Laennec and Broussais: the 'sympathetic' duel.
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Education, Medical↗
Biomedical subjects
J Duffin
Publications and source records attributed to J Duffin.
Synchronization of ventral-group, bulbospinal inspiratory neurons in the decerebrate rat.
We examined the synaptic connections between ventral-group, bulbospinal inspiratory neurons in 27 vagotomized, paralyzed, ventilated, and decerebrated rats using cross-correlation and spike-triggered averaging of intracellular potentials. The neurons were recorded in the medulla about the level of the obex and identified by their inspiratory firing pattern and antidromic activation from the spinal cord at C7. Whole C5 phrenic nerve recordings were made using bipolar electrodes from the central cut ends of the nerve. Most (108/137, 79%) inspiratory neurons discharged only during inspiration but some (29/137, 21%) also discharged during early expiration. Their intracellular membrane potentials displayed a pattern of depolarization during inspiration, repolarization during early expiration, and hyperpolarization during late expiration. Intracellular chloride iontophoresis changed the inspiratory membrane potential trajectories from augmenting to decrementing in 11 of 19 neurons tested (58%), and demonstrated the presence of both early-decrementing and late-augmenting waves of inhibitory postsynaptic potentials during expiration in 11 of 19 neurons tested (58%). Cross-correlation histograms were computed between pairs of extracellularly recorded neurons to detect short time scale synchronizations indicative of synaptic connections (26 ipsilateral; 23 contralateral). While none of the cross-correlation histograms for contralateral pairs showed peaks, most (23, 88%) of those for ipsilateral pairs showed peaks (mean half-amplitude width +/- SD = 1.3 +/- 0.4 ms) at time zero suggestive of common activation. Some of the latter (6, 23%) showed troughs superimposed on the central peaks (mean half-amplitude width +/- SD = 0.9 +/- 0.2 ms) at short latencies (mean latency +/- SD = 1.8 +/- 1.9 ms) suggestive of inhibition; others (8, 31%) had asymmetrical central peaks and two had bilateral peaks suggesting more complex interconnections. Averages of intracellular membrane potentials of inspiratory neurons (n = 24), triggered by action potentials of a nearby extracellularly recorded inspiratory neuron, were computed to detect synchronized postsynaptic potentials. Over half (16, 67%) showed postsynaptic potentials (mean amplitude +/- SD = 201 +/- 176 microV; mean half-amplitude width +/- SD = 2.3 +/- 0.8 ms) confirming the cross-correlation findings of common excitation. We conclude that in decerebrated rats, ventral-group inspiratory neurons projecting to the C7 spinal segment share powerful, ipsilaterally distributed excitatory inputs which enhance their synchronous activity during inspiration. They also receive inhibition during inspiration and early-decrementing and late-augmenting inhibitory inputs during expiration.
Action Potentials↗
The effect of hypoxia on the ventilatory response to carbon dioxide in man.
We used rebreathing with prior hyperventilation to measure ventilatory responses to CO2 at iso-oxic PO2's of 100, 80, 60 and 40 mmHg in seven subjects. The mean sub-threshold ventilation (S.E.) of 7.60 (1.31) L min-1 did not vary with iso-oxic PO2. The mean peripheral-chemoreflex threshold of 41 (0.6)) mmHg PCO2 at an iso-oxic PO2 of 100 was greater than 39 (1.2) and 39 (0.6) at 60 and 40, respectively. The mean peripheral-chemoreflex sensitivity of 11.5 (5.2) L min-1 mmHg-1 at an iso-oxic PO2 of 40 was significantly greater than 3.0 (1.3), 2.7 (1.2) and 2.4 (1.2) at 60, 80 and 100, respectively. The mean central-chemoreflex threshold of 45 (1.5) mmHg PCO2 at an iso-oxic PO2 of 40 was significantly less than 48 (0.4) and 48 (0.7) at 80 and 100, respectively. The mean central-chemoreflex sensitivity of 5.0 (1.1) L min-1 mmHg-1 did not vary with iso-oxic PO2. These findings provide insights into the control of breathing in humans, including the implication that CO2 must exceed its peripheral-chemoreflex threshold before hypoxia can effectively increase ventilation.
Adolescent↗
The ventilatory response to hypoxia below the carbon dioxide threshold.
