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Biomedical subjects

R C Brown

Publications and source records attributed to R C Brown.

At least 145 records · Page 8Linked to original sources
PubMed1987

The role of catalytic iron in asbestos induced lipid peroxidation and DNA-strand breakage in C3H10T1/2 cells.

The involvement of catalytic iron in the vitro activities of crocidolite asbestos has been investigated. Exposure of C3H10T1/2 cells to either the UICC crocidolite standard reference sample or a non fibrous (milled) derivative resulted in an increase of thiobarbituric acid reactive substances. This catalytic activity was inhibited by pretreatment with the iron chelator desferrioxamine. The effect of this activity on cellular DNA was measured in an assay based on the production of DNA-strand breaks. Increased levels of DNA-strand breaks were detected in cultures treated with both the milled and UICC crocidolite. Inclusion of desferrioxamine with the asbestos inhibited DNA-strand breakage. It is concluded the catalytic iron present on the dust is capable of damaging both lipid and DNA and that this could be an important mechanism in asbestos pathogenicity.

Asbestos↗
PubMed1987

Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay.

A direct immunoassay for circulating intact human PTH (hPTH) is described. The method relies on the formation of an immune complex of labeled antiamino-terminal PTH antibody, intact hPTH, and solid phase antimidregion PTH antibody. A chemiluminescent aryl acridinium ester is used as label. Serum samples (100 microL) are incubated with labeled antibody, and subsequently the bound fraction is separated by the addition of solid phase antibody. The bound luminescence is quantitated in an automatic luminometer. Luminescence intensity is directly proportional to the amount of intact PTH present in the sample. Only intact PTH was found to react in this system; there was no significant interference from PTH fragments. The assay detection limit of 0.8 pmol/L hPTH-(1-84) allowed detection of intact PTH in the serum of all normal subjects tested. A clear distinction was found between hypercalcemic individuals subsequently proven to have primary hyperparathyroidism and those with malignancies. The assay offers several advantages over previously described PTH immunoassays with regard to specificity, rapidity, and reagent stability. It, thus, provides a valuable means of investigating parathyroid physiology and clinical disorders of extracellular calcium metabolism.

Adult↗
PubMed1987

Effect of aluminum on the hepatic mixed function oxidase and drug metabolism.

The effect of aluminum injection on the hepatic mixed function oxidase was examined in male Wistar rats. A cannula was surgically implanted in both the control and aluminum treated animals to provide a common port for aluminum injection. In addition, the control animals were pair-fed to the aluminum treated animals. The treated animals accumulated aluminum at about 0.1 mg/gm dry weight of liver/day. At 14 days, the cytochrome P-450 was decreased 20%, but the other components, cytochrome b5 and cytochrome reductases, were unchanged. By day 21 both cytochrome P-450 and cytochrome b5 were reduced 25%. Although NADPH cytochrome c reductase was not affected, the other flavoprotein, NADH cytochrome c reductase, was reduced. Drug metabolism, O-demethylation of p-nitroanisole and p-hydroxylation of aniline, was not affected at 14 days. However, at 21 days O-demethylation was not affected, but aniline hydroxylation was decreased, indicating an affect of aluminum on a specific isoenzyme of cytochrome P-450. Uniquely, the nonactivated glucuronyl transferase activity was fourfold greater in the aluminum treated animals. The increase was greater than cation activation and was similar to the detergent activated activity. Thus, aluminum infusion does produce specific alterations in microsomal function, including drug metabolism and conjugation.

Aluminum↗
PubMed1987

Raised serum calcium in tuberculosis patients in Africa.

