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Biomedical subjects

J Duffin

Publications and source records attributed to J Duffin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Functional synaptic connections among respiratory neurons.

This presentation focuses on the application of methods to determine functional connections between neurons in the respiratory network of adult decerebrate rats. We employ a general network investigation paradigm that first examines the intracellular recordings of a respiratory neuron and then determines which neurons synapse with it to produce the observed membrane potential changes. It is used to pursue the source of respiratory excitation and inhibition from its arrival at phrenic motoneurons to respiratory neurons in the medulla, and then examine some of the interactions among these neurons that shape their patterns of activity. Findings include a demonstration that phrenic motoneuron activity is determined by excitation from medullary inspiratory premotor neurons and inhibition by Bötzinger complex expiratory neurons, and that the latter neurons inhibit both medullary inspiratory premotor neurons and themselves. We conclude that these functional interconnections explain the activity patterns of some respiratory neurons, but the connections between neurons thought to be involved in rhythm generation remain to be demonstrated in adult rats.

Animals↗
PubMed2000

Baring the sole. The rise and fall of the shoe-fitting fluoroscope.

One of the most conspicuous nonmedical uses of the x-ray was the shoe-fitting fluoroscope. It allowed visualization of the bones and soft tissues of the foot inside a shoe, purportedly increasing the accuracy of shoe fitting and thereby enhancing sales. From the mid 1920s to the 1950s, shoe-fitting fluoroscopes were a prominent feature of shoe stores in North America and Europe. Despite the widespread distribution and popularity of these machines, few have studied their history. In this essay we trace the origin, technology, applications, and significance of the shoe-fitting fluoroscope in Britain, Canada, and the United States. Our sources include medical and industrial literature, oral and written testimony of shoe retailers, newspapers, magazines, and government reports on the uses and dangers of these machines. The public response to shoe-fitting fluoroscopes changed from initial enthusiasm and trust to suspicion and fear, in conjunction with shifting cultural attitudes to radiation technologies.

Advertising↗
PubMed2000

Circadian rhythms in the chemoreflex control of breathing.

Mechanisms underlying the circadian rhythm in lung ventilation were investigated. Ten healthy male subjects were studied for 36 h using a constant routine protocol to minimize potentially confounding variables. Laboratory light, humidity, and temperature remained constant, subjects did not sleep, and their meals and activities were held to a strict schedule. Respiratory chemoreflex responses were measured every 3 h using an iso-oxic rebreathing technique incorporating prior hyperventilation. Subjects exhibited circadian rhythms in oral temperature and respiratory chemoreflex responses, but not in metabolic rate. Basal ventilation [i.e., at subthreshold end-tidal carbon dioxide partial pressure (PET(CO(2)))] did not vary with time of day, but the ventilatory response to suprathreshold PET(CO(2)) exhibited a rhythm amplitude of approximately 25%, mediated mainly by circadian variations in the CO(2) threshold for tidal volume. We conclude that the circadian rhythm in lung ventilation is not a simple consequence of circadian variations in arousal state and metabolic rate. By raising the chemoreflex threshold, the circadian timing system may increase the propensity for respiratory instability at night.

Adult↗
PubMed2000

Poisoning the spindle: serendipity and discovery of the anti-tumor properties of the Vinca alkaloids.

In 1995, Canadian scientists Robert Noble and Charles Beer were inducted into the Canadian Medical Hall of Fame for their 1950s "discovery" of Vinblastine. Their "chance" finding of an anticancer drug in the leaves of the periwinkle plant (Vinca rosea, Linn.), is used to explore the historical issue of discovery, accidental discovery, and priority. The elements of the discovery are reconstructed through the oral testimony of key players and their published and unpublished records. Several "unsung heroes" played key roles in this project and reasons for their relative invisibility will be presented. Special attention is paid to the relationship between the small Canadian academic group working at UWO and the large pharmaceutical company (Eli Lilly) engaged in similar research at the same time.

