Ming-Horng Tsai

Risk factors and outcomes for multidrug-resistant Gram-negative bacteremia in the NICU.

OBJECTIVES: To assess the risk factors antibiotic therapy and outcomes of multidrug-resistant (MDR) Gram-negative bacilli (GNB) bacteremia in NICU patients. METHODS: Episodes of MDR GNB bacteremia were compared with a non-MDR GNB bacteremia group in an 8-year cohort study. RESULTS: Of 1106 bacteremias, 393 (35.5%) were caused by GNB. Seventy (18.6%) were caused by an MDR strain. The most frequent mechanism of resistance was extended-spectrum β-lactamase production (67.1%), mainly by Klebsiella pneumoniae (59.6%). Previous antibiotic exposure to third-generation cephalosporin (odds ratio [OR]: 5.97; 95% confidence interval [CI]: 2.37–15.08; P < .001) and carbapenem (OR: 3.60; 95% CI: 1.26–10.29; P = .017) and underlying renal disease (OR: 7.08; 95% CI: 1.74–28.83; P = .006) were identified as independent risk factors for MDR GNB acquisition. Patients with MDR GNB bacteremia more likely received inadequate initial antibiotic therapy (72.9% vs 7.8%; P < .001) had higher rates of infectious complication (21.4% vs 10.5%; P = .011) and overall case fatality +rate (28.6% vs 10.5%; P < .001). Independent risk factors for overall mortality were presence of infectious complications after bacteremia (OR: 3.16; 95% CI: 1.41–7.08; P = .005) and underlying secondary pulmonary hypertension with or without cor pulmonale (OR: 6.19; 95% CI: 1.88–20.31; P = .003). CONCLUSIONS: MDR GNB accounted for 18.6% of all neonatal GNB bacteremia in the NICU, especially in those with previous broad-spectrum antibiotic therapy and underlying renal disease. The most frequent mechanism of resistance was extended-spectrum β-lactamase (ESBL) production. Neonates with MDR GNB were more likely to develop infectious complications, which were independently associated with a higher overall case-fatality rate.

Incidence, clinical characteristics and risk factors for adverse outcome in neonates with late-onset sepsis.

Background: Late-onset sepsis (LOS) is a common complication in the neonatal intensive care unit. We aimed to describe the epidemiology, clinical characteristics and risk factors for adverse outcome in neonates with LOS. Methods: We conducted a cohort study of all neonates with LOS at the neonatal intensive care unit of a Tertiary Taiwan Medical Center from January 2004 through December 2011 and used multivariate logistic regression to identify risk factors for final adverse outcome. Results: Among 5010 neonates over 253,644 neonate-days, 713 (14.2%) experienced a total of 942 episodes of LOS (incidence rate, 3.71 episodes per 1000 neonate-days). Although the rates of LOS were inversely proportional to birth weight and gestational age, the incidence rates were comparable among extremely preterm, late preterm and full term neonates. Fungemia was found to have significantly higher rate of infectious complication (30.8%), persistent bloodstream infection (19.2%) and sepsis attributable mortality (23.1%). The overall mortality rate was 12.6% (90/713), and sepsis attributable mortality rate was 7.2% (68/942 episodes). Independent predictors of in-hospital mortality were Pseudomonas LOS (adjusted odds ratio [OR], 14.31; 95% confidence interval [CI]: 3.87–53.0), fungemia (OR, 5.69; 95% CI: 2.48–13.01), presence of congenital anomalies (OR, 4.12; 95% CI: 1.60–10.60), neuromuscular comorbidities (OR, 3.34; 95% CI: 1.66–6.73) and secondary pulmonary hypertension with/without cor pulmonale (OR, 23.48; 95% CI: 5.96–92.49). Conclusions: LOS predisposes hospitalized neonates to increased risk of mortality or morbidity, especially caused by Pseudomonas aeruginosa or Candida spp. More aggressive treatment strategy is worth consideration in neonates with presumed LOS, particularly those with certain underlying chronic conditions.

