Biomedical subjects
Publications and source records attributed to A Guz.
An infinite number of possible combinations of tidal volume and breathing frequency, as well as pattern of airflow, can achieve the alveolar ventilation required for normal gas exchange. Individuals appear to select one particular pattern. This paper summarises our work relating to differences in the pattern of breathing between individuals when at rest and discusses the possible determinants of such individuality.
1. Changes in ventilation and cardiovascular variables which occur during exercise may be partly due to 'radiation' of activity in central neurones innervating exercising muscles to the respiratory and cardiovascular control areas. To test this hypothesis, we compared ventilatory and cardiovascular responses to two levels of steady-state exercise with each leg separately, in subjects with painless unilateral leg weakness. We assumed that exercise with a weak leg would require more central neural drive than the same level of exercise with the normal leg. 2. Ventilation during exercise with the weak leg was greater than with the normal leg (P less than 0.02). This was a result of greater tidal volume (Vt; P less than 0.005). There was a greater increase in heart rate (P less than 0.005), and systolic (P = 0.001) and diastolic (P less than 0.02) blood pressures during exercise with the weak leg compared to exercise with the normal leg. The increases in stroke volume and cardiac output during exercise were not different with the two legs. 3. These results support the hypothesis that ventilation, blood pressure and heart rate are influenced by the central neural drive to exercise.
Lipopolysaccharide (LPS) causes the syndrome of septic shock by initiating the release of endogenous mediators such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) from macrophages. Hypotension is one of the important clinical features of septic shock; however, TNF is only hypotensive in high doses. Therefore we have investigated the interactions of low, nonhypotensive doses of LPS, IL-1, and TNF in the restrained unanesthetized rabbit. Combinations of nonhypotensive doses of TNF, IL-1, and LPS produced significant (p less than 0.05) decreases in blood pressure as compared with doses of each of the substances alone. TNF bioactivity in animals that were made hypotensive with combinations of TNF, IL-1, and LPS was lower than in animals that were made hypotensive with TNF alone. This suggests that TNF release that is stimulated by LPS is not the sole cause of the hypotension that is seen in this model of endotoxic shock. In this model, interactions of LPS, IL-1, and TNF occur and may explain hypotension during some episodes of sepsis.
Sheep plasma proteinase inhibitor, analogous to human alpha 1-proteinase inhibitor (alpha 1 PI), was isolated to homogeneity. Purification was achieved by using (NH4)2SO4 precipitation, concanavalin A-Sepharose chromatography, Mono Q ion-exchange chromatography and PAGE. Sheep alpha 1 PI had an Mr of 56,000, inhibited human leucocyte elastase, pig pancreatic elastase and bovine trypsin on a 1:1 molar basis and had a plasma concentration of 1.6 +/- 0.21 g/l (mean +/- S.D.). Amino acid/carbohydrate composition (15% glycosylated) was similar to that of human alpha 1 PI (16% glycosylated); N-terminal analysis to 31 residues revealed 48-52% identity between the human and sheep proteins. Sheep alpha 1 PI was susceptible to oxidative inactivation by chloramine-T. Re-activation with the use of methionine sulphoxide peptide reductase and dithiothreitol indicated the presence of a methionine residue at the active site. These results establish that sheep alpha 1 PI has functional and structural characteristics close to those of human alpha 1 PI.
Desmosine is an amino acid specific to elastin. Animal studies suggest that urinary desmosine (UD) represents endogenous elastin degradation. Therefore, UD has previously been used to investigate endogenous elastolysis, but was not elevated in subjects with chronic obstructive airways disease (COAD), although accelerated pulmonary elastolysis is thought to contribute to COAD. We have investigated whether this reflects large day-to-day and between-subject variation in UD and whether, in man, dietary desmosine contributes significantly to that in urine. Mean 24-hour UD output (over 5 consecutive days) from 10 asymptomatic subjects (5 males) was higher in males than females (77.4 +/- 9.6 and 40.2 +/- 5.0 nmol/24 hours, respectively; mean +/- SD, P less than .001), but not significantly different when expressed in terms of creatinine (micrograms desmosine/100 mg creatinine: males, 2.5 +/- 0.4; females, 3.1 +/- 0.8; mean +/- SD). The lowest between-subject variation was observed when the mean of 5 days' 24-hour UD values was analyzed on the basis of gender (coefficient of variation [CV], 12.5%); when gender was not considered, the least between-subject variation was found for the mean of 5 days' desmosine/creatinine analysis (CV, 24.5%). Approximately 1% of dietary desmosine (ingested as [3H]elastin and [3H] desmosine) was excreted in the urine within 24 hours, contributing approximately 15% of UD while on a normal diet. Although ingestion of a low elastin diet (less than 1/10 desmosine/24 hours than a normal diet) resulted in lower within-subject variation in 24-hour UD excretion (mean CV decreased from 31.5% to 20.2%), the between-subject CV and UD levels did not alter.(ABSTRACT TRUNCATED AT 250 WORDS)
The ability to detect small changes in tidal volume (VT) during either volitional or passive breathing was compared in seven normal subjects. Passive breathing was achieved with positive pressure applied at the mouth by a ventilator. Although baseline breathing pattern was similar for each subject during the two types of breathing, the ability of the subjects to detect changes in VT was at least as good, and in general better, during passive as compared to volitional breathing. This suggests that the generation of a motor cortical command to inspire and the resultant respiratory muscle contraction are not essential to the perception of a change in lung volume. An increase in information from receptors in the mouth, pharynx and extrathoracic airways sensitive to positive pressure may be responsible for the increased ability of most subjects to detect changes in VT during passive breathing.
