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Biomedical subjects

J A Hirsch

Publications and source records attributed to J A Hirsch.

13 recordsLinked to original sources
PubMed1992

Respiratory and abdominal muscle responses to expiratory threshold loading in cystic fibrosis.

We hypothesized that the hyperinflation and pulmonary dysfunction of cystic fibrosis (CF) would distort feedback and therefore alter the abdominal muscle response to graded expiratory threshold loads (ETLs). We compared the respiratory and abdominal muscle responses with graded ETLs of seven CF patients with severe lung dysfunction with those of matched healthy control subjects in the supine and 60 degrees head-up positions. Breathing frequency, tidal volume, and ventilatory timing were determined from inspiratory flow recordings. Abdominal electromyograms (EMGs) were detected with surface electrodes placed unilaterally over the external and internal oblique and the rectus abdominis muscles. Thresholds, times of onset, and durations of phasic abdominal activity were determined from raw EMGs; peak amplitudes were determined from integrated EMGs. Graded ETLs were imposed by submerging a tube from the expiratory port of the breathing valve into a column of water at depths of 0-25 cmH2O. We found that breathing frequency, tidal volume, and expired minute ventilation were higher in CF patients than in control subjects during low ETLs; a change in body position did not alter these ventilatory responses in the CF patients but did in the control subjects. All CF patients, but none of the control subjects, had tonic abdominal activity while supine. CF patients recruited abdominal muscles at lower loads, earlier in the respiratory cycle, and to a higher recruitment level in both positions than the control subjects, but burst duration of phasic activity was not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
PubMed1991

Synaptic physiology of horizontal connections in the cat's visual cortex.

Horizontal connections are a principal component of intrinsic cortical circuitry. They arise mainly from pyramidal cells and course parallel to the brain's surface for distances as long as 8 mm, linking columns with shared orientation preference and allowing cells to integrate visual information from outside their receptive fields. We examined the synaptic physiology of the horizontal pathway in slices of the cat's striate cortex and found that activating lateral fibers produced both excitation and inhibition. We recorded the postsynaptic responses of identified pyramidal cells in layer 2 + 3 of area 17 to electrical shocks applied at three sites: in the home column of the impaled neuron either in layer 2 + 3 or 4, or at a lateral distance of 0.9-3 mm in layer 2 + 3. Within the home column, suprathreshold stimuli produced compound EPSPs with action potentials, followed by fast, GABAAergic IPSPs and a slower, GABABergic IPSP. For the distant stimulating site, the threshold response was an EPSP. Stronger shocks frequently evoked a disynaptic, GABAAergic IPSP that truncated the EPSP and could dominate the postsynaptic response. At the resting potential, the horizontally evoked EPSP was too small to elicit spikes. With depolarization of the membrane, however, it grew several hundred-fold. This amplification was blocked by N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), but not by 2-amino-5-phosphonovalerate (APV), indicating that it was mediated by Na+ channels, rather than by NMDA receptors. We propose that the horizontal connections provide the means for stimuli outside the receptive field to modulate activity elicited within its confines. The voltage-dependent enhancement of the laterally evoked EPSP may explain why stimulating the surround by itself fails to drive cells but can facilitate their response to stimuli within the receptive field. The ability to initiate disynaptic inhibition from lateral sites shows that recruiting appropriate groups of horizontal fibers can also have a suppressive effect. Thus, the effect of horizontal input is state dependent, with the size and sign of the laterally evoked response changing according to the balance of converging inputs.

2-Amino-5-phosphonovalerate↗
PubMed1990

Origin and selection of peripheral CD4-CD8- T cells bearing alpha/beta T cell antigen receptors in autoimmune gld mice.

