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Biomedical subjects

J H Lin

Publications and source records attributed to J H Lin.

At least 307 records · Page 17Linked to original sources

Presence of heme oxygenase and NADPH cytochrome P-450 (c) reductase in human corneal epithelium.

The presence of heme oxygenase and NADPH cytochrome P-450 (c) reductase, the latter an integral component of heme oxygenase and cytochrome P-450-dependent drug metabolizing enzymes, was demonstrated in human corneal epithelium. We reported for the first time that human corneal epithelium contains heme oxygenase activity as high as 20% of that reported for the human liver. Using immunological techniques, we demonstrated that heme oxygenase proteins from human cornea and liver are very similar; both have a molecular weight of 32,000 as demonstrated by Western blot analysis. We also studied the presence of NADPH cytochrome P-450 (c) reductase. The human corneal epithelium contains significant amount of NADPH cytochrome P-450 (c) reductase activity, and this corneal protein is similar to the known liver protein; both have a molecular weight of 71,000 and react with antibodies prepared against purified liver NADPH cytochrome P-450 (c) reductase. As the heme oxygenase system is the rate limiting step in heme degradation, this system plays a pivotal role in regulation of cellular heme in corneal epithelium, thus modulating the activity of hemoproteins such as catalase, tryptophan pyrrolase and thromboxane synthetase.

Animals↗

Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats.

The relative contribution of ether and ester glucuronidation to diflunisal metabolism was assessed by studying the effects of enzyme inducers, phenobarbital (PB), 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF). Treatment with either PB, 3-MC or BNF increased markedly the unbound intrinsic clearance of diflunisal. Saline-treated control rats showed a greater unbound intrinsic clearance of diflunisal than oil-treated controls indicating that repetitive treatment with oil had an effect on enzyme activity. Treatment with 3-MC and BNF appeared to cause a decrease in the biliary clearance of ether and ester glucuronide, but PB had little effect on the biliary clearance of glucuronides. Rats pretreated with PB showed a 3-fold increase in the fractional metabolite formation clearance of ether glucuronide and a 2-fold increase in the fractional metabolite formation clearance of ester glucuronide, suggesting differential effects of PB on ester and ether glucuronidation. A similar trend, but to a smaller extent, was also observed for 3-MC- and BNF-treated rats. These results suggest the possibility of selective induction of multiple forms of UDP-glucuronyltransferase involved in metabolism of diflunisal.

Animals↗

Bone marrow findings in acquired immunodeficiency syndrome (AIDS).

Bone marrow aspirates and biopsies from 35 AIDS/AIDS-related complex patients, consisting primarily of intravenous drug abusers, were studied. The most common findings included hypercellularity (86%), plasmacytosis (63%), reticular fibrosis (50%), and lymphocytosis (37%) occasionally admixed with histiocytes. Granulocytic hyperplasia was present in 27 patients (77%). Erythrocytic hypoplasia was observed in 15 patients (43%). Megaloblastic changes of intermediate form were seen in two cases and serous fat atrophy was noted in another three patients. One M. tuberculosis granuloma, a foreign body granuloma and two granulomas of undetermined etiology were seen, each in separate patients. A previously unreported focal vascular proliferation was seen in one case. The majority of cases showed increased stainable iron. Some of our findings are at variance with previous reports. This may reflect differences in patient population, geographic distribution, risk factors and epidemiologic mode in our cases.

Acquired Immunodeficiency Syndrome↗

In vitro detection of heparin-induced humoral antiplatelet activity.

We investigated the etiology of thrombocytopenia, with or without platelet thrombi, occurring while patients are receiving parenteral heparin. We used two in vitro methods to detect possible humoral factors in the sera of patients who became thrombocytopenic while receiving heparin. In the presence of heparin, four of four such patients' serum caused platelet aggregation. Only serum from the patient most severely affected clinically caused release of platelet factor 3 (PF3). All control sera gave negative results by both methods. We propose that platelet aggregation studies may be a sensitive and reliable method of confirming that thrombocytopenia occurring during heparin therapy is due to a humoral factor requiring the presence of heparin.

Adenosine Diphosphate↗

Genetic transformation of rifampicin resistance in Lactobacillus acidophilus.