Canada↗
PubMed2000

Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest.

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg(-1) I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 +/- 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2 in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 +/- 0.66 vs. 4.07 +/- 1.03 l x min(-1) (mmHg CO2)(-1), P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 +/- 0.92 vs. 1.33 +/- 0.46 l x min(-1) (mmHg CO2)(-1), P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.

Acetazolamide↗
PubMed1999

Temperature and pH affect respiratory rhythm of in-vitro preparations from neonatal rats.

We examined the respiratory rhythm of two in-vitro preparations from neonatal rats, the brainstem-spinal cord and transverse brainstem slice, recording the bursting activity of phrenic and hypoglossal nerves, respectively at 1 degree C intervals from 25 to 35 degrees C at two pH's, 7.4 and 7.1. In both preparations at either pH, burst frequency increased with temperature, burst duration declined and burst amplitude reached a peak at 30 degrees C. The shapes of the bursts changed from a decrementing pattern at low temperatures to a bell-shaped pattern at high temperatures. At reduced pH, frequency increased for temperatures between 25 and 32 degrees C in the brainstem-spinal cord but not in the slice. Burst duration was increased at reduced pH for temperatures between 27 and 29 degrees C in the brainstem-spinal cord, but not in the slice. Burst amplitude only changed with pH at the lower temperatures, decreasing at the lower pH in the brainstem-spinal cord and increasing in the slice. With respect to the effects of temperature, we concluded that both preparations were similarly affected, and that an increase in temperature alters the in-vitro burst pattern towards that observed in-vivo. With respect to the effects of pH, we concluded that effects differ between these in-vitro preparations and from in-vivo preparations, and that the difference between in-vivo and in-vitro preparations in their response to decreasing pH is not due to differences in temperature.

Animals↗
PubMed1999

Measuring central-chemoreflex sensitivity in man: rebreathing and steady-state methods compared.

We compared the central-chemoreflex sensitivities estimated from steady-state tests with those estimated from rebreathing tests in five subjects. In one laboratory, each subject underwent nine dynamic end-tidal forcing experiments. Three repetitions of 3, 6 and 9 mmHg step changes in the end-tidal partial pressure of carbon dioxide, from a pre-step partial pressure 1.5 mmHg above resting, were used to establish four points of the steady-state ventilatory response to carbon dioxide. In another laboratory, each subject underwent two rebreathing experiments, one using Read's rebreathing technique and the other a modified rebreathing method which included a prior hyperventilation. The central-chemoreflex sensitivities, estimated from the slopes of the ventilatory responses to carbon dioxide using different combinations of the four steady-state points. were compared to those estimated from the slopes of the rebreathing responses. The steady-state sensitivities were significantly lower than the Read rebreathing sensitivities. The ratio of modified rebreathing sensitivities to steady-state sensitivities was closest to one when steady-state sensitivities were estimated from the two middle points of the ventilatory responses. The mean (SE) ratio of the sensitivities was 1.22 (0.21) in this case. We identify a number of factors that may affect the estimation of central-chemoreflex sensitivity using each technique. These include a maximum limit of the ventilation response at high partial pressures of carbon dioxide, an inability to sustain high ventilation for the duration of the steady-state tests and the inclusion of parts of the ventilatory response whose carbon dioxide partial pressures lie below the central-chemoreflex threshold. We conclude that the modified rebreathing method provides the best estimate of central-chemoreflex sensitivity of the three methods.

Adult↗
PubMed1999

Bötzinger-complex, bulbospinal expiratory neurones monosynaptically inhibit ventral-group respiratory neurones in the decerebrate rat.

