 min later and monitored using [3H]thymidine incorporation into BALB/c 3T3 cells were found to contain 3-fold more stimulatory activity than control plasma samples. Addition of heparin directly to the 3T3 cells or to the plasma samples following their collection did not affect the level of stimulatory activity. A time course of stimulatory activity in rabbit plasma following heparin administration revealed that 3T3 cell stimulatory activity rapidly increased following heparin infusion, peaked at 30 min, and declined to control levels by 90-120 min. The anticoagulant action of heparin followed a different time course, providing evidence that these two effects of heparin are functionally distinct. The binding affinity of the plasma-derived stimulatory activity for heparin was used to demonstrate that the activity is FGF-like in nature. Additionally, administration of [125I]bFGF to rabbits that had been "precleared" by heparin infusion resulted in an immediate peak of circulating labeled bFGF that decreased to plateau level by 20-45 min following injection.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The effect of almitrine on the steady-state ventilatory response to carbon dioxide at rest and during exercise in man.
Almitrine has potential as a tool for testing the physiological role of the peripheral chemoreceptor. The effects of almitrine on CO2 chemosensitivity were studied at rest and during light exercise using a constant inflow technique that avoids the hyperoxia of rebreathing methods. The steady-state ventilatory response to CO2 was measured in two groups of six normal men before and 150 min after 100 mg oral almitrine bismesylate or placebo. One group was studied at rest, the other while pedalling at 50 W. The resting group showed a significant increase in CO2 response slope after almitrine when compared with placebo but there was no significant change in the response intercept. During exercise the individual results were very variable and after almitrine no significant change was seen in either the response slope or intercept. Control ventilation was not affected by almitrine in either group. Even in the absence of marked hyperoxia the effect of almitrine on CO2 sensitivity at rest in small. The lack of effect at 50 W is against any important role for the peripheral chemoreceptor during light exercise but other interpretations are possible.
Adult↗
The transient ventilatory response to carbon dioxide at rest and in exercise in man.
A new technique has been developed to measure the transient response to inhaled CO2 using 30 sec pulses at constant inflow. Multiple experiments are ensemble-averaged in order to define the resulting small signals. We measured the peak changes in ventilation (delta V') and in PCO2 (delta PCO2), taking the ratio (delta V'/delta PCO2) as an index of response. Six healthy volunteers performed experiments at rest, 50 W and 100 W exercise. Three runs, each containing three pulses, were performed at each workload and subsequently averaged. Analysis of variance showed no significant difference between successive pulses or among subjects. delta V' did not differ significantly with workload, but delta PCO2 was progressively smaller as workload increased, and hence the response, delta V'/delta PCO2, greater. The delay between the rise in PCO2 and the rise in ventilation was also progressively shorter as workload increased, being 16-18 sec at rest, 7-13 sec at 50 W, and 3-6 sec at 100 W. Our results suggest that there is increased sensitivity to CO2 in exercise, which may be due to progressive activation of the peripheral chemoreceptors as work load increases. The delay at rest is too long for the peripheral chemoreceptor. Therefore, with these small stimuli, the central chemoreceptor must account for the CO2 response at rest.
Adult↗
An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes.
Using an in vitro coculture system to mimic the interactions between the cells of the vessel wall, we have previously shown that pericytes and smooth muscle cells (SMC) inhibit the growth of capillary endothelial cells (EC). We have undertaken studies to determine the mechanism of this inhibition. Using conditioned media and affinity-purified antibodies to transforming growth factor beta (TGF-beta), we now demonstrate that activated TGF-beta produced in these cocultures mediates EC growth inhibition. No inhibitory activity was detected when media conditioned by individual cultures of EC, SMC, or pericytes were examined for their effect on EC growth. In contrast, media conditioned by cocultures of EC-SMC and EC-pericytes inhibited EC proliferation to the same degree as the coculture itself. Immunoadsorption of coculture-derived conditioned media with antibodies to TGF-beta eliminated the inhibitory activity. Acid activation of serum-free media conditioned by any of the cells cultured alone yielded inhibitory activity, whereas activation of coculture conditioned media did not increase its inhibitory activity. Addition of anti-TGF-beta neutralizing antibodies to cocultures blocked the pericyte-mediated EC growth inhibition. These results indicate that latent TGF-beta is produced by these cells and it is activated by a mechanism that requires contact between the two cell types.
Animals↗
Transient, steady-state and rebreathing responses to carbon dioxide in man, at rest and during light exercise.
