Locoregional radiotherapy improves survival outcomes in de novo metastatic nasopharyngeal carcinoma treated with chemoimmunotherapy.

BACKGROUND: We aimed to investigate the efficacy of locoregional radiotherapy (LRRT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) receiving chemotherapy combined with anti-programmed cell death receptor-1 monoclonal antibodies (anti-PD-1 mAbs) as first-line treatment and identify optimal candidates for LRRT. MATERIALS AND METHODS: We enrolled patients with dmNPC receiving platinum-based palliative chemotherapy and anti-PD-1 mAbs followed or not followed by LRRT from four centers. The endpoints were progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). We used the inverse probability of treatment weighting (IPTW) to balance the baseline characteristics of the LRRT and non-LRRT groups to minimize selection bias before comparative analyses. Multivariate analyses were carried out using the Cox proportional hazards model. RESULTS: We included 163 patients with dmNPC (median follow-up: 22 months). The median PFS was 20 months, and the ORR was 92.0%; the median OS was not achieved. After IPTW adjustments, patients who received LRRT had a significant survival benefit over those not receiving LRRT (median PFS: 28 versus 15 months, P < 0.001). The Epstein-Barr virus DNA (EBV DNA) level after four to six cycles of anti-PD-1 mAbs [weighted hazard ratio (HR): 2.19, 95% confidence interval (CI) 1.22-3.92, P = 0.008] and LRRT (weighted HR: 0.58, 95% CI 0.34-0.99, P = 0.04) were independent prognostic factors. Patients with undetectable EBV DNA levels after four to six cycles of anti-PD-1 mAbs (early EBV DNA clearance) benefitted from LRRT (HR: 0.41, 95% CI 0.22-0.79, P = 0.008), whereas those with detectable levels did not (HR: 1.30, 95% CI 0.59-2.87, P = 0.51). CONCLUSIONS: Palliative chemotherapy combined with anti-PD-1 mAbs followed by LRRT was associated with improved PFS in patients with dmNPC, especially for patients with early EBV DNA clearance.

Hysterectomy and risk of osteoarthritis in women: a nationwide nested case-control study.

OBJECTIVE: Hysterectomy is the most common gynaecological surgery, performed mainly for benign uterine pathologies in women. Studies have suggested that hysterectomy is associated with osteoarthritis (OA); however, the association remains controversial. This study aimed to investigate the association between hysterectomy and the risk of OA. METHOD: We performed a population-based nested case-control study using the National Health Insurance programme database from 2000 to 2016 in Taiwan. All medical conditions for each case and control were categorized using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10. A multiple conditional logistic regression model was applied to analyse the adjusted odds ratio (aOR) and 95% confidence interval (CI) for the association between hysterectomy and OA. RESULTS: Our analyses included 16 592 patients with OA and 66 368 matched controls. After adjustment for possible confounders, hysterectomy had a significant association with OA (aOR = 1.19, 95% CI = 1.09-1.30), especially knee OA (aOR = 1.25, 95% CI = 1.13-1.38). Furthermore, women who received oestrogen therapy (ET) alone and patients who underwent hysterectomy without ET showed a greater risk of OA development compared to women who did not receive ET (aOR = 1.14, 95% CI = 1.07-1.23, and aOR = 1.19, 95% CI = 1.08-1.31, respectively). CONCLUSION: Our findings indicate that hysterectomy is associated with OA, especially knee OA. We also found that women who received ET alone and patients who underwent hysterectomy without ET had an increased risk of OA.

The GroEL protein of Porphyromonas gingivalis accelerates tumor growth by enhancing endothelial progenitor cell function and neovascularization.

Porphyromonas gingivalis is a bacterial species that causes destruction of periodontal tissues. Additionally, previous evidence indicates that GroEL from P. gingivalis may possess biological activities involved in systemic inflammation, especially inflammation involved in the progression of periodontal diseases. The literature has established a relationship between periodontal disease and cancer. However, it is unclear whether P. gingivalis GroEL enhances tumor growth. Here, we investigated the effects of P. gingivalis GroEL on neovasculogenesis in C26 carcinoma cell-carrying BALB/c mice and chick eggs in vivo as well as its effect on human endothelial progenitor cells (EPC) in vitro. We found that GroEL treatment accelerated tumor growth (tumor volume and weight) and increased the mortality rate in C26 cell-carrying BALB/c mice. GroEL promoted neovasculogenesis in chicken embryonic allantois and increased the circulating EPC level in BALB/c mice. Furthermore, GroEL effectively stimulated EPC migration and tube formation and increased E-selectin expression, which is mediated by eNOS production and p38 mitogen-activated protein kinase activation. Additionally, GroEL may enhance resistance against paclitaxel-induced cell cytotoxicity and senescence in EPC. In conclusion, P. gingivalis GroEL may act as a potent virulence factor, contributing to the neovasculogenesis of tumor cells and resulting in accelerated tumor growth.

