Biomedical subjects

Kang-Hoe Lee

Publications and source records attributed to Kang-Hoe Lee.

16 recordsLinked to original sources

PubMed2006

Evaluating the pharmacoeconomic effect of adding tiotropium bromide to the management of chronic obstructive pulmonary disease patients in Singapore.

OBJECTIVE: To perform a pharmacoeconomic analysis on the treatment of chronic obstructive pulmonary disease (COPD) with the addition of tiotropium bromide. METHODS: Pharmacoeconomic modeling was performed utilizing the efficacy of tiotropium bromide from the literature on different settings and severity of COPD. Reductions in exacerbations, hospitalizations, and number of exacerbation days per year were derived from these studies. Cost of drug treatment, exacerbations, hospitalization, and loss of income were derived from local data in Singapore and reported in Singapore dollars (US$1=S$1.71). A model was constructed to calculate the impact of one-year treatment with tiotropium bromide, and the results were reported for the total incremental cost per year, cost per year needed to reduce one hospitalization in one year, and cost-savings from hospitalizations in one year. Sensitivity analysis were performed for different number of patients treated per year, differing cost of hospitalization, different cost for tiotropium bromide, different impact of tiotropium bromide on clinical outcomes, and the different amount of substitution drug utilized in the comparator group. RESULTS: Using the different clinical effects and looking at the impact on treating 1000, 2000, and 10,000 patients per year, most of the results showed a high level of decrease in overall cost per year that ranged from S$145.40 to S$840.37 per patient treated. Cost per year needed to reduce one hospitalization in one year ranged from S$3217.31 to S$18,148.92. Cost-savings from hospitalizations in one year per patient treated ranged from $57.16 to $322.49. This may contribute as high as 83% of the overall cost saving. Sensitivity analysis supports the cost savings finding. CONCLUSION: Adding tiotropium bromide for severe COPD patients would lead to a significant cost savings for the economy.

Bronchodilator Agents↗

PubMed2005

Temporal expression of hepatic inducible nitric oxide synthase in liver cirrhosis.

AIM: Nitric oxide (NO) has been implicated in the pathogenesis of liver cirrhosis. We have found inducible nitric oxide synthase (iNOS) can be induced in hepatocytes of cirrhotic liver. This study further investigated the temporal expression and activity of hepatic iNOS in cirrhosis development. METHODS: Cirrhosis was induced in rats by chronic bile duct ligation (BDL). At different time points after the operation, samples were collected to examine NO concentration, liver function, and morphological changes. Hepatocytes were isolated for determination of iNOS mRNA, protein and enzymatic activity. RESULTS: Histological examination showed early cirrhosis 1-2 wk after BDL, with advanced cirrhosis at 3-4 wk. Bilirubin increased dramatically 3 d after BDL, but decreased by 47% on d 14. Three weeks after BDL, it elevated again. Systemic NO concentration did not increase significantly until 4 wk after BDL, when ascites developed. Hepatocyte iNOS mRNA expression was identified 3 d after BDL, and enhanced with time to 3 wk, but reduced thereafter. iNOS protein showed a similar pattern to mRNA expression. iNOS activity decreased from d 3 to d 7, but increased again thereafter till d 21. CONCLUSION: Hepatic iNOS can be induced in the early stage, which increases with time as cirrhosis develops. Its enzymatic activity is significantly correlated with protein expression and histological alterations of the liver, but not with systemic NO levels, nor with absolute values of liver function markers.

Animals↗

PubMed2005

Overexpression of cyclooxygenase-2 in nasopharyngeal carcinoma and association with epidermal growth factor receptor expression.

