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Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4(-/-) mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN., (© 2015. Published by The Company of Biologists Ltd.)

Background: Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI., Materials and Methods: A mouse model of antibiotic-associated clostridial colitis was set up. NF-κB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines., Results: Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More-evident inflammatory responses were detected by in vivo imaging of NF-κB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI., Conclusions: Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Visfatin is both a systemic adipocytokine and the cytosolic enzyme, nicotinamide phosphoribosyl transferase (Nampt). This is a longevity protein, which extends the lifespan of human cells by activating sirtuin 1 (SIRT1). In this study, we sought a role for these proteins in obese pregnant women, who experience more postterm deliveries. Thus, 78 women (26 lean, 24 overweight, and 28 obese) were recruited and maternal blood and placental tissue collected prior to term labor. Plasma levels were measured by enzyme-linked immunosorbent assay and quantitative immunohistochemistry used for placenta. We confirmed maternal plasma interleukin 6 increased according to prepregnancy body mass index (BMI; P < .0001) and showed a linear relationship between BMI and syncytiotrophoblast visfatin/Nampt (P = .021) but not with its levels in maternal plasma. Both systemic and placental visfatin/Nampt were significantly associated with placental SIRT1 levels (P = .028 and .017). Thus, higher visfatin/Nampt may prevent a labor-associated decrease in SIRT1 leading to postterm delivery in obesity., (© The Author(s) 2015.)

Propionibacterium acnes is a key pathogen involved in acne inflammation. Wild bitter melon (WBM, Momordica charantia L. var. abbreviate Seringe) is consumed as both a vegetable and as folk medicine in Taiwan. We examined the inhibitory activity of the total phenolic extract (TPE) of WBM leaf on P. acnes-induced inflammatory responses in vivo and in vitro. Our data showed that TPE significantly attenuated P. acnes-induced ear swelling in mice along with microabscess. Flow cytometry analysis revealed that TPE treatment significantly decreased the migration of neutrophils and interleukin (IL)-1β(+) populations in vivo. In P. acnes-stimulated human monocytic THP-1 cells, TPE suppressed the mRNA levels and production of IL-8, IL-1β, and tumor necrosis factor (TNF)-αin vitro. In addition, TPE suppressed P. acnes-induced matrix metalloproteinase-9 levels. TPE blocked nuclear factor-κB (NF-κB) activation and inactivated mitogen-activated protein kinases (MAPK); these actions may partially account for its inhibitory effect on cytokine production. The quantitative HPLC analysis revealed gallic, chlorogenic, caffeic, ferulic, and cinnamic acids, myricetin, quercetin, luteolin, apigenin, and thymol in TPE. All these phenolics significantly suppressed P. acnes-induced IL-8 production in vitro. Our results suggest that WBM leaf extract effectively inhibits P. acnes-induced inflammatory responses and may be useful to relieve the inflammation of acne.

Purpose: Long-term follow-up studies of asbestos-related cancer in shipbreaking workers are lacking. This study examines the relationship between cancer incidence and asbestos exposure among former Taiwan shipbreaking workers., Methods: A total of 4,427 shipbreaking workers and 22,135 population-based matched controls were successfully followed in this study. The study cohort was linked to the Taiwan Cancer Registry for new cancer cases. The adjusted hazard ratio (aHR) for cancer was calculated for the shipbreaking workers with Total Exposure Potential Scores (TEP) for asbestos., Results: Follow-up generated 109,932 person-years, with 940 deaths and 436 cancer cases, among 4,427 shipbreaking workers from 1985 to 2008. The high asbestos exposure group also had a statistically significant increase in the risk of overall cancer (aHR= 1.71; 95% CI: 1.42-2.05), esophagus cancer (aHR= 2.31; 95% CI: 1.00-5.41), liver and intrahepatic bile duct cancer (aHR= 1.60; 95% CI: 1.08-2.36), and trachea, bronchus, and lung cancer (aHR= 3.08; 95% CI: 1.80-5.25). Mesothelioma cases were found in the high asbestos exposure group. Moreover, overall cancer, esophagus cancer, and trachea, bronchus, and lung cancer were seen in a dose-dependent relationship with asbestos exposure., Conclusions: This study presented the elevated trend of asbestos exposure with cancer incidence for overall cancer, esophagus cancer, and trachea, bronchus, and lung cancer among shipbreaking workers. Those workers previously exposed to asbestos should receive persistent monitoring in order to early detect adverse health outcomes.

