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Biomedical subjects

J H Lin

Publications and source records attributed to J H Lin.

At least 91 records · Page 5Linked to original sources
PubMed2000

Biotrickling filtration of nitric oxide.

A biotrickling filter with blast-furnace slag packings (sizes = 20-40 mm and specific surface area = 120 m2/m3) was utilized to treat NO in an air stream. The operational stability, as well as the effects of gas empty-bed retention time (EBRT) and nutrient addition on the removal ability of NO, were tested. Approximately six weeks were required for the development of a biofilm for NO degradation, and a two-week organic carbon deficiency resulted in the detachment of biofilms from the packing surfaces. A steady removal rate of 80% was attained at specified influent NO concentrations of 892 to 1237 ppm and an EBRT of 118 sec. The effluent NO concentration diminished exponentially with enlarging EBRT, with influent NO concentrations of 203-898 ppm, and EBRTs of 25 to 118 sec. Nutrient addition is essential for efficient removal of the influent NO. Mass ratios of C: P: N = 7: 1: 30 and NaHCO3: NO-N = 6.3 could be used for practical applications.

Air Pollution↗
PubMed2000

The promoter for the maize C4 pyruvate, orthophosphate dikinase gene directs cell- and tissue-specific transcription in transgenic maize plants.

The pyruvate,orthophosphate dikinase (PPDK) gene coding the chloroplast enzyme involved in C4 photosynthesis has a dual promoter system. The first promoter is responsible for the transcription of a larger transcript and its product is targeted to the chloroplast (hence, it is designated as C4Pdk promoter) while the second promoter is responsible for the transcription of a smaller transcript and its product remains in the cytosol. In this study, chimeric maize C4Pdk promoter (0.9 or 1.5 kb)-beta-glucuronidase or luciferase fusion genes were introduced into maize plants by Agrobacterium-mediated transformation. The cell- and tissue-specificities of the maize C4Pdk promoter in the transgenic maize plants were examined by histochemical and enzymic activity analyses of the reporters in different photosynthetic cells and tissues. The results showed that the reporter proteins are almost exclusively localized in leaf mesophyll cells. Among the tissues tested, leaf blade had the highest reporter activities with sheath exhibiting about 10% of the activities in blade. Husk, stem, tassel and root had no or very little reporter activities. Taken together, these results suggest that the maize C4Pdk promoter is specifically transcribed in the mesophyll cells of leaf blade and to a much less extent in the mesophyll cells of sheath, but not in leaf bundle sheath cells or other tissues. Furthermore, the 0.9 kb maize C4Pdk promoter sequences appear to contain the necessary cis-acting elements for its cell- and organ-specific expression.

Gene Expression Regulation, Enzymologic↗
PubMed2000

Recurrent hyperfunctioning parathyroid gland demonstrated on radionuclide imaging and an intraoperative gamma probe.

Radionuclide imaging with Tc-99m MIBI is the preferred mode of parathyroid localization in current practice. It also successfully identifies hyperfunctioning autotransplanted parathyroid tissue. The authors report a case with recurrent hyperparathyroidism after total parathyroidectomy and autotransplantation in the forearm. Double-phase Tc-99m MIBI imaging successfully localized the hyperfunctioning parathyroid tissue, which was missed by magnetic resonance imaging and ultrasonography. In addition, the parathyroid tissue was localized using an intraoperative probe at subsequent surgery.

Adenoma↗
PubMed2000

Evidence for the packaging of multiple copies of Tf1 mRNA into particles and the trans priming of reverse transcription.

Long terminal repeat (LTR)-containing retrotransposons and retroviruses are close relatives that possess similar mechanisms of reverse transcription. The particles of retroviruses package two copies of viral mRNA that both function as templates for the reverse transcription of the element. We studied the LTR-retrotransposon Tf1 of Schizosaccharomyces pombe to test whether multiple copies of transposon mRNA participate in the production of cDNA. Using the unique self-priming property of Tf1, we obtained evidence that multiple copies of Tf1 mRNA were packaged into virus-like particles. By coexpressing two distinct versions of Tf1, we found that the bulk of reverse transcription that was initiated on one mRNA template was subsequently transferred to others. In addition, the first 11 nucleotides of one mRNA were able to prime, in trans, the reverse transcription of another mRNA.