This paper describes some of the anatomical and physiological factors affecting the maintenance of upper airway patency in man. Such factors have particular relevance to the mechanisms responsible for maintaining upper airway patency during sleep, and the failure of these mechanisms in patients with the clinical syndrome of obstructive sleep apnoea: a condition in which repeated episodes of sleep-related inspiratory oropharyngeal collapse lead to recurrent hypoxaemia, disturbed sleep patterns and other clinical sequelae. The relationships between upper airway geometry, negative intrapharyngeal pressure, activation of upper airway dilator muscles, and sleep state are important factors affecting the maintenance of upper airway patency. The aim of this paper is not to consider such factors in isolation but to consider their interaction in affecting the adequacy of the upper airspace as a conduit for airflow.
Twenty-five consecutive elderly patients with hypothermia were studied. Data were gathered regarding their home conditions, the circumstances in which they had been found, and their recent medical history. Clinical and laboratory examinations were performed to establish accurate diagnoses of underlying illnesses present at the time of arrival in hospital. Patients were followed up until the completion of the study. Evidence of an underlying cause was found in all cases. Twenty-two patients had evidence of definite or probable infection at the time of admission. Drugs may have contributed in seven cases. There were multiple significant causes for hypothermia in nine cases. Only 12 patients survived the index admission, and six of these had previous or subsequent admissions with hypothermia.
In 76 unselected patients aged 70 years or over, the mean increase in rectal temperature in the 24 hours following admission to hospital was 0.4 degrees C. In those who did not receive antibiotics on admission, the mean increase in rectal temperature was 0.6 degrees C, with increases of up to 2.3 degrees C recorded. There were no significant changes in C-reactive protein, white cell count or erythrocyte sedimentation rate over that period, suggesting that the changes were due to passive warming rather than to progression of the underlying disease. Infected patients may have low or normal body temperatures on admission. Within 24 hours, nearly all infected patients (excluding a few with low or normal temperatures on admission, who receive antibiotics) have a raised body temperature. The most sensitive test for a raised body temperature is the rectal temperature measured at least 24 hours after admission. A patient who has a low or normal body temperature on admission has a 61% chance of having a raised body temperature the next day. At least 55% of patients admitted with a febrile illness have low or normal body temperatures on admission.
Fifty hospital inpatients were selected, who, on the basis of their history and on clinical and laboratory findings, were believed not to have a febrile illness. Body temperature was measured simultaneously at four sites, in order to compile a normal range of temperature at each site for patients under these conditions. The observed range of rectal temperature was 36.7-37.5 degrees C, auditory canal temperature 36.4-37.2 degrees C, sublingual temperature 36.2-37.0 degrees C, and axillary temperature 35.5-37.0 degrees C.
We studied 74 patients whose temperature was normal according to nurses' temperature charts and who were not on antibiotic treatment. The subjects were inpatients whose condition had deteriorated on the ward, or patients admitted the previous day in whom no diagnosis had been established. One simultaneous set of measurements was made of sublingual, rectal, axillary and proximal auditory canal temperatures. A fever was recorded in 63 of 74 patients (85%); 54 febrile patients had a raised rectal temperature, and 54 had a raised proximal auditory canal temperature; 60 patients were febrile at one or both of these sites. A further three patients had raised sublingual temperatures alone. All patients who were regarded as being definitely or probably infected were febrile at one or more sites. Eighty-one per cent of those considered to be possibly infected, and 71% of those with no clinical evidence of infection were also febrile. Rectal and proximal auditory canal temperatures can each detect fever in approximately 86% of febrile patients, sublingual temperature in 66%, and axillary temperature in 32%. Rectal temperature is clinically the most useful temperature measurement in elderly patients. We conclude that significant infections in patients in a warm environment result in a fever which often remains undetected when only sublingual temperature is measured.