Unlabelled: Pancreatic β-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how β-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue β-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic β-cells to translate fatty acid stimuli into a cellular adaptation mechanism., Key Message: PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect β-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.

Clostridium difficile infection (CDI) is known to be associated with prior exposure to many classes of antibiotics. Standard therapy for CDI (i.e., metronidazole and vancomycin) is associated with high recurrence rates. Although tetracycline derivatives such as tetracycline, doxycycline or tigecycline are not the standard therapeutic choices for CDI, they may serve as an alternative or a component of combination therapy. Previous tetracycline or doxycycline usage had been shown to have less association with CDI development. Tigecycline, a broad-spectrum glycylcycline with potency against many gram-positive or gram-negative pathogens, had been successfully used to treat severe or refractory CDI. The in vitro susceptibility of C. difficile clinical isolates to tigecycline in many studies showed low minimal inhibitory concentrations. Tigecycline can suppress in vitro toxin production in both historical and hypervirulent C. difficile strains and reduce spore production in a dose-dependent manner. Tetracycline compounds such as doxycycline, minocycline, and tigecycline possess anti-inflammatory properties that are independent of their antibiotic activity and may contribute to their therapeutic effect for CDI. Although clinical data are limited, doxycycline is less likely to induce CDI, and tigecycline can be considered one of the therapeutic choices for severe or refractory CDI.

Clostridium difficile can cause antibiotic-associated diarrhea in hospitalized patients. Asymptomatic colonization by C. difficile is common during the neonatal period and early infancy, ranging from 21% to 48%, and in childhood. The colonization rate of C. difficile in adult hospitalized patients shows geographic variation, ranging from 4.4% to 23.2%. Asymptomatic carriage in neonates caused no further disease in many studies, whereas adult patients colonized with toxigenic C. difficile were prone to the subsequent development of C. difficile-associated diarrhea (CDAD). However, the carriage of nontoxigenic C. difficile strains appears to prevent CDAD in hamsters and humans. Risk factors for C. difficile colonization include recent hospitalization, exposure to antimicrobial agents or gastric acid-suppressing drugs (such as proton-pump inhibitors and H2 blockers), a history of CDAD or cytomegalovirus infection, the presence of an underlying illness, receipt of immunosuppressants, the presence of antibodies against toxin B, and Toll-like receptor 4 polymorphisms. Asymptomatic C. difficile carriers are associated with significant skin and environmental contamination, similar to those with CDAD, and contact isolation and hand-washing practices should therefore be employed as infection control policies for the prevention of C. difficile spread. Treating patients with asymptomatic C. difficile colonization with metronidazole or vancomycin is not suggested by the currently available evidence. In conclusion, asymptomatic C. difficile colonization may lead to skin and environmental contamination by C. difficile, but more attention should be paid to the clinical impact of those with C. difficile colonization., (Copyright © 2014. Published by Elsevier B.V.)

Prenatal ultrasound has become an essential clinical tool for aneuploidy screening, detection of fetal congenital anomalies, and assessment of fetal growth and well-being. Maternal obesity, an increasing global problem, has been shown to decrease the accuracy of ultrasound examination in high-risk pregnancy. The purpose of this review is to provide an evidenced-based perspective on the challenges of performing fetal ultrasound in obese women and to provide a practical guide on how to care for these patients in the ultrasound suite., (Published by Elsevier Ltd.)

Background: Patients with toxigenic Clostridium difficile colonization (tCDC) are at risk of developing C. difficile-associated diarrhea (CDAD). However, the risk factors of hospitalized patients with tCDC developing CDAD are not clear., Methods: We conducted an 18-month prospective study at a medical ward in a district hospital in southern Taiwan. Within 48 hours of admission, weekly stool samples from asymptomatic hospitalized patients were obtained to detect fecal CDC. A polymerase chain reaction for tcdB was performed to determine toxigenic isolates. CDAD was diagnosed if the patient had diarrhea and toxigenic C. difficile present in a stool sample., Results: A total 483 patients with stool samples were eligible for the study. Eighty-six (17.8%) patients had tCDC after screening, of whom 14 (16.3%) developed CDAD during follow-up. Among those with tCDC, patients with subsequent CDAD were more likely to have diabetes mellitus (p = 0.01) and to have received piperacillin-tazobactam (p = 0.04), or proton-pump inhibitors (PPIs; p = 0.04) than those without developing CDAD. The variables were statistically significant as determined by multivariate analysis. However, the 60-day crude mortality rates among tCDC patients with and without subsequent development of CDAD were similar., Conclusion: Diabetes mellitus and recent receipt of piperacillin-tazobactam or PPIs are independent risk factors for the development of CDAD among hospitalized patients with tCDC., (Copyright © 2013. Published by Elsevier B.V.)