DNA, Complementary↗
PubMed2000

Ginseng flowers stimulate progesterone production from bovine luteal cells.

Our previous report first showed evidence that polysaccharides isolated from ginseng leaves obtained from Jilin, China possess luteotropic activities. In this study, we made further investigations on the root and flowers of Korean ginseng by means of the same bioassay system described briefly as follows. Frozen-thawed bovine luteal cells (1 x 10(5) cells/ml/well) in M199 were incubated in 24-well culture plates at 37 degrees C in a 5 % CO2 incubator. Ten microl of tested drugs with 1, 10 and 100 microg/ml were added into each well. After 4- and 24-hr incubation, the media were harvested and assayed for progesterone by an enzyme immunoassay. The production of progesterone from cells is the indicator for evaluating the action of tested drugs. Results showed that hot water extracts ofginseng flowers (GF-1) with 10 to 100 microg/ml significantly increased progesterone production, whereas those from ginseng root (GR-1) could not. Crude polysaccharides (GF-2) isolated from GF-1 is the active component and the small molecules (mw < 10,000 dalton) are excluded, indicating that the ginseng root has no luteotropic activities, but the polysaccharides of ginseng flowers have.

Animals↗
PubMed2000

Sense and nonsense in the prediction of drug-drug interactions.

Drug interactions are always a major concern in medicine and within the pharmaceutical industry. Fatal drug interactions have been reported, and several prominent drugs have been withdrawn from the market because of serious adverse reactions related to drug interactions. Therefore, drug interactions represent not only a medical problem for clinicians, but also an economic loss for pharmaceutical companies. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates in an attempt to minimize such losses and to more effectively safeguard the welfare of patients. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? These are the fundamental questions that industrial drug metabolism scientists must confront daily. Prediction of in vivo drug interactions from in vitro metabolic data is highly controversial, because of the complexities of factors that are involved in drug interactions. Some scientists believe that quantitative prediction of drug interaction is possible, whereas others are less optimistic, and believe that quantitative prediction is extremely difficult, if not impossible. The purpose of this review is to present and discuss the technical problems inherent in estimating in vitro Ki values and in measuring inhibitor concentration at the active-site of enzymes. Theoretic considerations are briefly reviewed, and representative examples are drawn from literature to illustrate the sense and nonsense in predicting in vivo drug interactions.

Algorithms↗
PubMed2000

Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4.

Caco-2 cells grown in the presence of 1alpha,25-di-OH vitamin D(3) (di-OH vit D(3)) were used as a model to evaluate the effects of P-glycoprotein (Pgp) efflux on CYP3A4-mediated metabolism of indinavir during intestinal absorption. Caco-2 cells grown under these conditions demonstrated significant CYP3A4 activity and maintained Pgp-mediated directional transport of indinavir. Metabolism of indinavir in the di-OH vit D(3)-treated cells correlated with the level of CYP3A activity and generated metabolites consistent with CYP3A4-mediated metabolism. During transport experiments, indinavir metabolites are selectively secreted into the apical compartment, consistent with Pgp-mediated efflux. Using formation of the most abundant metabolite, M6, as a marker for indinavir metabolism, we observed that the extent of indinavir metabolism is not significantly affected by the direction of indinavir transport or by inhibition of Pgp with cyclosporin A. However, because Pgp efflux results in higher indinavir transport in the basolateral-to-apical direction than in the apical-to-basolateral direction, the ratio of M6 produced normalized to the amount of drug transported across the monolayer was higher for apical-to-basolateral transport. Thus, Pgp efflux in a direction opposite to absorptive transport results in more metabolite produced per mole of drug that is absorbed. In summary, the results support a role of Pgp in increasing intestinal presystemic metabolism and in removal of CYP3A4-generated metabolites from the intracellular compartment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.

