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Biomedical subjects

R S Goldstein

Publications and source records attributed to R S Goldstein.

At least 109 records · Page 6Linked to original sources
PubMed1988

Reduction of sensory activity produced by cercal displacement modifies response of wind-sensitive interneurons in the cockroach.

The cockroach can reduce the amount of sensory activity received by its CNS from the cerci, paired wind-responsive appendages. This reduction is produced by medial displacement of the cerci, a movement the animal performs naturally during flying. We demonstrate here that this sensory reduction significantly reduces activity of the postsynaptic wind-sensitive interneurons in the abdominal nerve cord, cells which carry the wind information to higher centers of the nervous system. In addition, we have found that the wind-evoked activity of two identified giant interneurons that are involved in escape and locomotion behaviors, is significantly reduced by cercal displacement.

Action Potentials↗
PubMed1988

Modulation of activity in sensory neurons and wind-sensitive interneurons by cercal displacement in the cockroach.

1. The cockroach Periplaneta americana can modify the sensory activity received by its central nervous system from the cerci, paired abdominal wind-responsive appendages. Medial displacement of the cerci produces a reduction in the number of sensory action potentials (AP's) elicited by a wind stimulus (Fig. 2) (Libersat et al. 1987; Golstein and Camhi 1988). This movement occurs naturally, for example during flying. 2. This sensory reduction is present when measured as the integral of extracellularly recorded activity as well as when counting the number of AP's larger than a threshold voltage just larger than the background noise (Fig. 2C). 3. Histological results confirm prior physiological experiments suggesting that the reduction may be produced by mechanical forces on the sensory nerve, rather than synaptically (Fig. 4). 4. The wind-response of interneurons is significantly diminished by the sensory reduction when measured either extra- or intracellularly (Figs. 5, 6). Cells affected include identified ventral and dorsal giant interneurons (GI's), which carry directional information about wind from the abdominal cerci to the more anterior portions of the nervous system, and are involved in flying (Camhi 1980; Ritzmann 1984; Comer 1985). 5. The reduction in the interneuronal response was unaffected by the elimination of input from descending central pathways, and input from a cercal chordotonal organ that senses cercal position and inhibits some of the GI's (Fig. 5). Thus, the reduction in wind-evoked sensory activity can itself account for the modulation of interneuron activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

Biochemical mechanisms of cephaloridine nephrotoxicity.

Large doses of the cephalosporin antibiotic, cephaloridine, produce acute proximal tubular necrosis in humans and in laboratory animals. Cephaloridine is actively transported into the proximal tubular cell by an organic anion transport system while transport across the lumenal membrane into tubular fluid appears restricted. High intracellular concentrations of cephaloridine are attained in the proximal tubular cell which are critical to the development of nephrotoxicity. There is substantial evidence indicating that oxidative stress plays a major role in cephaloridine nephrotoxicity. Cephaloridine depletes reduced glutathione, increases oxidized glutathione and induces lipid peroxidation in renal cortical tissue. The molecular mechanisms mediating cephaloridine-induced oxidative stress are not well understood. Inhibition in gluconeogenesis is a relatively early biochemical effect of cephaloridine and is independent of lipid peroxidation. Furthermore, cephaloridine inhibits gluconeogenesis in both target (kidney) and non-target (liver) organs of cephaloridine toxicity. Since glucose is not a major fuel of proximal tubular cells, it is unlikely that cephaloridine-induced tubular necrosis is mediated by the effects of this drug on glucose synthesis.

Animals↗
PubMed1988

Age-related nephropathy in laboratory rats.

