Showing papers by "Taipei Veterans General Hospital published in 2011"

Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan

Abstract: Background Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS–TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS–TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. Methods From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them ...

Matrix stiffness regulation of integrin‐mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells

Abstract: Mesenchymal stem cells (MSCs) cultured on extracellular matrices with different stiffness have been shown to possess diverse lineage commitment owing to the extracellular mechanical stimuli sensed by the cells. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through the mechanotransducers Rho kinase (ROCK) and focal adhesion kinase (FAK) and subsequently regulates the osteogenic phenotype of MSCs. MSCs were cultured in osteogenic medium on tunable polyacrylamide hydrogels coated with type I collagen with elasticities corresponding to Young's modulus of 7.0 ± 1.2 and 42.1 ± 3.2 kPa. Osteogenic differentiation was increased on stiffer matrices, as evident by type I collagen, osteocalcin, and Runx2 gene expressions and alizarin red S staining for mineralization. Western blot analysis demonstrated an increase in kinase activities of ROCK, FAK, and ERK1/2 on stiffer matrices. Inhibition of FAK, an important mediator of osteogenic differentiation, and inhibition of ROCK, a known mechanotransducer of matrix stiffness during osteogenesis, resulted in decreased expression of osteogenic markers during osteogenic induction. In addition, FAK affects osteogenic differentiation through ERK1/2, whereas ROCK regulates both FAK and ERK1/2. Furthermore, α2-integrin was upregulated on stiffer matrices during osteogenic induction, and its knockdown by siRNA downregulated the osteogenic phenotype through ROCK, FAK, and ERK1/2. Taken together, our results provide evidence that the matrix rigidity affects the osteogenic outcome of MSCs through mechanotransduction events that are mediated by α2-integrin. © 2011 American Society for Bone and Mineral Research.

Taiwan's National Health Insurance Research Database: administrative health care database as study object in bibliometrics

Abstract: The trend to use administrative health care databases as research material is increasing but not well explored. Taiwan's National Health Insurance Research Database (NHIRD), one of the largest administrative health care databases around the world, has been used widely in academic studies. This study analyzed 383 NHIRD studies published between 2000 and 2009 to quantify the effects on overall growth, scholar response, and spread of the study fields. The NHIRD studies expanded rapidly in both quantity and quality since the first study was published in 2000. Researchers usually collaborated to share knowledge, which was crucial to process the NHIRD data. However, once the fundamental problem had been overcome, success to get published became more reproducible. NHIRD studies were also published diversely in a growing number of journals. Both general health and clinical science studies benefited from NHIRD. In conclusion, this new research material widely promotes scientific production in a greater magnitude. The experience of Taiwan's NHIRD should encourage national- or institutional-level data holders to consider re-using their administrative databases for academic purposes.

Klebsiella pneumoniae outer membrane porins OmpK35 and OmpK36 play roles in both antimicrobial resistance and virulence

Abstract: OmpK35 and OmpK36 are the major outer membrane porins of Klebsiella pneumoniae. In this study, a virulent clinical isolate was selected to study the role of these two porins in antimicrobial resistance and virulence. The single deletion of ompK36 (ΔompK36) resulted in MIC shifts of cefazolin, cephalothin, and cefoxitin from susceptible to resistant, while the single deletion of ompK35 (ΔompK35) had no significant effect. A double deletion of ompK35 and ompK36 (ΔompK35/36) further increased these MICs to high-level resistance and led to 8- and 16-fold increases in the MICs of meropenem and cefepime, respectively. In contrast to the routine testing medium, which is of high osmolarity, susceptibility tests using low-osmolarity medium showed that the ΔompK35 mutation resulted in a significant (≥ 4-fold) increase in the MICs of cefazolin and ceftazidime, whereas a ΔompK36 deletion conferred a significantly (4-fold) lower increase in the MIC of cefazolin. In the virulence assays, a significant (P < 0.05) defect in the growth rate was found only in the ΔompK35/36 mutant, indicating the effect on metabolic fitness. A significant (P < 0.05) increase in susceptibility to neutrophil phagocytosis was observed in both ΔompK36 and ΔompK35/36 mutants. In a mouse peritonitis model, the ΔompK35 mutant showed no change in virulence, and the ΔompK36 mutant exhibited significantly (P < 0.01) lower virulence, whereas the ΔompK35/36 mutant presented the highest 50% lethal dose of these strains. In conclusion, porin deficiency in K. pneumoniae could increase antimicrobial resistance but decrease virulence at the same time.