Increased risk of glomerulonephritis and chronic kidney disease in relation to the severity of psoriasis, concomitant medication, and comorbidity: a nationwide population-based cohort study.

BACKGROUND: Few studies have examined the association between psoriasis and glomerulonephritis (GN) as well as chronic kidney disease (CKD). OBJECTIVES: To determine the risk of CKD in patients with psoriasis and evaluate the impact of the severity of psoriasis, comorbidities and concomitant drugs on the risk of GN and CKD in patients with psoriasis. METHODS: We identified 4344 patients with psoriasis for the study cohort and randomly selected 13,032 subjects as a control cohort. Each subject was individually followed for up for 5 years to identify those who subsequently developed GN and CKD. RESULTS: After adjustment for traditional CKD risk factors, psoriasis was found to be independently associated with an increased risk of CKD during the follow-up period [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.14-1.44]. The increased incidence of GN in patients with psoriasis (HR 1.50, 95% CI 1.24-1.81) may contribute to the positive association between psoriasis and CKD. Patients with mild and severe psoriasis had an increased risk of CKD and GN compared with the control cohort; the risk increased with severity. Patients with psoriasis and arthritis exhibited a higher risk of CKD than patients without arthritis (HR 1.62 vs. 1.26). Among drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) have the strongest association with CKD in patients with psoriasis (adjusted odds ratio 1.69, 95% CI 1.14-2.49). CONCLUSIONS: Psoriasis was associated with a higher risk of developing CKD and GN. High severity, psoriatic arthritis involvement and concomitant NSAIDs use further increased the risk of CKD in patients with psoriasis.

The essential role of transient receptor potential vanilloid 1 in simvastatin-induced activation of endothelial nitric oxide synthase and angiogenesis.

AIMS: We investigated the role of transient receptor potential vanilloid receptor type 1 (TRPV1) in simvastatin-mediated activation of endothelial nitric oxide synthase (eNOS) and angiogenesis. METHODS: Fluo-8 NW assay was for Ca(2+) detection; Griess's assay was for NO bioavailability; Western blotting and immunoprecipitation were for protein phosphorylation and interaction; tube formation and Matrigel plug assay were for angiogenesis. RESULTS: In endothelial cells (ECs), treatment with simvastatin time-dependently increased intracellular level of Ca(2+). Pharmacological inhibition or genetic disruption of TRPV1 abrogated simvastatin-mediated elevation of intracellular Ca(2+) in ECs or TRPV1-transfected HEK293 cells. Loss of TRPV1 function abolished simvastatin-induced NO production and phosphorylation of eNOS and calmodulin protein kinase II (CaMKII) in ECs and in aortas of mice. Inhibition of TRPV1 activation prevented the simvastatin-elicited increase in the formation of TRPV1-Akt-CaMKII-AMPK-eNOS complex. In mice, Matrigel plug assay showed that simvastatin-evoked angiogenesis was abolished by TRPV1 antagonist and genetic ablation of TRPV1. Additionally, our results demonstrated that TRP ankyrin 1 (TRPA1) is the downstream effector in the simvastatin-activated TRPV1-Ca(2+) signalling and in the consequent NO production and angiogenesis as evidence by that re-expression of TRPA1 further augmented simvastatin-elicited Ca(2+) influx in TRPV1-expressed HEK293 cells and ablation of TRPA1 function profoundly inhibited the simvastatin-induced increase in the phosphorylation of eNOS and CaMKII, formation of TRPV1-Akt-CaMKII-AMPK-eNOS complex, NO bioavailability, tube formation and angiogenesis in ECs or mice. CONCLUSION: Simvastatin-induced Ca(2+) influx may through the activation of TRPV1-TRPA1 signalling, which leads to phosphorylation of CaMKII, increases in the formation of TRPV1-CaMKII-AMPK-eNOS complex, eNOS activation, NO production and, ultimately, angiogenesis in ECs.