Extracellularly recorded action potentials from 49 Bötzinger-complex, bulbospinal expiratory neurones were used as triggers to compute 162 spike-triggered averages (STAs) of intracellular potentials recorded from 167 respiratory neurones in the ventral respiratory group (VRG) near the obex in 15 vagotomized, paralysed, ventilated and decerebrated rats. All of the Bötzinger-complex expiratory neurones were antidromically activated from the ipsilateral border between the C2/C3 segments of the spinal cord and discharged only during the late part of expiration with an augmenting pattern. We found evidence for monosynaptic inhibitory post-synaptic potentials (IPSPs) in 74 (approximately 44%) of the STAs computed using 34 (approximately 69%) of the trigger neurones. For vagal motoneurones, IPSPs were found in 24 of the 53 STAs of expiratory motoneurones, but in none of the 12 STAs of inspiratory motoneurones. For inspiratory neurones, IPSPs were found in 23 of the 33 STAs of bulbospinal neurones and in 6 of the 26 STAs of not antidromically activated (NAA) neurones. For expiratory neurones, IPSPs were found in one of the two STAs of bulbospinal neurones and in 20 of the 36 STAs of NAA neurones. We conclude that Bötzinger-complex, bulbospinal expiratory neurones monosynaptically inhibit bulbospinal inspiratory neurones, expiratory vagal motoneurones and other unidentified inspiratory and expiratory neurones in the VRG of rats during the late part of expiration.

Action Potentials↗
PubMed1999

Mutual inhibition between Bötzinger-complex bulbospinal expiratory neurons detected with cross-correlation in the decerebrate rat.

We examined the synaptic connections between pairs of Bötzinger-complex, bulbospinal expiratory neurons in decerebrate rats. All were antidromically activated from the spinal cord at the C2-C3 border. Cross-correlation histograms of 18 ipsilateral pairs showed troughs on both sides of time zero (8) and to one side of time zero (4); most (12) were accompanied by peaks at time zero. Similarly, cross-correlation histograms of the contralateral pairs (12) showed troughs on both sides of time zero (3) and to one side of time zero (3); few (2) were accompanied by peaks at time zero. We considered the troughs in these cross-correlation histograms to be evidence of inhibition between the neurons and sought confirmation of the inhibitory connection. First, using the antidromic activation stimulus, we computed post-stimulus histograms of the extracellularly recorded discharge for six neurons and found that three showed troughs. Then, we continued this approach, computing post-stimulus averages of the membrane potentials recorded intracellularly from these neurons after iontophoresis of chloride to reverse inhibitory synaptic potentials. Depolarising potentials were observed in 15 of 16 of these averages. We interpreted these as reversed inhibitory post-synaptic potentials and concluded that Bötzinger-complex, bulbospinal expiratory neurons inhibit one another in rats as they do in cats.

Animals↗
PubMed1998

Bilaterally independent respiratory rhythms in the decerebrate rat.

In rats, respiratory neurons in the medulla oblongata are arranged in longitudinally distributed groups that are duplicated on each side of the neuraxis. Our aim was to determine whether respiratory rhythm is generated independently by each side. We made a complete mid-sagittal section of the medulla oblongata, 3.5 mm rostral and 3.5 mm caudal to the obex, in decerebrate, vagotomized, and paralysed adult rats. Respiratory rhythm, monitored by recording the activity of both left and right phrenic nerves, was maintained and became asynchronous between the left and right sides. We concluded that in the adult rat each half of the medulla oblongata is capable of generating respiratory rhythm independently.

Animals↗
PubMed1998

Synaptic connections to phrenic motoneurons in the decerebrate rat.

Phrenic motoneuron membrane potential trajectories in decerebrate rats exhibit three stages; depolarisation during inspiration, a decreased depolarisation during early expiration and hyperpolarization during late expiration. These trajectories are a result of excitation by ventral-group medullary inspiratory neurons and upper-cervical inspiratory neurons during inspiration and the early part of expiration, and inhibition from Bötzinger-complex expiratory neurons during the late part of expiration.

Animals↗
PubMed1998

The role of dorsal respiratory group neurons studied with cross-correlation in the decerebrate rat.