Risk Factors of Catheter-related Bloodstream Infection With Percutaneously Inserted Central Venous Catheters in Very Low Birth Weight Infants: A Center's Experience in Taiwan

BACKGROUND Infected percutaneously inserted central venous catheters (PICCs) are a problem in hospitalized patients, especially in the neonatal intensive care unit. The objective of this study was to assess the risk of infection and other PICC-associated complications in very low birth weight infants. METHODS Between January 2005 and December 2006, we studied 412 PICCs inserted in 267 neonates with a birth body weight ≤ 1500g. PICC-related bloodstream infections and other complications were recorded and analyzed. RESULTS These 412 PICCs were inserted for a mean duration of 16.6 ± 9.9 (SD) days. The most common catheter-related complications were catheter-related blood-stream infection (CRBSI; incidence: 8.3 per 1000 catheter days), followed by catheter occlusion (4.0 per 1000 catheter days), catheter site inflammation (3.5 per 1000 catheter days), and phlebitis (3.1 per 1000 catheter days). The most common pathogen of CRBSI was coagulase-negative staphylococcus (40.1%). Significant risk factors of CRBSI included catheters inserted at femoral sites (increased risk of CRBSI compared with nonfemoral catheters: 1.76; 95% confidence interval, 1.01-3.07, p = 0.045) and a longer duration of PICC placement (p < 0.001). A low birth body weight and gestational age were not found to significantly affect the risk of CRBSI. CONCLUSION It is important to avoid inserting a PICC at the femoral site. Strict catheter care protocol should also be applied to reduce local site bacterial colonization and removal of PICCs as soon as they are no longer essential for patient care to reduce the incidence of infection.

Eupafolin, a skin whitening flavonoid isolated from Phyla nodiflora, downregulated melanogenesis: Role of MAPK and Akt pathways.

ETHNOPHARMACOLOGICAL RELEVANCE In hyperpigmentation disorders marked by melanin overproduction in the skin, including melisma and freckles, melanogenesis is caused by tyrosinase overexpression. Natural medicinal resources, like Phyla nodiflora, a traditional Chinese herbal medicine, have been used for a long time to management of dermatological conditions, such as skin inflammation and melanogenesis. Eupafolin, a functional flavonoid isolated from Phyla nodiflora, is an herbal tea constituent and possesses anti-inflammatory and anticancer activities. However, molecular mechanisms of eupafolin-mediated antimelanogenesis remain unknown. We thus focused on its antimelanogenesis effects in B16F10 mouse melanoma cells. MATERIAL AND METHODS B16F10 cells were treated with eupafolin (0.01, 0.1, 1, and 10μM) in a dose-escalation-dependent manner for the determination of melanin, tyrosinase activity and melanogenesis protein levels by ELISA or western blot analysis. RESULTS Eupafolin treatment significantly reduced cellular melanin content and tyrosinase activity in a dose-dependent manner (P<0.05), and no cytotoxic effects were observed. Eupafolin was associated with reduction in the levels of phospho-cAMP response element-binding protein and microphthalmia-associated transcription factor (MITF), and downregulation of tyrosinase synthesis and tyrosinase-related protein expression, leading to inhibit melanin production. In addition, eupafolin significantly induced the phosphorylation of ERK1/2 and p38 MAPK, whereas the decreased effect was observed in the phosphorylation of Akt. Moreover, inhibitors of these signals recovered or attenuated the inhibitory effects of eupafolin on melanogenesis. CONCLUSIONS Our results seem that inhibition of Akt and activation of phospho-ERK or p38 MAPK may lead to the suppression of melanogenesis in eupafolin-treated B16F10 mouse melanoma cells.