Chronic progressive nephropathy is a spontaneous disease common among aging laboratory rats, often making it difficult to distinguish age-related from drug-related effects in chronic toxicity studies. Morphological changes of the kidney that occur with age include thickening of glomerular and proximal tubular basement membranes, mesangial proliferation, fusion of foot processes, and, ultimately, glomerular sclerosis. Proteinuria (specifically, albuminuria) is the most striking characteristic change in renal function of aging rats and, generally, correlates well with the severity of age-related glomerular pathology. Changes in tubular functions also may occur with aging but have not been investigated sufficiently. The pathogenesis of chronic progressive nephropathy is not known; however, hemodynamic adaptations after ad libitum consumption of protein-rich diets may be a contributing factor. High-protein diets increase glomerular pressures and flows, perhaps facilitating excretion of metabolic end products. These hemodynamic adaptations may impair the permselective properties of the glomerulus, leading to: enhanced accumulation of macromolecules in the mesangium, progressive mesangial expansion, and, ultimately, glomerular sclerosis. Indeed, decreasing total food or protein intake retards or prevents the progression of age-related nephropathy. Inasmuch as chronic toxicity studies are complicated by a high incidence of spontaneous nephropathy, implementation of a restricted dietary regimen may improve detection of drug-induced toxicity.

Aging↗
PubMed1988

Pulmonary infection with nontuberculous mycobacteria.

Nontuberculous mycobacterial infections (NTM) are being increasingly recognized as a cause of chronic pulmonary disease. We recently reviewed the clinical, radiologic, and bacteriologic presentation of 89 adult patients ill enough to have been hospitalized between 1981 and 1985 with the diagnosis of NTM. Preexisting lung disease was present in 82% and alcohol abuse in 40%. Although M. avium complex was identified in 51% of the patients, M. xenopi, which is usually reported to occur infrequently, accounted for 38% of our cases and M. kansasii for only 9%. Treatment was limited by a high incidence of associated disease, in vitro drug resistance, drug toxicity, and a mortality rate of 32% within 18 months of admission. Nevertheless, bacteriologic conversion occurred in 29% of those treated. M. xenopi appears to be an important pathogen in southern Ontario. It differs from the other NTM by having a different pattern of in vitro drug resistance but not by its clinical or radiologic presentation.

Adult↗
PubMed1988

Constant oxygen insufflation (COI) in a ventilatory failure model.

We examined the use of a constant insufflation of oxygen into the lungs to assist ventilation in a ventilatory failure model. The model consisted of 12 anesthetized dogs (17 to 32 kg) that were partially paralyzed using intermittent low doses of muscle relaxant; this produced a steady-state mean PaCO2 of 90 +/- 15.8 mm Hg (+/- SD). A catheter (1.5 mm ID) was inserted into each lung to the most distal position possible and withdrawn 1 to 2 cm. The effects of a constant insufflation of oxygen at rates of 5, 10, or 20 L/min were studied at this position (mean distance from the carina = 9 +/- 2 cm); at the carina; and using a single catheter located 2 cm above the carina. The changes in PaCO2 and minute ventilation (VE) due to the insufflation were calculated from the mean steady-state control values. Using the data for all catheter positions and flow rates, the insufflation was associated with a mean decrease in PaCO2 of 31 (+/- 7.6) mm Hg associated with a mean decrease in VE of 48 (+/- 12.9)%. The flow of 20 L/min caused a significantly greater drop in PaCO2 than the flow of 5 L/min (p = 0.02). This technique may prove beneficial for patients with various forms of ventilatory failure that are difficult to treat by conventional means.

Acute Disease↗
PubMed1987

Age-related differences in susceptibility to renal ischemia in rats.

These experiments were designed to determine the influence of age on the response of the kidney to ischemia. Renal ischemia was induced in female Fischer-344 rats, 3-4 or 37-38 months old, by renal arterial and venous occlusion followed by 0, 1, 24, or 96 hr of reflow. Age-matched controls were sham operated but were not subjected to ischemia. A transient postischemic increase in blood urea nitrogen (BUN) and serum creatinine was observed in young rats. In old rats, BUN and serum creatinine remained markedly elevated through 96 hr postischemia. In vitro renal cortical slice accumulation of organic ions was inhibited to a greater extent in old rats than in young rats 96 hr postischemia. Histologically, renal tubular damage was more severe in old than in young rats 24 and 96 hr postischemia. Tubular regenerative activity was similar in old and young rats at 96 hr, but restoration of tubular architecture was more complete in young rats. Organic ion accumulation by renal cortical slices from naive old rats was inhibited by in vitro anoxia (treatment with 100% N2) to a greater extent than tissue from young rats. These data suggest that old rats are more susceptible to renal ischemia than are young rats and these differences in susceptibility may reflect intrinsic age-related differences in basal renal metabolism.