We examined the role of dorsal respiratory group (DRG) inspiratory neurons as transmitters of respiratory drive to phrenic and intercostal motoneurons and as relays of afferent information to ventral respiratory group (VRG) bulbospinal, inspiratory neurons. Attempts to antidromically activate 76 DRG neurons from the spinal cord at the C7 segment resulted in only 4 (5.3%) successes (3 contralateral, 1 ipsilateral). Cross-correlating DRG neuron discharge with that of the ipsilateral (56) and contralateral (20) phrenic nerve detected common activation peaks in 2 and 3 cases respectively, with no evidence for monosynaptic connections. Cross-correlating DRG neuron discharge with that of bulbospinal, inspiratory VRG neurons found some evidence for interaction. Peaks in 7 of 73 (10%) cross-correlation histograms were attributed to a monosynaptic excitation of DRG neurons by VRG neurons, although a common activation cannot be ruled out; troughs, some with an accompanying peak, in 9 (12.3%) histograms were interpreted as a combined excitation of the DRG neuron and delayed inhibition of the VRG neuron. In addition, 2 cross-correlation histograms showed peaks with latencies and half-amplitude widths consistent with a disynaptic excitation of a DRG neuron by a bulbospinal inspiratory VRG neuron. Cross-correlating the discharge of 57 pairs of DRG inspiratory neurons (6 contralateral) detected common activation peaks in 7 (12.3%) cases (none contralateral) and one case interpreted as evidence for a disynaptic excitation. These findings suggest that the role of the DRG inspiratory neurons in rats differs from that in cats, primarily because they do not act to transmit respiratory rhythmic drive directly to phrenic and intercostal motoneurons. The results offer some support for an excitation of DRG neurons by VRG inspiratory neurons, but no support for a role of DRG inspiratory neurons as mediators of afferent information transfer to VRG bulbospinal inspiratory neurons.

Animals↗
PubMed1998

Bötzinger-complex expiratory neurons monosynaptically inhibit phrenic motoneurons in the decerebrate rat.

We examined respiratory neurons in the Bötzinger complex of the medulla oblongata in 18 vagotomized, paralyzed, ventilated, and decerebrated rats and tested the hypothesis that bulbospinal expiratory neurons in this region monosynaptically inhibit phrenic motoneurons. First, we surveyed the types of respiratory neurons found in the Bötzinger complex; only 11 of the 98 (approximately 11%) examined were bulbospinal, and all discharged only during late expiration (E2), usually with an augmenting discharge frequency (AUG). Then, we examined the spinal projections of 34 E2-AUG neurons using antidromic activation and found that all projected as far as the C4 or C5 segments of the spinal cord but no further caudally. Most (30, approximately 88%) had only unilateral projections, the majority (25, approximately 83%) ipsilateral, but 4 neurons (approximately 12%) had bilateral projections. Their axons could be antidromically activated at low currents (less than 10 microA) in the dorsal-lateral part of the spinal cord at the C2-3 border; 0.5-1.2 mm (mean+/-SD 0.84+/-0.23 mm) below the dorsal surface and 0.7-1.5 mm (1.19+/-0.25 mm) lateral from the midline. We sought evidence for connections from bulbospinal E2-AUG neurons to 118 phrenic motoneurons by computing spike-triggered averages (STAs) of their intracellular potentials triggered by the action potentials of 38 unilaterally-projecting E2-AUG neurons. Resting phrenic motoneuron membrane potentials ranged from -40 to -75 mV (-56+/-8 mV) and fluctuations with the respiratory cycle from 7 to 20 mV (14+/-4 mV). Of the 118 STAs computed, hyperpolarizations were evident in 18 (approximately 15%) STAs, evoked by 11 of 38 (approximately 29%) E2-AUG neurons. Their amplitudes varied from 35 to 550 microV (105+/-113 microV), 10-90% fall times from 0.4 to 0.9 ms (0.63+/-0.17 ms), and half-amplitude widths from 1.3 to 3.2 ms (2.0+/-0.52 ms). Most (16/95, approximately 17%) of the STAs that displayed hyperpolarizations were associated with ipsilateral trigger neurons but some (2/23, approximately 9%) resulted from contralateral trigger neurons. We conclude that Bötzinger-complex, expiratory neurons project to the C4 and/or C5 segments of the cervical spinal cord but no further caudal. Their axons are located dorsolaterally in the upper cervical segments of the spinal cord, and they monosynaptically inhibit phrenic motoneurons during the late part of expiration.

