Phases in a drug's use.
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Bone Marrow Transplantation↗
Biomedical subjects
J Duffin
Publications and source records attributed to J Duffin.
The death of Sarah Lovell and the constrained feminism of Emily Stowe.
In 1879 a coroner's inquest was held on the body of Sarah Lovell, a young, unmarried woman who was thought to have died of an attempt at procuring an abortion. Suspicion fell on Emily Stowe, Toronto's first woman doctor. Stowe had graduated 12 years earlier from a US medical college but had not yet been granted a licence to practise in Ontario. She admitted to having seen and spoken to Lovell but denied any involvement in an abortion. Less than a year later she obtained the long-desired licence. The author has used newspapers, journals and other archival sources to explore the nature of Stowe's testimony and its relation to her acceptance by the profession.
Abortion, Legal↗
Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis.
Christmas disease was first reported as a distinct clinical entity in two manuscripts published in 1952. The eponym associated with this disorder, is the surname of the first patient examined in detail and reported by Biggs and colleagues in a paper describing the clinical and laboratory features of seven affected individuals. This patient has severe factor IX coagulant deficiency (less than 0.01 units/ml) and no detectable circulating factor IX antigen (less than 0.01 units/ml). Coding sequence and splice junctions of the factor IX gene from this patient have been amplified in vitro through the polymerase chain reaction (PCR). One nucleotide substitution was identified at nucleotide 30,070 where a guanine was replaced by a cytosine. This mutation alters the amino acid encoded at position 206 in the factor IX protein from cysteine to serine. The non conservative nature of this substitution, the absence of this change in more than 200 previously sequenced factor IX genes and the fact that the remainder of the coding region of this gene was normal, all provide strong circumstantial evidence in favour of this change being the causative mutation in this patient. The molecular characterization of this novel mutation in the index case of Christmas disease, contributes to the rapidly expanding body of knowledge pertaining to Christmas disease pathogenesis.
Amino Acid Sequence↗
Role of upper cervical inspiratory neurons studied by cross-correlation in the cat.
Axonal projections and synaptic connectivity of upper cervical inspiratory neurons (UCINs) were investigated in anaesthetised cats to clarify their role as propriospinal respiratory interneurons. Antidromic mapping showed axonal collaterals near phrenic and intercostal motonuclei. Of the UCINs tested, 37% had collaterals at T3-4; 55% had ipsilateral projections and 45% had contralateral projections. Ipsilateral or contralateral cross-correlations of the activity of pairs of UCINs (one on each side of the spinal cord) with the discharge of internal intercostal, external intercostal (T3-4) or phrenic nerves revealed similar features. Those with the internal intercostal and phrenic nerves were interpreted as evidence for shared or oligosynaptic excitation, those with the external intercostal nerve as shared excitation and inhibition. No evidence for monosynaptic connections was found. Monosynaptic connections could also not be demonstrated between inspiratory intercostal neurons located near (less than 0.5 mm) the UCINs collateral arborizations in T3-4, examined by cross-correlation. Afferent feedback from internal intercostal nerves (T3-4) was investigated by cross-correlating nerve stimulation with UCINs activity. Ipsilateral and contralateral cross-correlograms had similar features, providing evidence for excitation in some cases and inhibition in others. Finally, cross-correlations between ipsilateral UCINs and cervical sympathetic nerves were featureless. The results suggest that the role of UCINs as part of a respiratory propriospinal control system analogous to forelimb motor control is untenable, although they may be part of an intercostal afferent feedback loop.
Action Potentials↗
Changes in ventilation in response to ramp changes in treadmill exercise load.
These experiments examined the changes in ventilation during a 40-s ramp increase in exercise load, produced by increasing either the speed of the treadmill or the grade, to equivalent end-points of oxygen uptake. Six subjects underwent five trials each for grade and speed, while ventilation was monitored breath-by-breath. For each subject, ventilation versus time for all five of the speed trials was plotted on a single graph and fitted by linear regression. The data for the grade trials were similarly treated. For all subjects, the slope of the regression line for the speed plots was found to be significantly (P < 0.05) greater than that for the grade plots. We concluded that these experimental results support the hypothesis that the neural drive to ventilation persists as exercise continues and is proportionately related to the frequency of limb movement.