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1. To determine if negative upper airway pressure causes reflex pharyngeal dilator muscle activation, we used intra-oral bipolar surface electrodes to record genioglossus electromyogram (EMG) activity in response to 500 ms duration pressure stimuli of 0, -2.5, -5, -15, -25 and -35 cm H2O (0-90% rise time less than 30 ms) in ten normal, conscious, supine subjects. 2. With the subjects relaxed at end-expiration, stimuli were applied in each of three conditions: (i) glottis open (GO), (ii) glottis closed (GC) and (iii) controls with the mouth and nose closed. 3. Six rectified and integrated EMG responses were bin averaged for each pressure in each experimental condition. Response latency was defined as the time when the EMG activity significantly increased above pre-stimulus levels. Response magnitude was quantified as the ratio of the EMG activity for 80 ms post-stimulus to 80 ms prestimulus; data from after the subject's voluntary reaction time (for tongue protrusion) were not analysed. 4. Negative airway pressure activated the genioglossus. The median latency of activation (34 ms) was much faster than the time for voluntary activation (184 ms) indicating a reflex response. 5. Significant activation, compared to 0 cmH2O controls and controls with mouth and nose closed, occurred with pressures of at least -5 cm H2O (GC) and -15 cm H2O (GO). At -25 and -35 cm H2O, responses with GO were significantly greater than with GC. 6. The magnitude ('strength') of the responses differed between subjects; these differences were repeatable. 7. We conclude that negative airway pressure causes reflex pharyngeal dilator muscle activation in man. Responses with GC suggest that upper airway receptors can mediate the response but larger responses with GO indicate a contribution from subglottal receptors.
1. To determine the afferent pathways mediating pharyngeal dilator muscle activation in response to negative airway pressure in man, we recorded genioglossus electromyogram (EMG) activity (via intra-oral bipolar surface electrodes) in response to 500 ms duration pressure stimuli of -15 and -25 cm H2O in normal, conscious, supine subjects relaxed at end-expiration; responses were compared before and after upper airway anaesthesia. 2. Six rectified and integrated EMG responses were bin averaged for pressure stimuli applied with the glottis open (GO) and closed (GC) and to the outside of the face only (controls). Response magnitude was quantified as the ratio of the EMG activity for an 80 ms post-stimulus period (before the subject's reaction time for tongue protrusion) to an 80 ms pre-stimulus period. 3. In eight subjects, upper airway anaesthesia reduced the EMG responses with GC to a level indistinguishable from controls. After anaesthesia, responses with GO remained higher than those with GC. 4. With GC, the mean EMG responses decreased by 43% after selective anaesthesia of the nasal mucosa (trigeminal nerves) in two subjects, 32% after selective anaesthesia of the laryngeal mucosa (superior laryngeal nerves) in six subjects and by 21% after selective anaesthesia of the oropharyngeal mucosa (glossopharyngeal and lingual nerves) in four subjects. 5. We conclude that upper airway afferents mediate pharyngeal dilator muscle activation in response to negative pressure with GC and that subglottal receptors caused the increased activation with GO. With GC, the trigeminal and superior laryngeal nerves mediate an important component of the responses with the glossopharyngeal nerves playing a less important role.
1. Ventilation has been studied during hypocapnia produced by passive mechanical ventilation in ten normal human subjects. 2. During wakefulness, disconnection of the ventilator led to inconsistent apnoea of only brief duration. During sleep, at a similar degree of hypocapnia, disconnection of the ventilator led more consistently to apnoea which was also of much longer duration; the deeper the sleep stage, the longer the apnoea. 3. The resumption of breathing during sleep could precede or follow arousal or be unaccompanied by arousal; in the absence of prior arousal, the evidence suggests that a starting end-tidal CO2 pressure (PET, CO2) less than 41 mmHg could result in an apnoea during sleep stages I and II. 4. Subjects did not report any common sensation which led them to breathe following an apnoea whilst awake. 5. Prior hyperoxia in one subject prolonged the apnoea duration in both slow-wave sleep and rapid eye movement sleep. 6. The results are interpreted as showing that even during light sleep, the maintenance of the respiratory rhythm is critically dependent on the arterial CO2 and O2 tensions. During wakefulness, other behavioural drives, which may not reach consciousness, supervene.