We have analyzed the origin and development of unusual CD4-CD8- alpha/beta T cell receptor-positive peripheral T cells produced in large numbers by mice homozygous for the gld mutation (C3H-gld/gld). These mice may be an important model for investigating processes controlling T cell development. Bone marrow transfers demonstrated that the gld defect was intrinsic to bone marrow-derived cells. Clonal deletion of potentially autoreactive cells was observed in peripheral gld CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells, as well as mature thymocytes. This suggests that gld CD4-CD8- T cells have passed through the thymus in ontogeny and that gld autoimmunity does not result from a general defect in elimination of self-reactive thymocytes. These observations, combined with demethylation of the CD8 gene in the CD4-CD8- population, support prior expression of CD4 and/or CD8 in gld CD4-CD8- T cell ontogeny, perhaps at a CD4+CD8+ stage. Steroid sensitivity of gld thymocytes and CD4-CD8- T cells was normal. Therefore, we found no gross abnormalities in two major mechanisms of inducible cell death in the gld thymus, the clonal deletion process associated with tolerance and the steroid-inducible endogenous endonuclease thought to be involved in apoptosis of unselected thymocytes. The data suggest that if gld CD4-CD8- T cells arise via escape from normal elimination in the thymus, they must do so by a novel defect in thymic selection (perhaps related to aberrant positive signals) and/or are expanded by an extrathymic process which allows clonal deletion to occur.

Animals↗
PubMed1990

Lateral interactions in visual cortex.

The findings presented in these studies have brought out different ideas concerning the mechanisms of processing in primary visual cortex than were held at the outset. Rather than thinking of receptive fields as being restricted in their extent, with the process of integration of the components of an image occurring at a much later stage along the visual pathway, we have shown that the integrative process is a progressive one, beginning in the primary visual cortex (or perhaps even earlier) and building up in a cascading series of converging and diverging connections. Rather than thinking of the filter characteristics of a cell as being fixed, it is apparent that they are dynamic and can be modified by the context in which features are presented. Finally, rather than a cortex with a functional architecture that is fixed after a critical period ending in infancy, we find that perturbing the system can lead to long-term topographical reorganization. Other examples of contextual interactions have been demonstrated in the submodalities of motion, where a cell's directional selectivity is modulated by the presence of movement in the surround (Allman et al. 1985; Tanaka et al. 1986; Gulyas et al. 1987; Orban et al. 1987). In the domain of color, the phenomenon of color constancy, reported for cells in visual area V4 (Zeki 1983), also requires lateral interactions in visual space, comparing the wavelength distribution of light coming from surfaces in different parts of the visual field. The influences presented in these studies, as in our own work in the domain of orientation, are modulatory. The long-term changes in cortical topography following removal of somatosensory input (Merzenich et al. 1984, 1988) or by retinal lesions suggest that with the appropriate manipulations the lateral interactions can be enhanced to the point of activating the postsynaptic cells. Although retinal lesions clearly represent an abnormal disruption of sensory input, they may nevertheless be representative of long-term reorganizations of neural networks occurring under normal circumstances, such as those required for memory.

Animals↗
PubMed1989

Resting oxygen consumption and ventilation in cystic fibrosis.

Resting oxygen consumption (VO2) and minute ventilation (VE) were measured on nine control subjects and 13 patients with cystic fibrosis (CF). In patients with CF, VO2 was 20% higher (P less than 0.01) when expressed per m2 and 47% higher (P less than 0.001) when expressed per kg body weight, and VE was 58% higher when expressed per m2 and 94% higher when expressed per kg body weight (P less than 0.001) than in control subjects. Repeated measures of VO2 and VE were highly reproducible over 2 hours (within-subject coefficients of variation: in controls, VO2 = 5.5%, VE = 7.4%; in CF, VO2 = 3.1%, VE = 5.1%). Since the increases in VE were greater than those in VO2, the ventilatory equivalent (VE/VO2) was 32% higher in CF than in controls. We conclude that size-corrected total energy expenditures and VE at rest are higher in patients with CF than in control subjects. Ventilation appears mechanically inefficient but necessary to keep arterial PCO2 from rising and oxygen saturation from falling at rest. Our results are consistent with observations that these patients have an abnormally large physiological dead space (Featherby et al.: Ann Rev Respir Dis 1969; 102:737).

