Biomedical subjects
D J Kim
Publications and source records attributed to D J Kim.
Demonstration of organotropic effects of chemopreventive agents in multiorgan carcinogenesis models.
Organotropic chemopreventive effects of three (pro)vitamins and three unsaturated fatty acids were examined using mouse and rat multiorgan carcinogenesis models. For the study of (pro)vitamins, male and female B6C3F1 mice were treated with N,N-diethylnitrosamine (DEN) and N-methyl-N-nitrosourea (MNU) during the first 11 weeks, then from weeks 12 to 32 they received alpha-carotene (0.4 mg/mouse), beta-carotene (0.4 mg/mouse) or alpha-tocopherol (40 mg/mouse) three times a week by gavage; control mice received vehicle alone. In male mice, alpha-carotene significantly reduced liver weights, representing a reduced tumour mass (P < 0.001), and alpha-carotene, beta-carotene and alpha-tocopherol significantly reduced the numbers of liver tumours (adenomas and carcinomas combined) (P < 0.001-0.01) as compared with control mice, the effects being greatest with alpha-carotene. In female mice, alpha-carotene significantly decreased the number of liver tumours (P < 0.001). In the lung, alpha-carotene and alpha-tocopherol reduced the area of lesions (hyperplasias and adenomas combined) only in males (P < 0.05). For the study of unsaturated fatty acids, F344 male rats were treated with DEN, MNU, N-butyl-N-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and N,N-bis(2-hydroxy)propylnitrosamine during the first 5 weeks, then from weeks 6 to 36 they were given docosahexaenoic acid (C22:6), eicosapentaenoic acid (C20:5) or linoleic acid (C18:2) at 1.0 g/rat, three times a week by gavage; control rats were treated with oleic acid (C18:1) using the same protocol. All animals were fed a low linoleic acid and calorie-adjusted basal diet during fatty acid administration. Docosahexaenoic acid and linoleic acid reduced tumours in the large and small intestines, respectively. However, they did not influence the yield of preneoplastic liver, lung, kidney, forestomach and urinary bladder lesions. The data thus provide evidence for organotropic effects of carotenoids and unsaturated fatty acids on carcinogenesis.
Microsatellite-centromere mapping in the zebrafish (Danio rerio).
Ten (CA)n microsatellite simple sequence repeat (SSR) markers, 1, 2, 12, 14, 16, 18, 20, 22, 26, and 29, were used to show high chiasma interference and to determine centromere-marker map distances in the zebrafish (Danio rerio). Of these, SSR 12 exhibited no recombinant tetratypes among 175 half-tetrad embryos, placing this marker within 1 cM of the centromere of Linkage Group XVII. Fractions of heterozygous half-tetrads for the remaining nine markers ranged from 0.64 to 0.89. Of these, six recombinant fractions were more than 0.67 (P < 0.05), indicating strong chiasma interference during female meiosis in the zebrafish. Consistent with previous mapping data, SSRs 2 and 20 of Linkage Group VI were tightly linked. Half-tetrad analysis will allow the mapping of the remaining centromeres and may be useful in the mapping of new genes and mutations in the zebrafish.
Prothrombin Molise I: documentation of a second incidence of replacement of a critical Arg near the active site.
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[Pain management in cancer patients].
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Factors XWenatchee I and II: compound heterozygosity involving two variant proteins.
Variant factor X in an individual with a mild bleeding tendency was suspected based on deficient procoagulant activity (10-20% of normal) and antigen (30-35% of normal) levels of plasma factor X. Heteroduplex analysis of factor X gene exons indicated heterozygosity for mutations in both exons 6 and 4, confirmed by direct sequencing of the amplified exons. Substitution of C by T at nucleotide position 13,984 (Arg-139 to Cys) was found in the factor X gene exon 6 of the propositus. This mutation creates a BsmI site and the patient tested heterozygous for the BsmI cleavage involved, as did one of his two daughters. In addition, exon 4 was found to have the normal A and a novel C (Asn-57 to Thr) at nucleotide position 9338. The exon 4 mutation creates a BsaJI site, detectable after amplification mismatch to remove an existing BsaJI site. Both the patient and the second of his two daughters were heterozygous for this cleavage. The two variant proteins are called factors XWenatchee I (Arg-139 to Cys) and II (Asn-57 to Thr). A mixed variant isolate derived from the plasma of the propositus exhibited heavy/light chains of normal size, as well as an apparent single-chain molecule not dissociable by reducing agent. A single-chain molecule would be predicted for form I, if the mutation blocks processing cleavages that normally remove a tripeptide interposed between the heavy and light chains. A Western blot of partially purified factor X from the daughter who inherited the form I defect revealed a component migrating the same as the putative single-chain species. Based upon the factor X activity vs. antigen ratios for the propositus and both daughters, both forms I and II are probably dysfunctional molecules.
Localization of serotonin in taste buds: a comparative study in four vertebrates.
To investigate monoaminergic synaptic mechanisms in taste buds, we examined taste buds of mice, rats, rabbits, and mudpuppies for the presence of the neurotransmitter candidate, serotonin. Immunocytochemistry revealed serotonin-like immunostaining in cells in mammalian taste buds and Merkel-like basal cells in taste buds of mudpuppies. In untreated mudpuppies and in mammals injected with the precursor to serotonin, L-tryptophan, certain taste cells showed serotonin-like immunoreactivity, although in mammalian taste buds the immunostaining was relatively weak. After pretreating mammals with 5-hydroxytryptophan (5-HTP), the intermediate precursor between L-tryptophan and serotonin, several taste cells showed strong immunoreactivity for serotonin. These findings indicate that mammalian taste cells normally contain serotonin and that taste cells can take up 5-HTP and convert it to serotonin. Immunocytochemistry on wholemount preparations demonstrated that serotonergic cells of mudpuppies (i.e., Merkel-like basal cells) were disposed in a ring at the periphery of taste buds. Similarly, serotonergic cells in mammalian taste buds tended to be located at the periphery of taste buds. Based on the position of serotonergic cells in the taste bud and on recent physiological studies on the actions of serotonin in taste buds, we postulate that serotonin functions as a neuromodulator or neurotransmitter in vertebrate taste buds.
Factor XKetchikan: a variant molecule in which Gly replaces a Gla residue at position 14 in the light chain.
To seek the possible molecular defect in a patient with deficient factor X plasma procoagulant activity, factor X gene exosn and splice junctions were subjected to heteroduplex analyses and sequencing. A mutation in exon 2 was confirmed as substitution of A by G at nucleotide position 206, coding for Gly instead of a Glu which is a normal precursor for gamma-carboxylated glutamic acid (Gla) at amino acid position 14. An abolished TaqI restriction site was used to indicate homozygosity of the defect, but occurrence of a gene deletion with attendant heterozygosity could not be excluded. The deletion of a Gla residue could affect the Ca(2+)-binding properties of factor X or confer a flexibility interfering with the interactive properties of the light chain. The defect could explain the decreased functional activity of circulating factor X and the mild bleeding tendency of the propositus.
ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity.
Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 methyl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotinic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine in rodents. A series of experiments was conducted to determine the discriminative stimulus properties of ABT-418 in comparison with (-)-nicotine, and to determine the relative potencies of these compounds on ventral tegmental area (VTA) neurons. While rats were able to discriminate (-)-nicotine 1.9 mumol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 mumol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 mumol/kg (-)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mumol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 mumol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78-82% generalization at the 6.2 mumol/kg dose. The predominant metabolites of (-)-nicotine and ABT-418 (continine and A-87770, respectively) were devoid of any effect in nicotine-trained rats. The reduced potency of ABT-418 in nicotine-trained rats is consistent with the electrophysiological findings showing that ABT-418 is 3-fold less potent than (-)-nicotine in activating dopamine-containing neurons in the VTA area.