Serine protease inhibitor gabexate mesilate attenuates american cockroach-induced bronchial damage and inflammatory cytokine release

Background and objective: Allergic airway diseases are not only a TH2-mediated chronic airway inflammation, but also a condition of epithelial barrier defects and dysfunction. Allergens with protease activities are known factors that initiate respiratory epithelial damage. Cockroach allergy is the second leading cause of allergic respiratory airway diseases in Taiwan, and cockroach allergens have strong serine protease activity. This study aimed to determine the protective effect of the direct local administration of gabexate mesilate (GM) on American cockroach allergen (CraA)-induced human bronchial epithelial cell inflammation. Methods: BEAS-2B cells, from the human bronchial epithelial cell line, were stimulated with CraA or co-cultured with different doses of GM. Cellular morphologic changes were observed by microscopy and changes in chemokine mRNA expression and protein levels were determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. Effects of specific inhibitors of ERK1/2 (U0126), JNK (SP600125), and p38 MAPK (SB203580) on CraA-induced chemokine mRNA expression were also tested by RT-PCR. Results: GM prevented CraA-induced bronchial epithelial cell detachment and morphological changes. It had superior and more extensive suppression effects than specific target MAPK inhibitors in CraA-induced mRNA expression of IL-8, monocyte chemotactic protein (MCP) 1, chemokine (C-C motif) ligand 20, and granulocyte-macrophage colony-stimulating factor from the cells in a dose-dependent manner. CraA-induced IL-8 and MCP-1 protein production from BEAS-2B cells was also attenuated by GM. Conclusions: The serine protease inhibitor GM has local protective effects against CraA-induced bronchial epithelial inflammation. The development of an inhaled or intranasal protease inhibitor may be a potential strategy for the treatment of allergic airway diseases induced by allergens with protease activities (AU)

Antecedentes y objetivo: Las enfermedades alergicas de las vias respiratorias no son solo fruto de una inflamacion cronica de las vias respiratorias mediada por Th2, sino que tambien se encuentran defectos fisicos y funcionales de la barrera epitelial. En este sentido, es conocido el papel de los alergenos con actividad proteasa que son los factores conocidos de inicio del dano epitelial respiratorio. La alergia a las cucarachas es la segunda causa principal de enfermedades alergicas de las vias respiratorias en Taiwan y estos alergenos poseen una potente actividad serin-proteasa. Este estudio tuvo como objetivo determinar el efecto protector del mesilato de gabexate (GM) contra la inflamacion inducida por la administracion local directa de alergenos de la cucaracha americana (CRAA), sobre las celulas epiteliales bronquiales humanas. Metodos: Se empleo la linea de celulas epiteliales bronquiales, celulas BEAS-2B, las cuales se estimularon con CRAA o fueron co-cultivadas con diferentes dosis de GM. Se analizaron los cambios morfologicos celulares por microscopia y los cambios en la expresion de ARNm de diferentes quimiocinas, asi como los niveles de proteina. Se utilizaron metodos semi-cuantitativos de RT-PCR y ELISA. Los efectos de inhibidores especificos de ERK1/2 (U0126), JNK (SP600125), y p38 MAPK (SB203580) en las expresion de ARNm de quimiocinas inducidas por CRAA, tambien se ensayaron por RT-PCR. Resultados: El mesilato de gabexate impidio el desprendimiento de las celulas epiteliales y los cambios morfologicos inducidos con CRAA a nivel bronquial. Sus efectos supresores fueron mas potentes y prolongados que los obtenidos con inhibidores especificos de MAPK sobre la expresion del ARNm de IL-8, MCP-1, CCL20 y GMSF en una forma dosis-dependiente. La produccion proteica de IL-8 y MCP-1 de las celulas BEAS-2B tambien fue menor cuando se anadio GM. Conclusiones: El mesilato de gabexate, inhibidor serin-proteasa , tiene efectos protectores locales contra la inflamacion bronquial epitelial inducida por la cucaracha americana. El desarrollo de un inhibidor de la proteasa, por via inhalada o intranasal, puede ser una estrategia potencial para el tratamiento de enfermedades de las vias respiratorias alergicas inducidas por alergenos con actividad proteasa (AU)

Human leucocyte antigen-Cw6 as a predictor for clinical response to ustekinumab, an interleukin-12/23 blocker, in Chinese patients with psoriasis: a retrospective analysis.