Aging↗
PubMed1987

Mechanisms mediating cephaloridine inhibition of renal gluconeogenesis.

Incubation of renal cortical slices with cephaloridine (CPH) markedly inhibits pyruvate-supported gluconeogenesis, an effect which is independent of CPH-induced lipid peroxidation. CPH was found to inhibit pyruvate-supported gluconeogenesis in a time-and concentration-dependent manner. Pyruvate-supported gluconeogenesis was inhibited as early as 10 min following incubation of renal cortical slices with 5 mM CPH. Similarly, endogenous gluconeogenesis was impaired following CPH treatment. CPH depressed the renal cortical slice content of ATP by 50%, but only following 90 and 120 min of drug exposure, suggesting that mitochondrial dysfunction does not mediate the inhibition of gluconeogenesis by CPH. To identify the intracellular site(s) of CPH inhibition of gluconeogenesis, the effects of CPH on glucose production were evaluated using substrates catalyzed by rate-limiting reactions. CPH inhibited renal cortical slice gluconeogenesis when the following substrates were used: pyruvate (mitochondrial), oxaloacetate and fructose-1,6-diphosphate (FDP) (postmitochondrial), and glucose-6-phosphate (G6P, endoplasmic reticulum). Inhibition of G6P-supported gluconeogenesis occurred within 5 min of incubation with 5 mM CPH. Direct addition of CPH to microsomal suspensions inhibited G6Pase activity in a concentration-dependent fashion. By contrast, addition of CPH to cytosolic fractions did not affect FDPase activity. CPH increased the Km and decreased the Vmax of G6Pase, indicating mixed competitive and noncompetitive inhibition. These data indicate that the profound inhibition of renal cortical slice gluconeogenesis by CPH is mediated by inhibition of microsomal G6Pase activity.

Animals↗
PubMed1987

Cisplatin nephrotoxicity: role of filtration and tubular transport of cisplatin in isolated perfused kidneys.

Isolated perfused rat kidneys were used to determine the contribution of filtration and tubular transport of cisplatin to its nephrotoxicity. Perfusion of kidneys with 0.5 mM cisplatin concomitantly reduced tubular reabsorption of electrolytes and glomerular filtration rate in a time-dependent manner. These renal functional changes were similar to those obtained following in vivo cisplatin treatment (10 mg/kg). In vitro exposure to cisplatin reduced the renal clearance of organic ions without reducing renal perfusate flow, suggesting that renal hemodynamic changes do not mediate cisplatin-induced proximal tubular dysfunction. Inhibition of organic ion transport also was observed in non-filtering perfused kidneys treated with 0.5 mM cisplatin, implying that filtration of cisplatin is not a prerequisite for induction of toxicity. These data also suggest that cisplatin transport from a basolateral site may be important in the development of acute nephrotoxicity.

Absorption↗
PubMed1987

Nonsynaptic regulation of sensory activity during movement in cockroaches.

Here we describe a nonsynaptic mechanism for filtering out potentially perturbing sensory feedback during locomotion. During flight, the cockroach moves its cerci, two abdominal sensory appendages, about their joint with the body and holds them in place. The cerci bear highly sensitive wind-receptive hairs, which would be strongly stimulated by flight wind. Such wind could cause habituation of the synaptic connections from these cercal receptors onto interneurons responsible for the running escape response to an approaching predator. We have found that the cercal displacement blocks one-third to one-half of the action potentials along the sensory nerve, possibly aiding in protection against such habituation. This block occurs if one experimentally displaces a cercus, and the block persists in the complete absence of any connections with the central nervous system. The block appears to be nonsynaptic and to result instead from mechanical pressure on the nerve near the joint. The results suggest that activity in peripheral nerves in other animals may also be affected by the position or movement of joints through which the nerves pass.

Action Potentials↗
PubMed1987

Reversal of sleep-induced hypoventilation and chronic respiratory failure by nocturnal negative pressure ventilation in patients with restrictive ventilatory impairment.