OBJECTIVES: To examine the association between cyclooxygenase-2 (COX-2) expression with epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and latent membrane protein 1 (LMP-1) expression and with COX-2 promoter methylation status in primary nasopharyngeal cancer (NPC) tumors and to determine COX-2 promoter methylation status in NPC cell lines. DESIGN: Retrospective study. SETTING: Patients with NPC were referred to the Department of Otolaryngology-Head and Neck Surgery for treatment. PATIENTS: Formalin-fixed, paraffin-embedded NPC specimens from 42 patients were obtained. INTERVENTIONS: Immunohistochemical expression of COX-2, EGFR, VEGF, iNOS, and LMP-1 was performed in 42 NPC samples. COX-2 promoter methylation status was studied in 20 separate specimens and in 4 NPC cell lines. MAIN OUTCOME MEASURES: (1) COX-2, EGFR, VEGF, iNOS, and LMP-1 expression; and (2) COX-2 promotor methylation status. RESULTS: COX-2 was overexpressed in 79% of NPC specimens and was associated with EGFR status (P = .03) but not with LMP-1 or iNOS. In primary NPC tissue, methylation of the COX-2 promoter was seen in 4 of 7 COX-2-negative and 1 of 13 COX-2-positive immunohistochemical cases. COX-2 promoter methylation was found in the CNE-1 cell line. CONCLUSIONS: Nasopharyngeal cancer may be a useful target for selective COX-2 inhibition. The absence of promoter methylation may be a necessary component of COX-2 overexpression, and promoter methylation may be one of the mechanisms that regulate COX-2 expression.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Chronic administration of aminoguanidine reduces vascular nitric oxide production and attenuates liver damage in bile duct-ligated rats.

BACKGROUND: Nitric oxide (NO) has been implicated in the pathogenesis of liver cirrhosis. This study investigated the activity of nitric oxide synthase (NOS) in cirrhosis induced by bile duct-ligation (BDL) with NOS inhibitors. METHOD: Three days after operation, rats were randomized to receive aminoguanidine (AG, 25 mg/kg/day) or L-N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg/day) for 21 days. RESULTS: Vascular NO production, which was increased in BDL cirrhotic rats, was reduced by 75% with AG but not L-NAME chronic administration. AG treatment attenuated liver damage, while L-NAME aggravated it. AG significantly suppressed inducible NOS (iNOS) expression in aorta of BDL rats at both mRNA and protein level, but much less efficient in reducing it in liver. In contrast, endothelial NOS (eNOS) expression was not markedly affected. Calcium-independent NOS activity, which was dramatically increased in aorta of BDL rats, was abolished by AG treatment. In liver, however, both calcium-dependent and -independent NOS activity were increased by AG treatment. CONCLUSION: Chronic administration of AG could reduce systemic NO levels as well as suppress iNOS expression and activity in aorta of BDL rats. It also improved liver function, possibly because of its ability to increase hepatic NOS activity, and to correct the systemic hemodynamic disorders by decreasing vascular NO production.

Animals↗

PubMed2005

Outcome from molecular adsorbent recycling system (MARS) liver dialysis following drug-induced liver failure.

RATIONALE: Fulminant liver failure from drug ingestion is associated with a high mortality, and the introduction of liver transplantation has improved the mortality significantly if done in a timely fashion. Recently, molecular adsorbent recycling system (MARS) liver dialysis has been introduced as a support for liver failure with varying results. We review our experience with drug-induced liver failure and the impact of MARS liver dialysis on the outcome, in a setting where cadaveric liver transplantation is rarely available. RESULTS: A total of 13 patients were treated, and 40 sessions of MARS liver dialysis were conducted in the intensive care unit. The majority of cases were because of herbal medicine toxicity. Total bilirubin, conjugated bilirubin, and delta bilirubin were significantly reduced, with no change in unconjugated bilirubin. All patients satisfied the criteria for urgent liver transplantation with an average Model End Stage Liver Disease (MELD) score of 35. Only one patient received a liver transplantation from a live donor (right lobe). Overall mortality was 85%. Median time-to-death from the start of MARS was 8 days. CONCLUSIONS: MARS liver dialysis in a setting without timely liver transplantation is associated with a poor outcome. It does, however, provide a window of time for consideration of living donors in the setting of limited cadaveric donors.

Adult↗

PubMed2005

In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: a retrospective study.