The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 microM, whereas those for all others ranged from 14 to >150 microM. Except for nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone 6beta-hydroxylation and midazolam 1'-hydroxylation) after 30-min preincubation with NADPH. IC(50) values for the inhibition of testosterone 6beta-hydroxylase obtained in the NADPH-preincubation experiment for nicardipine (1 microM), verapamil (2 microM), and diltiazem (5 microM) were within 10-fold, whereas those for amlodipine (5 microM) and felodipine (13 microM) were >200-fold of their respective plasma concentrations reported after therapeutic doses. Similar results also were obtained based on midazolam 1'-hydroxylase activity. Unlike the observations with mibefradil, a potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A activity by nicardipine and verapamil was completely reversible on dialysis, whereas that by diltiazem was partially restored (80%). Additional experiments revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent of complex formation ( approximately 30% at 100 microM), and was a much faster-acting inhibitor (maximal inhibition rate constant approximately 2 min(-1)) as compared with verapamil and diltiazem. These present findings that the CYP3A inhibition caused by nicardipine, verapamil, and diltiazem is, at least in part, quasi-irreversible provide a rational basis for pharmacokinetically significant interactions reported when they were coadministered with agents that are cleared primarily by CYP3A-mediated pathways.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Coexistence of epilepsy, myasthenia gravis and psoriasis vulgaris.

We report the case of a 36-year-old Chinese man with a history of complex partial seizure of temporal lobe origin since the age of 12 years, superimposed by myasthenia gravis since the age of 27 years and psoriasis vulgaris since the age of 29 years. With an eight-year follow-up, the above three diseases remained without complete remission. Anticonvulsant therapy (phenytoin and trimethadione) caused drug-induced myasthenia gravis, which should gradually disappear after discontinuing the drugs. However, the myasthenic symptoms and serum acetylcholine receptor antibody persisted following the discontinuation of phenytoin in our patient. Myasthenia gravis and psoriasis are both autoimmune diseases and correlate with specific human histocompatibility antigens. This suggests a close connection between these two diseases. The coexistence of epilepsy, myasthenia gravis and psoriasis vulgaris has not been previously reported, and to the best of our knowledge, our patient is the first reported case. The relationship among these three diseases requires further investigation.

Adult↗
PubMed2000

Route-dependent nonlinear pharmacokinetics of a novel HIV protease inhibitor: involvement of enzyme inactivation.

L-754,394, a furanopyridine derivative, is an experimental HIV protease inhibitor. Previous studies from this laboratory have demonstrated that L-754,394 is cleared very rapidly in animals, and that this drug is a potent mechanism-based inactivator (suicide inhibitor) for CYP3A4 in human liver microsomes. Because L-754,394 is a high-clearance drug and an enzyme inactivator, it is expected that this drug will be subject to significant first-pass metabolism, and that the degree of enzyme inactivation will be dependent not only on the dose, but also on the route of administration. The purpose of this study is to examine the effects of dose and route of administration on the kinetics of L-754,394 using rats and dogs as animal models. In both rats and dogs, L-754,394 exhibited marked dose-dependent pharmacokinetics after i.v. and oral administration. Irrespective of i.v. or oral administration, the area under the plasma concentration-time curve from zero to infinity increased with dose in a greater than proportional manner. However, the magnitude of area under the plasma concentration-time curve from zero to infinity increase was much greater after oral dosing than after i.v. administration, indicating route-dependent pharmacokinetics. Data from in vitro and in vivo studies suggested that the dose- and route-dependent pharmacokinetics were due mainly to the inactivation (destruction) of the enzymes responsible for its own metabolism.

Administration, Oral↗
PubMed2000

Fibrinofibrous pericarditis mimicking a pericardial tumor.

Primary pericardial disease is rare in children. The clinical features usually reflect limited venous return and cardiac output. Tuberculous pericarditis is the leading cause of pericardial disease in developing nations. A definitive diagnosis in children is frequently difficult and the manifestations are protean. We report a 10-month-old girl with fibrinofibrous pericarditis that manifested as constrictive pericarditis with prolonged fever, hepatomegaly, edema, and poor appetite. Echocardiography showed a solid mass that originated from the thickened pericardium and compressed the whole heart. In contrast, computed tomography revealed pericardial thickening with fluid collection. The symptoms and signs dramatically improved after surgical pericardiectomy. Pathologic analysis confirmed the diagnosis of tuberculous fibrinofibrous pericarditis. The patient received a 1-year course of antituberculosis therapy and has remained symptom free for 2 years. We suggest that a discrepancy between echocardiography and computed tomography (CT) findings might indicate a diagnosis of fibrinofibrous pericarditis.

Diagnosis, Differential↗
PubMed2000

Comparison of imidazole- and 2-methyl imidazole-containing farnesyl-protein transferase inhibitors: interaction with and metabolism by rat hepatic cytochrome P450s.