The aim of this study was to develop a simple and reliable high-performance chromatographic (HPLC) method for simultaneous analysis of adapalene and benzoyl peroxide in pharmaceutical formulation by response surface methodology (RSM). An optimized mobile phase composed of acetonitrile, tetrahydrofuran and water containing 0.1% acetic acid at a ratio of 25:50:25 by volume was successfully predicted by using RSM. An isocratic separation was achieved by using the condition. Furthermore, the analytical method was validated in terms of specificity, linearity, accuracy and precision in a range of 80% to 120% of the expected concentration. Finally, the method was successfully applied to the analysis of a commercial product.

Background: Advances in Aeromonas taxonomy have led to the reclassification of aeromonads. Hereon, we aimed to re-evaluate the characteristics of Aeromonas bacteremia, including those of a novel species, Aeromonas dhakensis., Methodology/principal Findings: A retrospective study of monomicrobial Aeromonas bacteremia at a medical center in southern Taiwan from 2004-2011 was conducted. Species identification was based on rpoB sequencing. Of bacteremia of 153 eligible patients, A. veronii (50 isolates, 32.7%), A. dhakensis (48, 31.4%), A. caviae (43, 28.1%), and A. hydrophila (10, 6.5%) were the principal causative species. A. dhakensis and A. veronii bacteremia were mainly community-acquired and presented as primary bacteremia, spontaneous bacterial peritonitis, or skin and soft-tissue infection, whereas A. caviae was associated with hospital-onset bacteremia. The distribution of the AmpC β-lactamase and metallo-β-lactamase genes was species-specific: bla(AQU-1), bla(MOX), or bla(CepH) was present in A. dhakensis, A. caviae, or A. hydrophila, respectively, and bla(CphA) was present in A. veronii, A. dhakensis, and A. hydrophila. The cefotaxime resistance rates of the A. caviae, A. dhakensis, and A. hydrophila isolates were higher than that of A. veronii (39.5%%, 25.0%, and 30% vs. 2%, respectively). A. dhakensis bacteremia was linked to the highest 14-day sepsis-related mortality rate, followed by A. hydrophila, A. veronii, and A. caviae bacteremia (25.5%, 22.2%, 14.0%, and 4.7%, respectively; P = 0.048). Multivariate analysis revealed that A. dhakensis bacteremia, active malignancies, and a Pitt bacteremia score ≥ 4 was an independent mortality risk factor., Conclusions/significance: Characteristics of Aeromonas bacteremia vary between species. A. dhakensis prevalence and its associated poor outcomes suggest it an important human pathogen.

This study aimed to gain new insights into both systemic and placental leptin and its receptors, with reference to the maternal prepregnancy body mass index (BMI). Thus, 84 women (29 lean, 24 overweight, and 31 obese) were recruited and maternal, cord blood, and placental tissues collected prior to term labor. Plasma levels were measured by enzyme-linked immunosorbent assay and for placenta, immunohistochemistry and messenger RNAs (mRNAs) were quantitated. We confirmed that maternal leptin increased linearly as the soluble receptor decreased with BMI (P = .001). Fetal leptin increased with maternal BMI (P = .02) and birth weight (P = .006) and was higher in female infants (P < .001). Placental mRNA levels of leptin and its receptors showed no change in BMI. However, we show a significant (P = .043) linear increase in leptin in the placental vascular endothelial cells with maternal obesity, while leptin in syncytiotrophoblast showed no statistical change. Leptin receptors localized to syncytiotrophoblast and intravillous macrophages and were unchanged with BMI., (© The Author(s) 2014.)