Complication Rates With Central Venous Catheters Inserted at Femoral and Non-femoral Sites in Very Low Birth Weight Infants

Objective: To compare the complication rates of femoral versus nonfemoral sites of percutaneously inserted central venous catheters (PICCs) in very low birth weight infants. Methods: Between 2004 and 2006, 518 PICCs inserted in 334 neonates with a birth body weight ≥1500 g were studied. 278 catheters were inserted at nonfemoral sites, and 240 catheters at a femoral site. All catheter-related complications were recorded and analyzed. Results: The infants with femoral PICCs had a significantly higher rate of catheter-related sepsis (CRS) than those with nonfemoral PICCs (22.5% vs. 12.2%, P = 0.002) and the incidence rate was also significantly higher (10.9 vs. 6.8 episodes per 1000 catheter days, P = 0.012). The infants with nonfemoral PICCs had significantly higher rates of phlebitis, catheter site inflammation, and need for early removal than those with femoral PICCs. Multiple logistic regression analysis showed that the significant contributors to CRS were duration of the PICC placement (P < 0.001) and insertion of the PICC at a femoral site (P = 0.010). Conclusions: Because of a higher rate of CRS, the femoral site should not be considered for the placement of PICCs in VLBW infants, when possible.

Curcumin Nanoparticles Ameliorate ICAM-1 Expression in TNF-α-Treated Lung Epithelial Cells through p47 phox and MAPKs/AP-1 Pathways

Upregulation of intercellular adhesion molecule-1 (ICAM-1) involves adhesions between both circulating and resident leukocytes and the human lung epithelial cells during lung inflammatory reactions. We have previously demonstrated that curcumin-loaded polyvinylpyrrolidone nanoparticles (CURN) improve the anti-inflammatory and anti-oxidative properties of curcumin in hepatocytes. In this study, we focused on the effects of CURN on the expression of ICAM-1 in TNF-α-treated lung epithelial cells and compared these to the effects of curcumin water preparation (CURH). TNF-αinduced ICAM-1 expression, ROS production, and cell-cell adhesion were significantly attenuated by the pretreatment with antioxidants (DPI, APO, or NAC) and CURN, but not by CURH, as revealed by western blot analysis, RT-PCR, promoter assay, and ROS detection and adhesion assay. In addition, treatment of TNF-α-treated cells with CURN and antioxidants also resulted in an inhibition of activation of p47 phox and phosphorylation of MAPKs, as compared to that using CURH. Our findings also suggest that phosphorylation of MAPKs may eventually lead to the activation of transcription factors. We also observed that the effects of TNF-α treatment for 30 min, which includes a significant increase in the binding activity of AP-1 and phosphorylation of c-jun and c-fos genes, were reduced by CURN treatment. In vivo studies have revealed that CURN improved the anti-inflammation activities of CURH in the lung epithelial cells of TNF-α-treated mice. Our results indicate that curcumin-loaded polyvinylpyrrolidone nanoparticles may potentially serve as an anti-inflammatory drug for the treatment of respiratory diseases.

Urban particulate matter down-regulates filaggrin via COX2 expression/PGE2 production leading to skin barrier dysfunction

We explored the regulation of filaggrin, cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) expression induced by urban particulate matter (PM) in human keratinocytes. In addition, we investigated the signaling pathways involved in PM-induced effects on COX2/PGE2 and filaggrin. PMs induced increases in COX2 expression and PGE2 production, and decreased filaggrin expression. These effects were attenuated by pretreatment with COX2 inhibitor and PGE2 receptor antagonist, or after transfection with siRNAs of the aryl hydrocarbon receptor (AhR), gp91phox and p47phox. Furthermore, PM-induced generation of reactive oxygen species (ROS) and NADPH oxidase activity was attenuated by pretreatment with an AhR antagonist (AhRI) or antioxidants. Moreover, Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38, and JNK, which then activated the downstream molecules NF-κB and AP-1, respectively. In vivo studies in PMs-treated mice showed that AhRI and apocynin (a Nox2 inhibitor) had anti-inflammatory effects by decreasing COX2 and increasing filaggrin expression. Our results reveal for the first time that PMs-induced ROS generation is mediated through the AhR/p47 phox/NADPH oxidase pathway, which in turn activates ERK1/2, p38/NF-κB and JNK/AP-1, and which ultimately induces COX2 expression and filaggrin downregulation. Up-regulated expression of COX2 and production of PGE2 may lead to impairment of skin barrier function.