The efficacy of negative pressure ventilation (NPV) in alleviating sleep-induced reductions in alveolar ventilation and in producing long-term clinical benefits was studied in 5 patients (54 +/- 8 yr of age; mean +/- SD) with chronic respiratory failure secondary to restrictive ventilatory impairment (VC, 40 +/- 14% predicted; TLC, 72 +/- 18% predicted; FEV1/FVC, 89 +/- 15%). In control sleep studies, arterial O2 saturation decreased from 81 +/- 6% during wakefulness to 79 +/- 1% during non-REM sleep and to 67 +/- 3% during REM sleep, and transcutaneous PCO2 increased from 80 +/- 16 mm Hg during wakefulness and non-REM sleep to 87 +/- 16 mm Hg during REM sleep. Nocturnal NPV in a cuirass ventilator improved baseline ventilation during wakefulness and prevented deterioration of alveolar ventilation during sleep. Upper airway obstruction during sleep induced by NPV was successfully managed with either a tricyclic medication or nasal CPAP. After 8 wk of nocturnal NPV, all patients felt considerably better. Daytime resting arterial PCO2 decreased from 56 +/- 2 to 46 +/- 3 mm Hg (p less than 0.05) and PO2 increased from 51 +/- 9 to 70 +/- 10 mm Hg (NS). Four patients have continued NPV at home on a regular basis and have returned to full-time employment. We conclude that nocturnal NPV is an effective method of preventing sleep-induced reductions in alveolar ventilation and a practical method of long-term management of patients with nonobstructive chronic respiratory failure.

Carbon Dioxide↗
PubMed1987

Assisting ventilation in respiratory failure by negative pressure ventilation and by rocking bed.

The present study was undertaken to evaluate the effectiveness of acute ventilation by rocking bed (RB) and by negative-pressure ventilator (NPV) on arterial oxygenation and carbon dioxide tension in seven patients in whom respiratory failure (PaCO2 [+/- SD], 64 +/- 4 mm Hg; PaO2, 54 +/- 10 mm Hg) was consequent on nonobstructive ventilatory impairment. The increase in SaO2 (percent above baseline, 5 percent RB and 6 percent NPV) was similar for both methods, but a greater fall in PCO2 (percentage change in PCO2, 3 percent RB; 15 percent NPV; p less than 0.05) was observed during NPV. Diaphragmatic and accessory muscle electrical activity was markedly reduced during NPV but remained unchanged or increased on RB. Asynchronous breathing was frequently observed with RB but only rarely with NPV. These preliminary results suggest that effective mechanical ventilatory support could be achieved with either RB or NPV. However, their long-term effects as compared with those of positive-pressure ventilation remain to be explored.

Beds↗
PubMed1986

Effect of pertussis toxin on water metabolism in the rat.

Pertussis toxin administered to rats resulted in a polyuric state that was due to enhanced renal water excretion. Pertussis toxin also induced a defect in renal water conservation. These abnormalities in renal water excretion could not be attributed to polydipsia, impaired synthesis and/or release of arginine vasopressin or renal tubular dysfunction with solute diuresis. No evidence of pertussis toxin-induced renal tubular damage was present. These results indicate that pertussis toxin induces nephrogenic diabetes insipidus and this defect occurs at the level of the renal collecting tubule.

Animals↗
PubMed1986

Biochemical mechanisms of cephaloridine nephrotoxicity: time and concentration dependence of peroxidative injury.

These experiments were designed to elucidate the initiating biochemical events mediating cephaloridine (CPH) nephrotoxicity. Renal cortical slices from naive male Fischer-344 rats were incubated at 37 degrees C in a phosphate- or bicarbonate-buffered medium containing 0, 1, 5, or 10 mM CPH. Slices were incubated for 15, 30, 45, 60, 90, 120, and 180 min and evaluated for accumulation of organic ions [p-aminohippurate (PAH) and tetraethylammonium (TEA)], pyruvate-stimulated gluconeogenesis, malondialdehyde (MDA) production, and reduced glutathione (GSH) content. Renal cortical slice accumulation of PAH and TEA was decreased by 5 and 10 mM CPH as early as 120 and 90 min of incubation, respectively. CPH-induced MDA production by renal cortical slices preceded the effects of CPH on organic ion accumulation. Coincubation of CPH with the antioxidants promethazine and N,N'-diphenyl-p-phenylenediamine inhibited CPH-induced lipid peroxidation and changes in organic ion accumulation. In contrast, 5 or 10 mM CPH inhibited gluconeogenic capacity at all time points examined, an effect which was not influenced by antioxidant treatment. Depletion of renal cortical GSH by 5 or 10 mM CPH was evident following 30 min of incubation and was also unaffected by antioxidant treatment. These results support the hypothesis that lipid peroxidation mediates the effects of CPH on renal organic ion transport. The early and profound inhibition of gluconeogenesis by CPH suggests that the biochemical pathways of gluconeogenesis are either proximal to or represent a primary target for CPH nephrotoxicity.