The ventilatory response to acute progressive hypoxia below the carbon dioxide threshold using rebreathing was investigated. Nine subjects rebreathed after 5 min of hyperventilation to lower carbon dioxide stores. The rebreathing bag initially contained enough carbon dioxide to equilibrate alveolar and arterial partial pressures of carbon dioxide to the lowered mixed venous partial pressure (approximately equal to 30 mmHg), and enough oxygen to establish a chosen end-tidal partial pressure (50-70 mmHg), within one circulation time. During rebreathing, end-tidal partial pressure of carbon dioxide increased while end-tidal partial pressure of oxygen fell. Ventilation increased linearly with end-tidal carbon dioxide above a mean end-tidal partial pressure threshold of 39 +/- 2.7 mmHg. Below this peripheral-chemoreflex threshold, ventilation did not increase, despite a progressive fall in end-tidal oxygen partial pressure to a mean of 37 +/- 4.1 mmHg. In conclusion, hypoxia does not stimulate ventilation when carbon dioxide is below its peripheral-chemoreflex threshold.
Acute Disease↗
The pattern of breathing following a 10-breath voluntary hyperventilation during hyperoxic rebreathing.
The pattern of breathing following a 10-breath voluntary hyperventilation period during hyperoxic rebreathing was compared to that without hyperventilation in 6 subjects (3 male and 3 female). The aim was to measure the posthyperventilation short-term potentiation of ventilation without changes in respiratory chemoreflex drives induced by the voluntary hyperventilation. Hyperoxia was used to reduce the peripheral chemoreflex drive, and rebreathing to prevent the decrease in arterial carbon dioxide tension normally produced by hyperventilation. There were significant differences between the male and female responses. However, in all subjects, ventilation and heart rate were increased during hyperventilation but end-tidal partial pressures of carbon dioxide and oxygen were unchanged. Following hyperventilation, ventilation immediately returned to the values observed when hyperventilation was omitted. Hyperventilation did not induce a short-term potentiation of ventilation under these conditions; changes in chemoreflex stimuli brought about by cardiovascular changes induced by hyperventilation may play a role in the short-term potentiation observed under other circumstances.
Adult↗
Effects of stimulation of phrenic afferents on cervical respiratory interneurones and phrenic motoneurones in cats.
1. In ten decerebrate, paralysed and ventilated cats, we tested the hypothesis that cervical (C5) respiratory interneurones mediate inhibition of phrenic motoneurone activity resulting from single shocks to the phrenic nerve. 2. Stimulus intensities sufficient to activate all afferents elicited (latency, 4.0 +/- 0.9 ms, mean +/- S.D.) a graded suppression of ipsilateral, but not contralateral (five of seven cats) phrenic nerve activity lasting, in six of seven cats, more than 70 ms and interrupted by a brief (approximately 6-18 ms duration) excitation at latencies between 7 and 30 ms. 3. In twenty-five ipsilateral motoneurones, peristimulus time average of the membrane potentials (-61 +/- 10 mV) showed no effect in eleven; of the fourteen that responded, ten had initial EPSPs (latency, 17.6 +/- 3.0 ms) and four initial IPSPs (latencies, 2.25-4.3 ms). Only one motoneurone had both. No responses with latencies > 60 ms were observed. 4. Peristimulus time averages of extracellular activity of thirty ipsilateral interneurones, twenty-five firing in inspiration (I) and five in expiration (E), showed diverse responses. The initial response of I interneurones was an excitation in eleven, a suppression of activity in nine, and no response in five. Latencies of excitations ranged from 2 to 36.5 ms (median, 14 ms) with durations ranging from 2 to 7 ms (mean, 4.4 +/- 1.6 ms). Latencies of suppression of activity ranged from 2 to 29 ms (median, 10 ms). Two E interneurones were excited (latencies, 11 and 15 ms; durations, 3.5 and 2 ms), two inhibited (latencies, 2 and 12 ms; durations, > 40 and 17 ms, respectively), and one did not respond. 5. In nine interneurones (seven I, two E), peristimulus time averages of the membrane potentials (mean, -62 +/- 14 mV) revealed no effect on three (all I). Of the six that responded, four (three I) had initial IPSPs, two (one I, one E) initial EPSPs. EPSPs had latencies of 11.5 (I interneurone) and 22 ms (E interneurone); the latencies of the IPSPs were 2.75, 3.20, and 2.3 ms for the I interneurones and 15.9 ms for the E interneurone). No responses with latencies > 30 ms were observed. 6. The diverse responses of cervical respiratory interneurones indicates that they do not mediate the prolonged suppression of ipsilateral phrenic activity elicited by stimulation of phrenic afferents. The suppression may result from activation of normally quiescent inhibitory interneurones or from presynaptic inhibition.