Comorbidity profiles among patients with alopecia areata: the importance of onset age, a nationwide population-based study.

Abstract: Background Alopecia areata (AA) is considered an autoimmune disease with undetermined pathogenesis. Age at onset predicts distinct outcomes. A nationwide study of the relationship of AA with associated diseases stratified by onset age has rarely been reported. Objective We sought to clarify the role of atopic and autoimmune diseases in AA, thereby better understanding its pathogenesis. Methods A total of 4334 patients with AA were identified from the National Health Insurance Database in Taiwan from 1996 to 2008. A national representative cohort of 784,158 persons served as control subjects. Results Among patients with AA, there were significant associations with vitiligo, lupus erythematosus, psoriasis, atopic dermatitis, autoimmune thyroid disease, and allergic rhinitis. Different ages at onset resulted in disparate comorbidities. Increased risk of atopic dermatitis (odds ratio [OR] 3.82, 95% confidence interval 2.67-5.45) and lupus erythematosus (OR 9.76, 95% confidence interval 3.05-31.21) were found in childhood AA younger than 10 years. Additional diseases including psoriasis (OR 2.43) and rheumatoid arthritis (OR 2.57) appeared at onset age 11 to 20 years. Most atopic and autoimmune diseases were observed at onset ages of 21 to 60 years. With onset age older than 60 years, thyroid disease (OR 2.52) was highly related to AA. Moreover, patients with AA had higher risk for more coexisting diseases than control subjects. Limitations We could not differentiate hypothyroidism from hyperthyroidism. Conclusions AA is related to various atopic and autoimmune diseases. Different associated diseases in each onset age group of AA can allow clinician to efficiently investigate specific comorbidities.

Self-Organizing and Stochastic Behaviors During the Regeneration of Hair Stem Cells

Abstract: Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs.

Molecular Typing and Virulence Analysis of Serotype K1 Klebsiella pneumoniae Strains Isolated from Liver Abscess Patients and Stool Samples from Noninfectious Subjects in Hong Kong, Singapore, and Taiwan

Abstract: Serotype K1 Klebsiella pneumoniae with multilocus sequence type 23 (ST23) has been strongly associated with liver abscess in Taiwan. Few data regarding the strain types and virulence of this serotype from other Asian countries are available. Serotype K1 K. pneumoniae strains isolated from liver abscess and stool samples from subjects hospitalized in Hong Kong, Singapore, and Taiwan hospitals were examined. Forty-seven serotype K1 isolates were identified: 26 from liver abscess samples and 21 from stool samples. MLST revealed 7 sequence types: 85.1% (40 of 47 isolates) belonged to ST23, 1 isolate belonged to ST163 (a single-locus variant of ST23), and 2 isolates were ST249 (a 3-locus variant of ST23). New STs, namely, ST367, ST425, and ST426, were allocated to 3 of 4 isolates from stool samples. The virulence of these strains was determined by neutrophil phagocytosis and mouse infection models. Except for two ST23 isolates, all Klebsiella pneumoniae isolates were resistant to phagocytosis. Resistance to serum killing varied in isolates of ST23, while all non-ST23 strains were susceptible to serum killing except one with ST249 from a liver abscess. All hypervirulent isolates with a 50% lethal dose of <10(2) CFU were from ST23, were resistant to phagocytosis and serum killing, and also carried both virulence-associated genes, rmpA and aerobactin. Multilocus sequence typing genotype 23 was the most prevalent sequence type among serotype K1 K. pneumoniae isolates from both liver abscess and stool samples in the Asia Pacific region. Serotype K1 K. pneumoniae isolates with capsule expression leading to phagocytic resistance and with the aerobactin gene were associated with hypervirulence.

Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study.

Abstract: BACKGROUND: The possible effect of pulmonary tuberculosis (TB) on subsequent lung cancer development has been suspected, but the evidence remains inconsistent The purpose of this study was to perform a nationwide population-based cohort study to investigate the risk of lung cancer after pulmonary TB infection METHODS: This nationwide population-based cohort study was based on data obtained from the Taiwan National Health Insurance Database In total, 5657 TB patients and 23,984 controls matched for age and sex were recruited for the study from 1997 to 2008 RESULTS: The incidence rate of lung cancer (269 of 100,000 person-years) was significantly higher in the pulmonary TB patients than that in controls (153 of 100,000 person-years) (incidence rate ratio [IRR], 176; 95% confidence interval [CI], 133-232; P < 001) Compared with the controls, the IRRs of lung cancer in the TB cohort were 198 at 2 to 4 years, 142 at 5 to 7 years, and 159 at 8 to 12 years after TB infections The multivariate Cox proportional hazards model revealed pulmonary TB infections (hazard ratio [HR], 164; 95% CI, 124-215; P < 001) and chronic obstructive pulmonary disease (HR, 109; 95% CI, 103-114; P = 002) to be independent risk factors for lung cancer CONCLUSIONS: Pulmonary infection with TB is associated with an increased risk of lung cancer Cancer 2011 © 2010 American Cancer Society

Hypoxia Inhibits Osteogenesis in Human Mesenchymal Stem Cells through Direct Regulation of RUNX2 by TWIST

Abstract: Background Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxic conditions and readily differentiate into osteoblasts by standard induction protocols, they are a good in vitro model to study the effects of hypoxia on osteoblast differentiation.

Comorbidity profiles among patients with bullous pemphigoid: a nationwide population‐based study

Abstract: Summary Background Bullous pemphigoid (BP) has been associated with neurological and psychiatric diseases; however, large-scale population-based study of different comorbid diseases in patients with BP is quite limited. Objectives We sought to analyse the prevalence of neurological, psychiatric, autoimmune and inflammatory skin diseases prior to the diagnosis of BP and their associations with BP among patients with BP from a nationwide database in Taiwan. Methods A total of 3485 patients with BP and 17 425 matching controls were identified from the National Health Insurance Database in Taiwan from 1997 to 2008. Conditional logistic regression analyses for a nested case–control study were performed to examine the prevalence of comorbidities prior to the diagnosis of BP between these two groups. Results Overall, our results showed that stroke [odds ratio (OR) 3·30; 95% confidence interval (95% CI) 3·03–3·60], dementia (OR 4·81; 95% CI 4·26–5·42), Parkinson disease (OR 3·49; 95% CI 3·05–3·98), epilepsy (OR 3·97; 95% CI 3·28–4·81), schizophrenia (OR 2·56; 95% CI 1·52–4·30) and psoriasis (OR 2·02; 95% CI 1·54–2·66) were significantly associated with BP. Among them, the association with schizophrenia and psoriasis was predominant in female and male patients, respectively, with BP. It remains for all these comorbid diseases to be independently associated with BP by multivariate analysis. Conclusions Patients with BP are more likely to have various neurological diseases, schizophrenia and psoriasis prior to the diagnosis of BP, supporting associations found in other studies. Further research is required to elucidate the tentative causal association with BP.

MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells.

Abstract: MicroRNA-200c (miR200c) is emerging as an important regulator of tumourigenicity and cancer metastasis with a strong capacity for inducing epithelial-mesenchymal transitions. However, the role of miR200c in head and neck squamous cell carcinoma (HNSCC) and HNSCC-associated cancer stem cells (HNSCC-CSCs) is unknown. In this study, the expression of miR200c in the regional metastatic lymph node of HNSCC tissues was significantly decreased, but BMI1 expression was increased as compared to parental tumours. Importantly, site-directed mutagenesis with a luciferase reporter assay showed that miR200c targeted the 3' UTR of BMI1 in HNSCC cells. Isolated HNSCC-derived ALDH1(+) /CD44(+) cells displayed CSC-like tumour initiating and radio-resistant properties. The expression levels of miR200c were significantly down-regulated while BMI1 was increased in HNSCC-ALDH1(+) /CD44(+) compared to the other subsets of HNSCC cells. Furthermore, increased miR200c expression or knockdown of BMI1 could significantly inhibit the malignant CSC-like properties of ALDH1(+) /CD44(+) cells. miR200c over-expression further down-regulated the expressions of ZEB1, Snail and N-cadherin, but up-regulated E-cadherin expression in ALDH1(+) /CD44(+) cells. Finally, a xenotransplantion study confirmed that over-expression of miR200c or BMI1 knockdown effectively inhibited the lung metastatic ability and prolonged the survival rate of ALDH1(+) /CD44(+) -transplanted mice. In summary, miR200c negatively modulates the expression of BMI1 but also significantly inhibits the metastatic capability of epithelial-mesenchymal transitions in malignant HNSCC by reducing the expression of BMI1/ZEB1. Restoration of miR200c in HNSCC and CSCs may be a promising therapeutic approach.

Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27

Abstract: BACKGROUND: In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells). METHODS: A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence-based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell-enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model. RESULTS: Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase-9 and caspase-3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy-induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo. CONCLUSIONS: The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy. Cancer 2011. © 2010 American Cancer Society.

miR-181 as a putative biomarker for lymph-node metastasis of oral squamous cell carcinoma

Abstract: J Oral Pathol Med (2011) 40: 397–404 Background: Oral squamous cell carcinoma (OSCC) is an important malignant disease around the world. Aberrant expression of MicroRNAs (miRNAs) has been implicated in carcinogenesis of various cancers. In previous studies, up-regulation of miR-181 was observed when OSCC progressed from leukoplakia, dysplasia to invasive carcinoma. However, the function of miR-181 in oral tumorigenesis remains unclear. Materials and methods: The expression levels of miR-181 in the tissue and plasma of OSCC patients were measured by quantitative RT-PCR. The correlation between miR-181 level and multiple clinical variables were then checked by Mann–Whitney test and Wilcoxon matched pairs test. To study the functional meaning of up-regulated miR-181, migration assay and invasion assay by transwells and colony forming assay were applied to analyze the tumorigenic phenotypes of OSCC cells with ectopical expression of miR-181. Results: Among different clinical variables, over-expression of miR-181 was correlated with lymph-node metastasis, vascular invasion, and a poor survival. Functional assays revealed ectopically over-expressed miR-181 would enhance cell migration and invasion, but not the ability of anchorage-independent growth of OSCC cells. In addition, the up-regulation of miR-181 could be detected both in tumor tissues and plasma. Conclusion: miR-181 may enhance lymph-node metastasis through regulating migration, which could potentially be exploited as a putative biomarker for patients with OSCC.

Maneuvers to decrease laparoscopy-induced shoulder and upper abdominal pain: A randomized controlled study

Abstract: Objective To evaluate the effectiveness of the pulmonary recruitment maneuver (PRM) and intraperitoneal normal saline infusion (INSI) in removing postlaparoscopic carbon dioxide from the abdominal cavity to decrease laparoscopy-induced abdominal or shoulder pain after surgery. Design, Setting, and Patients A prospective, randomized, controlled trial was conducted at Taipei Veterans General Hospital, Taipei, Taiwan, from August 1, 2009, through June 30, 2010. One hundred fifty-eight women undergoing laparoscopic surgery for benign gynecologic lesions were randomly assigned to 3 groups: the PRM group (n = 53), the INSI group (n = 54), and the control group (n = 51). Interventions Postoperative maneuvers included PRM and INSI. Main Outcome Measures Evaluation of pain, including abdominal pain and shoulder pain, was performed at 12, 24, and 48 hours postoperatively. Results The frequency of postoperative shoulder pain at 24 and 48 hours was significantly decreased in the INSI group compared with that of either the PRM or control group (40.7% and 24.1% in the INSI group vs 66.0% and 50.9% in the PRM group [P = .009 and .004, respectively] or vs 72.5% and 54.9% in the control group [both P Conclusions Both PRM and INSI could effectively reduce pain after laparoscopic surgery, but INSI might be better for both upper abdominal and shoulder pain. Trial Registration clinicaltrials.gov Identifier: NCT01135836

The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan.

Abstract: Objective The association of rheumatoid arthritis (RA) and malignancy has rarely been explored in Asian populations. The aim of this study was to investigate the relative risk of cancer in Taiwanese patients with RA and to identify groups of patients with a high risk of cancer. Methods We conducted a nationwide cohort study of the risk of cancer among 23,644 patients with RA who had no history of malignancies, using the National Health Insurance database of Taiwan from 1996 to 2007. Standardized incidence ratios (SIRs) for various cancers were analyzed. Results Among the patients with RA, 935 cancers were observed. Patients with RA had an increased risk of cancer (SIR 1.23, 95% confidence interval [95% CI] 1.22–1.23), especially hematologic cancers (SIR 2.74, 95% CI 2.68–2.81). The relative risk of cancer was higher among younger patients. Most cancer cases were detected within the first year following the diagnosis of RA. The relative risk of cancer decreased as the duration of observation increased. Among hematologic cancers, the risk of non-Hodgkin's lymphoma was greatest (SIR 3.54, 95% CI 3.45–3.63). Among solid tumors, the risk of cancers of the kidney and vagina/vulva was highest. A decreased risk of cancers of the cervix and nonmelanoma skin cancer in patients with RA was also observed. Conclusion Patients with RA have an increased risk of cancer, especially hematologic and kidney cancers. The relative risk of cancer in patients with RA decreased with long-term followup. Cancer screening with continued vigilance is recommended for patients with RA.

Reversible cerebral vasoconstriction syndrome: current and future perspectives

Abstract: Reversible cerebral vasoconstriction syndromes (RCVS) are characterized by recurrent acute severe headaches, namely thunderclap headaches, and multifocal segmental vasoconstrictions. Interest has arisen in the definitions, clinical presentations, differential diagnoses, risk factors and complications of RCVS. This article will comprehensively review the milestone monographs and the latest research work addressing these issues. Studies that have focused on the relationship between RCVS and thunderclap headache will be detailed. We will also discuss research on the enigmatic pathophysiology and potential therapeutic approaches. Up-to-date information and challenges, undergoing studies and future research directions will be deeply probed.

Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder.

Abstract: Sun C-H, Chang Y-H & Pan C-C (2011) Histopathology58, 1054–1063 Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder Aims: Phosphatidylinositol3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of urothelial carcinoma. However, its clinical relevance has not been substantially validated in human samples. The aim of this study was to assess the expression of the pathway in a large cohort of bladder cancers using the tissue microarray technique. Methods and results: Immunohistochemical stains for phosphatase and tensin homologue (PTEN), phosphorylated Akt, mTOR, S6 and 4E-BP1 were performed for 887 cases, and the results were correlated with clinicopathological characteristics. The high expression of p-S6 and p-Akt corresponded significantly with high-grade and advanced-stage, while losses of PTEN and p-4E-BP1 were observed more often in high-grade and high-stage tumours. High expression of p-Akt and p-S6 predicted progression and cancer-specific mortality for non-muscle-invasive cancers treated by transurethral resection, and p-Akt was an independent factor in multivariate analysis. High expression of p-mTOR and p-Akt correlated with higher cumulative incidence of cancer-specific mortality for muscle-invasive cancer, and p-mTOR was an independent prognostic factor. Conclusions: We have demonstrated the impact of PI3K/Akt/mTOR alteration on the biological behaviour of bladder tumours. Proper immunohistochemical examination of the PI3K/Akt/mTOR pathway can provide useful prognostic information, and the findings may represent an additional therapeutic avenue in the treatment of bladder cancers.