Reports of raised serum calcium in the presence of tuberculosis have tended to be from centres where sunlight is plentiful. U.K.-based data have suggested that normocalcaemia prevails. In a prospective study of 15 African patients with pulmonary tuberculosis, resident in East Africa, corrected serum calcium was significantly lower in a control healthy group (2.59 mmol/l +/- 0.08 and 2.49 +/- 0.06 mmol/l respectively: P less than 0.001). Serum 25-hydroxy vitamin D was significantly lower in the patient group (median, 15.9 ng/ml, range 6.7-35.7) compared with the control group (median 26.2 ng/ml, range 10.5-45.9, P less than 0.05). No significant difference was found between patients and controls for 1,25-dihydroxy vitamin D or parathyroid hormone. No correlation was found between serum calcium and 1,25 (OH)2 D3. Serum albumin showed a negative correlation with radiographic extent of disease and with extent of cavitation. Where sunlight is plentiful, relatively high serum 25-hydroxy Vitamin D may give rise to raised serum calcium in the presence of tuberculosis.

Adult↗
PubMed1987

Studies in patients with hyperparathyroidism using a new two-site immunochemiluminometric assay for circulating intact (1-84) parathyroid hormone.

A recently developed chemiluminescent immunoassay for 1-84 intact parathyroid hormone (PTH) demonstrated increased specificity by virtue of two-site antibody binding and increased sensitivity by use of a chemiluminescent technique. Basal PTH levels were measured in three groups of subjects: (1) normal (n = 82), (2) hyperparathyroidism (n = 31), and (3) patients with hypercalcemia of malignancy (n = 16). There was good discrimination between normal (1.2 to 9.4 pmol/L) and hyperparathyroid subjects (9.2 to 53.4 pmol/L). In persons with hypercalcemia of malignancy all PTH levels were within the normal range (0.8 to 5.2 pmol/L) or suppressed. PTH release was stimulated by the intramuscular injection of 100 IU salmon calcitonin in 6 normal controls, 10 patients with primary hyperparathyroidism due to adenoma, and 5 with four-gland hyperplasia. There was no significant rise in PTH concentration and out of the normal range in the control subjects, but the adenoma patients demonstrated a mean rise of 24.4%, 26%, and 33%, and hyperplasia patients, a mean rise of 37%, 47%, and 37% over basal levels at 120, 180, and 240 minutes. The mean absolute rise in PTH concentration was 13.4 +/- 7.7 pmol/gm of parathyroid tissue in the adenomas and 27.2 +/- 9.5 pmol/gm of parathyroid tissue in the hyperplastic glands; this difference was significant (p less than 0.05). Serial blood samples from a central vein were taken at surgery for hyperparathyroidism, and the rate of decay of the intact hormone was studied in 9 patients after removal of the parathyroid tissue. This decay was rapid with a half-life of 300 seconds. We conclude that this new specific and sensitive intact PTH assay will provide a valuable means of investigating dynamic aspects of parathyroid physiology.

Adult↗
PubMed1986

Familial hypocalciuric hypercalcaemia as a differential diagnosis of hyperparathyroidism: studies in a large kindred and a review of surgical experience in the condition.

We have studied 46 members of a large kindred with familial hypocalciuric hypercalcaemia (FHH) after a neck exploration failed to cure hypercalcaemia in an asymptomatic patient. Serum calcium, serum phosphate, plasma parathormone and vitamin D metabolites do not distinguish affected members from patients with hyperparathyroidism. Because of the continuing debate as to whether or not FHH is a variant of, or distinct from, hyperparathyroidism, we have carried out a review of surgical experience with subtotal parathyroidectomy in hyperparathyroidism secondary to parathyroid hyperplasia and in FHH. Whereas the procedure is successful in 90 per cent of the former cases only one case of FHH has been cured by it. This provides evidence for the two conditions being aetiologically distinct. Before patients with asymptomatic hypercalcaemia are referred for parathyroid surgery the calcium:creatinine clearance ratio should be measured using a 2 h urine sample collected after an overnight fast and a fasting blood sample. If this ratio is less than 0.01 then screening of first degree relations should be undertaken before any parathyroid surgery is performed. Unnecessary surgery can therefore be avoided.

Adult↗
PubMed1986

Response of perifused alveolar macrophages to glass fibers: effect of exposure duration and fiber length.