1. The transient ventilatory response to CO2, measured using short pulses at constant inflow, was compared with the steady-state response at rest and during exercise at 50 W, and with the rebreathing response at rest, in nine healthy subjects. At rest CO2 was given at flow rates of 0.2 and 0.4 l min-1 and during exercise, to compensate for the smaller inhaled CO2 fraction as ventilation increased, at flow rates of 0.4 and 0.8 l min-1. 2. We calculated two indexes of gain for the transient response: the ratio of the peaks of the ventilation and PCO2 pulses, and the ratio of their integrals. 3. The steady-state response was greater than the transient response at rest and during exercise, but there was no correlation between the two. The rebreathing response was greater than both. Both the transient and the steady-state responses were greater during exercise than at rest. 4. To assess alinearity, the steady-state responses to the two CO2 flow rates were compared. At rest, there was no significant difference. During exercise, the response was greater to 0.4 than 0.8 l min-1, indicating alinearity concave downwards. 5. We conclude that the transient response as we calculate it is not representative of steady-state gain, and that the CO2 response in light exercise is steeper, and concave downwards in shape. The rebreathing technique overestimates CO2 sensitivity near the control point.
Adult↗
CO2 response and pattern of breathing in patients with symptomatic hyperventilation, compared to asthmatic and normal subjects.
We studied six patients with symptomatic hyperventilation, using new techniques to quantify baseline variability of respiratory variables, and to assess CO2 sensitivity around the control point using a stimulus not detectable by the subject. We compared them with six normal subjects and six patients with mild asthma. Symptomatic hyperventilators had normal mean ventilation and end-tidal carbon dioxide tension (PETCO2) at rest. Asthmatic subjects had higher ventilation and lower PETCO2. Symptomatic hyperventilators had a larger number of sighs and abnormally wide fluctuations in baseline for inspiratory time, expiratory time, and PETCO2. These could not be explained by an abnormal ventilatory response to a transient CO2 input; the transient response near the control point was undoubtedly normal.
Adult↗
Medical manpower and student numbers.
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Physicians↗
Tyrosine phosphorylation regulates the biochemical and biological properties of pp60c-src.
To investigate the importance of tyrosine phosphorylation in the regulation of pp60c-src, we have substituted phenylalanine for tyrosine at positions 416, 519, and 527. Cells expressing the 527 or the 519/527 mutant but not the 416 or the 519 mutant were morphologically transformed, grew in soft agar, and formed foci. In addition, the 527 and 519/527 mutants had elevated kinase activities in vitro. Modifying Tyr 416 to phenylalanine in the 527 or the 519/527 mutants only partially inhibited their kinase activities yet abolished their ability to induce focus formation and promote growth in soft agar. These results suggest that two events must occur to activate the full transforming potential of pp60c-src: hypophosphorylation at Tyr 527 and hyperphosphorylation at Tyr 416.
Animals↗
Ventilatory responses to inhaled carbon dioxide at rest and during exercise in man.
1. Rapid steady-state CO2 responses were determined in six normal subjects at rest and five subjects at four different work loads up to 125 W, by injecting pure CO2 at constant flow into a small mixing chamber in the inspiratory limb of a breathing circuit. 2. The time course of the response of ventilation (V) and mean alveolar PCO2 (PACO2) was checked in separate experiments, where the flow rate of injected CO2 was changed abruptly and the effects were followed for 10 min. 3. V and PACO2 were measured every breath, and the results ensemble-averaged for each subject (two or three runs per subject) and then for the groups as a whole, in 30 s or 60 s time bins. 4. PACO2 during exercise was estimated by graphical reconstruction from the sloping alveolar plateau, and separately by the empirical equation of Jones, Robertson & Kane [1]. At rest, PACO2 was assumed equal to end-tidal PCO2 (PetCO2). 5. With the constant inflow technique, 4 min was required to reach steady-state V and PACO2 during exercise, and 6 min at rest. 6. At rest, with 4 min steps (doubtful steady state) the averaged CO2 response was concave up. With 6 min steps the response was almost linear. In neither case was the deviation from linearity statistically significant. 7. During exercise, the averaged CO2 responses were essentially isocapnic at work loads greater than 75 W with either method of deriving PACO2.
Adult↗
How our house physicians live now.
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Humans↗
The GMC and education of doctors.
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Education, Medical↗
Cough response to citric acid aerosol in occasional smokers.
Twenty two normal women volunteers underwent a standard cough provocation test by inhaling solutions of citric acid of progressively increasing concentration. Eight were non-smokers, eight moderate smokers, and six occasional smokers. All the non-smokers and moderate smokers coughed. Moderate smokers tended to cough more than non-smokers, but not significantly so. None of the occasional smokers coughed at all (p less than 0.001). Possibly the ability to smoke occasionally with enjoyment is a marker for a diminished cough reflex.