Purpose: The purpose of this study is to identify the possible factors for preserving the eyes after late or suboptimally treated endogenous endophthalmitis secondary to Klebsiella pneumoniae (KP) liver abscess., Methods: A retrospective chart review was conducted for patients admitted with KP liver abscess from January 1991 to June 2012., Results: Six hundred and ninety-three patients with KP liver abscess were recorded, in which endophthalmitis was identified in 53 cases (65 eyes, 8.29%). Diabetes was significantly associated with the development of endophthalmitis ( p = 0.014). Eleven eyes received their last ocular treatment ≥10 days and final vision ≥ counting fingers, and were defined as benign type KP endophthalmitis. The absence of diabetes was the only consistent candidate factor for benign type KP endophthalmitis., Conclusion: A lack of ongoing diabetes is an important factor in preserving eyes with late or suboptimally treated endogenous endophthalmitis second to KP liver abscess., Competing Interests: Conflicts of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Proper control of Ca(2+) signaling is mandatory for effective cell migration, which is critical for embryonic development, wound healing, and cancer metastasis. However, how Ca(2+) coordinates structural components and signaling molecules for proper cell motility had remained elusive. With the advance of fluorescent live-cell Ca(2+) imaging in recent years, we gradually understand how Ca(2+) is regulated spatially and temporally in migrating cells, driving polarization, protrusion, retraction, and adhesion at the right place and right time. Here we give an overview about how cells create local Ca(2+) pulses near the leading edge, maintain cytosolic Ca(2+) gradient from back to front, and restore Ca(2+) depletion for persistent cell motility. Differential roles of Ca(2+) in regulating various effectors and the interaction of roles of Ca(2+) signaling with other pathways during migration are also discussed. Such information might suggest a new direction to control cancer metastasis by manipulating Ca(2+) and its associating signaling molecules in a judicious manner.

Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury, possibly attracted by inflammatory cytokines. Although many cytokines can induce stem cell migration, the underlying mechanism is not fully understood. We found that tail vein-injected MSCs migrate to the pancreas in nonobese diabetic (NOD) mice. An ELISA assay revealed that hyperglycemic NOD mice have higher pancreatic levels of interleukin-1β (IL-1β) than normal NOD mice and that IL-1β stimulates MSC migration in a Transwell assay and electric cell-substrate impedance sensing system. Microarray analysis showed that myosin light chain kinase (MLCK) is involved in IL-1β-induced MSC migration, while Western blots showed that IL-1β stimulates MLCK expression and activation and that MLCK-siRNA transfection reduces MSC migration. Kinase inhibitors, chromatin immunoprecipitation, and a knockdown study revealed that IL-1β-induced MLCK expression is regulated by the PKCδ/NF-κB signaling pathway, and a kinase inhibitor study revealed that IL-1β-induced MLCK activation occurs via the PKCα/MEK/ERK signaling pathway. These results show that IL-1β released from the pancreas of hyperglycemic NOD mice induces MSC migration and that this is dependent on MLCK expression via the PKCδ/NF-κB pathway and on MLCK activation via the PKCα/MEK/ERK signaling cascade. This study increases our understanding of the mechanisms by which MSCs home to injury sites.

Background. Type 1 diabetes mellitus results from autoimmune destruction of β-cells. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) in human tissues decrease blood glucose levels and improve survival in diabetic rats. We compared the differential ability and the curative effect of IPCs from three types of human tissue to determine the ideal source of cell therapy for diabetes. Methods. We induced MSCs from Wharton's jelly (WJ), bone marrow (BM), and surgically resected pancreatic tissue to differentiate into IPCs. The in vitro differential function of these IPCs was compared by insulin-to-DNA ratios and C-peptide levels after glucose challenge. In vivo curative effects of IPCs transplanted into diabetic rats were monitored by weekly blood glucose measurement. Results. WJ-MSCs showed better proliferation and differentiation potential than pancreatic MSCs and BM-MSCs. In vivo, WJ-IPCs significantly reduced blood glucose levels at first week after transplantation and maintained significant decrease till week 8. BM-IPCs reduced blood glucose levels at first week but gradually increased since week 3. In resected pancreas-IPCs group, blood glucose levels were significantly reduced till two weeks after transplantation and gradually increased since week 4. Conclusion. WJ-MSCs are the most promising stem cell source for β-cell regeneration in diabetes treatment.

Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic β-cells. Systemic administration of mesenchymal stem cells (MSCs) brings about their incorporation into a variety of tissues with immunosuppressive effects, resulting in regeneration of pancreatic islets. We previously showed that human MSCs isolated from Wharton's jelly (WJ-MSCs) represent a potential cell source to treat diabetes. However, the underlying mechanisms are unclear. The purpose of this study was to discern whether undifferentiated WJ-MSCs can differentiate into pancreatic insulin-producing cells (IPCs) and modify immunological responses in nonobese diabetic (NOD) mice. Undifferentiated WJ-MSCs underwent lentiviral transduction to express green fluorescent protein (GFP) and then were injected into the retro-orbital venous sinus of NOD mice. Seven days after transplantation, fluorescent islet-like cell clusters in the pancreas were apparent. WJ-MSC-GFP-treated NOD mice had significantly lower blood glucose and higher survival rates than saline-treated mice. Systemic and local levels of autoaggressive T-cells, including T helper 1 cells and IL-17-producing T-cells, were reduced, and regulatory T-cell levels were increased. Furthermore, anti-inflammatory cytokine levels were increased, and dendritic cells were decreased. At 23 days, higher human C-peptide and serum insulin levels and improved glucose tolerance were found. Additionally, WJ-MSCs-GFP differentiated into IPCs as shown by colocalization of human C-peptide and GFP in the pancreas. Significantly more intact islets and less severe insulitis were observed. In conclusion, undifferentiated WJ-MSCs can differentiate into IPCs in vivo with immunomodulatory effects and repair the destroyed islets in NOD mice.

Background: Several wild bitter melon (WBM; Momordica charantia Linn. var. abbreviata Ser.) cultivars were developed in Taiwan. However, little information is available regarding biological function of WBM leaf. Therefore, the objectives of this study were to investigate the nutrient content, antioxidant, cell protection and anti-melanogenic properties of wild bitter melon leaf., Results: Methanolic leaf extracts were prepared from a variety and two cultivars of WBM. All extracts exerted potent nitric oxide and hydroxyl radical scavenging capacities. Furthermore, all extracts effectively reduce the production of reactive oxygen species and prevent cell death in UVB-irradiated HaCaT keratinocytes. The cell protective effect of leaf extract was also investigated by the prevention of HaCaT cells from sodium nitroprusside or menadione-induced toxicity, and significant cyto-protective activities were observed for all of them. Additionally, all extracts significantly suppressed tyrosinase activity and melanin levels in B16-F10 melanocytes., Conclusions: WBM leaf extract showed significant antioxidant, cyto-protective and anti-melanogenic activities. These findings suggested that WBM leaves may be beneficial for preventing the photo-oxidative damage and melanogenesis of skin.

Introduction: Several virulent Clostridium difficile clones, designated as polymerase chain reaction (PCR) ribotypes 017, 027, or 078, are well recognized in western countries. However, the ribotype distribution of clinical C. difficile isolates in Taiwan remains unclear., Method: Between 2010 and 2012, we identified three patients with C. difficile-associated diarrhea (CDAD) at a hospital in southern Taiwan. The C. difficile strains isolated from these patients were further characterized by PCR detection of tcdA, tcdB, tcdC, cdtA, and cdtB, toxinotyping, multilocus sequence typing, ribotyping and repetitive-based PCR., Results: Three C. difficile strains harbored tcdCΔ39 and belonged to multilocus sequence typing 11 (ST11), toxinotype V, and ribotype 126 (a ribotype 078-like clone). Notably, one patient developed pseudomembranous colitis and recurrent CDAD. These three isolates were noted between January 2012 and June 2012 and were identical, as evidenced by repetitive sequence-based PCR, suggestive of case clustering., Conclusion: A hypervirulent C. difficile clone, ribotype 126, causing pseudomembranous colitis and recurrent CDAD, is present in southern Taiwan., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