Animals↗
The possible role of C5 segment inspiratory interneurons investigated by cross-correlation with phrenic motoneurons in decerebrate cats.
We tested the role of C5 segment inspiratory interneurons in transcribing central respiratory drive to phrenic motoneurons and mediating intersegmental reflexes by cross-correlating the spontaneous activity of 26 interneurons with that of the ipsi -and contralateral C5 phrenic nerves in decerebrate cats. There were 10 interneurons that discharged only during inspiration (phrenic burst) and 16 that discharged tonically with increased firing during inspiration. Of the cross-correlograms for 26 of the interneurons with the ipsilateral phrenic, 20 were flat and 2 had peaks centred about time zero, interpreted as a common activation of the interneurons and motoneurons. The cross-correlograms for 4 other interneurons had troughs centred about time zero, interpreted as a synchronous excitation of the interneurons and inhibition of the motoneurons. Of the cross-correlograms for 23 interneurons with the contralateral phrenic, 22 were flat and 1 had a peak centred about time zero, interpreted as a common activation of the interneuron and motoneurons. Nine of ten cross-correlograms between pairs of interneurons were flat; one had a peak centred about time zero. We conclude that, despite their inspiratory modulated discharge patterns, there is no evidence from this study that the C5 segment inspiratory interneurons convey central respiratory drive to C5 phrenic motoneurons.
Animals↗
Spinal connections of ventral-group bulbospinal inspiratory neurons studied with cross-correlation in the decerebrate rat.
We examined the synaptic connections from ventral-group bulbospinal inspiratory neurons to upper-cervical inspiratory neurons and phrenic and intercostal motoneurons in decerebrate rats using cross-correlation. Inspiratory neurons were recorded in the medulla (n = 28) at the level of the obex and from the upper-cervical segments (C1 and C2) of the spinal cord (n = 29) in 18 vagotomized, paralyzed, ventilated, and decerebrated rats. The neurons were identified by their inspiratory firing pattern and antidromic activation from the spinal cord at C7. Whole-nerve recordings were made using bipolar electrodes from the central cut ends of the C5 phrenic nerve and the external and internal intercostal nerves at various thoracic levels. Cross-correlation histograms were computed between these recordings to detect short time scale synchronizations indicative of synaptic connections. Cross-correlation histograms (n = 20), computed between the activities of ventral-group bulbospinal inspiratory neurons and the phrenic nerve, all showed peaks (mean half-amplitude width +/- SD, 1.1 +/- 0.3 ms) at short latencies (mean latency +/- SD, 2.0 +/- 0.6 ms) suggestive of monosynaptic excitation. Cross-correlation histograms (n = 33), computed between the activities of ventral-group bulbospinal inspiratory neurons and upper-cervical inspiratory neurons, displayed four (12%) peaks (mean half-amplitude width +/- SD, 0.9 +/- 0.1 ms) at short latencies (mean latency +/- SD, 1.8 +/- 0.6 ms) suggestive of monosynaptic excitation, and six (18%) peaks (mean half-amplitude width +/- SD, 1.4 +/- 0.4 ms) at latencies near zero suggestive of excitation from a common source. Cross-correlation histograms (n = 34), computed between the activities of ventral-group bulbospinal inspiratory neurons and the internal and external intercostal nerves at various thoracic levels (T2-8), showed six (18%) peaks (mean half-amplitude width +/- SD, 2.5 +/- 0.5 ms) at short latency (mean latency +/- SD, 4.5 +/- 1.1 ms) suggestive of oligosynaptic connections. Cross-correlation histograms (n = 42) computed between activities of intercostal nerves at various levels of the thoracic spinal cord showed central peaks suggestive of excitation from a common source. Although the size of the peaks decreased with segmental separation, the displacement of the peaks from time zero did not increase with segmental separation (mean displacement +/- SD, 0.6 +/- 0.6 ms) as would be expected if the common excitation resulted from a descending monosynaptic excitation by a source such as the ventral-group bulbospinal inspiratory neurons. We conclude that all ventral-group bulbospinal inspiratory neurons make monosynaptic connections to phrenic motoneurons, a few make monosynaptic connections to upper-cervical, inspiratory neurons, but connections to intercostal motoneurons are made via interneurons.
