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Biomedical subjects

D A Goldstein

Publications and source records attributed to D A Goldstein.

At least 55 records · Page 3Linked to original sources
PubMed1984

On the redox conformational change in cytochrome c.

The relationship between the crystal structures of oxidized and reduced tuna cytochrome c has been reexamined by a superposition method motivated by recent studies of the cytochrome c-cytochrome c peroxidase complex. It is shown that the observed structural changes precisely reflect the binding face suggested by chemical modification studies. It is further suggested that the large observed motion of lysine-27 and a smaller overall motion of the two binding edges constitute a redox binding-affinity switch and that the driving force for the conformational change of the protein is provided by the internal conformational change and charge redistribution of the heme, which cause it to tilt, under the influence of covalent and nonbonded interactions, within its protein envelope. A picture is presented of the molecule as an electron storage/transfer machine with three elements--a binding module, an electron storage module, and a conformational energy-storage module.

Animals↗
PubMed1984

Production and partial purification of rat fibroblast-derived interferon induced in a newly established cell line.

Interferon (IFN) production induced by either Newcastle disease virus (NDV) or Sendai virus was compared in 10 different rat cell lines. Although there was variation in the IFN titers produced, NDV proved to be the best inducer in each cell line with optimum IFN yields occurring with a multiplicity of infection (MOI) of 1.0. A new continuous rat fibroblast cell line (CD) produced high titers of IFN similar to those reported for other high producers; while Ratec cells were shown to be the most sensitive to the antiviral activity of rat IFN. Partial purification and characterization of IFN produced in CD cells was accomplished by column chromatography. Four sorbents with varying modes of action for binding the IFN (Affi-Gel 202, Poly(U)-Sepharose 4B, CM-Sepharose CL-6B, and Phenyl-Sepharose CL-4B) were compared. The Phenyl-Sepharose CL-4B matrix proved to be the most successful for purification of rat IFN; one passage through this column, increased the specific activity more than 100-fold, with a concomitant recovery of 90%-95% biologic activity. The binding characteristics of rat IFN on each of the column matrices, however, demonstrated differences between the physicochemical nature of CD rat IFN and murine and hamster IFNs.

Animals↗
PubMed1984

Role of uremia, brain calcium, and parathyroid hormone on changes in electroencephalogram in chronic renal failure.

Acute uremia is associated with increased calcium (Ca) in brain and changes in electroencephalogram (EEG), and both derangements are related to excess parathyroid hormone (PTH). Also changes in EEG in patients with chronic renal failure (CRF) correlated directly with blood levels of PTH, and fall in PTH was followed by improvement in EEG. We examined whether chronic uremia per se has an effect on brain calcium or EEG. Uremia was produced by 5/6 nephrectomy and maintained for 32-70 wk in seven thyroparathyroidectomized (TPTX) and seven control dogs. There were no differences in creatinine clearance and serum electrolytes except for HCO3, which was lower in control animals (P less than 0.01). Serum PTH was undetectable in TPTX dogs but was significantly elevated in control animals (32.3 +/- 3.3 mu leq /ml). Calcium in gray and white matter was significantly increased in both groups but much higher in control animals. The percent waves of less than 7 Hz in EEG were similar in both groups prior to uremia (TPTX 4.6 +/- 0.8 vs. control 4.2 +/- 0.5%) but remained unchanged in TPTX animals and increased significantly in control dogs (19.0 +/- 1.3%) after uremia. These data suggest that CRF per se is associated with marked rise in Ca in both gray and white matter and increment is higher in the presence of PTH. Disturbance in EEG in a state of CRF requires the presence of excess PTH and is prevented despite increased Ca in brain if hyperparathyroidism is not allowed to develop.

Animals↗
PubMed1984

Disturbances in the hypothalamic-pituitary-gonadal axis in male patients with acute renal failure.

The function of the hypothalamic-pituitary-gonadal (HPG) axis was examined in 20 male patients with acute renal failure. During the oliguric phase of the disease, the serum concentrations of follicle stimulating hormone (FSH) and total and unbound testosterone were markedly reduced, those of prolactin were elevated while those of luteinizing hormone (LH) were normal. The serum concentrations of sex hormone binding globulin were normal. During the diuretic phase of the illness, the serum levels of FSH and testosterone remained low but those of prolactin fell towards normal. After recovery of renal function, the abnormalities in the serum concentrations of these hormones were reversed. The responses of LH and FSH to gonadotropin releasing hormone and of prolactin to thyrotropin releasing hormone were abnormal and became normal after recovery of renal function. The results demonstrate that: (1) abnormalities in HPG axis occur early in the course of acute renal failure; (2) many features of these derangements are similar to those seen in chronic renal failure, and (3) the alterations in the function of the HPG axis are reversible when renal function is restored. The data suggest that loss of renal function, uremia per se and/or a metabolic consequence of uremia such as secondary hyperparathyroidism are responsible for these derangements.