Adult↗
Changes in ventilation at the start and end of moderate and heavy exercise of short and long duration.
These experiments examined the effect of exercise intensity and duration on the magnitude of the abrupt change in ventilation at the start (VE,start) and end (VE,end) of exercise. Five subjects performed constant load treadmill exercise at 50% and 80% of their maximum oxygen consumption (VO2max) for 6 and 10 min while inspiring atmospheric air. The subjects also completed additional exercise tests at 80% VO2max for 10 min while inspiring an oxygen-enriched gas mixture. During each exercise trial ventilation was measured breath-by-breath. The VE,start and VE,end were determined by using non-linear curve-fitting techniques. The results showed that VE,start was greater at the start of the 80-% exercise tests compared to the 50-% tests and that VE,start at each level of exercise was greater than VE,end. The results also demonstrated that VE,end was inversely related to the intensity and duration of exercise. Furthermore, the VE,end was not altered subsequent to the inspiration of oxygen-enriched air. These findings have led us to postulate that the stimulus responsible for VE,start is reduced during exercise and that the degree of reduction is related to the intensity and duration of exercise. In addition, it was concluded that these changes might occur independently of peripheral chemoreceptor activity.
Adult↗
Projections to Bötzinger expiratory neurons by dorsal and ventral respiratory group neurons.
Bötzinger complex (BOT) augmenting expiratory neuron efferent connection are well established, but little is known concerning the afferent neural projections to BOT. The dorsal (DRG) and ventral (VRG) respiratory groups were extensively searched in 17 pentobarbital anaesthetized cats for inspiratory neurons that were anti-dromically activated from BOT. Only 1 of the 60 VRG inspiratory neurons with confirmed spinal projection was antidromically activated from BOT. Another 3 VRG inspiratory neurons and 4 of the 30 DRG inspiratory neurons were activated from BOT, but none of these neurons had confirmed spinal cord projections. All 15 early burst neurons were antidromically activated from BOT. Neural projections to BOT from DRG and VRG inspiratory neurons are rare, but neural projections from early burst neurons are common.
Afferent Pathways↗
"Anti-moine; anti-biotique": the public fortunes of the secret properties of antimony potassium tartrate (tartar emetic).
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Antimony Potassium Tartrate↗
Paucity of dorsal inspiratory neuron collateral projections to ventral inspiratory neurons.
The inspiratory region of the ventral respiratory group was mapped in six Nembutal anaesthetized cats. Records multi-unit activity were taken in five or six locations at 0.5 mm spacings. These locations were then used as stimulating sites to test for the antidromic activation of 40 bulbospinal, inspiratory neurons recorded in the ipsilateral, dorsal respiratory group. Only four (10%) were antidromically activated. In a single anatomical experiment, rhodamine labelled microspheres were injected into the ventral group, and Flurogold was injected into the contralateral spinal cord. No neurons in the dorsal group were found to be double-stained. It was concluded that, ipsilateral collaterals from inspiratory dorsal group neurons to the inspiratory region of the ventral group are rare.
Animals↗
A model of respiratory rhythm generation.
A new hypothesis is proposed to explain the generation of respiratory rhythm by the respiratory neurons of the medulla. The basis of the oscillator is a mutual inhibition between early-burst inspiratory, propriobulbar neurons and Bötzinger complex expiratory, bulbospinal neurons, with only the early burst inspiratory neurons possessing adaptive properties. Only one theoretical connection, unsupported by experimental observations, needs to be assumed for this model, that of an inhibitory connection from Bötzinger complex expiratory neurons to early-burst inspiratory neurons. A mathematical simulation of the model was used to test the hypothesis. The oscillating patterns of activity produced by the model were similar to those observed experimentally in these neurons. It is therefore concluded that, based on reasonable assumptions, the proposed hypothesis will produce oscillations similar to those of respiration.
Animals↗
The propriobulbar respiratory neurons in the cat.