The effect of glass fibers on rat alveolar macrophages was studied with a new perifusion technique which allows the sequential determination of cell-derived inflammatory mediators as well as estimation of cell viability and aggregation at the end of the incubation period. Our results showed that glass fibers induced dose-dependent release of prostaglandins and beta-glucuronidase from macrophages and the aggregation and death of these cells. These deleterious effects were clearly related to the length of the fibers, with the longer fibers (greater than or equal to 4-5 micron) being more active than the shorter ones (less than 3 micron). Furthermore, a short exposure of 1 hr followed by an 18-hr perifusion induced the same inflammatory and toxic effects on the macrophages as did leaving the fibers undisturbed for the complete 18-hr perifusion. It is concluded that glass fibers produce effects in cultures of rat alveolar macrophages qualitatively similar to those of asbestos, and that fiber length appears to be a critical determinant of toxicity.

Animals↗
PubMed1986

Inhibitin: a specific inhibitor of sodium/sodium exchange in erythrocytes.

An inhibitor of ouabain-insensitive sodium/sodium exchange in erythrocytes has been isolated from leukemic promyelocytes. To explore the specific effects of this inhibitor, named inhibitin, sodium transport experiments were carried out in human erythrocytes. Inhibitin reduced ouabain-insensitive bidirectional sodium transport. It did not change net sodium fluxes, had no significant effect on rubidium influx, and did not inhibit sodium-potassium-ATPase activity. The inhibitory effect of inhibitin was studied on sodium/sodium exchange and on sodium/lithium countertransport in 140 mM sodium and in sodium-free media. In the presence of sodium, inhibitin reduced sodium and lithium efflux to that observed in sodium-free medium. Inhibitin showed no reduction in sodium or lithium efflux when sodium was replaced by choline chloride or Mg2+. When inhibitin was combined with one or more of the other transport inhibitors (i.e., ouabain, furosemide, or bumetanide and amiloride), its inhibitable component remained distinct and it did not overlap with that of the other inhibitors. These studies show that inhibitin is a specific inhibitor of carrier-mediated sodium/sodium exchange and sodium/lithium countertransport processes in human erythrocytes.

Cell Line↗
PubMed1986

Abnormal vitamin D metabolism, intestinal calcium transport, and bone calcium status in the spontaneously hypertensive rat compared with its genetic control.

Abnormalities of intestinal calcium absorption and the vitamin D axis in the spontaneously hypertensive rat (SHR) are controversial. The present report documents a reduction in circulating 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in the 12-14-wk-old male SHR with evidence of its functional significance. Both plasma 1,25(OH)2D3 and mucosa-to-serosa duodenal calcium flux (Jm-s), measured by the Ussing chamber, were significantly lower (approximately 60% of value in Wistar-Kyoto rats [WKY]) in SHR on both normal (1%) and low (0.1%) calcium diets than in corresponding control WKY. Low dietary calcium increased both 1,25(OH)2D3 and Jm-s by approximately 80% in SHR and WKY, with levels of both parameters rising in the SHR to levels found in the WKY under baseline conditions. The latter fact suggests the improbability of intestinal resistance to the action of 1,25(OH)2D3 in the SHR. Plasma 25-hydroxyvitamin D3 (25(OH)D3) was not significantly different between the strains. Intraperitoneal 1,25(OH)2D3 increased Jm-s in 12-14-wk-old SHR to levels observed in equivalent WKY. In 20-24-wk-old SHR, calcium deprivation was associated with significantly reduced Jm-s compared with equivalent WKY. Bone density and bone calcium content in 20-30-wk-old SHR were significantly reduced. In summary, we provide evidence that the SHR was unable to sustain appropriate circulating levels of 1,25(OH)2D3, an impairment which resulted in reduced duodenal calcium absorption.

Animals↗
PubMed1986

In vitro release of arachidonic acid and in vivo responses to respirable fractions of cotton dust.