Animals↗
Connections from upper cervical inspiratory neurons to phrenic and intercostal motoneurons studied with cross-correlation in the decerebrate rat.
We examined the synaptic connections from upper cervical inspiratory neurons to phrenic and intercostal motoneurons in decerebrate rats using cross-correlation. Upper cervical inspiratory neurons (n = 79) were recorded from the C1 and C2 segments of the spinal cord in 38 vagotomized, paralyzed, ventilated, and decerebrate rats. The neurons were identified by their inspiratory firing pattern and antidromic activation from the ipsilateral spinal cord at C7. Whole-nerve recordings were made using bipolar electrodes from the central cut ends of the C5 phrenic nerve and the external and internal intercostal nerves at various thoracic levels. Cross-correlation histograms were computed between these recordings to detect short time-scale synchronizations indicative of synaptic connections. The 55 cross-correlation histograms computed between the upper cervical inspiratory neurons and the ipsilateral phrenic nerve showed seven (13%) narrow peaks (mean half-amplitude width +/- SD, 1.09 +/- 0.15 ms) at short latencies (mean latency +/- SD, 1.29 +/- 0.26 ms) suggestive of monosynaptic excitation, and four (7%) broader peaks (mean half-amplitude width +/- SD, 1.50 +/- 0.17 ms) at short latencies (mean latency +/- SD, 1.40 +/- 0.24 ms) suggestive of oligosynaptic excitation. Another 14 (25%) cross-correlation histograms displayed a central broad peak (mean half-amplitude width +/- SD, 1.59 +/- 0.23 ms) suggestive of common activation. The eight cross-correlation histograms computed between the upper cervical inspiratory neurons and the contralateral phrenic nerve were featureless. The 77 cross-correlation histograms computed between the upper cervical inspiratory neurons and the internal and external intercostal nerves at various thoracic levels (T2-8) showed no peaks suggestive of synaptic connections. We conclude that some upper cervical inspiratory neurons make monosynaptic and paucisynaptic connections to phrenic motoneurons but not to intercostal motoneurons.
Animals↗
The effect of a rise in body temperature on the central-chemoreflex ventilatory response to carbon dioxide.
We assessed the central-chemoreflex ventilatory responses to carbon dioxide in six male volunteers using a hyperoxic rebreathing technique. Hyperventilation prior to rebreathing allowed both the threshold and the sensitivity of the response to be measured. We used immersion in water to control the body temperature (tympanic). The water temperature was adjusted to be either thermo-neutral or hot so that body temperature either remained normal [+0.2 (0.04) degrees C, mean (SEM)] or was elevated by 1.5 (0.08) degrees C. The sensitivities of the central-chemoreflex ventilatory responses to carbon dioxide were increased at elevated body temperatures, changing from a mean of 1.8 (0.2) 1.min-1. Torr-1 to 2.7 (0.1) 1.min-1. Torr-1. However, the thresholds did not change with temperature, and the mean threshold was 48(1) Torr at both normal and elevated temperatures. For all of the volunteers, ventilation was increased at elevated body temperatures for all levels of carbon dioxide, mainly by changes in respiratory frequency due to reductions in expiratory times. At subthreshold levels of carbon dioxide, mean ventilation changed significantly from 6.3(1.1) 1.min-1 at normal temperatures to 10.8 (1.9) 1.min-1 at elevated temperatures. Heart rates also increased significantly with temperature, changing from a mean of 66 (4) beats.min-1 to 102 (3) beats.min-1 at threshold levels of carbon dioxide. The mean rates of rise of carbon dioxide partial pressure during rebreathing were significantly increased with temperature as well, changing from 0.075 (0.008) Torr.min-1 to 0.089 (0.004) Torr.min-1. We concluded that elevating the body temperatures of our subjects not only increased their ventilation, heart rates and metabolic rates at all levels of carbon dioxide, but it also increased the sensitivity of their central chemoreflex ventilatory responses to carbon dioxide. Despite these increases, the thresholds of the central-chemoreflex ventilatory responses to carbon dioxide remained unchanged.