BACKGROUND: Ustekinumab, an interleukin-12/23 inhibitor, is effective in the treatment of psoriasis. A recent Italian study showed more favourable response to ustekinumab in patients with positive human leucocyte antigen (HLA)-Cw6. Nonetheless, there are differences in genetic susceptibility to psoriasis between races, and no studies have specifically assessed the candidate genetic markers in predicting therapy outcome in Chinese patients with psoriasis treated with ustekinumab. OBJECTIVES: To determine whether HLA gene polymorphisms can predict the response to ustekinumab in Chinese patients with psoriasis. METHODS: Sixty-six patients with psoriasis treated with ustekinumab were included in the study, and the effectiveness of ustekinumab therapy was evaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI). RESULTS: More HLA-Cw6-positive patients achieved a PASI 75 response at week 4 compared with HLA-Cw6-negative patients (38% vs. 9%, P = 0·019). Similarly, at week 16, patients carrying the HLA-Cw6 allele showed a higher likelihood of achieving PASI 50, 75 and 90 than Cw6-negative patients, although this was not statistically significant. At week 28, a significantly higher percentage of HLA-Cw6-positive patients maintained PASI 90 response compared with Cw6-negative patients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele polymorphisms did not show significant associations with therapeutic response to ustekinumab. CONCLUSIONS: This pharmacogenetic study provides preliminary data indicating that positive HLA-Cw6 is associated with a good response to ustekinumab treatment in Chinese patients with psoriasis.

Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population.

UNLABELLED: Evidence of the incidence and risk of osteonecrosis of the jaw (ONJ) in Asian osteoporosis populations receiving different osteoporosis medications is lacking. We found that there is no excess incidence of or risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin under real-world conditions in Taiwan. INTRODUCTION: To provide information on ONJ in Asian populations, this study compares the incidence and risk of ONJ between patients receiving alendronate and those receiving non-bisphosphonate osteoporosis medications in Taiwan. METHODS: Enrollees in the National Health Insurance Research Database (NHIRD) from 2003 to 2007, aged above 50 years, with vertebral/hip fracture, and new to osteoporosis therapy were recruited. Patients with Paget's disease or cancer during the baseline period were excluded. Patients were classified into either the alendronate or the calcitonin/raloxifene (control) group according to their exposure during follow-up. Previously proposed possible ONJ diagnosis codes were adopted as potential ONJ cases, but qualifying cases also had a repeated ONJ diagnosis within 8 weeks of the first diagnosis and received one or more broad-spectrum oral antibiotics. Cox modeling compared the risk of ONJ between the alendronate and the control groups, which were matched using propensity scores. Results were examined in series sensitivity analyses, including different cumulative dose groups. RESULTS: We found 25 potential ONJ cases in the alendronate (N = 18,030) and 21 in the control groups (N = 25,615). Over the 6-year follow-up period, no increased risk of ONJ in the alendronate group in the original (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.47-1.58) or propensity score-matched cohorts (HR, 0.86; 95% CI, 0.44-1.69) was found. All comparison groups exhibited a similar incidence of ONJ, ranging from 6.9 to 8.2/10,000 person-years. CONCLUSION: Under real-world conditions, there is no excess risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin.

Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis.

AIMS: Soluble guanylyl cyclase (sGC) is a key modulator in the regulation of vascular tone. However, its role and involving mechanism in cholesterol metabolism of macrophages and atherosclerosis remain unclear. METHODS: Oil red O staining, Dil-oxidized low-density lipoprotein (oxLDL)-binding assay and cholesterol efflux assay were performed in biology of foam cells. Levels of cytokines or intracellular lipid were evaluated by ELISA or colorimetric kits. Expression of gene or protein was determined by quantitative real-time PCR or Western blotting. Histopathology was examined by haematoxylin and eosin staining. RESULTS: Soluble guanylyl cyclase was expressed in macrophages of mouse atherosclerotic lesions. Treatment with 1H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, sGC inhibitor) exacerbated oxLDL-induced cholesterol accumulation in macrophages. In contrast, 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1, sGC activator) attenuated the oxLDL-induced cholesterol accumulation because of increased cholesterol efflux. Additionally, YC-1 dose dependently increased the protein expression of ATP-binding cassette transporter A1 (ABCA1) but did not alter that of scavenger receptor class A (SR-A), CD36, SR-BI or ABCG1. Moreover, YC-1-upregulated ABCA1 level depended on liver X receptor α (LXRα). Inhibition of the LXRα-ABCA1 pathway by LXRα small interfering RNA (siRNA), ABCA1 neutralizing antibody or ABCA1 siRNA abolished the effect of YC-1 on cholesterol accumulation and cholesterol efflux. In vivo, YC-1 retarded the development of atherosclerosis, accompanied by reduced serum levels of cholesterol and pro-inflammatory cytokines, in apolipoprotein E-deficient mice. CONCLUSION: Activation of sGC by YC-1 leads to LXRα-dependent upregulation of ABCA1 in macrophages and may confer protection against atherosclerosis.