Methylation at the 2-position of the imidazole ring of IBN (I), a 1, 5-substituted imidazole-containing compound, was carried out to minimize its inhibition of rat cytochrome P450 (CYP)3A activity. The resulting analog 2-MIBN (II) exhibited an inhibitory potency 70-fold weaker (K(i) = 25 microM) than that of I (K(i) = 0.3 microM) toward CYP3A, the major rat liver microsomal P450 isoform(s) for the metabolism of I and II by rat liver microsomes in the presence of NADPH. The structural modification did not switch the major metabolic pathways for I and II, but significantly decreased the affinity of II to the metabolizing enzyme(s) as reflected by the difference in their K(i) values for CYP3A. Enzyme kinetic studies also demonstrated that I had a lower apparent K(m) (0.3 microM) than than II (18 microM), but an apparent V(max) 14 times lower than II. This finding indicates that methylation at the imidazole ring reduced the affinity of the compound to CYP3A, but increased the catalytic capacity, turning I as a substrate of low K(m) value but low capacity into a compound of high K(m) but high capacity for the metabolism. Our results suggest the significance of substrate concentration in comparing the metabolic stability of compounds with different kinetic parameters. Although higher intrinsic clearance is implied for I when the substrate concentration is below or close to its K(m) value, higher metabolic rate was constantly seen with II over micromolar range. The different kinetic parameters of I and II may also explain the observation that no significant difference in pharmacokinetic behavior was seen after an i.v. administration of I and II to the rat.

Alkyl and Aryl Transferases↗
PubMed2000

Efficiency and effectiveness of stroke rehabilitation after first stroke.

PURPOSE: To investigate predictive variables of rehabilitation efficiency and achievement of rehabilitation potential following stroke rehabilitation. METHODS: We prospectively studied 110 first-stroke patients consecutively admitted to the inpatient rehabilitation department of our university hospital from 1 January to 31 December 1997. Functional recovery was measured as improvement in the ability to perform the Functional Independence Measure (FIM) instrument. Major medical (side of paralysis, stroke etiology, risk factors, Brunnstrom motor recovery stage, etc.), rehabilitative (initial FIM subscore, interval from stroke onset to rehabilitation commencement, rehabilitation stay, etc.), and demographic (age, years of education, occupation, marital and living status, care-giver, etc.) variables were examined. RESULTS: The mean FIM score was 57.7 +/- 24.5 at admission and 77.3 +/- 26.3 at discharge. The mean rehabilitation efficiency (0.7 +/- 0.7) and effectiveness (30.6 +/- 24.0%) of stroke rehabilitation were determined. Rehabilitation efficiency and rehabilitation effectiveness were significantly predicted by length of stay and arm motor recovery stage, and by age and arm motor recovery stage, respectively. The variance explained only 21% of the rehabilitation efficiency and 24% of the achievement of rehabilitation potential. CONCLUSIONS: The results of this study suggest that the large proportion of the unexplained variance in rehabilitation efficiency and effectiveness is due to nonmedical factors influencing the selection of patients for rehabilitation.

Adult↗
PubMed2000

Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine.

The metabolism of diclofenac to its 5-hydroxylated derivative in humans is catalyzed by cytochrome P450 (CYP)3A4. We report herein that in vitro this biotransformation pathway is stimulated by quinidine. When diclofenac was incubated with human liver microsomes in the presence of quinidine, the formation of 5-hydroxydiclofenac increased approximately 6-fold relative to controls. Similar phenomena were observed with diastereoisomers of quinidine, including quinine and the threo epimers, which produced an enhancement in the formation of 5-hydroxydiclofenac in the order of 6- to 9-fold. This stimulation of diclofenac metabolism was diminished when human liver microsomes were pretreated with a monoclonal inhibitory antibody against CYP3A4. In contrast, neither cytochrome b(5) nor CYP oxidoreductase appeared to mediate the stimulation of diclofenac metabolism by quinidine, suggesting that the effect of quinidine is mediated through CYP3A4 protein. Further kinetic analyses indicated that V(max) values for the conversion of diclofenac to its 5-hydroxy derivative increased 4.5-fold from 13.2 to 57.6 nmol/min/nmol of CYP with little change in K(m) (71-56 microM) over a quinidine concentration range of 0 to 30 microM. Conversely, the metabolism of quinidine was not affected by the presence of diclofenac; the K(m) value estimated for the formation of 3-hydroxyquinidine was approximately 1.5 microM, similar to the quinidine concentration required to produce 50% of the maximum stimulatory effect on diclofenac metabolism. It appears that the enhancement of diclofenac metabolism does not interfere with quinidine's access to the ferriheme-oxygen complex, implicating the presence of both compounds in the active site of CYP3A4 at the same time. Finally, a approximately 4-fold increase in 5-hydroxydiclofenac formation was observed in human hepatocyte suspensions containing diclofenac and quinidine, demonstrating that this type of drug-drug interaction occurs in intact cells.