Adult↗
The effect of exercise duration on the fast component of exercise hyperpnoea at work rates below the first ventilatory threshold.
We examined the effect of exercise duration on the fast component of exercise hyperpnoea for light and moderate work rates [mean oxygen uptakes (SD) = 1.00 (0.27) 1.min-1 and 1.77 (0.53) 1.min-1, respectively]. Ten subjects exercised on a motor-driven treadmill while ventilation and end-expiratory partial pressures of carbon dioxide and oxygen were recorded on a breath-by-breath basis. The magnitude of the fast component of exercise hyperpnoea was determined by quantifying the abrupt changes in ventilation at the beginning and end of exercise. Five exercise tests with durations ranging from 1 min to 8 min were completed at each of the two periods of exercise at different work rates. Subsequent statistical analysis revealed that the rapid changes in ventilation at the end of exercise were significantly smaller than those at the start [pooled means (SE) = 6.27 (0.48) and 13.05 (1.06) 1.min-1 for light and moderate exercises respectively] regardless of exercise duration. Further statistical analysis failed to find a relationship between the fast ventilatory changes present at the end of exercise, expressed as a proportion of those at the start of exercise, and either exercise duration or work rate (73% and 62% for light and moderate exercises respectively). We conclude that the fast component of exercise hyperpnoea declines rapidly in the first minute of exercise, and interpret this decline as an indication that the fast neural drive to ventilation, proportional to limb movement frequency, adapts quickly at the start of exercise.
Adult↗
Sigerist in Saskatchewan: the quest for balance in social and technical medicine.
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Delivery of Health Care↗
Bilateral connections from ventral group inspiratory neurons to phrenic motoneurons in the rat determined by cross-correlation.
We examined the functional connections from inspiratory neurons in the ventrolateral medulla to phrenic motoneurons in 11 Sprague-Dawley rats with intact vagi anaesthetized with sodium pentobarbital and paralysed with pancuronium bromide. Cross-correlation histograms were computed between the extracellular activity of 70 of these neurons and the discharge of the phrenic nerves; 38 contralateral only, 10 ipsilateral only and 22 bilaterally. A total of 22 peaks were detected in the cross-correlation histograms. These were classified as indicating common activation or synaptic connection according to their latencies to onset, and those suggesting connections as monosynaptic or paucisynaptic according to their half-amplitude widths. Nine peaks suggesting monosynaptic excitation of phrenic motoneurons were detected for 7 ventral group inspiratory neurons; 4 with contralateral connections and not tested for ipsilateral connections, 2 with bilateral connections, and 1 with a monosynaptic contralateral connection and a paucisynaptic ipsilateral connection. Four peaks suggesting paucisynaptic excitation of phrenic motoneurons were detected for 3 ventral group inspiratory neurons; 1 with bilateral connections, 1 with a contralateral connection only, and 1 (previously mentioned) with a paucisynaptic ipsilateral connection and a monosynaptic contralateral excitation. The remaining 9 peaks were classified as due to a common activation of the phrenic motoneurons and the ventral group inspiratory neurons. Cross-correlation histograms were also computed between the left and right phrenic nerve discharges in 5 rats and all displayed central broad peaks indicative of common activation, possibly due to excitation from bilaterally projecting medullary inspiratory neurons. We concluded that there is a substantial bilateral excitation of phrenic motoneurons by inspiratory neurons in the ventral medullary group of the rat.
Animals↗
Cross-correlation of augmenting expiratory neurons of the Bötzinger complex in the cat.