It was considered that the fall in lung function seen after exposure to cotton dust may be attributable in part to the activity of arachidonic acid metabolites, such as leucotrienes as well as to the more established release of histamine by cotton dust. However, we found that cotton and barley dusts elicited poor release of arachidonic acid from an established macrophage like cell line compared with that observed with other organic dusts. In the experimental animal, pulmonary cellular responses to both cotton and barley dust were similar to those evoked by moldy hay and pigeon dropping dusts, although after multiple doses a more severe response was seen to cotton and barley. Since both moldy hay and pigeon droppings elicit a greater arachidonic acid release than cotton or barley, a role for arachidonic acid in inducing the cellular response is less likely than other factors. There are limitations to our conclusions using this system, i.e., the arachidonic acid may be released in a nonmetabolized form, although it is noted that the two dusts with the greatest arachidonic acid release produce their clinical responses in humans largely by hypersensitivity mechanisms.

Animals↗
PubMed1986

The in vitro activities of a highly carcinogenic mineral fibre--potassium octatitanate.

The in vitro activities of a highly carcinogenic potassium octatitanate fibre (Fybex) have been investigated. This material caused a low level of in vitro transformation in C3H10T1/2 cells and is thus more active in this assay than the UICC amphibole asbestos samples but less active than fibrous erionite. This ranking is in accord with carcinogenicity in vivo. However Fybex had no detectable activity in an assay for DNA damage based on the S1-nuclease sensitivity of the DNA from exposed cells. In that assay crocidolite asbestos was more active than either of the more carcinogenic dusts. It is suggested that the activities of amphibole asbestos in assays for genetic toxicity may depend on the production of free radicals via a catalytic reaction requiring the presence of transition elements which are either not present or only present at low concentrations in erionite or Fybex. This type of reaction may not be related to in vivo carcinogenicity. The action of fibrous dusts against macrophage-like cells, measured in this instance by the release of arachidonic acid, remains one of the best measures of biological activity.

Aluminum Silicates↗
PubMed1986

Acute responses of parathyroid hormone and 1,25 dihydroxyvitamin D3 to unilateral nephrectomy in healthy donors.

Plasma immunoreactive parathyroid hormone (iPTH), 1,25(OH)2D3, calcium and phosphate and urinary creatinine, calcium and phosphate were measured before and following unilateral nephrectomy in six kidney donors. Unexpectedly, plasma calcium rose, from 2.27 +/- 0.02 mmol/l (mean +/- SEM) to 2.41 +/- 0.03 mmol/l on day 7 and to 2.37 +/- 0.02 mmol/l on day 30 (P less than 0.02). A parallel rise in iPTH occurred, from 0.61 +/- 0.16 ng/ml initially, to 1.83 +/- 0.54 ng/ml on day 7 (P less than 0.05) and to 1.18 +/- 0.18 on day 30 (P less than 0.01). The ratio of maximal tubular reabsorption of phosphate to GFR (TmP/GFR) fell by day 2 (P less than 0.01), remaining reduced on day 30 (P less than 0.05). The significance of elevated iPTH in renal insufficiency was further assessed by determining the time course of the disappearance of iPTH after parathyroidectomy in three haemodialysis subjects. Fifty per cent baseline iPTH level occurred after an average of 104.7 min, suggesting that the assay did not predominantly recognize C-terminal PTH fragments. By day 2, plasma 1,25(OH)2D3 had fallen from 34.3 +/- 4.5 pg/ml to 22.8 +/- 3.8 pg/ml (P less than 0.001), but by day 4 had regained its pre-nephrectomy value. Our results suggest that hypocalcaemia may not be the sole stimulus to parathyroid hormone secretion. It is speculated that reduction in circulating 1,25(OH)2D3 may be involved.

Adult↗
PubMed1986

Release of a sodium transport inhibitor (inhibitin) from cultured human cancer cells.