Cytochrome P-450 CYP3A↗
PubMed2000

Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine.

Caspofungin acetate (MK-0991) is a semisynthetic pneumocandin derivative being developed as a parenteral antifungal agent with broad-spectrum activity against systemic infections such as those caused by Candida and Aspergillus species. Following a 1-h i.v. infusion of 70 mg of [(3)H]MK-0991 to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 h postdose contained predominantly unchanged MK-0991, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-acetylation.

Anti-Bacterial Agents↗
PubMed2000

Histopathologic analysis of sentinel lymph nodes in breast carcinoma.

BACKGROUND: Intraoperative lymphatic mapping and identification of the first draining lymph node (the sentinel lymph node) may allow some patients with breast cancer to avoid the morbidity of formal axillary clearance. The aim of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy in predicting axillary nodal involvement. METHODS: From August, 1998 until July, 1999, 41 patients with clinically node-negative breast cancer underwent SLN biopsy that was immediately followed by axillary lymph node dissection. If the SLN section was found free of metastasis by routine hematoxylin and eosin staining (H&E), then an additional four sections of the SLN were cut and examined for the presence of tumor cells by H&E staining (three sections) and by cytokeratin immunohistochemical staining (IHC) (one section). If the SLN had metastatic cells and the other remaining nonsentinel axillary lymph nodes were free of metastases by routine H&E staining, then an additional three sections of the nonsentinel axillary lymph nodes were cut and examined for the presence of tumor cells by H&E staining. RESULTS: The 41 patients had a mean of 2.2 sentinel (range, 1-7) and 14.6 nonsentinel (range, 5-32) lymph nodes excised per patient. Routine H&E staining identified 13 patients (31.7%) with SLN metastases and 28 patients (68.3%) with tumor-free SLNs. Applying IHC and the additional three sections stained with H&E to these tumor-free SLNs showed one additional patient with sentinel node metastasis. The conversion rate from being a sentinel node-negative patient to a sentinel node-positive patient was 3.6% (1/28). Overall, SLN metastases were detected in 14 (34.1%) of the 41 patients. The SLNs were negative in 27 patients (65.9%), two of whom had at least one positive nonsentinel lymph node each (7.4% "skip" metastasis). Biopsy of SLNs was 92.6% accurate in predicting the absence of nonsentinel nodal metastasis (p=0.001). CONCLUSIONS: Our results suggest that formal axillary lymph node dissection may need only be performed in SLN-positive patients. Nonetheless, further experience and refinement are needed to perfect this technique.

Adult↗
PubMed2000

Factors influencing functional independence outcome in stroke patients after rehabilitation.

The purpose of this study was to identify predictive variables relevant to functional independence outcomes for stroke patients following rehabilitation therapy. We prospectively studied 150 stroke patients consecutively admitted to the inpatient rehabilitation department of a university hospital from January 1 to December 31, 1997. Functional ability was assessed with the Functional Independence Measure (FIM) instrument on admission, on discharge of inpatient rehabilitation program, and at the 6 months follow-up visit after discharge. Severity of stroke was determined by using the Canadian Neurological Scale (CNS) on admission. In addition, major medical and sociodemographic factors were documented during hospitalization as independent variables. Of the 142 subjects surveyed, 23 (16.2%) stroke patients achieved functional independence at home when re-visited. Univariate test and multiple logistic regression analyses indicated that the significant factors affecting functional independence included age of onset, occupation, prior heart problems, the presence of medical complications, bilateral hemiplegia, and the functional ability (FIM score) and the severity of stroke (CNS score) on admission. The results of this study suggest that the admission CNS and FIM scores are useful in the prediction of functional independence outcome for stroke survivors following rehabilitation therapy.

Activities of Daily Living↗