Animals↗
PubMed1998

Chemoreflex thresholds to CO2 in decerebrate cats.

We used a modified rebreathing technique to measure chemoreflex thresholds to CO2 in decerebrate, paralyzed and ventilated cats. Cats were hyperventilated to neural apnea (PaCO2 < 15 mmHg) with one ventilator and then switched to a rebreathing circuit consisting of a balloon inside a bottle connected to a second ventilator. The volume of the circuit was approximately 110 ml. The balloon contained 5% CO2:95% O2 for hyperoxic rebreathing or approximately 5% CO2 with 11 or 6.5% O2 for moderately and severely hypoxic rebreathing. A plateau in CO2 concentration at the onset of rebreathing indicated equilibration of CO2 between the circuit, alveolar gas and venous and arterial blood. After rapid equilibration of CO2 between the cat and the circuit, CO2 increased linearly with time during rebreathing. Under hyperoxic conditions, phrenic activity began to increase at an end-tidal P(CO2) (PET(CO2)) of 35.1 +/- 6.1 (SD) mmHg (n = 8); during hypoxia, phrenic activity began to increase at a significantly lower PET(CO2) of 27.8 +/- 4.8 mmHg (P < 0.01, n = 6). We interpret these values as the central and peripheral chemoreflex thresholds to CO2, respectively. Persistent phrenic activity prevented determination of a threshold during severe hypoxic rebreathing. Our modified method of hyperoxic and hypoxic rebreathing allows detection of the effects of hypoxia on the central and peripheral chemoreflex thresholds and, within a cat, measurements of chemoreflex sensitivities.

Animals↗
PubMed1998

Entrainment, instability, quasi-periodicity, and chaos in a compound neural oscillator.

We studied the dynamical behavior of a class of compound central pattern generator (CPG) models consisting of a simple neural network oscillator driven by both constant and periodic inputs of varying amplitudes, frequencies, and phases. We focused on a specific oscillator composed of two mutually inhibiting types of neuron (inspiratory and expiratory neurons) that may be considered as a minimal model of the mammalian respiratory rhythm generator. The simulation results demonstrated how a simple CPG model--with a minimum number of neurons and mild nonlinearities--may reproduce a host of complex dynamical behaviors under various periodic inputs. In particular, the network oscillated spontaneously only when both neurons received adequate and proportionate constant excitations. In the presence of a periodic source, the spontaneous rhythm was overridden by an entrained oscillation of varying forms depending on the nature of the source. Stable entrained oscillations were inducible by two types of inputs: (1) anti-phase periodic inputs with alternating agonist-antagonist drives to both neurons and (2) a single periodic drive to only one of the neurons. In-phase inputs, which exert periodic drives of similar magnitude and phase relationships to both neurons, resulted in varying disruptions of the entrained oscillations including magnitude attenuation, harmonic and phase distortions, and quasi-periodic interference. In the absence of significant phasic feedback, chaotic motion developed only when the CPG was driven by multiple periodic inputs. Apneic episodes with repetitive alternation of active (intrinsic oscillation) and inactive (cessation of oscillation) states developed when the network was driven by a moderate periodic input of low frequency. Similar results were demonstrated in other, more complex oscillator models (that is, half-center oscillator and three-phase respiratory network model). These theoretical results may have important implications in elucidating the mechanisms of rhythmogenesis in the mature and developing respiratory CPG as well as other compound CPGs in mammalian and invertebrate nervous systems.

Animals↗