Adult↗
Where will this month's medical school intake go?
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Career Choice↗
Within-breath changes of airway calibre in patients with airflow obstruction by continuous measurement of respiratory impedance.
We bench-tested a commercially available instrument for measuring respiratory impedance (Siregnost FD5: Siemens) and found that resistance (R) and phase changes were accurately recorded in models. In a single human subject, total respiratory resistance (R(l)) was closely comparable to resistance measured by the Mead-Whittenberger technique. The derived continuous variable (R(os)) was similar to R at less than 4 cmH2O . litres-1 . sec, but underestimated R at higher values. Ros was highly correlated with airways resistance by body plethysmography (R(aw)), but with a low slope and high intercept (R(os) = 1.38 + 0.59 R(aw): r = 0.89). Because of turbulence, both in model larynxes and in normal subjects, R(os) tends to rise with increases in flow in either direction. R(os) also tends to fall as lung volume rises, and vice versa, reflecting cyclic changes in airway calibre. We devised indices of expiratory narrowing of airways from the maximum flow-volume loop, and the plethysmographic alveolar pressure-flow loop, and compared them with the slope of the relation between R(os) and lung volume during tidal breathing, in nine normal subjects and 16 patients with airflow obstruction. Twelve of the 16 patients, all with abnormal flow-volume loops, had high R(os)-volume slopes, demonstrating excessive expiratory narrowing even during tidal breathing. We found no patients with normal inspiratory R(os) together with an abnormal R(os)-volume slope. Thus unstressed inspiratory calibre was never dissociated from airways narrowing on expiration.
Adult↗
Ventilatory sensitivity to inhaled carbon dioxide around the control point during exercise.
Rapid steady-state CO2 responses were determined in five normal adults at rest and at up to six levels of exercise by injecting pure CO2 at a constant flow into the inspiratory limb of a breathing circuit. Ventilation (V) was measured with a dry gas meter and PCO2 at the mouth was recorded by a mass spectrometer. Mean alveolar PCO2 (PACO2) was taken as equal to end-tidal PCO2 at rest, and during exercise was derived graphically from the sloping alveolar plateaus. The accuracy of the latter method was checked in separate experiments against arterial PCO2 (PaCO2). The mean results showed a linear relationship between change in PACO2 and change in V for work loads ranging from rest to 75 W (r = 0.94-0.98). Above 75 W the response became concave down with an initial essentially isocapnic phase. This suggests that during exercise there is a large increase in CO2 sensitivity about the control point.
Blood Gas Analysis↗
Ventilation and cardiac output during the onset of exercise, and during voluntary hyperventilation, in humans.
Three normal subjects performed rest--exercise transitions on a cycle ergometer, from rest to unloaded pedalling (0 W), 50, 100 and 150 W. Each experiment was performed in triplicate, with randomized work load order, in two sessions. Ventilation was obtained breath-to-breath by integration of a pneumotachygraph signal, and cardiac output beat-to-beat by a new development of the Doppler technique. Results were bin-averaged in 4 s bins over the first 20 s, and compared to resting values. Both ventilation and cardiac output increased significantly in the first 2 s. This initial rise in ventilation was due entirely to an increase in rate, the subsequent rise mainly to increase in tidal volume. Cardiac output increased predominantly through change in rate with smaller increases in stroke volume. A striking feature was a tendency for ventilation and cardiac output responses to be biphasic with an initial rise followed by a slight fall at the 14 s mark, and a subsequent rise, at all work loads. Overall correlation between ventilation and cardiac output was therefore high (r = 0.92). Six normal subjects hyperventilated for 45 s voluntarily, (a) at rate 24/min and normal tidal volume; (b) at normal rate and tidal volume of 1.5 l; (c) at rate 24/min and tidal volume of 1.5 l. Cardiac output, averaged over 10-45 s, rose by 0.4, 0.5, and 1.0 l min-1 respectively, with falls in end-tidal PCO2 of 4, 6, and 8 mmHg. Six normal subjects hyperventilated for 60 s with rate 24/min and tidal volume of 1.4 l, and end-tidal PCO2 maintained at 38 +/-2 mm Hg. Cardiac output, averaged from 10-60 s, rose by 1.0 l min-1. With increased rate and tidal volume, whether isocapnic or hypocapnic, cardiac output responses showed an overshoot with a peak value at about 30 s. The hypothesis of 'cardiodynamic hyperpnoea' considers a possible effect of increasing cardiac output on ventilation. The effects of ventilation on cardiac output must also be considered. We propose an extended hypothesis involving stable positive feed-back.
Adult↗