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Animals↗
The chemoreflex control of breathing and its measurement.
The chemoreflex control of breathing is described in terms of a graphical model. The central chemoreflex, the ventilatory response to carbon dioxide mediated by the central chemoreceptors, is modelled as a straight-line relation between the ventilatory response and the arterial level of carbon dioxide. The peripheral chemoreflex, the ventilatory response to carbon dioxide and hypoxia mediated by the peripheral chemoreceptors, is broken into two relations. First, a straight-line relation between the ventilatory response and the arterial level of carbon dioxide whose slope (sensitivity) increases as the oxygen level varies from hyperoxic to hypoxic. Second, a rectangular hyperbolic relation between the ventilatory response and the arterial level of oxygen with ventilation increasing with increasing hypoxia. The three ventilatory response relations (one central and two peripheral) add to produce the total chemoreflex ventilatory response which forms the feedback part of the respiratory regulator. The forward part consists of the relation between the arterial level of carbon dioxide and ventilation when ventilation is controlled (the metabolic hyperbola). The forward and feedback parts of the respiratory regulator can be combined so as to predict resting ventilation and carbon dioxide levels under a number of circumstances. Methods of measurement of these chemoreflex ventilatory responses are also described so as to illustrate the physiological principles involved in the model.
Carbon Dioxide↗
The effect of metabolic acid-base changes on the ventilatory changes at the end of heavy exercise.
The purpose of this study was to determine the effect of altered metabolic acid-base status on the changes in ventilation in the transition from heavy exercise above anaerobic threshold to rest. Seven subjects ingested, in a randomized and blind manner, either NaHCO3 or CaCO3 (placebo) at a dose of 300 mg.kg-1 body mass and ran on a treadmill for five minutes (90% VO2max and above anaerobic threshold) on ten different occasions. Changes in minute ventilation in the exercise transitions were studied by starting and stopping the treadmill abruptly with a remote switch. The fast increase in ventilation at the start of exercise was not accompanied by a corresponding fast drop in ventilation at the end of exercise (P less than or equal to 0.001) and the effects of chemicals on these changes were not significantly different (P greater than 0.05). A single-component exponential model, without a time delay, was used to determine the time constants of off-transitional decay in ventilation for the two chemicals in each subject. Parametric and non-parametric statistical tests revealed that the time constants were not as significantly different as the venous pH measurements which were significantly higher with NaHCO3 (P less than or equal to 0.001). The results indicate that the absence of fast change in ventilation at the end of heavy exercise is not due to lactic acidosis and the consequent slow ventilatory changes in the off-transition of heavy exercise are at least partly mediated by non-humoral factors such as a central neural reverberatory mechanism.
Acid-Base Equilibrium↗
Changes in ventilation at the end of heavy exercise of different durations.
The purpose of this study was to examine the effects of duration and the concomitant ventilatory drift of heavy exercise on the changes in ventilation following the cessation of exercise. Seven male subjects ran on a motor-driven treadmill at a constant work-rate of 90% of VO2max for either 5 min or 7 min on 60 occasions. The exercise was terminated abruptly by stopping the treadmill with a remote switch while recording inspired minute ventilation (VI) breath by breath. The fast drop in VI at the end of exercise is significantly less than the corresponding increase at the onset of exercise (P less than 0.05) and this difference is greater with longer duration of exercise. The time constants of the slow ventilatory decline are significantly increased following 7 min of exercise (P less than 0.05). They are also positively related to the drift in VI that occurs with the continuation of heavy exercise beyond 3 min. This relationship is however not statistically significant (P greater than 0.05). These results indicate that the rate of ventilatory decline is slower after the end of a longer duration of exercise and this is caused by mechanism/s that also contribute/s to the ventilatory drift of heavy exercise. As, of the many different possibilities, only the respiratory after-discharge (central neural reverberatory) mechanism is likely to be more activated with a longer duration of exercise and on the basis of our previous observations (Jeyaranjan et al. 1988, 1989), the results suggest that the mechanism of after-discharge is an important mediator of ventilatory response during as well as after the cessation of heavy exercise.