Ipsilateral and contralateral pairs of augmenting expiratory neurons were recorded simultaneously from the Bötzinger complex using glass-coated tungsten microelectrodes in pentobarbitone-anaesthetized cats. The neurons were identified both by firing pattern and by antidromic activation from the contralateral site of the dorsal respiratory group. Cross-correlation histograms of the extracellularly recorded action potentials were calculated in order to detect short time-scale synchronizations of firing indicative of synaptic connections between the neurons. The cross-correlation histograms for 40 ipsilateral pairs of neurons less than 1 mm apart showed eight (20%) narrow troughs (mean half-amplitude width +/- SD, 1.1 +/- 0.37 ms) at short latencies (mean latency +/- SD, 1.0 +/- 0.35 ms) suggestive of monosynaptic inhibition. These included two cross-correlation histograms which showed troughs on both sides of time zero, indicating a mutual inhibition. For another four pairs of neurons (10%), a central broad peak suggestive of common activation due to either excitation or release from inhibition was evident. Contralateral pairs of expiratory neurons of the Bötzinger complex were examined in a similar manner. The cross-correlation histograms for 43 pairs of neurons showed five (12%) narrow troughs (mean half-amplitude width +/- SD, 1.2 +/- 0.67 ms) at short latencies (mean latency +/- SD, 2.7 +/- 1.47 ms) suggestive of monosynaptic inhibition. These included one cross-correlation histogram which showed troughs (one not statistically significant) on both sides of time zero, indicating a mutual inhibition. For another two pairs of neurons (4.6%) a central, broad peak suggestive of common activation due to either excitation or release from inhibition was evident. We conclude that inhibitory interconnections exist between augmenting expiratory neurons of the Bötzinger complex ipsilaterally and contralaterally. These connections may synchronize the expiratory burst of activity within this population and assist in the patterning of the burst.
Action Potentials↗
A review of the control of breathing during exercise.
During the past 100 years many experimental investigations have been carried out in an attempt to determine the control mechanisms responsible for generating the respiratory responses observed during incremental and constant-load exercise tests. As a result of these investigations a number of different and contradictory control mechanisms have been proposed to be the sole mediators of exercise hyperpnea. However, it is now becoming evident that none of the proposed mechanisms are solely responsible for eliciting the exercise respiratory response. The present-day challenge appears to be one of synthesizing the proposed mechanisms, in order to determine the role that each mechanism has in controlling ventilation during exercise. This review, which has been divided into three primary sections, has been designed to meet this challenge. The aim of the first section is to describe the changes in respiration that occur during constant-load and incremental exercise. The second section briefly introduces the reader to traditional and contemporary control mechanisms that might be responsible for eliciting at least a portion of the exercise ventilatory response during these types of exercise. The third section describes how the traditional and contemporary control mechanisms may interact in a complex fashion to produce the changes in breathing associated with constant-load exercise, and incorporates recent experimental evidence from our laboratory.
Animals↗
An aid to the determination of the ventilatory threshold.
Detection of the ventilatory threshold during an incremental load exercise test by eye can be difficult. Although various alternative methods employing information other than the ventilation can be used to assist in determining the ventilatory threshold, they rely on underlying assumptions about the physiological basis for the ventilatory threshold. The method presented here (CUSUM) uses only the ventilation data, and therefore avoids such assumptions. Twelve subjects performed a total of 47 incremental exercise tests to exhaustion. Determinations of the ventilatory thresholds made by eye from the ventilation data (mean of three independent observers) were used as a standard for comparison with determinations using the modified V-slope method and the CUSUM method. A mean (SD) difference of 0.6 (2.84) ml.min-1.kg-1 was found between the standard ventilatory thresholds and those determined using the modified V-slope method. A similar comparison between the standard ventilatory thresholds and those determined using the CUSUM method yielded a difference of -0.11 (2.35) ml.min-1.kg-1. It was concluded that the CUSUM method was a useful aid for the detection of the ventilatory threshold using the ventilation data alone.
Adult↗
Infiltrating the curriculum: an integrative approach to history for medical students.
I believe that the purpose of history in a medical school can be related to two simple goals: first, to make students a bit skeptical about everything else they are to be taught in the other lectures--skepticism fosters humility and life-long learning; second, to make them aware that medical history is a research discipline as compelling as any of the basic and clinical sciences they are traditionally taught. In the fall of 1988, I was given an opportunity to build a "course" in history for medical students--a course with no fixed time slot, no fixed syllabus, and no fixed content. I wanted to teach history of anatomy during anatomy sessions, history of pathology during pathology, history of obstetrics during obstetrics, and so on. I hoped to end each session with a disciplinary controversy that extended into present practice. The ultimate manifestation of infiltration would be to have one question on every exam that the students would write during their medical school experience. This is the story of how my medical history teaching moved from nothing to a program integrated throughout four years of medical studies, complete with goals and objectives and two questions of every exam. The content, advantages, and problems of the approach in the Queen's University experience will be presented.
Canada↗
Great moments. Parke, Davis and Company and the creation of medical art.
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Advertising↗