Acute Kidney Injury↗
PubMed1984

Intact and carboxyterminal PTH do not cross the blood-cerebrospinal fluid barrier.

In order to examine whether parathyroid hormone (PTH) enters the cerebrospinal fluid (CSF), the blood levels of the hormone were acutely elevated either by infusion of parathyroid extract or by stimulation of the parathyroid glands by hypocalcemia. Despite marked elevations in the blood levels of the hormone, PTH could not be detected in the CSF. The data indicate the intact PTH or its carboxyterminal fragment do not cross the blood-CSF interface of the blood-brain barrier. The results, therefore, suggest that the action of PTH on brain must be mediated by an effect on the blood-brain interface of the blood-brain barrier.

Animals↗
PubMed1982

Autonomic nervous system dysfunction and impotence in uremia.

The relationship between abnormalities in nocturnal penile tumescence (NPT) and autonomic function, measured by the Valsalva maneuver, was evaluated in 25 uremic patients and 22 normal subjects. NPT in uremic patients (45 +/- 6.8 min/night) was lower (p less than 0.01) than in normals (85 +/- 10.4 min/night). Valsalva ratio in uremics (1.58 +/- 0.07) was also lower (p less than 0.01) than in normal subjects (2.05 +/- 0.11). NPT and Valsalva ratio were significantly correlated in uremic patients (r = 0.62, p less than 0.01). The 12 uremic patients with abnormal Valsalva maneuver had NPT of 22 +/- 5.2 min/night, a value lower (p less than 0.01) than that (67 +/- 8.7 min/night) observed in the 13 uremic patients with normal Valsalva maneuver. There was also a significant correlation (r = 0.56, p less than 0.05) between the Valsalva ratio and the frequency of intercourse per month in the uremic patients, who had steady and active sexual partners. The data suggest that a dysfunction of the autonomic nervous system may be an important factor in the genesis of erectile abnormalities in patients with uremia.

Adult↗
PubMed1981

The effects of terbutaline on acid base, serum electrolytes, and glucose homeostasis during the management of preterm labor.

Terbutaline (T) is a beta-adrenergic compound which is commonly employed as a tocolytic agent in preterm labor. We evaluated the metabolic and biophysical consequences of infusion of T into six pregnant women in preterm labor. Our results showed that the infusion of T led to the development of hyperglycemia, hyperinsulinemia, hyperlactacidemia, hypokalemia, a fall in serum colloid osmotic pressure and pH, a rise in maternal heart rate, and a fall in maternal blood pressure. These changes in electrolytes in the serum occurred in the absence of any significant alterations in their urinary excretion. These data suggest that the infusion of T causes hyperglycemia that results in a rise in serum insulin and lactate, which, in turn, leads to a fall in serum potassium, ionized calcium, and pH. Volume expansion as manifested by a fall in colloid osmotic pressure may contribute to the reduction in the levels of ionized and total calcium. Thus, careful monitoring of electrolytes and hydration status is warranted when beta-mimetic agents are used, specifically T, for tocolytic therapy.

Acid-Base Equilibrium↗
PubMed1981

Predisposition to phenytoin hepatotoxicity assessed in vitro.

Arene oxide metabolites of phenytoin may be involved in the pathogenesis of drug-induced hepatotoxicity. We examined individual susceptibility to toxicity from such metabolites by exposing human lymphocytes to metabolites generated by a murine hepatic microsomal system. Cells from 17 controls showed no toxicity at concentrations of phenytoin from 31 to 125 microM. Cells from three patients with phenytoin hepatotoxicity manifested dose-dependent toxicity from the metabolites. Phenytoin alone was not toxic to cells. The patients' dose-response curves resembled the response of control cells in which epoxide hydrolase (a detoxification enzyme for arene oxides) was inhibited. Detoxification of non-arene oxide metabolites (e.g., of acetaminophen) was normal in patients' cells. Cells from parents of two patients had intermediate responses. Cells from a sibling of one patient showed no toxicity; a sibling of another patient had a response similar to that of the patient. A heritable defect in response to arene oxides thus may predispose some patients to phenytoin hepatotoxicity.

Adult↗
PubMed1981

Sexual dysfunction in the male patient with uremia: a reappraisal.

Partial or complete impotence is common in uremia. It is not clear whether the impotence is organic or psychogenic in nature and whether uremia itself or the state of chronic illness is responsible for it. We examined these questions, by psychiatric interviews and nocturnal penile tumescence (NPT), in 50 normal subjects, 48 patients with chronic uremia, including 23 patients treated with maintenance dialysis, and 22 patients with chronic illness and normal renal function. About 40 to 50% of patients with uremia, but not those with chronic illness and normal renal function, complained of erectile dysfunction and reported a significant decrease in frequency of intercourse. There were no significant differences between patients with uremia prior to initiation of therapy and those treated with maintenance hemodialysis. NPT declines after 40 years of age. In all age groups, NPT was significantly (P less than 0.01) lower in uremics than in normals or those with chronic illness. There was no correlation between erectile complaints, frequency of intercourse or NPT, and the presence or absence of depression. The frequency of intercourse correlated significantly (r = 0.68, P less than 0.01) with NPT in patients with uremia. Data indicate that 50% of male patients with uremia have partial or complete impotence, which is most probably organic in nature and is related to uremia or its metabolic or hormonal consequences rather than to the state of chronic illness.