Lactobacillus acidophilus strain 100-33, originally isolated from swine faeces, was transformed to rifampicin resistance with DNA from spontaneous rifampicin-resistant mutants derived from it. Cells of the recipient strain were treated with lysozyme and mutanolysin, mixed with donor DNA and polyethylene glycol and grown on a regeneration medium overnight. After 48 h incubation, the numbers of rifampicin-resistant cells in the populations of regenerated cells were estimated from numbers of colonies. Efficiency of the lysozyme/mutanolysin treatment (the ratio of the number of osmotically fragile cells after the enzyme treatment to the initial cell number) was about 99%. The regeneration frequency of the enzyme-treated cells varied from 5 to 67%. The transformation frequency varied from about 0.2 X 10(-8) to 8.0 X 10(-8) transformants per regenerated cell per microgram DNA. To our knowledge, this method for genetic transformation is the first to be reported for a Lactobacillus strain.

DNA, Bacterial↗

Possible mechanisms for reduced plasma clearance of diflunisal in rat experimental renal failure.

To provide insight into the reported reduction in the plasma clearance of diflunisal in human renal failure, this investigation evaluated several possible mechanisms for this effect in experimental renal failure. Rats with renal failure, induced by uranyl nitrate or by ureteral ligation, had both a lower plasma clearance and an increased apparent volume of distribution, a pattern resembling that seen in human renal failure. Steady-state diflunisal concentration and unbound fraction were determined in studies during a constant infusion of diflunisal to establish the relationships of concentration, protein binding and intrinsic clearance. The infusion studies revealed that the intrinsic clearance of diflunisal, i.e., the ability of enzyme system(s) to metabolize the drug, was decreased in uremia. Also, plasma protein binding of diflunisal was decreased, which may explain the increase in apparent volume of distribution in uremic rats. The decreased intrinsic clearance of diflunisal in uremic rats may be due partly to saturation of biotransformation process(es) by increasing unbound concentration as a consequence of impairment of plasma protein binding of diflunisal, and partly due to the diminished enzyme activity of glucuronidation by renal failure. The lack of an effect of the esterase inhibitor phenylmethylsulfonyl fluoride on the intrinsic clearance of diflunisal in uremic rats suggested that the reduced intrinsic clearance of diflunisal was not attributable to the systemic enzymatic hydrolysis of the ester glucuronide.

Animals↗

[Nail fold microcirculation in patients with chest malignancy].

Nail fold microcirculation was observed in 90 patients suffering from chest malignancies. 33 were patients with esophageal cancer, 41 cancer of gastric cardia, 4 esophageal and cardiac cancer, 11 lung cancer and 1 malignant neurogenic tumor in the posterior mediastinum. The results indicate that, in cancer patients, marked microcirculatory disturbances are present in the form of marked exudation, cloudy visual field, abnormal and dilated capillary loops, granular and slow blood flow. There is no obvious difference in the various kinds of malignancies. Nor is there any difference between the operable and inoperable cases. Indication of operation is not predicted by this method. The probable cause and clinical significance of microcirculatory disturbances are discussed.

Adult↗

Effect of prevention of inorganic sulfate depletion on the pharmacokinetics of acetaminophen in rats.

The elimination of large doses of acetaminophen is associated with substantial depletion of endogenous inorganic sulfate which is utilized for the formation of acetaminophen sulfate. This depletion has pronounced dose- and time-dependent effects on the pharmacokinetics of acetaminophen. The purposes of this investigation were to determine the pharmacokinetics of acetaminophen in rats when endogenous sulfate depletion is prevented by administration of inorganic sulfate and to develop a simple, physiologically based pharmacokinetic model for the elimination of acetaminophen under these conditions. Adult Sprague-Dawley rats received an i.v. injection and a continuous infusion of sodium sulfate as well as an i.v. injection of acetaminophen, either 15, 30, 150 or 300 mg/kg. Serum inorganic sulfate concentrations remained at or above the physiologic level at all times. Plasma concentrations of acetaminophen declined exponentially with time after the two lower doses but exhibited initial downward curvature in log-linear plots after the two larger doses. The time-averaged plasma clearance of acetaminophen decreased with increasing dose whereas the terminal half-life was dose-independent. Most of the drug was eliminated in the urine as acetaminophen sulfate but the dose fractions of acetaminophen glucuronide and unmetabolized drug excreted in the urine increased with increasing dose. The renal clearance of acetaminophen did not exhibit dose-dependence but the apparent formation clearance of acetaminophen glucuronide tended to decrease with increasing dose. The formation of acetaminophen sulfate is describable by Michaelis-Menten kinetics, with a Vmax of about 6.5 mumol/min/kg and an in vivo KM (referenced to plasma) of about 100 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

Assay methodology for quantification of the ester and ether glucuronide conjugates of diflunisal in human urine.