In this study we investigated whether the sodium transport inhibitor, inhibitin, originally isolated from leukemic promyelocytes, was also elaborated by some other neoplastic cells in culture. Like culture medium from the leukemic promyelocytes (HL60), the media from two other leukemic cell lines (erythroblasts K562 and monoblasts U937) also showed significant inhibitory activity on ouabain-insensitive sodium efflux rate constant in normal erythrocytes. Similarly, culture media from three neoplastic cell lines (H.Ep2, MRC5, and HX99) also showed significant inhibitin-like inhibitory activity. Using high-performance liquid chromatography to isolate inhibitin, culture media from HL60 and H.Ep2 cells were identically treated, and inhibitin isolated from H.Ep2 cells had the same retention time as that shown by promyelocyte inhibitin. H.Ep2 inhibitin reduced ouabain- and bumetanide-insensitive sodium efflux rate constant from 0.1510 +/- 0.0275 (SD) to 0.0988 +/- 0.0110 (P less than 0.005). Like promyelocyte inhibitin, H.Ep2 inhibitin reduced sodium efflux and influx by equivalent amounts suggesting thereby that it is a sodium/sodium exchange inhibitor. These studies show that a factor exhibiting inhibitory activity on sodium/sodium exchange is secreted by a variety of leukemic and neoplastic cells in culture.

Biological Transport, Active↗
PubMed1986

Nutritional parameters that alter hepatic drug metabolism, conjugation, and toxicity.

A major concern of contemporary medicine is the adverse effects resulting from the use of prescribed and over-the-counter pharmacologic agents. In many cases more than one drug is taken at the same time, which increases the risk of overloading the detoxification mechanisms. If the individual has poor nutritional status, the system becomes even more inefficient. The liver contains the most important of these detoxification systems: the cytochrome P-450-dependent mixed function oxidase (MFO) and several conjugation enzymes, e.g., sulfotransferase, glucuronyl transferase, and glutathione transferase, which convert lipophilic compounds to more water-soluble products to enhance their excretion. The balance of these reactions determines the rate of metabolism and clearance of xenobiotic agents, and regulates in part the degree of intracellular damage. Nutritional factors, including proteins, carbohydrates, fats, vitamins, and minerals, affect the efficiency of these reactions. Changes in intracellular metabolism can alter not only the enzyme levels but also the availability of their cofactors, e.g., NADPH, UDPGA (uridine diphosphate glucuronic acid), PAPS (3'-phosphoadenosine-5'-phosphosulfate), and GSH. Diets restricted in calories, protein, or essential fatty acids, as well as those having low quality protein or high sugar content, can affect the component enzymes, cytochrome P-450 and the cytochrome P-450 reductase, and the MFO activity toward a variety of drugs. In addition, deficiencies of specific vitamins (riboflavin, ascorbic acid, and vitamins A and E) and minerals (iron, copper, zinc, and magnesium) affect the components and activities of the system in unique ways. Insight into the regulation of the hepatic detoxification mechanism can be gained by using nutrient variables to perturb the system.

Animals↗
PubMed1986

1,25-dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: effects of simultaneous protein and phosphorus restriction.

Vitamin D3 metabolites and immunoreactive parathyroid hormone (iPTH) were measured in sera obtained from subjects with advanced chronic renal failure (CRF) (creatinine clearance less than 10 ml/min) before and after 3 months on a diet very low in protein (less than 0.2 g/kg/day), phosphorus (less than 500 mg/day), and supplemented with a mixture of essential amino acids and ketoacid analogues of essential amino acids. iPTH and phosphate fell in all subjects (p less than 0.02). 1,25-dihydroxycholecalciferol (1,25[OH]2D3) fell in all but one of the subjects (p less than 0.02), while no significant change was seen in creatinine clearance or in serum 25-hydroxycholecalciferol (25[OH]D3) levels. A strongly positive correlation was found between initial serum levels of 25(OH)D3 and 1,25(OH)2D3 (r = 0.95, p less than 0.001). Thus in contrast with the reported effects of dietary phosphorus reduction in subjects with early and moderate CRF and in normal subjects, this regime was associated with decreased 1,25(OH)2D3 levels in subjects with advanced CRF.

Calcitriol↗