Adolescent↗
PubMed1988

Intrinsic properties of neurones in the dorsal cochlear nucleus of mice, in vitro.

1. Intracellular recordings were made from the dorsal cochlear nucleus (DCN) in slices of the cochlear nuclear complex. Probably the larger and most frequent cells were impaled. 2. The steady-state current-voltage (I-V) properties of all cells impaled were nonlinear. The I-V curve was steepest in the voltage range depolarized from the resting potential and most shallow when the cell was hyperpolarized from rest by more than about 10 mV. Thus, the inwardly rectifying I-V characteristics of cells in the DCN distinguish them from those of ventral cochlear nuclear neurones (Oertel, 1983). 3. When depolarized with current, most cells fired trains of large, all-or-none action potentials. The undershoot after single spikes comprised an initial, fast component followed by a second, slower wave. A few cells (15%) generated bursts of smaller, graded spikes in addition to the large ones. 4. Repetitive firing evoked by depolarizing pulses of current was followed by an after-hyperpolarization whose magnitude depended on the strength and duration of the preceding current pulse. 5. Blocking the large action potentials with tetrodotoxin (TTX) revealed Ca2+-dependent spikes in all cells examined. 6. The steady-state I-V relationship became linear in the presence of TTX, suggesting that a persistent Na+ conductance probably mediates the inward rectification seen above the resting potential. 7. Muscarine at micromolar concentrations excited cells and increased their input resistance.

4-Aminopyridine↗
PubMed1988

Synaptic connections in the dorsal cochlear nucleus of mice, in vitro.

1. Intracellular recordings were made from the dorsal cochlear nucleus (DCN) in slices that contained the root of the auditory nerve and parts of the dorsal and ventral cochlear nuclei. Probably the largest and most common cells were impaled. 2. Weak shocks to the nerve usually evoked an excitatory postsynaptic potential (EPSP) that lasted about 90 ms and whose latency was often less than 1.2 ms, indicating monosynaptic input. 3. Stronger shocks elicited a larger EPSP and a later train of inhibitory postsynaptic potentials (IPSPs). Increasing the stimulus voltage shortened the latency of the train of IPSPs and increased its efficacy so that at large stimulus strengths inhibition dominated the synaptic response. 4. To determine whether any of the neuronal circuitry which generated the synaptic responses involved the ventral cochlear nucleus, recordings were made from slices containing only the dorsal nucleus. Synaptic responses to stimulation of the pial surface of the isolated DCN resembled those driven from the nerve root. That is, weak shocks evoked long-lasting, monosynaptic EPSPs and stronger stimuli elicited a larger EPSP followed by trains of IPSPs. The DCN, therefore, contains intrinsic inhibitory interneurones. 5. The parallel fibres of the DCN course superficially, near the stimulating electrodes, whereas the axons of the auditory nerve terminate in deeper areas. Thus, the monosynaptic EPSPs evoked from the pial surface are probably generated by parallel fibres. Apparently the inhibitory interneurones are also excited by a circuit including parallel fibres. 6. The putative neurotransmitter of parallel fibres, glutamate, excited all neurones tested. 7. Cells were sensitive both to glycine and to gamma-aminobutyric acid (GABA). Only strychnine, however, not picrotoxin or bicuculline, blocked IPSPs.

Action Potentials↗
PubMed1976

Effect of oxygen in graded concentrations upon tracheal mucous velocity. A study in anesthetized dogs.