Diflunisal is a salicylate derivative with analgesic and anti-inflammatory properties. It is excreted in the urine as an ether glucuronide, a 1-O-acyl glucuronide and as unchanged drug. The 1-O-acyl glucuronide rearranges to isomeric esters of glucuronic acid under neutral to alkaline pH conditions. The development of a urine assay for the conjugates enables the elucidation of diflunisal non-linear pharmacokinetics. The assay quantitates the ether and ester glucuronides and free diflunisal in urine at 0.5-1.0 micrograms/ml. Analysis of the glucuronides does not require authentic standards.

Chromatography, High Pressure Liquid↗

Overwhelming post-splenectomy infection with Plesiomonas shigelloides in a patient cured of Hodgkin's disease. A case report.

The immune deficiencies of Hodgkin's disease persist to some degree even after the patients are clinically cured; these may be amplified by loss of splenic immunologic functions after staging laparotomy and splenectomy. The authors submit a case report wherein a bacterium of relatively low virulence, Plesiomonas shigelloides, was associated with a rapidly fulminant septicemia, disseminated intravascular coagulation, Waterhouse-Friderichsen syndrome, and death in a splenectomized patient free of Hodgkin's disease for approximately five years. This emphasizes the need for prolonged observation, rapid diagnosis, and aggressive intervention in immunocompromised patients, especially those supposedly cured of previous hematologic malignancy.

Adult↗

Diurnal variations in responsiveness of the hypothalamo-pituitary-adrenocortical axis of the rat.

Hypothalami, anterior pituitary gland segments and adrenal glands were removed from female Wistar-derived rats decapitated at various times of the day. Blood and tissue hormone concentrations were measured and the tissues challenged with appropriate stimuli in vitro. Both bioactive and immunoreactive corticotrophin-releasing factor (CRF) content of the hypothalami were significantly higher in the evening than in the morning, as was the basal release of bioactive CRF in vitro. The response of the hypothalami to serotonin or acetylcholine added in vitro did not change with time of day. Basal bioactive and immunoreactive adrenocorticotrophin (ACTH) release from the anterior pituitary gland was significantly increased in the evening, as was the response to synthetic ovine CRF in vitro. Plasma ACTH concentrations in intact rats given crude CRF (hypothalamic extract) in vivo were higher in the evening at all times after injection tested, but this difference was markedly reduced in animals with mediobasal hypothalamic lesions. Corticosterone released basally from adrenal glands in vitro was significantly increased in the evening and the response to added ACTH 1-24 was slightly enhanced. For adrenal glands removed from lesioned rats, the pattern was reversed, corticosterone release in vitro being lower in the evening for all doses of ACTH added. Similarly in vivo, in intact rats given ACTH 1-24, plasma corticosterone concentrations and corticosterone release in vitro from adrenal glands removed after the injection were higher in the evening. After the placement of basal hypothalamic lesions, the situation was reversed, the response to ACTH administration in vivo being greater in the morning.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

The adrenocortical function of alloxan-induced diabetic rats.

The purpose of this study is to investigate the adrenocortical function of alloxan-induced diabetic rats. Male rats of Wistar strain, weighing 200-250 gm were used. The results indicated that the adrenocortical response to stress and exogenous corticotropin (ACTH1-24) is decreased during the early diabetic stages (up to 6 days). Evidence from in vivo and in vitro studies shows that the depression is caused by the toxicity of alloxan on the adrenal cortex cells and not by the sudden rise of blood glucose levels. Streptozotocin (another diabetogen) has the same effect as alloxan on adrenal cortex cells.

Adrenal Cortex↗

Dose-dependent pharmacokinetics of diflunisal in rats: dual effects of protein binding and metabolism.

The purpose of this study was to define the dual effects of saturable metabolism and saturable protein binding on the pharmacokinetics of diflunisal. Steady-state diflunisal concentration and its unbound fraction were examined in seven groups of rats to determine the relationships of infusion rate, concentration and total and unbound clearances. The total body plasma clearance decreased initially and then went up as the concentration of diflunisal increased, whereas the intrinsic clearance of unbound drug decreased with increasing concentration. The former is a consequence of saturable metabolism as well as saturable protein binding; the latter is a consequence of saturable metabolism. The fraction of unbound diflunisal increased with concentration. The biliary excretion data of ester and ether glucuronide suggested that both the ester and ether glucuronidation processes are capacity-limited, although the enzyme system for ether glucuronide has a lower Km and capacity than the system responsible for the ester glucuronidation.

Animals↗