Activation of transient receptor potential vanilloid 1 decreases endothelial nitric oxide synthase phosphorylation at Thr497 by protein phosphatase 2B-dependent dephosphorylation of protein kinase C.

AIMS: We investigated the effects and underlying molecular mechanism of transient receptor potential vanilloid 1 (TRPV1), a calcium (Ca(2+) )-permeable non-selective cation channel, on phosphorylation of endothelial nitric oxide synthase (eNOS) at threonine 497 (Thr497) in bovine aortic endothelial cells (BAECs) and in mice. METHODS: Western blotting and immunoprecipitation were used for the evaluation of protein phosphorylation; protein phosphatase 2B (PP2B) activity was assessed by convention kit; Griess assay was for NO production; tube formation and Matrigel plug assay were used for angiogenesis. RESULTS: In BAECs, treatment with the TRPV1 ligand evodiamine decreased the phosphorylation of eNOS at Thr497, protein kinase Cα (PKCα) at Serine 657 (Ser657) and PKCß2 at Ser660. Evodiamine increased protein phosphatase 2B (PP2B) activity and promoted the formation of a PP2B-PKC complex. Inhibition of TRPV1 activation by the pharmacological antagonists, removal of extracellular Ca(2+) or pharmacological inhibition of PI3K/Akt/calmodulin-dependent protein kinase II/AMP-activated protein kinase signalling pathway abolished the evodiamine-induced alterations in phosphorylation of eNOS at Thr497, PKCα at Ser657, PKCß2 at Ser660 and PP2B activity, as well as the formation of a PP2B-PKC complex. Inhibition of PP2B activation partially reduced the evodiamine-induced NO bioavailability and tube formation in endothelial cells (ECs) and angiogenesis in mice. Moreover, evodiamine decreased the phosphorylation of eNOS at Thr497, PKCα at Ser657 and PKCß2 at Ser660 in apolipoprotein E (ApoE)-deficient mouse aortas but not TRPV1-deficient or ApoE/TRPV1 double-knockout mice. CONCLUSION: TRPV1 activation in ECs may elicit a Ca(2+) -dependent effect on PP2B-PKC signalling, which leads to dephosphorylation of eNOS at Thr497 in ECs and in mice.

Herpes simplex virus infection and erectile dysfunction: a nationwide population-based study.

Both erectile dysfunction (ED) and herpes simplex virus (HSV) infections are related to cardiovascular events. However, the relationship between ED and HSV infections remains undetermined. The aim of our study was to investigate the possible influence of HSV infections on the development of ED using the Taiwan National Health Insurance database. We identified patients with HSV type 1 or type 2 infections from the 1 000 000 sampling cohort data set. Male patients of age 18 years or older who had been diagnosed as cases of HSV infection since January 1, 2001 were enroled. Patients with previous history of stroke, spinal cord injury or malignancy were excluded. A control group was selected, comprising male patients without HSV infection, stroke, spinal cord injury or malignancy. The age, time of enrolment and comorbidities were matched in the two groups. A total of 1 717 HSV subjects (mean age 43.29 ± 15.97 years) and 6 864 control subjects were enroled. During an average of 3.91 ± 1.93 years' follow-up, HSV-infected subjects experienced a higher incidence of ED than control subjects (1.7% vs. 0.7%, respectively). The log-rank test showed that patients with HSV infections had a significantly higher incidence of ED than those without HSV infections (p < 0.001). After Cox proportional hazard regression model analysis, HSV infections were independently associated with the increased risk of ED (hazard ratio, 2.90; 95% CI, 1.82-4.63, p < 0.001). In conclusion, HSV infections were associated with risk of ED in this cohort.

Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study.

BACKGROUND: Few large population-based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients. AIMS: To investigate if cirrhotic patients have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients. METHODS: Using the National Health Insurance Research Database, a nationwide population-based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log-rank test was used to analyse differences in accumulated PUB-free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients. RESULTS: During the 7-year follow-up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log-rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37-5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro-oesophageal variceal bleeding and use of nonsteroidal anti-inflammatory drugs were risk factors for PUB in cirrhotic patients. CONCLUSION: Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication.