1. To investigate the relative contributions of increases in cardiac output and arteriovenous oxygen difference to the increase in oxygen consumption during exercise, the ventilatory and cardiovascular responses to a sudden transition from unloaded cycling to 70 or 80 W were measured in six normal healthy subjects. 2. Oxygen consumption (VO2) was measured breath-by-breath and corrected for changes in lung gas stores. Cardiac output (Q) was measured beat-by-beat using pulsed Doppler ultrasound, and blood pressure was measured beat-by-beat using a non-invasive finger cuff (Finapres). All data were calculated off-line, second-by-second. 3. Arteriovenous oxygen difference (A-VO2) was calculated from Q and VO2 using the Fick Principle. Left ventricular afterload was calculated by dividing Q by mean blood pressure. 4. The data for Q and VO2 were closely fitted by single exponential curves (mean r2 0.84 and 0.90 respectively; r is the correlation coefficient). These curves yielded mean time constants for the increases in Q and VO2 of 28 and 55 s respectively following the increase in exercise level. In each individual subject, the time course of adjustment of Q was faster than that of VO2. There was a mean lag of 15 s from the start of the new exercise level before the derived A-V O2 began to increase; the mean time constant for A-V O2 was 57 s. 5. If A-V O2 had remained constant, the observed rise in Q alone would have resulted in an average of 87% of the increase in VO2 which was observed after 5 s. If Q had remained constant, the observed increase in A-V O2 would have led to only 8% of the actual increase in VO2 after 5 s. 6. Mean and systolic blood pressure rose and afterload fell immediately after the onset of the increased workload. The time constants of the systolic blood pressure and afterload responses to exercise varied widely and ranged from 37 to 81 and 10 to 26 s respectively (n = 4). 7. We conclude that Q is responsible for most of the early increase in VO2 following a sudden increase in exercise workload. Blood pressure responses to exercise are slower than Q and VO2 responses, probably due to the rapid decrease in afterload. 8. The dominant contribution of Q to adaptation to changing workload may be physiologically important particularly in heart disease, where decreased ability to increase cardiac output may limit the capacity to cope with changing metabolic needs during everyday activities.
1. Positron emission tomographic imaging of brain blood flow was used to identify areas of motor activation associated with volitional inspiration in six normal male subjects. 2. Scans were performed using intravenous infusion of H2(15)O during voluntary targeted breathing and positive pressure passive ventilation at the same level. 3. Regional increases in brain blood flow, due to active inspiration, were derived using a pixel by pixel comparison of images obtained during the voluntary and passive ventilation phases. 4. Pooling data from all subjects revealed statistically significant increases in blood flow bilaterally in the primary motor cortex (left, 5.4%; right, 4.3%), in the right pre-motor cortex (7.6%), in the supplementary motor area (SMA; 3.1%) and in the cerebellum (4.9%). 5. The site of increased neural activation in the motor cortex, associated with volitional inspiration, is consistent with an area which when stimulated, either directly during neurosurgery or transcranially with a magnetic stimulus, results in activation of the diaphragm. 6. The presence of additional sites of neural activation in the pre-motor cortex and SMA appears analogous to the results of studies on voluntary limb movement. The site of the increase in the SMA was posterior to that previously reported for arm movements. These areas are believed to have a role 'upstream' of the motor cortex in the planning and organization of movement. 7. This technique provides a means of studying the volitional motor control of respiratory related tasks in man.
1. Transcranial magnetic stimulation was performed using a figure-of-eight-shaped coil over the right motor cortex with the aim of identifying those areas involved with activation of the diaphragm. 2. The response of the right and left hemi-diaphragms was recorded using surface electrodes in either the 7th or 8th intercostal spaces 3 cm lateral to the anterior costal margin on either side. 3. The compound muscle action potentials recorded over the left diaphragm in response to transcranial magnetic stimulation were maximal when the centre of the figure-of-eight coil was placed approximately 3 cm to the right of the mid-line and 2-3 cm anterior to the auricular plane. 4. The amplitude of the response recorded from the diaphragm depended upon the angulation of the figure-of-eight coil and hence the direction of the stimulating current. 5. The response of the inspiratory muscles to magnetic stimulation of one side of the brain was predominantly contralateral but a small response was seen on the ipsilateral side. Ultrasonic techniques confirmed that the diaphragm was responding contralaterally and not ipsilaterally.