Graded concentrations of oxygen were used to establish dose-duration relations for the effect of oxygen on tracheal mucous velocity and tracheobronchial histologic findings in the anesthetized dog. Observations of tracheal mucous velocity were made during 30-hour periods of breathing air (100-percent humidified and warmed to 38 degrees C) and oxygen mixtures (also 100-percent humidified and warmed to 38 degrees C). In animals breathing oxygen mixtures, the baseline tracheal mucous velocity was taken as the value while breathing room air at the experiment's start. No statistically significant differences in tracheal mucous velocity occurred during air breathing. Tracheal mucous velocity fell 45 percent from the baseline value after breathing 100-percent oxygen for two hours (P less than 0.01), fell 42 percent after 75-percent oxygen for nine hours (P less than 0.01) and fell 51 percent after 50-percent oxygen for 30 hours (P less than 0.001). Histologic examination of the trachea and major bronchi after six hours of 100-percent oxygen and 12 hours of 75-percent oxygen revealed signs of acute tracheobronchitis. Minor histologic alterations in the tracheobronchial tree occurred both in animals breathing air and 50-percent oxygen for 30 hours; therefore, histologic evidence of oxygen toxicity could not be established at 30 hours. These findings indicate that in the anesthetized dog, oxygen depresses mucous transport as a function of inspired oxygen concentration (FIO2) and that even FIO2 as low as 0.05 might be deleterious.

Acute Disease↗
PubMed1975

Tracheal mucous transport in Beagles after long-term exposure to 1 ppm sulfur dioxide.

Tracheal mucous velocity was determined in eight purebred beagle dogs exposed intermittently to 1 ppm sulfur dioxide for 12 months. Three control dogs were also studied. Teflon disks filmed at constant speed through a bronchofiberscope served as indicators of mucous motion. An average of 16 disks were analyzed in each dog. Although there was no significant difference in average velocity for controls and the SO-2-exposed animals, the frequency distribution curve of individual disk velocities in SO-2-exposed dogs revealed significant slowing. No significant differences in mechanics of breathing and gas exchange were found between the two groups. It appears that long-term exposure to low levels of SO-2 produces an impairment of mucociliary activity as one of the first signs of pulmonary dysfunction.

Animals↗
PubMed1975

Effects of topical and general anesthetic agents on tracheal mucous velocity of sheep.

Tracheal mucous velocity was estimated in eleven sheep by means of cine-bronchofiberscopic technique in which Teflon discs placed on the tracheal mucosa were filmed as markers. The procedure was done using a transnasal approach in conscious nonanesthetized sheep, and in the same sheep using topical and/or general anesthetic agents. The average mucous velocity in conscious sheep was 17.3 plus or minus 6.2 (SD) mm/min; in sheep anesthetized with intravenous pentobarbital or thioamylal, the average velocity was significantly depressed to 11.1 plus or minus 3.6 mm/min. No Significant differences in tracheal mucous velocity were found when 10 ml of 2 percent lidocaine was instilled into the tracheas of either conscious sheep or sheep under general anesthesia. Sheep as an animal model appear to be ideal in the study of the responses of tracheal mucous velocity to physical and chemical agents since they tolerate bronchofiberscopy quite well without the use of topical or general anesthetic agents. The basis for the depression of tracheal mucous velocity by barbiturates cannot be ascertained from the present study but the model should be useful for comparing different types of anesthetic agents.

Anesthesia, General↗
PubMed1975

Effects of dry air and subsequent humidification on tracheal mucous velocity in dogs.

The impairment of mucociliary transport by dry air breathing and the restoration of function with subsequent humidification of inspired air were investigated in anesthetized dogs. Tracheal mucous velocity was measured by a cinebronchofiberscopic technique. The breathing of dry air through an uncuffed endotracheal tube produced almost complete cessation of the flow of tracheal mucus after 3 h. Subsequent breathing of air at 38 degrees C with 100% relative humidity restored tracheal mucous velocity to control values by the end of and additional 3 h. Histologic examination of the trachea at the end of the 3-h dry air breathing period revealed focal areas of sloughing of the ciliated epithelium and submucosal inflammation. Although morphometry was not employed, the inflammatory changes appeared to have progressed during 3 h of breathing fully humidified air subsequent to the dry air breathing period. These findings were consistent with previous reports that the inflammatory response to injury of the tracheobronchial mucosa might be delayed and that the mucociliary transport system has a great deal of functional reserve. We found that an artificial heat and moisture exchanger placed on the proximal end of an endotracheal tube partially protects against the suppression of tracheal mucous velocity caused by dry air breathing.

Animals↗