Animals↗
PubMed1986

Cephaloridine nephrotoxicity in aging male Fischer-344 rats.

Age-related differences in susceptibility to cephaloridine nephrotoxicity were evaluated in male Fischer-344 rats. Rats, 2.5, 4, 10-12 and 27-29 months old, were administered a single intraperitoneal dose of cephaloridine and renal function evaluated 24 h later. Susceptibility to cephaloridine-induced nephrotoxicity was age-related. Older rats (10-12 and 27-29 months) were the most susceptible to cephaloridine nephrotoxicity as indicated by a dose-related increase in relative kidney weight, elevation in blood urea nitrogen concentrations and a diminished capacity of renal cortical slices to accumulate the organic anion, p-aminohippurate (PAH) and the organic cation, tetraethylammonium (TEA). Impaired renal function following cephaloridine treatment was not detected in 2.5-month-old, apparent to a slight extent in 4-month-old, and most pronounced in 10-12- and 27-29-month-old rats. Serum and renal cortical concentrations of cephaloridine tended to be greater in older rats compared to that of young adults. Thus, the enhanced susceptibility of older rats to cephaloridine nephrotoxicity may be related in part to the increased renal cortical accumulation of cephaloridine.

Age Factors↗
PubMed1986

Daily maintenance dose of a long-acting theophylline from a single theophylline serum level.

A single point method has recently been described whereby the daily maintenance dose of theophylline required to achieve a desired steady state serum concentration can be established from a nomogram with the aid of a single blood sample drawn after a test dose. This approach has been validated for intravenous administration and for a rapidly absorbed elixir (coefficient of absorption ka 2.3 h-1) given to children. In order to study whether this method could be applied to a slowly absorbed preparation (ka 0.44 h-1), we gave theophylline (Theo-Dur) to nine adults as a single dose and for one week. In applying a nomogram, we found that a sample taken nine hours after a test dose would more accurately predict the daily dose required to achieve a desired steady state concentration than a sample taken at six hours as has previously been recommended (error nine hours -16.8 percent to +29 percent, six hours -59.7 percent to +29.4 percent).

Aged↗
PubMed1985

Relationship between red blood cell uptake and methemoglobin production by nitrobenzene and dinitrobenzene in vitro.

Nitrobenzene increases methemoglobin formation when incubated with native hemoglobin but not when incubated with red blood cell suspensions. These experiments were designed to determine if transport of nitrobenzene across the red blood cell membrane is a limiting factor for methemoglobin production by red blood cell suspensions. Incubation of [14C]-m-, o- or p-dinitrobenzene, but not mononitrobenzene, with red blood cell suspensions caused a time-dependent increase in methemoglobin. All three dinitrobenzenes and mononitrobenzene crossed the red blood cell membrane and accumulated in the erythrocytes after only 1 min of incubation. Incubation of mononitrobenzene with hemolysates did not result in methemoglobin production. Incubation of red blood cells with the dinitrobenzenes or mononitrobenzene for 1 and 10 min at 4 degrees C did not influence red blood cell uptake of the nitrobenzenes, suggesting that these compounds do not enter the red blood cell by an active process. Dinitrobenzene-induced methemoglobin production was markedly inhibited at 4 degrees C, and may be a result of decreased interaction with hemoglobin and/or decreased metabolism to reactive intermediates which mediate methemoglobin production. These data indicate that red blood cell transport of nitrobenzene is not the limiting factor in methemoglobin production in vitro.

Animals↗