Adolescent↗
PubMed1981

The duodenal mucosa in patients with renal failure: response to 1,25(OH)2D3.

The structure of the duodenal mucosa was evaluated in duodenal biopsy samples obtained from patients with moderate renal failure (MRF) and in dialysis patients (HD) in an effort to examine the possibility that changes in duodenal mucosa may contribute to the impaired calcium absorption in renal failure (RF). The effect of therapy with 1,25(OH)2D3 on the duodenal mucosa in the HD patients was also studied. The results show that both MRF and HD patients have reduction in calcium reabsorption and in the length of their intestinal villi and crypts of Lieberkuhn. In the HD patients, these structural changes were more severe. Treatment with 1,25(OH)2D3 produced significant improvement in calcium reabsorption (P less than 0.01) as well as in length of villus and crypt (P less than 0.02) and increased mitotic activity in the crypts (P 0.02). Electron microscopy revealed the microvilli to be shorter, irregularly distributed, moth-eaten, and grainy, with these abnormalities disappearing after treatment. The data show that duodenal mucosa in RF exhibits structural abnormalities, which were normalized after 1,25(OH)2D3 therapy, and suggest that these derangements may play a role in the defective calcium reabsorption in RF.

Adult↗
PubMed1981

Modification of sodium and potassium channel gating kinetics by ether and halothane.

The effect of ether and halothane on the kinetics of sodium and potassium currents were investigated in the crayfish giant axon. Both general anesthetics produced a reversible, dose-dependent speeding up of sodium current inactivation at all membrane potentials, with no change in the phase of the currents. Double-pulse inactivation experiments with ether also showed faster inactivation, but the rate of recovery from inactivation at negative potentials was not affected. Ether shifted the midpoint of the steady-state fast inactivation curve in the hyperpolarizing direction and made the curve steeper. The activation of potassium currents was faster with ether present, with no change in the voltage dependence of steady-state potassium currents. Ether and halothane are known to perturb the structure of lipid bilayer membranes; the alterations in sodium and potassium channel gating kinetics are consistent with the hypothesis that the rates of the gating processes of the channels can be affected by the state of the lipids surrounding the channels, but a direct effect of ether and halothane on the protein part of the channels cannot be ruled out. Ether did not affect the capacitance of the axon membrane.

Action Potentials↗
PubMed1981

Vitamin D metabolites and calcium metabolism in patients with nephrotic syndrome and normal renal function.

Patients with nephrotic syndrome (NS) lose 25-hydroxyvitamin D3 (25OHD3) in the urine and have low blood levels of this metabolite. This abnormality may be responsible for the hypocalcemia, i.e. low ionized calcium. The mechanism of the hypocalcemia is not evident. It is possible that the low value of 25OHD results in low blood levels of other vitamin D metabolites, such as 1,25-dihydroxyvitamin D [1,25-(OH)2D] and 24,25-(OH)2D3; a deficiency of these compounds may cause defective intestinal absorption of calcium (alpha) and resistance to the calcemic action of parathyroid hormone (PTH), resulting in hypocalcemia. Studies were performed in 12 patients with NS and normal renal function to evaluate these questions. Blood levels of 25OHD, 1,25-(OH)2D, and 24,25-(OH)2D were all significantly (P < 0.01) lower in NS (4.0 +/- 0.8 ng/ml, 7.0 +/- 2.3 pg/ml, 1.8 +/- 0.2 ng/ml, respectively) compared to normal subjects (37.0 +/- 1.5 ng/ml, 37.0 +/- 1.2 pg/ml, and 3.4 +/- 0.2 ng/ml). Both alpha (0.21 +/- 0.2 vs. 0.27 +/- 0.1; P < 0.05) and the calcemic response to PTH (0.50 +/- 0.1 vs. 1.35 +/- 0.16 mg/dl; P < 0.01) in NS subjects were significantly lower than normal. The data indicate that 1) a deficient state of all of these vitamin D metabolites exists in patients with NS and normal renal function, 2) this abnormality underlies the defect in alpha and the resistance to the calcemic response to PTH, and all participate in the genesis of the hypocalcemia, 3) secondary hyperparathyroidism develops, and 4) both vitamin D deficiency and elevated blood levels of PTH are responsible for the bone lesions in these patients.

24,25-Dihydroxyvitamin D 3↗