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Biomedical subjects

J A Kim

Publications and source records attributed to J A Kim.

At least 73 records · Page 4Linked to original sources
PubMed2000

Pavlovian psychopharmacology: the associative basis of tolerance.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms.

Animals↗
PubMed2000

Role of NAD(P)H oxidase in the tamoxifen-induced generation of reactive oxygen species and apoptosis in HepG2 human hepatoblastoma cells.

Previously, tamoxifen (TAM) has been shown to induce apoptosis through elevation of intracellular Ca2+ in HepG2 human hepatoblastoma cells. In this study we investigated the role of reactive oxygen species (ROS) in the TAM-induced apoptosis, and interrelationship between intracellular Ca2+ and ROS. TAM induced a slow and sustained increase in intracellular ROS level. An antioxidant, N-acetylcysteine significantly inhibited both ROS production and apoptosis induced by TAM, suggesting that ROS may play an essential role in the TAM-induced apoptosis. In a time frame ROS generation followed intracellular Ca2+ increase, and the extracellular and intracellular Ca2+ chelation with EGTA and BAPTA/AM, respectively, completely inhibited the TAM-induced ROS production, indicating that intracellular Ca2+ may mediate the ROS generation. Inhibitors of NAD(P)H oxidase, diphenylene iodonium, phenylarsine oxide and neopterine, significantly blocked the TAM-induced ROS generation and apoptosis, implying that this oxidase may act as a source enzyme for the production of ROS. These results suggest that non-phagocytic NAD(P)H oxidase may play a novel role as a mediator of the apoptosis associated with intracellular Ca2+ in HepG2 cells.

Antineoplastic Agents, Hormonal↗
PubMed2000

The effect of intratracheal pulmonary ventilation on the decrease of dead space in rabbits with acute respiratory failure.

OBJECTIVE: A technique that improves the efficiency of alveolar ventilation should decrease the pressure required and reduce the potential for lung injury during mechanical ventilation. High partial pressure of carbon dioxide (PaCO2) can be tolerated if associated with a lower airway pressure as in permissive hypercapnia (PH). Intratracheal pulmonary ventilation (ITPV) was developed to allow a decrease in physiological dead space during mechanical ventilation. We compared the effect of hybrid ventilation (HV) as a modification of ITPV with PH on the decrease of tidal volume and airway pressures in rabbits with acute respiratory failure. METHODOLOGY: Tracheostomy was performed in seven rabbits ventilated under volume-controlled mode in the supine position. Arterial blood gas analysis, airway pressures, and dead space ventilation were measured at respiratory rates of 20/min as control values. Oleic acid (OA) of 0.06 mL/kg was injected to induce acute respiratory failure. Tidal volume (V(T)) was elevated to maintain PaCO2 in the normal range. These same parameters were measured as OA values. Then V(T) was reduced to the control level to allow PH. Hybrid ventilation was initiated by inserting a reverse thrust catheter (RTC) into the endotracheal tube. Hybrid ventilation consists of a pressure-controlled mode of mechanical ventilation and ITPV while flushing fresh gas continuously via the RTC. Respiratory parameters were compared under control, OA, PH and HV conditions. RESULTS: Oleic acid injection decreased partial pressure of oxygen (PaCO2) from 401+/-35 mmHg to 129+/-39 mmHg, increased V(T) from 42+/-5 mL to 52+/-10 mL, and increased dead space (V(D))/V(T) ratio from 0.65+/-0.07 to 0.71+/-0.07. During PH, the increase in PaCO2 was accompanied by an increase in V(D)/V(T) ratio from 0.71+/-0.07 to 0.79+/-0.03 and by a decrease of peak inspiratory pressure (PIP) from 19.4+/-4.0 cmH2O to 16.8+/-3.1 cmH2O. PaCO2 was lowered from 50+/-5 mmHg in PH to 39+/-5 mmHg in HV with a lower V(T). V(D)/V(T) ratio in HV which was as low as that in control. CONCLUSIONS: Hybrid ventilation is an effective and easy-to-use ventilatory modality to reduce PaCO2 and airway pressures by the reduction in V(D)/V(T) ratio in acute respiratory failure model.

Acute Disease↗
PubMed2000

Experimental model of hepatic fibrosis following repeated periportal necrosis induced by allylalcohol.

BACKGROUND/AIMS: In most patients with chronic viral hepatitis the predominant lobular location of hepatic necrosis and fibrosis is the periportal zone. We established a new simple model of hepatic fibrosis in rats by repetitive periportal necrosis with allylalcohol. METHODS: Of 40 male adult rats, 30 were injected with 0.62 mmol/kg of allylalcohol intraperitoneally twice a week, the remaining 10 with normal saline as controls. Ten rats were killed at each of 4, 8, and 16 weeks later. The extent of fibrosis was evaluated according to the portal-portal extent. Transforming growth factor (TGF) beta1 mRNA in liver tissues was detected by reverse transcriptase polymerase chain reaction, and its levels were determined by the endpoint titers of serial two-fold dilutions of cDNA. RESULTS: After 4 weeks, periportal fibrosis was produced in only 6 out of 10 rats, and was mild in extent. However, after 8 weeks, 8 out of 9 survivors showed moderate to severe fibrosis, which corresponded to a score of 7 or more. The extent of fibrosis correlated significantly with the amount of collagen and TGFbeta1 mRNA expression in liver tissues. The collagen content and expression of TGFbeta1 mRNA were also upregulated significantly in liver tissues with a fibrosis score of 7 or more. CONCLUSIONS: Hepatic fibrosis can be sufficiently induced by repetitive intraperitoneal injection of 0.62 mmol/kg of allylalcohol twice a week for 8 weeks. This simple model of hepatic fibrosis, in which TGFbeta1 is overexpressed at the transcriptional level, may be useful in the study of patients who have predominantly periportal necrosis and fibrosis.

Animals↗
PubMed2000

Effects of flupyrazofos on liver microsomal cytochrome P450 in the male Fischer 344 rat.

1. The effects of flupyrazofos on liver microsomal cytochrome P450 were investigated in the male Fischer 344 rat. When rats were treated intraperitoneally with flupyrazofos for 3 consecutive days, the activities of ethoxyresorufin O-deethylase and testosterone 2 beta-hydroxylase were significantly reduced, whereas the activities of pentoxyresorufin beta-depentylase and testosterone 6beta- and 7 alpha-hydroxylases were induced in liver microsomes. 2. Within 24 h after treatment with 50 m kg(-1) flupyrazofos, most enzyme activities were decreased, indicating the interaction of flupyrazofos with cytochrome P450. 3. In Western immunoblotting, cytochrome P4502B1/2 proteins were clearly induced by treatment with flupyrazofos, whereas P4501A1/2 and 2C6 proteins were reduced in liver microsomes. 4. The present results indicate that flupyrazofos modulates the expression of cytochrome P450 in rat.

Animals↗
PubMed2000

Inhibitors of Na+/Ca2+ exchanger prevent oxidant-induced intracellular Ca2+ increase and apoptosis in a human hepatoma cell line.

Oxidative stress appears to be implicated in the pathogenesis of various diseases including hepatotoxicity. Although intracellular Ca2+ signals have been suggested to play a role in the oxidative damage of hepatocytes, the sources and effects of oxidant-induced intracellular Ca2+ increases are currently debatable. Thus, in this study we investigated the exact source and mechanism of oxidant-induced liver cell damage using HepG2 human hepatoma cells as a model liver cellular system. Treatment with 200 microM of tert-butyl hydroperoxide (tBOOH) induced a sustained increase in the level of intracellular reactive oxygen intermediates (ROI) and apoptosis, assessed by 2',7'-dichlorofluorescein fluorescence and flow cytometry, respectively. Antioxidants, N-acetyl cysteine (NAC) or N,N'-diphenyl-p-phenylenediamine significantly inhibited both the ROI generation and apoptosis. In addition, tBOOH induced a slow and sustained increase in intracellular Ca2+ concentration, which was completely prevented by the antioxidants. An intracellular Ca2+ chelator, bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid/cetoxymethyl ester significantly suppressed the tBOOH-induced apoptosis. These results imply that activation of an intracellular Ca2+ signal triggered by increased ROI may mediate the tBOOH-induced apoptosis. Both intracellular Ca2+ increase and induction of apoptosis were significantly inhibited by an extracellular Ca2+ chelator or Na+/Ca2+ exchanger blockers (bepridil and benzamil), whereas neither Ca2+ channel antagonists (verapamil and nifedipine) nor a nonselective cation channel blocker (flufenamic acid) had an effect. These results suggest that tBOOH may increase intracellular Ca2+ through the activation of reverse mode of Na+/Ca2+ exchanger. However, tBOOH decreased intracellular Na+ concentration, which was completely prevented by NAC. These results indicate that ROI generated by tBOOH may increase intracellular Ca2+ concentration by direct activation of the reverse mode of Na+/Ca2+ exchanger, rather than indirect elevation of intracellular Na+ levels. Taken together, these results suggest that the oxidant, tBOOH induced apoptosis in human HepG2 cells and that intracellular Ca2+ may mediate this action of tBOOH. These results further suggest that Na+/Ca2+ exchanger may be a target for the management of oxidative hepatotoxicity.

Acetylcysteine↗
PubMed2000

A phase II study of a daily x4 schedule of vinorelbine plus cisplatin for advanced non-small cell lung cancer.

BACKGROUND: Because dose intensity may be important as a determinant response to vinorelbine, we explored the possibility of increasing the dose intensity of vinorelbine on a daily x4 schedule. METHODS: Between February 1998 and March 1999, 31 patients with previously untreated advanced non-small cell lung cancer were enrolled. Vinorelbine 15 mg/m2 and cisplatin 20 mg/ m2 were administered intravenously daily for 4 days and repeated every 21 days. RESULTS: A total 96 cycles were administered (median 3, range 1-6); 42% of vinorelbine and 39% of cisplatin injections were dose-reduced or delayed owing to toxicity. The actual dose intensity (DI) of vinorelbine was 17.7 mg/m2/week and that of cisplatin was 24 mg/m2/week. These figures represent 88 and 90% of the theoretical DI, respectively. The overall response rate was 40% (12/30, one CR). The main toxicity was myelosuppression: granulocytopenia WHO grade 3 and 4 in 24 patients (77%) and thrombocytopenia grade 3 in two patients (6%). The non-hematological toxicity was mild and tolerable. After a median follow-up of 7.5 months (range 3-21 months), the median progression-free survival and overall survival times were 5 months (95% CI, 3.8-6.2) and 8 months (95% CI, 4.5-11.5), respectively. CONCLUSIONS: This regimen has a comparable therapeutic activity in patients with advanced lung cancers. However, despite supportive care there were excessive hematological toxicities. In view of increased toxicity and similar efficacy, this regimen is not indicated outside a clinical trial.

Adult↗
PubMed2000

Insulin reverses bupivacaine-induced cardiac depression in dogs.

UNLABELLED: We tested the hypothesis that an insulin infusion would effectively treat bupivacaine-induced cardiac depression in dogs. In 24 mongrel dogs anesthetized with pentobarbital (5 mgkg(-1)h(-1), IV), 0.5% bupivacaine was administrated at a rate of 0.5 mgkg(-1)min(-1) until the mixed venous oxygen saturation decreased to 60% or less. The bupivacaine infusion induced a decrease in mean arterial pressure, cardiac output, and heart rate. The dogs were randomly assigned to one of four groups after the end of bupivacaine infusion. The Control (C, n = 6) and Glucose (G, n = 6) groups received an IV infusion of normal saline (2 mL/kg) and glucose (2 mL/kg of 50% dextrose in water) for 15 min, respectively. The Insulin-Glucose (IG, n = 6) group received an IV bolus of regular insulin (1 U/kg), plus a glucose infusion (2 mL/kg of 50% dextrose in water) for 15 min. The Insulin-Glucose-Potassium (IGK, n = 6) group received the same dose of insulin and glucose as the IG group, plus potassium (1-3 mEqkg(-1)h(-1)). Mean arterial pressure, cardiac output, heart rate, and mixed venous oxygen saturation recovered toward baseline level more rapidly in the IG and IGK groups than in the C group (within 5 min versus more than 20 min). These results suggest that the infusion of insulin and glucose might reverse bupivacaine-induced cardiac depression in dogs. IMPLICATIONS: We found that insulin and glucose rapidly reversed hemodynamic abnormality in dogs with bupivacaine-induced cardiac depression. This study implies a possible clinical application of insulin treatment for bupivacaine-induced cardiac depression.

Anesthetics, Local↗
PubMed2000

Regulation of Brucella abortus catalase.

All aerobic organisms have mechanisms that protect against oxidative compounds. Catalase, peroxidase, superoxide dismutase, glutathione, and thioredoxin are widely distributed in many taxa and constitute elements of a nearly ubiquitous antioxidant metabolic strategy. Interestingly, the regulatory mechanisms that control these elements are rather different depending on the nature of the oxidative stress and the organism. Catalase is well documented to play an important role in protecting cells from oxidative stress. In particular, pathogenic bacteria seem to use this enzyme as a defensive tool against attack by the host. To investigate the significance of catalase in hostile environments, we made catalase deletion mutations in two different B. abortus strains and used two-dimensional gel analysis, survival tests, and adaptation experiments to explore the behavior and role of catalase under several oxidative stress conditions. These studies show that B. abortus strains that do not express catalase activity exhibit increased sensitivity to hydrogen peroxide. We also demonstrate that catalase expression is regulated in this species, and that preexposure to a sublethal concentration of hydrogen peroxide allows B. abortus to adapt so as to survive subsequent exposure to higher concentrations of hydrogen peroxide.

Adaptation, Physiological↗
PubMed2000

Identification of Brucella abortus OxyR and its role in control of catalase expression.

We report the cloning and sequencing of the Brucella abortus oxyR homolog and provide evidence that the transcription product of this gene binds to the B. abortus catalase promoter region. A gene replacement/deletion Brucella oxyR mutant exhibits increased sensitivity to prolonged exposure to H(2)O(2) and is unable to adapt to H(2)O(2) in the environment.

Bacterial Proteins↗
PubMed2000

Ca2+ influx mediates apoptosis induced by 4-aminopyridine, a K+ channel blocker, in HepG2 human hepatoblastoma cells.

Apoptosis appears to be implicated in the pathogenesis and therapeutic applications of cancer. In this study we investigated the induction of apoptosis by 4-aminopyridine (4-AP), a K(+) channel blocker, and its mechanism in HepG2 human hepatoblastoma cells. 4-AP reduced cell viability and induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. In addition, 4-AP induced a sustained increase in intracellular Ca(2+) concentration, which was completely inhibited by the extracellular Ca(2+) chelation with EGTA. 4-AP also induced Mn(2+) influx, indicating that the 4-AP-induced increased intracellular Ca(2+) levels were due to activation of Ca(2+) influx pathway. 4-AP also depolarized membrane potential that was measured by using di-O-C(5)(3), a voltage-sensitive fluorescent dye. 4-AP-induced Ca(2+) influx was significantly inhibited not by voltage-operative Ca(2+) channel blockers (nifedipine or verapamil), but by flufenamic acid (FA), a known nonselective cation channel blocker. Quantitative analysis of apoptosis by the flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca(2+) chelator, significantly inhibited the 4-AP-induced apoptosis. Taken together, these results suggest that the observed 4-AP-induced apoptosis in the HepG2 cells may result from Ca(2+) influx through the activation of voltage-sensitive Ca(2+)-permeable non-selective cation channels. These results further suggest that membrane potential change by modulation of K(+) channel activity may be involved in the mechanism of apoptosis in human hepatoma cells.

4-Aminopyridine↗
PubMed2000

Pseudomembranous necrotizing bronchial aspergillosis.

We report a case of pseudomembranous necrotizing bronchial aspergillosis in a patient with acute myelocytic leukaemia who died of massive haemoptysis. Lobar collapse was demonstrated on chest radiography. CT showed a marked necrotic thickening of the lobar bronchus with extension of the disease in to the peribronchial region.

Aspergillosis↗
PubMed2000

CD4+ T cells in adoptive immunotherapy and the indirect mechanism of tumor rejection.

Tumor-specific CD4+ effector T cells often play a decisive role in immunologic tumor rejection, in some cases without evident co-participation of CD8+ T cells. During such CD4+ T-cell-mediated rejection there is often no detectable direct contact between T cells and tumor cells. Optimally prepared, adoptively transferred CD4+ T cells can reject established tumors with great efficiency even when targeted tumor cells express no MHC Class II molecules, implying that recognition of tumor antigen (Ag) occurs via MHC Class II-expressing host antigen-presenting cells (APC) within the tumor. Because consequent rejection also excludes Ag-specific contact between CD4+ T cells and MHC Class IIneg tumor cells, the most critical CD4+ T-cell-mediated event is likely cytokine release, resulting in an accumulation and activation of accessory cells such as tumoricidal macrophages and lymphokine-activated killer cells. Although such an indirect rejection mechanism may appear antithetical to popular strategies centered on CD8+ cytotoxic T cell (CTL), current evidence suggest that even CD8+ T-cell-mediated recognition/rejection often bypasses direct tumor cell contact and is largely cytokine mediated. While CTL are likely to participate prominently in many models of tumor rejection, indirect mechanisms of recognition/rejection have the theoretical advantage of remaining operative even when individual tumor cells evade direct contact by down-regulating MHC and/or Ag expression.

Animals↗
PubMed2000

Mechanical properties and fiber type composition of chronically inactive muscles.

A role for neuromuscular activity in the maintenance of skeletal muscle properties has been well established. However, the role of activity-independent factors is more difficult to evaluate. We have used the spinal cord isolation model to study the effects of chronic inactivity on the mechanical properties of the hindlimb musculature in cats and rats. This model maintains the connectivity between the motoneurons and the muscle fibers they innervate, but the muscle unit is electrically "silent". Consequently, the measured muscle properties are activity-independent and thus the advantage of using this model is that it provides a baseline level (zero activity) from which regulatory factors that affect muscle cell homeostasis can be defined. In the present paper, we will present a brief review of our findings using the spinal cord isolation model related to muscle mechanical and fiber type properties.

Animals↗
PubMed1999

Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells.

The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca2+. This effect was completely inhibited by the extracellular Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly inhibited by flufenamic acid (FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.

Apoptosis↗
PubMed1999

Glibenclamide induces apoptosis through inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels and intracellular Ca(2+) release in HepG2 human hepatoblastoma cells.

Glibenclamide, an inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels, induced apoptosis in a dose- and time-dependent manner in HepG2 human hepatoblastoma cells. Glibenclamide increased intracellular Ca(2+) concentration, which was significantly inhibited by Ca(2+) release blockers dantrolene and TMB-8. BAPTA/AM, an intracellular Ca(2+) chelator, and the Ca(2+) release blockers significantly inhibited glibenclamide-induced apoptosis. Glibanclamide also increased intracellular Cl(-) concentration, which was significantly blocked by CFTR Cl(-) channel activators levamisole and bromotetramisole. These activators also significantly inhibited both intracellular Ca(2+) release and apoptosis induced by glibenclamide. The expression of CFTR protein in the cells was confirmed by Western blot analysis. These results suggest that glibenclamide induced apoptosis through inhibition of CFTR Cl(-) channels and intracellular Ca(2+) release and that this protein may be a good target for treatment of human hepatomas.

Apoptosis↗
PubMed1999

Cellular immunotherapy for patients with metastatic colorectal carcinoma using lymph node lymphocytes localized in vivo by radiolabeled monoclonal antibody.

BACKGROUND: The authors showed previously that radiolabeled monoclonal antibody (MoAb) and a hand-held, gamma-detecting probe can be used to localize tumor-reactive lymph nodes in vivo. The authors examined the feasibility, safety, and biologic effects of cellular immunotherapy using autologous cells expanded from these lymph nodes in patients with metastatic colorectal carcinoma. METHODS: Tumor-reactive lymph nodes containing radiolabeled MoAb were localized and excised from 32 patients with metastatic, unresectable colorectal carcinoma at laparotomy. Lymph nodes were dissociated, and cells were cultured ex vivo for 10-14 days. Patients received a single infusion of autologous, expanded cells with no systemic interleukin (IL)-2. RESULTS: A mean of 1.6 x 10(10) expanded autologous lymph node cells were infused with toxicity limited to occasional fevers or chills. The cells infused predominately were activated CD3+ T-cells that expressed genes for IL-4, IL-5, interferon-gamma, and granulocyte-macrophage colony stimulating factor (GM-CSF) by using reverse transcriptase-polymerase chain reaction. Indium-111 labeled cells were observed to traffic initially to the lungs, bone marrow, liver, and spleen. One patient on study achieved a partial response (>80% reduction), and mixed or minor responses were noted in 4 other patients. The responding patient's cell characteristics were notable for high levels of GM-CSF and IL-4 secretion on restimulation with immobilized anti-CD3 in vitro, and biopsies of the tumor were characterized by macrophage infiltration. The median survival of the cell-treated group compared favorably with a similar group of patients who underwent radioimmunoguided surgery without cell treatment (12.5 months vs. 5.8 months) CONCLUSIONS: The infusion of cells expanded from tumor-reactive lymph nodes localized with radiolabeled MoAb in vivo is reproducible and safe and has biologic activity, even in the absence of systemic IL-2 infusion. This approach represents a novel application of MoAb technology, in that MoAbs are used not to diagnose or treat disease directly but rather to identify lymph node cells with therapeutic potential.

Adult↗