STUDY OBJECTIVES: The prognosis of patients with COPD requiring admission to the ICU is generally believed to be poor. There is a paucity of long-term survival data. We undertook a study to examine both the in-hospital and 5-year mortality rates and to identify the clinical predictors of these outcomes. DESIGN: We conducted a retrospective cohort study of 57 patients admitted to the ICU between January 1999 and December 2000 for acute respiratory failure attributable to COPD. RESULTS: The mean (+/-SD) age of the study population was 70 +/- 8 years. More than 90% of patients required intubation, and the mean duration of mechanical ventilation (MV) was 2.3 +/- 2.2 days. The in-hospital mortality rate for the entire cohort was 24.5%. The mortality rates at 6 months and 1, 3, and 5 years were 39.0%, 42.7%, 61.2%, and 75.9%, respectively, following admission to the ICU. The median survival time for all patients was 26 months. The mortality rate at 5 years was 69.6% for patients who were discharged alive from the hospital. Using multivariate analysis, hospital mortality correlated positively with age, previous history of MV, long-term use of oral corticosteroids, ICU admission albumin level, APACHE (acute physiology and chronic health evaluation) II score, and duration of hospitalization. No factors predictive of mortality at 5 years were identified. CONCLUSIONS: We support previous findings of good early survival and significant but acceptable long-term mortality rates in patients who have been admitted to the ICU for acute exacerbation of COPD. Increased age, previous history of MV, poor nutritional status, and higher APACHE II score on ICU admission could be identified as risk factors associated with increased mortality rates. Long-term survival of patients with COPD who required MV for an acute exacerbation of their disease cannot be predicted simply from data available at the time of intubation. Physicians should incorporate these factors in their decision-making process.

Acute Disease↗

PubMed2003

Feasibility of using low-volume tissue samples for gene expression profiling of advanced non-small cell lung cancers.

PURPOSE: The majority of patients with non-small cell lung cancer (NSCLC) present at an advanced clinical stage, when surgery is not a recommended therapeutic option. In such cases, tissues for molecular research are usually limited to the low-volume samples obtained at the time of diagnosis, usually via fine-needle aspiration (FNA). We tested the feasibility of performing gene expression profiling of advanced NSCLCs using amplified RNA from lung FNAs. EXPERIMENTAL DESIGN AND RESULTS: A total of 46 FNAs was tested, of which 18 yielded RNA of sufficient quality for microarray analysis. Expression profiles of these 18 samples were compared with profiles of 17 pairs of tumor and normal lung tissues that had been surgically obtained. Using a variety of unsupervised and supervised analytical approaches, we found that the FNA profiles were highly distinct from the normal samples and similar to the tumor profiles. CONCLUSIONS: We conclude that when RNA amplification is successful, gene expression profiles from NSCLC FNAs can determine malignancy and suggest that with additional refinement and standardization of sample collection and RNA amplification protocols, it will be possible to conduct additional and more detailed molecular analysis of advanced NSCLC using lung FNAs.

Biopsy, Needle↗

PubMed2003

Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers.

The ubiquitin-like modifier (UBL) family has recently generated much interest in the scientific community, as it is implicated to play important regulatory roles via novel protein-protein modification. FAT10 (diubiquitin) belongs to this family of proteins, comprising two ubiquitin-like moieties fused in tandem, and has been implicated to be involved in the maintenance of spindle integrity during mitosis. As FAT10 may play a role in the regulation of genomic stability, we examined if there is an association between FAT10 expression and hepatocellular carcinoma (HCC) or other cancers. Northern blot analyses revealed upregulation of FAT10 expression in the tumors of 90% of HCC patients. In situ hybridization as well as immunohistochemistry utilizing anti-FAT10 antibodies localized highest FAT10 expression in the nucleus of HCC hepatocytes rather than the surrounding immune and non-HCC cells. FAT10 expression was also found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system. In conclusion, we demonstrated upregulation of FAT10 expression in various gastrointestinal and gynecological cancers. Its overexpression is unrelated to the general increase in protein synthesis or a general immune/inflammatory response to cancer. Rather, FAT10 may modulate tumorigenesis through its reported interaction with the MAD2 spindle-assembly checkpoint protein.

Carcinoma, Hepatocellular↗

PubMed2003

Expression of haem oxygenase in cirrhotic rat liver.

The haem oxygenase (HO)/carbon monoxide (CO) system has been implicated as a modulator of hepatobiliary function. This study investigated HO expression in the process of cirrhosis development, as well as its relationship to nitric oxide synthase (NOS). Liver cirrhosis was induced in rats by chronic bile duct ligation (BDL). HO mRNA expression was evaluated by competitive RT-PCR, while protein expression was determined by immunoblotting and immunohistochemistry. In liver tissue where cirrhosis had fully developed, the expression levels of HO-1 were greatly enhanced at both mRNA and protein level compared with sham livers. Immunohistochemistry showed that HO-1 was induced in hepatocytes and enhanced in some of the Kupffer-like cells in BDL livers. In contrast, there was no difference between the sham and the BDL livers for the expression levels of HO-2. Interestingly, administration of the NOS inhibitor aminoguanidine (AG) or N(G)-nitro-L-arginine methyl ester inhibited HO-1 expression. To study further the role of HO-1 in the development of liver cirrhosis, hepatocytes were isolated from the rats at different time points after BDL operation. HO-1 was expressed in hepatocytes at high levels during the early onset of cirrhosis but dropped slightly at a later stage of cirrhosis. Zinc protoporphyrin IX (ZnPP), an HO inhibitor, blocked HO-1 expression in hepatocytes from BDL cirrhotic rats, but enhanced the activity of inducible NOS (iNOS) in BDL hepatocytes. In conclusion, HO-1 was induced in the hepatocytes of rats undergoing cirrhosis, suggesting that HO-1 plays a role in the development of liver cirrhosis. Induction of HO-1 may be mediated partially by iNOS. However, once it is induced, HO-1 may be important in modulating iNOS activity, thus playing a protective role in liver cirrhosis.

Animals↗

PubMed2003

Hypoglycemia in nondiabetic patients undergoing albumin dialysis by molecular adsorbent recirculating system.

It was observed that patients developed episodes of hypoglycemia during molecular adsorbent recycling system (MARS) treatment. The aim of this study is to assess the effect of MARS treatment on blood glucose concentration to formulate appropriate dextrose replacement guidelines during MARS dialysis. Five patients with liver failure each underwent a 6- to 8-hour MARS treatment. No patient had a history of diabetes or was administered insulin or oral antihyperglycemic agents throughout the period of albumin dialysis. There was no active intervention or restriction on glucose intake. Rather, a dextrose drip and boluses were allowed based on each patient's condition and the clinical judgment of the attending physician. Blood glucose concentration was monitored hourly during the period of MARS treatment. Glucose loss in dialysate fluid was quantified hourly by measuring the total volume of dialysate fluid and assaying the glucose concentration in dialysate fluid. Mean glucose removal during a 6-hour MARS session was 37.19 +/- 5.58 g. Mean glucose removal rate was 6.20 +/- 0.93 g/h. In addition to a maintenance drip supporting the caloric requirement of patients, a dextrose replacement drip that paralleled the rate of glucose removal would prevent patients from experiencing episodes of hypoglycemia during MARS treatment. Dextrose replacement at a mean rate of 6 g/h (range, 5 to 7 g/h) in patients without diabetes undergoing albumin dialysis by MARS is recommended.

Adult↗

PubMed2003

Acute liver failure with concurrent bupropion and carbimazole therapy.

OBJECTIVE: To report a case of fatal liver failure possibly associated with concurrent use of bupropion and carbimazole. CASE SUMMARY: A 41-year-old Chinese man with a history of hyperthyroidism had been treated with carbimazole and propranolol for the past 5 years. He received a 10-day course of bupropion as an aid for smoking cessation 10 weeks prior to presentation. He developed acute liver failure with rapid deterioration of renal function. Liver biopsy showed evidence of nonspecific drug-induced acute liver injury. His condition was further complicated by sepsis and coagulopathy. Death resulted 19 days after the onset of symptoms. The likelihood that bupropion induced hepatotoxicity in our patient was possible, based on the Naranjo probability scale. DISCUSSION: Although there is increasing evidence of hepatotoxicity induced by bupropion, this is the first case of fatality that could have resulted from acute liver failure in a patient receiving bupropion while on concomitant treatment with carbimazole. CONCLUSIONS: Clinicians should be aware of the possibility of acute liver insult induced by bupropion given concurrently with other hepatotoxic drugs.

Bupropion↗

PubMed2003

Role of clinical judgment in the application of a nucleic acid amplification test for the rapid diagnosis of pulmonary tuberculosis.

BACKGROUND: Several nucleic acid amplification (NAA) tests for Mycobacterium tuberculosis (MTB) have been licensed for the rapid diagnosis of active pulmonary tuberculosis (PTB) in respiratory secretions. There is uncertainty however regarding the practical application of these tests in clinical decision making. OBJECTIVE: To evaluate the utility of the COBAS AMPLICOR assay (Roche Diagnostics; Singapore) for MTB as applied by specialists for the rapid diagnosis of PTB in the routine clinical setting. DESIGN: A prospective study of consecutive patients suspected of PTB and tested with the AMPLICOR assay under the care of respiratory physicians. The final diagnosis was based on all relevant clinical information after at least 3 months of follow-up. Accuracy of the NAA test was compared with that of the initial expectant treatment. Expectant treatment was based on an integrated approach that incorporated clinical evaluation with results of direct smear and NAA tests. RESULTS: The incidence of PTB in 168 patients was 32%. The basis for expectant treatment of PTB was positive smear result in 47%, clinical suspicion in 26%, and positive AMPLICOR result in 23%. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the AMPLICOR test were 77%, 100%, 99%, 90%, and 93%, respectively. In comparison, they were 96%, 97%, 94%, 98%, and 97%, respectively, for the integrated clinical approach. CONCLUSIONS: In the rapid diagnosis of PTB, the clinical judgment of specialists augmented the utility of the NAA test: (1) specialists selected patients with high-to-moderate pretest probabilities, (2) they commenced treatment promptly on a positive NAA test result, and (3) they were willing to start treatment in some patients on the basis of high clinical suspicion despite negative smear and negative NAA test results.

Adolescent↗

PubMed2002

Induction of arginase II in livers of bile duct-ligated rats.

Nitric oxide (NO) has been implicated in playing a role in liver cirrhosis, but the regulatory mechanisms are still unclear. As arginase shares a common substrate with NO synthase (NOS), the aim of this study was to investigate the expression of arginase I and II in cirrhotic liver. Liver cirrhosis was induced in rats by chronic bile duct ligation (BDL). Controls were sham-operated. Competitive polymerase chain reaction was performed to assay the expression of messenger RNA of arginase I and II. Protein expression was detected by immunohistochemistry and western-blotting. The level of arginine in plasma was lower in BDL rats, while the ornithine level in plasma was correspondingly higher (r= -0.96, P<0.0001). Arginase I messenger RNA was reduced significantly in BDL rats (3.34+/-0.32 vs. 1.32+/-0.21 x 10(4) attomole/microg of total RNA, sham vs. BDL, P<0.001), as well as arginase I protein. In contrast, arginase II mRNA was induced in the livers of BDL rats, with negligible expression in controls (0.35+/-0.11 vs. 3.64+/-0.54 attomole/microg of total RNA, sham vs. BDL, P<0.001). Arginase II protein was localized in some hepatocytes and hyperplastic bile ductular epithelial cells of cirrhotic livers but not in control livers. In conclusion, arginase II was induced in BDL livers, while the expression of arginase I was down-regulated. These data suggest that arginase I and II are regulated differently and may have different functions in the livers of BDL rats. Reduction of arginase I in BDL livers may be responsible for the lowering of arginine levels in the plasma, while induction of arginase II could be important in regulating NO synthesis as well as other important mechanisms involved in liver cirrhosis.

Animals↗

PubMed2002

Differential expression and localization of nitric oxide synthases in cirrhotic livers of bile duct-ligated rats.

Increased vascular nitric oxide (NO) production has been implicated in the pathogenesis of the hyperdynamic circulation in liver cirrhosis. This study investigated the expression of three isoforms of NO synthase (NOS) in rat cirrhotic livers. Cirrhosis was induced by chronic bile duct ligation (BDL). NOS enzyme activity was assessed by L-citrulline generation. Competitive RT-PCR was performed to detect the mRNA levels of NOS. In situ hybridization was done to localize NOS mRNA. Protein expression of NOS was evaluated by Western blotting and immunohistochemistry. The L-citrulline assay showed that constitutive NOS (cNOS) enzymatic activity was decreased, while inducible NOS (iNOS) activity was increased in BDL livers. Both endothelial NOS (eNOS) and neuronal NOS (nNOS) mRNA were detected in BDL and sham rats, but with enhanced expression in BDL rats. eNOS protein was redistributed with less expression in sinusoidal endothelial cells, but the total levels in liver were not changed. nNOS was induced in hepatocytes of BDL rats, in contrast to only a weak signal observed around some blood vessels in sham livers. Intense mRNA and protein expression of iNOS was induced in livers of BDL rats and was localized in hepatocytes, with no or a negligible amount in control livers. In conclusion, iNOS was induced in cirrhotic liver with its activity increased. In contrast, cNOS activity was impaired, regardless of unchanged eNOS protein levels and enhanced nNOS expression. These results suggest that all three types of NOS have a role in cirrhosis, but their expression and regulation are different.

Animals↗

PubMed2002

What is the optimal approach for using a direct amplification test in the routine diagnosis of pulmonary tuberculosis? A preliminary assessment.

OBJECTIVE: The aim of this study was to determine the most appropriate strategy for the rapid diagnosis of pulmonary tuberculosis (PTB) using a nucleic acid amplification (NAA) test. METHODOLOGY: This was a prospective study of 128 adult patients in whom respiratory secretions were tested for Mycobacterium tuberculosis by the AMPLICOR assay. The basis for starting PTB treatment was noted for each patient. The optimal approach was determined by using Bayes' theorem to compare different combinations of pretest probability, smear results with the AMPLICOR test. RESULTS: The incidence of PTB was 15.6%. In only one patient was treatment for PTB commenced because of a positive AMPLICOR result. The rest were managed according to the conventional approach which relied upon clinical judgment and direct smear. The optimal approach was to treat patients with high or intermediate pretest risk for PTB who returned positive AMPLICOR tests. The overall accuracies of the conventional approach, AMPLICOR test and optimal approach were 89.8, 95.3 and 96.1%, respectively. CONCLUSION: This small study suggests that NAA testing be limited to patients with high or intermediate pretest risk of PTB. In this group, positive results demand treatment while the management of those with negative results still relies on clinical judgment.

Adult↗

PubMed2002

Predicting the decrease of conjugated bilirubin with extracorporeal albumin dialysis MARS using the predialysis molar ratio of conjugated bilirubin to albumin.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system (MARS) machine is a new supportive intervention for patients with liver failure. It removes bilirubin and other albumin-bound toxins from the patient and has been shown by preliminary studies of liver failure patients to be beneficial. Our study examines the ability of predialysis molar ratio of bilirubin to albumin to predict the decrease of bilirubin by MARS. We had 5 patients and results from 29 treatments. The results showed a significant correlation between the predialysis molar ratio of bilirubin (total and conjugated) to albumin to the reduction in bilirubin (total and conjugated): R(2) = 0.27 and 0.62 respectively, P <.005 for both. There was no significant correlation with the predialysis molar ratio of unconjugated bilirubin to albumin to the reduction in unconjugated bilirubin. The ratio of change in total bilirubin (micromol/L) to the predialysis molar ratio of total bilirubin to albumin and the ratio of change in conjugated bilirubin (micromol/L) to the predialysis molar ratio of conjugated bilirubin to albumin were 6.2 (+/- 4.2) and 10.8 (+/- 4.3), respectively (mean (+/- SD)). The results enable us to predict the likely reduction in bilirubin (especially conjugated) after each MARS treatment and also suggest to us that albumin infusion before MARS treatment may reduce the efficacy of bilirubin removal. Whether this ratio applies to other albumin-bound toxins remains open for investigation.

Bilirubin↗