Nitric oxide inhibits androgen receptor-mediated collagen production in human gingival fibroblasts.

UNLABELLED: Lin S-J, Lu H-K, Lee H-W, Chen Y-C, Li C-L, Wang L-F. Nitric oxide inhibits androgen receptor-mediated collagen production in human gingival fibroblasts. J Periodont Res 2012; 47: 701-710. © 2012 John Wiley & Sons A/S Background and Objective: In our previous study, we found that flutamide [an androgen receptor (AR) antagonist] inhibited the up-regulation of collagen induced by interleukin (IL)-1ß and/or nifedipine in gingival fibroblasts. The present study attempted to verify the role of nitric oxide (NO) in the IL-1ß/nifedipine-AR pathway in gingival overgrowth. MATERIAL AND METHODS: Confluent gingival fibroblasts derived from healthy individuals (n = 4) and those with dihydropyridine-induced gingival overgrowth (DIGO) (n = 6) were stimulated for 48 h with IL-1ß (10 ng/mL), nifedipine (0.34 µm) or IL-1ß + nifedipine. Gene and protein expression were analyzed with real-time RT-PCR and western blot analyses, respectively. Meanwhile, Sircol dye-binding and the Griess reagent were, respectively, used to detect the concentrations of total soluble collagen and nitrite in the medium. RESULTS: IL-1ß and nifedipine simultaneously up-regulated the expression of the AR and type-I collagen α1 [Colα1(I)] genes and the total collagen concentration in DIGO cells (p < 0.05). IL-1ß strongly increased the expression of inducible nitric oxide synthase (iNOS) mRNA and the nitrite concentration in both healthy and DIGO cells (p < 0.05). However, co-administration of IL-1ß and nifedipine largely abrogated the expression of iNOS mRNA and the nitrite concentration with the same treatment. Spearman's correlation coefficients revealed a positive correlation between the AR and total collagen (p < 0.001), but they both showed a negative correlation with iNOS expression and the NO concentration (p < 0.001). The iNOS inhibitor, 1400W, enhanced IL-1ß-induced AR expression; furthermore, the NO donor, NONOate, diminished the expression of the AR to a similar extent in gingival fibroblasts derived from both healthy patients and DIGO patients (p < 0.05). CONCLUSION: IL-1ß-induced NO attenuated AR-mediated collagen production in human gingival fibroblasts. The iNOS/NO system down-regulated the axis of AR/Colα1(I) mRNA expression and the production of AR/total collagen proteins by DIGO cells.

Chronic obstructive pulmonary disease: an independent risk factor for peptic ulcer bleeding: a nationwide population-based study.

BACKGROUND: Peptic ulcer bleeding remains a major healthcare problem despite decreasing prevalence of peptic ulcer disease. The role of chronic obstructive pulmonary disease (COPD) in the risk of peptic ulcer bleeding has not yet been established. AIM: To determine if COPD patients have a higher risk of peptic ulcer bleeding than the general population and to identify the risk factors of peptic ulcer bleeding in COPD patients. METHODS: From Taiwan's National Health Insurance research database, 62,876 patients, including 32,682 COPD and 30,194 age-gender-matched non-COPD controls, were recruited. Cox proportional hazard regression was performed to evaluate independent risk factors for ulcer bleeding in all patients and to identify risk factors in COPD patients. RESULTS: During the 8-year follow-up, COPD patients had a significant higher rate of peptic ulcer bleeding than the control group (P < 0.001, by log-rank test). By Cox proportional hazard regression analysis, COPD [hazard ratio (HR) 1.93, 95% CI 1.73-2.17] was an independent risk factor after adjusting for age, gender, underlying comorbidities and ulcerogenic medication. Age > 65 years, male, comorbidities of hypertension, diabetes, heart failure, history of peptic ulcer disease, and chronic renal disease and use of nonsteroidal anti-inflammatory drugs were risk factors of ulcer bleeding in COPD patients. CONCLUSION: Patients with chronic obstructive pulmonary disease have a higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like underlying comorbidities and ulcerogenic medication.

The use of polyethylenimine-DNA to topically deliver hTERT to promote hair growth.

The present study investigates the efficacy of polyethylenimine (PEI)-DNA complex that expressed human telomerase reverse transcriptase (hTERT) to transfect hair follicle stem cells and produce sufficient hTERT to stimulate hair growth. Transfection with pLC-hTERT-DNA-PEI complex (D+P group) in vitro induced expression of proliferating cell nuclear antigen in 35.8% of the purified stem cell population, suggesting enhanced cell proliferation. In vivo transfection efficiency of rat dorsal skin was determined by staining for ß-gal activity. Cells positive for ß-gal were located in the bulge region and dermal sheath of hair follicles. The follicles in the hTERT-transfected region entered anagenon day 15 after transfection, whereas non-transfected (Neg) controls remained in telogen. The similar effect was observed in 50-day-old rat dorsal skin. D+P group displayed a specific expression of hTERT and sufficient to initiate a transition to the anagen phase and promote new hair synthesis 18 days after the transfection. hTERT promoted follicle neogenesis following wounding. In all, 60 days after wounding, tissues of the D+P group showed more newly regenerating hair follicles (83±52 regenerated follicles per rat) in contrast to control group tissues (15±15 regenerated follicles per rat). These studies provide a potential approach for gene therapy of skin disease.

[Evaluation of noninvasive diagnostic criteria for hepatocellular carcinoma on pretransplant MRI (2010): correlation between MR imaging features and histological features on liver specimen]. / Évaluation des critères diagnostiques non invasifs du carcinome hépatocellulaire sur IRM pré-greffe hépatique (2010) : corrélations IRM - anatomopathologiques sur explants hépatiques.

PURPOSE: To validate the 2010 diagnostic criteria from the American Association for the Study of Liver Diseases (AASLD) for hepatocellular carcinoma (HCC) on MRI using the surgical liver specimen as a gold standard. PATIENTS AND METHODS: A total of 21 liver transplant recipients were retrospectively included. Each underwent surgery because of HCC between January 2007 and January 2008. Pre-transplant MRI was performed on a 1.5 Tesla MR unit. The T1W and T2W signal and kinetic contrast enhancement were correlated for each lesion with the surgical specimen. Lesion diameters between MRI and specimen were compared (Spearman). A multivariate model was created (R statistics software package) to predict the presence and grade of tumor differentiation (WHO, Edmonson Steiner). RESULTS: A total of 71 nodules were detected at histology, including 54 HCC (mean size: 25.3mm) compared to 68 on MRI. There was moderate agreement (r=0.58, P<0.001) between the maximum lesion diameters measured on MRI and at histology. Wash-out on MRI provided an accuracy of 75 % for the detection of HCC (sensitivity=75 %, specificity=76 %). Adding T2W hyperintensity to the AASLD criteria increased the sensitivity of MRI from 70.3 % to 77.7 % for the diagnosis of HCC and from 67.6 % to 79 % for nodules less than 20mm in diameter, without affecting specificity. On multivariate analysis, wash out as a single variable was significantly associated with a diagnosis of HCC (P<0.01, odds ratio 12.0, CI 95 % [2.6-55.5]). T1W hyperintensity (P=0.04, odds ratio 5.4) and loss of signal on opposed-phase images (P=0.02, odds ratio 9.2) were predictive of good differentiation. CONCLUSION: On MRI, the AASLD criteria or presence of wash out within a liver nodule in patients with underlying chronic hepatocellular disease are suggestive of tumoral transformation. The addition of T2W hyperintensity to the AASLD criteria increases the detection of HCC, especially nodules smaller than 20mm.

Alendronate adherence and its impact on hip-fracture risk in patients with established osteoporosis in Taiwan.

A pharmacoepidemiology study was conducted using the health insurance database in Taiwan to assess compliance with osteoporosis drug regimens and the impact of compliance on the risk for secondary fractures. Patients >50 years of age with vertebral/hip fracture who had been started on alendronate therapy for the first time only after the fracture were included. Compliance was measured using the medication possession ratio (MPR) and was included as a time-dependent covariate in the Cox model to compare the difference between compliant (MPR ≥ 80%) and noncompliant patients (MPR <80%) with respect to risk for subsequent hip fractures. Only 38% of the study population remained compliant during the first year of treatment. Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than that among the noncompliant ones (adjusted hazard ratio (HR) 0.30). Among patients with osteoporosis in Taiwan who had experienced a fracture and had started alendronate therapy, compliance with the dosage regimen was suboptimal. It was also found that compliance significantly reduced the risk of secondary hip fracture up to 4 years.

Maternal mental health and childrearing context in the development of children at 6, 18 and 36 months: a Taiwan birth cohort pilot study.

BACKGROUND: This study investigated a possible pathway of the childrearing context and maternal mental health at 6 months, and how these factors influence children's development at 6, 18 and 36 months. METHODS: Using random sampling, 2048 children and mothers were selected. The mother's health status was evaluated using the Taiwanese version of the 36-Item Short Form Health Survey (SF-36), and infant development was assessed using the high reliable Taiwan birth cohort study instrument. All data were collected using parental self-report, and were analysed using multiple linear regression analysis and further pathway using structural equation modelling. RESULTS: This study showed that 12 factors effected children's development at 6 months, and some dissipated with growth. Of these, maternal education had an enduring effect on different domains of child development, and this effect intensified as the child grew older. Children who grew up in a family with more siblings would show a delay in language development at 6 months; they have a delay in motor and social development at 18 and 36 months. Additionally, maternal mental health effected the children's fine motor development at 6 months. However, this effect disappeared at 18 months, and influenced children's social development at 36 months. CONCLUSIONS: This study demonstrated that the development of children at as young as 6 months is affected by various factors. These factors may dissipate, continue to influence child development up to 3 years of age, turn from being disadvantageous to beneficial, or affect different domains of child development. Also, parental self-report instrument might be has its limitation and could be contributed by several confounding factors. Thus, continuous longitudinal follow-up on changes in maternal conditions, family factors, and environmental factors is vital to understand how these early infantile factors affect each other and influence the developmental trajectories of children into early childhood.

Ambulatory pulse pressure as a novel predictor for long-term prognosis in essential hypertensive patients.

The prognostic value of ambulatory blood pressure (BP) monitoring for long-term prognosis varies in recent studies. The study aimed to investigate the role of ambulatory BP parameters in mortality and cardiovascular (CV) events in hypertensive patients. A series of 412 participants (59.3 ± 4.0 years) who received ambulatory BP monitoring for their fluctuated BP, either untreated or treated since 1995, were enroled. The mortality and CV events were obtained by follow-up and linked to the National Death Registry in Taiwan. There were 233 untreated and 179 treated patients. The latter were older with more comorbidity when compared with the former. After follow-up for 8.5 ± 1.7 years, both ambulatory systolic BP and pulse pressure (PP) could predict all-cause mortality, non-CV mortality, CV disease and stroke after adjusting for baseline covariates. However, only ambulatory PP could predict CV mortality and coronary heart disease. Ambulatory PP is better than ambulatory systolic BP, particularly in prediction of all-cause mortality. There was no predictive value of office BP in any outcome. In conclusion, ambulatory PP is a good predictor for long-term outcomes in hypertensive patients. The parameters of ambulatory rather than office BP could be applied for risk stratification either before or under antihypertensive treatment.

Impact of food and antacids on the pharmacokinetics of anti-tuberculosis drugs: systematic review and meta-analysis.

OBJECTIVE: To compare the effects of food and antacids on the bioavailability of first-line anti-tuberculosis drugs. METHOD: Systematic search of electronic databases PubMed (January 1950-May 2009), and the Cochrane Library database (January 1974-May 2009), including the Cochrane Centre register of controlled trials, and ongoing trials from research registers using key terms 'food', 'antacids', 'meal', 'controlled trial', 'diet', and the first-line anti-tuberculosis drugs isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and pyrazinamide (PZA). Meta-analysis was performed using RevMan software 5 to assess the impact of food or antacids on the maximum plasma concentrations (C(max)) and area under the plasma concentration time curve (AUC) of anti-tuberculosis drugs. RESULTS: Twelve trials involving 157 patients were included in the meta-analysis. The overall effects showed that food significantly reduced the C(max) mean difference (C(max) MD; C(max) MD -1.42, 95%CI -1.56--1.28, P < 0.00001) and AUC (C(max) MD -3.33, 95%CI -4.05--2.62, P < 0.00001) of INH but antacids did not. Food also significantly reduced the C(max) MD (C(max) MD -2.47, 95%CI -3.30--1.64, P < 0.00001) but not the AUC of RMP. Antacids had no effect on the C(max) MD or AUC of RMP. The C(max) and AUC of PZA were unaffected by both food and antacids. Both food and antacids reduced the C(max) but not the AUC of EMB. CONCLUSION: From a pharmacokinetic point of view, it seems that the better option for patients with gastrointestinal upsets during chemotherapy would be to add antacids rather than dosing with meals.