Adult↗
Projections from inspiratory neurons of the nucleus retroambigualis to phrenic motoneurons in the cat.
The connection between the inspiratory neurons of the nucleus retroambigualis and the phrenic motoneurons was examined using the techniques of antidromic mapping to discover collaterals and spike-triggered averaging to detect postsynaptic potentials. Axon collaterals within the region of the C5 phrenic nucleus were found for 17 of 26 (65%) inspiratory neurons and 6 of these 17 (35%) were shown to generate excitatory postsynaptic potentials in at least one phrenic motoneuron. It was concluded that these results demonstrate a strong connection for those inspiratory neurons of the nucleus retroambigualis with a collateral within the phrenic nucleus.
Animals↗
Inhibition of inspiratory neurons of the nucleus retroambigualis by expiratory neurons of the Botzinger complex in the cat.
The connection between expiratory neurons of the Botzinger Complex and contralateral inspiratory neurons of the nucleus retroambigualis was examined using the technique of spike-triggered averaging of intracellular potentials. Out of a total of 34 expiratory neurons found in the Botzinger Complex, 25 (73%) could be antidromically activated from the inspiratory region of the contralateral nucleus retroambigualis. The spike activities of 15 of these antidromically activated expiratory neurons were used as triggers for the averaging of the intracellular potentials recorded from 39 inspiratory neurons in the region of the contralateral nucleus retroambigualis. Unitary, inhibitory, postsynaptic potentials were observed in 11 of the 39 (28%) averages, from 6 of the 15 (40%) trigger neurons. It was concluded that these experiments demonstrate a monosynaptic inhibitory connection from expiratory neurons in the Botzinger Complex to inspiratory neurons in the contralateral nucleus retroambigualis.
Action Potentials↗
The connections from botzinger expiratory neurons to upper cervical inspiratory neurons in the cat.
These experiments examined possible inhibitory inputs to upper cervical inspiratory neurons from the expiratory neurons of the Botzinger complex. Eighty-one Botzinger neurons were tested with antidromic mapping for a projection to the C1 segment of the spinal cord; 44/81 (54%) were found to project, 27/79 (34%) contralaterally, 17/68 (25%) ipsilaterally, and 1/66 (2%) both contralaterally and ipsilaterally. Antidromic mapping in contralateral C1 demonstrated the presence of a collateral in 3/15 (20%) of the Botzinger neurons tested, while 3/9 (33%) had collateral arborizations in ipsilateral C1. The collaterals mapped were not localized to the region of the upper cervical inspiratory neurons. Microstimulation in C3 (12-17 microA, 0.2-ms duration) at locations which produced short-latency (2.7-3.5 ms) inhibition of phrenic nerve discharge resulted in the short latency (3.0 ms) inhibition of 1/27 (3.7%) upper cervical inspiratory neurons as demonstrated by cross-correlation. It was concluded that while some upper cervical inspiratory neurons may be inhibited during expiration by the Botzinger expiratory neurons, this connection is not a strong one.
Animals↗
Role of lactic acidosis in the ventilatory response to heavy exercise.
The purpose of this study was to determine the role of lactic acidosis in the ventilatory response to heavy exercise above anaerobic threshold. Seven subjects ingested either NaHCO3 or CaCO3 at a dose of 300 mg/kg body weight and ran on a motor-driven treadmill at a work load corresponding to 90% of VO2max and above anaerobic threshold for a period of 5 min while minute ventilation and PETCO2 were recorded breath by breath. A total of 10 runs, 5 with CaCO3 and 5 with NaHCO3 in a randomized and blind order, were done in each subject. Statistical analyses of the effects of the chemicals on minute ventilation during the 15 s between min 4.75 and 5 of exercise showed that the differences in ventilation did not reach statistical significance (p greater than 0.05) in 5 of the 7 subjects. Venous pH measurements at the end of exercise revealed a significant increase with NaHCO3 (p much less than 0.05). It is concluded that lactic acidosis is not an essential determinant of ventilatory response to heavy exercise above anaerobic threshold in the majority of the subjects.
Acidosis, Lactic↗