Clofibrate-induced neoplastic development in the rat liver is associated with decreased connexin 32 expression but not with a co-ordinated shift in expression of marker enzymes.
Altered enzyme phenotype and expression of connexin 32 (Cx32), a gap junction protein were studied during the development of rat liver tumors induced by the non-genotoxic carcinogen, clofibrate. (1) In contrast to previous findings for nitrosamine-induced lesions, preneoplastic enzyme-altered foci (EAF) and neoplastic nodules (NN) lacked any clear association with degree of altered enzyme expression because of an almost complete negativity for GST-P and GGT. (2) Immunohistochemically demonstrated Cx32 spots on the hepatocyte membranes showed a clear decrease in clofibrate-induced lesions. (3) Naturally occurring EAF demonstrating GST-P and/or GGT positivity did not show a significant decrease of Cx32 counts suggesting a reversible nature. Therefore, the Cx32 decrease appears closely linked to progression of hepatocarcinogenesis irrespective of the enzyme phenotype of neoplastic focal lesions and the carcinogens used for their induction.
Relation between ischemic preconditioning and the duration of sustained ischemia.
It has been reported that repetitive brief periods of ischemia and reperfusion (ischemic preconditioning, IP) cause a significant reduction in the extent of myocardial necrosis or in the incidence of reperfusion arrhythmias in rat heart. However, recent reports have stated that IP effect is diminished or lost in the canine or bovine heart if ischemia (mostly regional) is sustained for 40 min or longer. The main objective of this study is to assess whether IP provides myocardial protection in prolonged sustained ischemia under the condition of global ischemia in isolated rabbit heart. The hearts were subjected to 10-60 min sustained ischemia (SI) followed by 60 min reperfusion with (IP heart) or without IP (ISCH heart). IP was induced by 4 cycles of 5 min global ischemia and 5 min reperfusion. Left ventricular function (LVF), extent of infarction (EI) and ultrastructural changes were examined. As a whole, the LVF began to recover on reperfusion but there was no significant difference in the functional parameters. However, extracellular Ca2+ concentration was lower in the ISCH hearts (p < 0.05) and the EI was significantly different between the hearts which had received 60 min SI (67% in the ISCH versus 32% in the IP heart, p < 0.01). Ultrastructural changes were homogeneous in the ISCH hearts and became irreversible in accordance with increase of the duration of ischemia, while these changes were heterogeneous and restricted in the IP heart. These results suggest that IP does not attenuate the postischemic dysfunction in prolonged ischemia but it can provide an infarct size-limiting effect and delay ultrastructural changes. This cardioprotective effect may be related to calcium homeostasis.
A human case of invasive fascioliasis associated with liver abscess.
A 56 year-old Korean housewife/farmer/goat keeper suffered from right upper quadrant pain and fever with chills. In the abdominal sonogram and computerized tomography, multiple, 2-3 cm, irregular shaped cavities were observed in the right lobe of liver. A liver biopsy revealed extensive central necrosis with Characot-Leyden crystals surrounded by palisading histiocytes, eosinophil-rich inflammatory infiltration. Worm was not observed. However, the serologic test for Fasciola-specific IgG antibody by micro-ELISA was positive. Prior antibody levels did not differ and eosinophilia persisted 6 and 16 months after praziquantel treatment although the cavitary lesions in the liver disappeared 6 months after the treatment. Reported herein is a human case of invasive fascioliasis diagnosed clinically by a combination of radiological, histopathological and serological studies.
Immune suppression therapy in aplastic anemia: influencing factors on response and survival.
OBJECTIVES: Immune suppression (IS) therapy has provided another opportunity of cure or improvement in the aplastic anemia patients who cannot receive bone marrow transplantation due to many causes. There are a few reports regarding the factors that affect response, survival and prognosis after IS therapy, including antilymphocyte globulin (ALG) in aplastic anemia. Therefore, we analysed our experience to determine the prognostic factors. METHODS: Statistically analysed were 172 patients, from April 1982 to July 1992, who were diagnosed as severe aplastic anemia and treated with IS therapy, including ALG, at Catholic University Medical College, St. Mary's Hospital. RESULTS: Among 172 severe aplastic anemia (SAA) patients who entered the study from April 1982 to July 1992, 144 patients were analysed for response and 122 patient for survival. 58.4% (84/144) responded after the first course of IS therapy. Among those who did not respond on the first course an additional 44% (11/25) responded after the second course of IS therapy. Prognostic factors that might affect the response to the treatment and survival were analysed. In a univariate analysis of patients with no previous history of treatment before is therapy, and a shorter interval between diagnosis and treatment, higher hemoglobin levels before IS therapy, and higher granulocyte counts and combined use use of cyclosporin A(CSA) were positively associated with response (p < 0.05). The combined use of CSA during IS therapy, younger age, lower monthly requirement of platelets transfusion before IS therapy, higher leukocyte counts, higher percent of polymorphonuclear leukocytes, lower percent of lymphocyte, higher bone marrow cellularity and response were positively associated with survival (p < 0.05). In a multivariate analysis, shorter interval between diagnosis and treatment, no combined use of hemopoietic stimulants, such as androgen, and lesser total amount of transfusion were positively associated with Response (p < 0.05). Higher leukocyte counts before IS therapy and the combined use of CSA during IS therapy were significantly associated with longer survival (p < 0.05). Patients with complete or partial response had excellent prognosis (96.7%-100% of 5 year survival rates). In contrast, patients with no response after IS therapy had 45.1% of 5 year survival rates. CONCLUSIONS: With these results from the retrospective study of IS therapy, we find many valuable factors that have an influence on response or survival. IS therapy improves the survival of responded patients with SAA, and we confirmed that IS therapy is an important therapeutic tool for the SAA patients who are not feasible candidates for bone marrow transplantation.
TNFB gene polymorphism in patients with systemic lupus erythematosus in Korean.
OBJECTIVES: To elucidate the gene frequency of TNFB Ncol polymorphism and its association with HLA class II antigen in patients with systemic lupus erythematosus(SLE) in Korea. METHODS: We investigated the gene frequency of the TNFB alleles using DNA obtained from peripheral mononuclar cells in 141 healthy controls and in 58 patients with SLE. The polymorphisms of TNFB gene (735 bp) were studied by Ncol PCR-RELP. A portion of TNFB gene(735 bp) was amplified by PCR and its products were digested with Ncol restriction enzyme. The digested samples of amplified DNA were analyzed by agarose gel electrophoresis. TNFB*1 and TNFB*2 alleles were identified according to polymorphic fragments on Ncol restriction site in the first intron of the TNFB gene. The generic types of HLA-DRBI were also determined by PCR with sequence specific primers(SSP) using genomic DNA from the same subjects. RESULTS: The genotypic frequency of TNFB*2 homozygote was significantly increased in patients with SLE compared with controls(RR = 2.36, P = 0.011). The frequency of HLA-DRBI*15 was also significantly increased in patients (RR = 2.27, P = 0.029). However, the increased frequency of TNFB*2 homozygote was apparently increased in nephritis group (RR = 2.79, P = 0.035), whereas the significance of TNFB*2 homozygote was weakend in non-nephritis group. CONCLUSIONS: Our results suggest that genetic predisposition of TNFB*2 homozygote is another risk factor in Korean SLE, especially in DR2 negative patients. In addition, TNFB*2 homozygote could have a tendency for the development of nephritis in patients with SLE.
Esophageal aspergillosis in a patient with acute leukemia.
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Shikonin production by extractive cultivation in transformed-suspension and hairy root cultures of Lithospermum erythrorhizon.
Effects of in situ extraction, fungal elicitation, a permeabilizing agent, and the oxygen transfer rate on shikonin production in transformed suspension and hairy root cultures of Lithospermum erythrorhizon were studied. Shikonin production with in situ extraction in transformed cell and hairy root cultures by n-hexadecane was 7.6 and 3 times higher than those of the control culture. Shikonin production of transformed L. erythrohizon increased with the enhanced gas exchange, and in situ extraction also increased sucrose consumption and shikonin production. The optimal volume of n-hexadecane in the hairy root culture was similar to that in the transformed cell cultures. In situ extraction at an earlier stage significantly enhanced shikonin production both in transformed cell and hairy root cultures. Dimethylsulfoxide used as a permeabilizing agent was harmful to cell growth and shikonin production, and permeabilizing was unnecessary when in situ extraction was applied. This occurred because with the solvent addition, most shikonin was spontaneously released from the cells and was dissolved in the solvent layer. The combined addition of n-hexadecane of the extract of the fungus Penicillium as an elicitor seemed to result in a higher production of shikonin both in cell suspensions and transformed root cultures. However, an increase of shikonin induction by fungal elicitation in a hairy root culture was not significant in comparison with that of normal cell cultures.
Phenotypic alteration of hepatocellular foci in rats treated with clofibrate and phenobarbital.
In male F344 rats pretreated with diethylnitrosamine (DEN), subsequent administration of clofibrate increased the proportion of eosinophilic foci, to become the most abundant type, and reduced numbers of basophilic, clear and vacuolated foci, the total not being changed. A similar shift towards eosinophilia was also observed in phenobarbital-treated animals, but in this case clear increases in total number and area were apparent. Expression of the glutathione S-transferase placental form (GST-P) in foci was much lowered by clofibrate treatment, while the proportion of positive foci was very high in both phenobarbital and control groups. A marked contrast was found with eosinophilic foci, with 74% positive after phenobarbital as compared to only 15% for clofibrate. Thus, the decrease in GST-P positive foci by clofibrate was mainly due to increased negativity in the most abundant eosinophilic type foci. In a long-term feeding study without DEN initiation, similar negativity of foci was observed and, furthermore, only minimal effects of clofibrate on foci development was revealed in both young and old animals.
Clozapine attenuates the discriminative stimulus properties of (-)-nicotine.
Rats were trained to discriminate 1.9 mumol/kg (-)-nicotine (0.3 mg/kg) from saline in a standard two-bar operant conditioning paradigm with food reinforcement. The effect of neuronal nicotinic acetylcholine receptor (nAChR) agonists and antagonists were verified, and the participation of dopaminergic receptors subtypes in the expression of the (-)-nicotine cue was investigated with cis-flupentixol (D1-D2 antagonist), haloperidol (D2 antagonist) and clozapine (D4 antagonist). The stereoselectivity of the behavioral response was indicated by the 10-fold less sensitivity to (+)-nicotine in (-)-nicotine-trained rats. (+/-)-Anabasine and (-)-cytisine exhibited partial agonist profiles at the 1.9 mumol/kg dose while (-)-lobeline was devoid of any effect in doses up to 19 mumol/kg. (-)-Lobeline did not show antagonist properties in this paradigm. The nicotinic channel blockers mecamylamine, chlorisondamine and hexamethonium were inactive on their own but mecamylamine and chlorisondamine were able to block the effect of (-)-nicotine. Clozapine attenuated the (-)-nicotine cue while cis-flupentixol and haloperidol were ineffective. Similar doses of cis-flupentixol significantly blocked the locomotor stimulant effect of (-)-nicotine in rats indicating that blockade of dopaminergic receptors was achieved at the doses used in the drug discrimination studies. These data suggest that the discriminative stimulus properties of (-)-nicotine are mediated through neuronal nAChRs and involves the activation of dopaminergic receptors of the D4 subtype.