The relationship between attention deficit hyperactivity disorder and premature infants in Taiwanese: a case control study

BackgroundPreterm survivors from the neonatal intensive care unit (NICU) are considered to be at risk for some neurobehavioral disorders such as attention-deficit/hyperactivity disorder (ADHD). The current study aimed to explore the relationship between ADHD and premature infants in Taiwan.MethodsA total of 195 children (157 males and 38 females) diagnosed with ADHD based on DSM-IV and aged between 6 to 12 years and a control group of 212 (164 males, 48 females) age- and sex-matched healthy children were enrolled. The ADHD-Rating scale and CGI severity were performed by child psychiatrists. Demographic data of the children, including birth history, perinatal neurological and respiratory problems were collected to facilitate the investigation of whether a correlation exists between ADHD and prematurity.ResultsThe ADHD group had a significantly higher rate of prematurity and significantly higher rate of low birth body weight (defined as <2500 g) than the control group (both P = 0.003). Pearson correlation showed a significantly negative correlation between gestational age and ADHD-RS score, inattentive score, hyperactivity and CGI-S score (P = 0.004, 0.013, 0.015 and 0.002, respectively). However, only a CGI-S score (P = 0.018) showed a significantly correlation between low birth weight and ADHD.ConclusionsPremature infants have significantly more severe symptoms of ADHD at school age and they were highly correlated. Further study is necessary to determine the main effect and pathogenesis of moderate as well as extreme preterm birth on the development of ADHD.

Recurrent late-onset sepsis in the neonatal intensive care unit: incidence, clinical characteristics and risk factors

We aimed to characterize the incidence, clinical features, risk factors and outcomes of recurrent late-onset sepsis (LOS) in the neonatal intensive care unit (NICU). All neonates with LOS from the NICU of a tertiary-level teaching hospital in northern Taiwan between 2004 and 2011 were enrolled for analyses. A case-control study was performed to determine risk factors for recurrence. Of 713 neonates with LOS, 150 (21.0%) experienced recurrence and 48 (6.7%) had >1 recurrences; c. two-thirds of recurrent LOS occurred in infants with birth weight (BW)≦1500 g or gestational age (GA)≦30 weeks. The recurrent LOS episodes were significantly more severe and had a higher sepsis-attributable mortality rate than the first episodes. The overall in-hospital mortality rate was 30.7% for neonates with recurrent LOS and 7.8% for those with single LOS (odds ratio (OR), 5.22; 95% CI, 3.28-8.30). When both BW and GA were controlled, neonates with recurrent LOS had a significantly prolonged hospitalization compared with the controls (median 109 vs. 84 days, p<0.001). After multivariate logistic regression, longer duration of total parenteral nutrition (TPN; OR, 1.30; 95% CI, 1.10-1.52 for every 10-day increment), presence of congenital anomalies (OR, 2.64; 95% CI, 1.10-6.35) and neurological co-morbidities (OR, 4.14; 95% CI, 1.14-15.10) were identified as the independent risk factors for LOS recurrence. We concluded that c. one-fifth of neonates with LOS had recurrence, which significantly resulted in prolonged hospitalization and increased mortality. Longer TPN administration, presence of congenital anomalies and neurological co-morbidities are independently associated with recurrent LOS.

Eupafolin inhibits PGE2 production and COX2 expression in LPS-stimulated human dermal fibroblasts by blocking JNK/AP-1 and Nox2/p47phox pathway

Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation and decreased reactive oxygen species (ROS) generation and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-Jun and c-Fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPK phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases.