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.

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.

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.

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.

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.

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.

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.

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.

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor.

Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 x 10⁻²5), rs495828 (P=3.5 x 10⁻8) and rs8176746 (P=9.3 x 10⁻5) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.

A systematic review and meta-analysis on the therapeutic equivalence of statins.

BACKGROUND: Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues to increase, information regarding the relative efficacy and safety of statins is required for decision-making. OBJECTIVE: This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low-density lipoprotein cholesterol (LDL-C) lowering effect. METHODS: Publications of head-to-head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966-2004), MEDLINE (2005-April of 2006), EMBASE (2005-April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta-analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins. RESULTS: Seventy-five studies reporting RCTs of head-to-head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40-80 mg, and simvastatin 20 mg could decrease LDL-C by 30-40%, and fluvastatin 40 mg, lovastatin 10-20 mg, pravastatin 20-40 mg, and simvastatin 10 mg could decrease LDL-C by 20-30%. The only two statins that could reduce LDL-C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta-analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data. CONCLUSIONS: At comparable doses, statins are therapeutically equivalent in reducing LDL-C.

Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors.

BACKGROUND: Hereditary and environmental factors contribute to the occurrence of atopic dermatitis (AD). However, the interaction of these two factors is not totally understood. OBJECTIVES: To evaluate the early risk factors for infantile AD at the age of 6 months and to develop a predictive model for the development of AD. METHODS: In 2005, a representative sample of mother and newborn pairs was obtained by multistage, stratified systematic sampling from the Taiwan national birth register. Information on hereditary and environmental risk factors was collected by home interview when babies were 6 months old. Multivariate regression analysis was applied to determine the risk factors for AD in the infants. RESULTS: A total of 20 687 pairs completed the study satisfactorily. AD was diagnosed in 7.0% of 6-month-old infants by physicians. Parental asthma, atopic dermatitis and allergic rhinitis, and maternal education levels were risk factors for AD in infants. Among environmental factors, fungus on walls at home and renovation/painting in the house during pregnancy were significantly associated with early infantile AD. Using these factors, the probability of having infantile AD was estimated and grouped into low, high and very high. With five runs of tests in mutually exclusive subsets of this population, the likelihood of AD for 6-month-old infants was consistent in all the groups with the predictive model. The highest predicted probability of AD was 70.1%, among boys with maternal education levels > 12 years, both parents with AD, renovation and painting of the house during pregnancy and fungus on walls at home. The lowest probability was 3.1%, among girls with none of the above factors. CONCLUSIONS: This investigation provides a technique for predicting the risk of infantile AD based on hereditary and environmental factors, which could be used for developing a preventive strategy against AD, especially among those children with a family history of atopy.

Pharmacist intervention in activated protein C therapy for severe sepsis: influence on health and economic outcomes.

OBJECTIVE: To assess the health and cost outcomes of pharmacist intervention versus non-intervention in activated protein C (drotrecogin alpha) therapy for patients with severe sepsis. METHOD: This is a retrospective study. We reviewed the medical records of patients aged 18 years and older who were admitted to our hospital for severe sepsis from January 1, 2003 to December 31, 2007. Only patients who are prescribed activated protein C for the treatment of severe sepsis according to the reimbursement criteria can be reimbursed by the Taiwan Bureau of National Health Insurance (BNHI). Our hospital stipulated that the criteria check list must be evaluated by a clinical pharmacist and the prescribing physician as to whether the patient is eligible to receive activated protein C. To assess the influence of pharmacist intervention on outcomes, we divided eligible patients into two groups, pharmacist-intervention group (Group A; n = 19) and non-pharmacist intervention group (Group B; n = 19). Both groups received a 96-h intravenous infusion of activated protein C at 24 microg/kg/h. We defined evident severe sepsis as concurrent antibiotic plus ventilator and/or vasopressor use. We compared group characteristics, 28-day in-hospital mortality, length of stay and direct medical costs between the two groups. One-way ANOVA was used for analysis. RESULTS: 50% of patients in each group met the reimbursement criteria of the BNHI. Activated protein C therapy was initiated within 1.37 +/- 0.4 days and 7.21 +/- 7.8 days of admission to the ICU in Group A and Group B, respectively (p < 0.01). All of the patients in Group A (19/19) and 42.1% of the patients in Group B (8/19) received activated protein C within 12 - 48 h of admission to the Intensive care unit (ICU) (p < 0.01). 28-day mortality was lower for Group A than for Group B (26.7% and 43.8%, respectively). The length of stay in the ICU for patients in Group A was shorter than that in Group B (14.1 +/- 7.7 vs. 19.7 +/- 11.1, respectively; p < 0.079). Total direct medical costs for survivors in Group A were less than those in Group B (US$ 20,632.3 vs. US$ 24,785.8, respectively; p < 0.05). CONCLUSIONS: Pharmacist intervention in prescribing activated protein C for patients with severe sepsis might reduce direct medical costs and promote earlier initiation of therapy. The potential impact of pharmacist intervention on the timing of activated protein C therapy and the direct medical costs of treatment warrant further study.

Twin-singleton influence on infant development: a national birth cohort study.

BACKGROUND: While studying the development of twins, gestational age and birthweight were suggested as two of the major mediators to be considered. In addition, maternal age, maternal education, parental income and assisted reproductive technologies (ART) also should be considered as moderators. Thus the purpose of this study was to investigate the mediators and moderators of twin and singleton development. METHODS: Being a national birth cohort study, 21 648 infants were randomly selected and developmental measures were assessed at 6 and 18 months post partum. Children's development at 6 and 18 months were measured using the high reliable Taiwan Birth Cohort Study instrument, which measures children's development in four domains of gross motor, fine motor, language and social development. Additionally, maternal sociodemographics including maternal age, maternal education and parental income; children's characteristics including gender, birthweight, gestational age, single or multiple births, ART or natural conception information were also collected. These data were analysed using a three-step multiple linear regression analysis and further validated using structural equation modelling. RESULTS: Parental sociodemographics, children characteristics and being twin all had effect on children's development. Additionally, ART and twin were mediators between maternal age and children's development. Mothers aged over 40 were more likely to choose ART, thus increases their likelihood of having twins. Additionally, mothers aged over 40 were more likely to give birth to premature or low-birthweight babies, regardless if they were twin or not. Twins had a higher prevalence of prematurity or low birthweight, which also affected their development in all four domains at 6 and 18 months. Thus prematurity and low birthweight were mediating factors between twin and children's development; with these two mediating factors controlled, there were no difference between twin and singleton development. CONCLUSIONS: The conceptual construct of structural equation modelling showed these factors interacted and influenced children's development through multiple pathways. Medical intervention may facilitate children's development through prenatal growth and premature care.

Effect of cyclosporin A on interleukin-15-activated umbilical cord blood natural killer cell function.

BACKGROUND: Interleukin (IL)-15-activated natural killer (NK) cells may provide a graft-versus-leukemia (GvL) effect post-umbilical cord blood (CB) transplantation. The effect of cyclosporin A (CsA), a calcineurin-inhibitor used for prophylaxis of graft-versus-host disease (GvHD), on IL-15-mediated activation, cytotoxic function and target-induced apoptosis of CB NK cells, was examined in comparison with adult peripheral blood (APB) NK cells. METHODS: CsA was added to anti-CD3+/-IL-15-stimulated CB and APB mononuclear cells (MNC) for a 5-day incubation. CD3- CD56+ NK cell recovery was determined by flow cytometric analysis. Magnetic bead-purified CB and APB NK cells were stimulated with IL-15 for 18 h under the influence of CsA. NK activation (CD69), K562 cytotoxicity and NK-K562 interactions (CD54, perforin and annexin-V expression 4 h following contact with K562 cells) were assessed by flow cytometry. RESULTS: CsA decreased CD3- CD56+ NK cell recovery in anti-CD3-stimulated CB MNC 5-day cultures, an effect that could be counteracted by IL-15; comparable effects were observed with APB. Short-term (18-h) experiments revealed that CsA down-regulated K562 cytotoxicity of IL-15-activated (P=0.018) but not resting (P=0.268) purified CB NK cells. IL-15-induced CB NK CD69 expression showed increased CsA sensitivity over APB (P=0.012). CsA down-regulated K562 cell-induced CD54 (P=0.028) but not perforin (P=0.416) expression of IL-15-activated CB NK cells. Target-induced apoptosis of IL-15-activated CB (P=0.043) but not APB (P=0.144) NK cells was decreased by CsA. DISCUSSION: We have demonstrated differential CsA sensitivity of IL-15-activated CB and APB NK cells. These results may be used to improve the design of IL-15-activated NK cell adoptive immunotherapy in cancer patients receiving CsA post-CB transplantation.

Clinical predictors of the response to short-term thiazide treatment in nondiabetic essential hypertensives.

Blood pressure (BP) response to diuretics is varied in hypertensive patients. This study aimed to identify the patients who may respond better or worse to thiazide diuretics. Nondiabetic patients with treated or untreated hypertension were evaluated if they did not take diuretics and their office systolic BP (SBP) >140 mm Hg or diastolic BP (DBP) >90 mm Hg. Diet and life style modification were advised in addition to the concomitant medication, if there were, for 2 weeks. Additional hydrochlorothiazide 50 mg was given per day for another 2 weeks. Both office and 24-h ambulatory BP were checked. The changes of office SBP were used for the response to thiazide treatment. A total of 92 patients were enrolled. Compared with those in the quartile of worst response, patients in the quartile of best response were older with increased baseline SBP and pulse pressure (PP) and reduced heart rate. Reduced baseline awake, but not increased sleep DBP was associated with better response to thiazide. Besides, baseline age, SBP and PP were correlated to the response to thiazide treatment. Among these variables, increased baseline mean BP independently predicted the best and reduced SBP predicted the worst responders. Accordingly, patients with higher mean BP respond better to thiazide treatment no matter with or without concomitant medication. Patients with mainly diastolic hypertension with lower SBP responded poorly to thiazide treatment. The findings may help to individualized use of thiazide in nondiabetic hypertensives.

Fatal amiodarone-induced hepatotoxicity: a case report and literature review.

OBJECTIVE: To report a fatal case of amiodarone-induced acute hepatotoxicity after intravenous amiodarone administration and similar fatal cases review. CASE SUMMARY: A 72-year-old woman with a history of hypertension, prior cardiovascular disease, atrial fibrillation and diabetes mellitus was admitted to the hospital with acute pyelonephritis and transferred to the intensive care unit due to cerebral infarction. An antidiabetic drug, a low dose of aspirin and intravenous amiodarone therapy was started. After receiving a second dose of amiodarone (1,200 mg; injection rate 1 mg/min), the woman developed ascites, jaundice, high levels of serum transaminases, decreased prothrombin time, and finally became unconscious. Immediately after treatment was discontinued, her extremely high hepatic parameters returned to normal. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The occurrence of acute liver damage after intravenous amiodarone is rare but harmful. It can be induced by polysorbate 80, a solubilizer, by immunomediated centrilobular necrosis, or by the presence of a functional PPAR-I+/- gene. CONCLUSION: Amiodarone is an effective antiarrhythmic agent for preventing and treating atrial and ventricular arrhythmias. The molecular mechanism causing acute hepatic damage after amiodarone treatment is not clear. Therefore, amiodarone must be administered with care, and liver function should be monitored closely in patients treated with this drug.

Effect of interleukin-15 on effector and regulatory function of anti-CD3/anti-CD28-stimulated CD4(+) T cells.

Autologous transfer of anti-CD3/anti-CD28 (CD3/CD28)-activated CD4(+) T cells may benefit patients receiving autologous stem cell transplant with severe CD4 lymphopenia. Interleukin (IL)-15, an IL-2-like cytokine that promotes T cell survival may enhance immune reconstitution in conjunction with adoptive immunotherapy. We investigated the effect of IL-15 on effector and regulatory function of CD3/CD28-activated CD4(+) T cells. IL-15 upregulated CD45RO and CD25 whereas it down regulated CD62L expression of CD3/CD28-stimulated CD4(+) T cells. Both type 1 (IFN-gamma, tumor necrosis factor (TNF)-alpha) and type 2 (IL-5 and IL-10) production by CD3/CD28-activated CD4(+) T cells was further enhanced by IL-15. Co-culture experiments revealed that CD3/CD28-activated CD4(+) T cells down regulated proliferation of autologous peripheral blood lymphocytes (PBLs) and CD8(+) PBL subsets upon TCR ligation, a contact-dependent effect that was further enhanced by pretreatment with IL-15. Flow cytometric analysis of cell mixture with carboxyfluorescein diacetate succinimidyl ester and Annexin-V-PE staining revealed that CD3/CD28+IL-15-activated CD4(+) T cells showed increased apoptosis over CD4(+) T cells stimulated with CD3/CD28 alone. Taken together, pretreatment of CD3/CD28-activated CD4(+) T cells with IL-15 may increase regulatory function but may aggravate activation-induced apoptosis of CD3/CD28 CD4(+) T cells.

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.

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.