An 85 year-old male initially admitted for septic shock due to urinary tract infection experienced Clostridium difficile-associated diarrhea during hospitalization and was treated by oral vancomycin. His clinical course was complicated by cytomegalovirus colitis and then vancomycin-resistant Clostridium innocuum bacteremia, which was cured by uneventfully parenteral piperacillin-tazobactam therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Brain functions express rhythmic fluctuations accompanied by sleep and wakefulness each day, but how sleep regulates brain rhythms remains unclear. Following the dose-dependent local sleep concept, two succeeding questions emerge: (1) is the sleep regulation a network-specific process; and (2) is the awakening state dependent on the previous sleep stages? To answer the questions, we conducted simultaneous EEG and fMRI recordings over 22 healthy male participants, along pre-sleep, nocturnal sleep and awakening. Using paired comparisons between awakening and pre-sleep conditions, three scenarios of the regional specificity were demonstrated on awakening: (1) the default-mode and hippocampal networks maintained similar connectivity and spectral power; (2) the sensorimotor network presented reduced connectivity and spectral power; and (3) the thalamus demonstrated substantially enhanced connectivity to the neo-cortex with decreased spectral power. With regard to the stage effect, the deep sleep group had significant changes in both functional connectivity and spectral power on awakening, whereas the indices of light sleep group remained relatively quiescent after sleep. The phenomena implied that slow-wave sleep could be key to rebooting the BOLD fluctuations after sleep. In conclusion, the regional specificity and the stage effect were verified in support of the local awakening concept, indicating that sleep regulation leads to the reorganization of brain networks upon awakening., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to compare virulence among different Aeromonas species causing bloodstream infections., Methodology/principal Findings: Nine of four species of Aeromonas blood isolates, including A. dhakensis, A. hydrophila, A. veronii and A. caviae were randomly selected for analysis. The species was identified by the DNA sequence matching of rpoD. Clinically, the patients with A. dhakensis bacteremia had a higher sepsis-related mortality rate than those with other species (37.5% vs. 0%, P = 0.028). Virulence of different Aeromonas species were tested in C. elegans, mouse fibroblast C2C12 cell line and BALB/c mice models. C. elegans fed with A. dhakensis and A. caviae had the lowest and highest survival rates compared with other species, respectively (all P values <0.0001). A. dhakensis isolates also exhibited more cytotoxicity in C2C12 cell line (all P values <0.0001). Fourteen-day survival rate of mice intramuscularly inoculated with A. dhakensis was lower than that of other species (all P values <0.0001). Hemolytic activity and several virulence factor genes were rarely detected in the A. caviae isolates., Conclusions/significance: Clinical data, ex vivo experiments, and animal studies suggest there is virulence variation among clinically important Aeromonas species.

Background: Antiviral therapy in addition to immunoprophylaxis at birth has been shown to further reduce perinatal transmission of hepatitis B virus (HBV) in highly viremic women., Aims: The aim of this study was to describe the use of tenofovir disoproxil fumarate (TDF) prophylaxis to reduce maternal HBV DNA levels and potentially vertical transmission in highly viremic women., Methods: After receiving IRB approval, we performed a retrospective chart review of mothers positive for hepatitis B surface antigen (HBsAg) who delivered between 2009 and 2012. We identified women with HBV DNA levels ≥6 log copies/mL who were treated with TDF in pregnancy., Results: There were 22 women identified. The majority were of Micronesian ethnicity. All were negative for hepatitis C antibody and HIV infection. The median gestational age of TDF initiation was 31 weeks with a median duration of treatment of 45 days. There was a reduction in median HBV DNA levels from baseline 9.0 ± 2.0 to 5.4 ± 1.1 log copies/mL after treatment. There were five (22.7 %) preterm deliveries and five (22.7 %) cesarean deliveries. All infants received immunoprophylaxis at birth. Postnatal HBsAg testing at 9-12 months was available for 13 infants, 12 of which were negative. There was one case of perinatal transmission., Conclusions: This is the second published case series to date on the use of TDF prophylaxis in HBV mono-infected, highly viremic mothers. This series suggests the use of TDF in pregnancy reduces maternal HBV DNA levels and is well tolerated.

Astragalus membranaceus, a traditional Chinese herb, has been used to improve airway inflammation and asthma. The present study investigated whether A. membranaceus has immunotherapeutic effects on asthma, a chronic inflammatory mucosal disease that is associated with excess production of IgE, eosinophilia, T helper 2 (Th2) cytokines, and bronchial hyperresponsiveness. An ovalbumin (OVA)-induced, chronic inflammatory airway murine asthma model was used to examine the status of pulmonary inflammation after the administration of A. membranaceus. The IgE levels in serum and bronchoalveolar lavage fluid showed a tendency to decrease after the administration of A. membranaceus. The number of eosinophils decreased and infiltration of inflammatory cells and collagen deposition declined in lung sections after A. membranaceus administration. The RNA and protein levels of Th2 cytokines and the ratio of the GATA3/T-bet mRNA levels decreased after A. membranaceus treatment. Furthermore, the mRNA level of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor, increased in the lung tissues of A. membranaceus-treated mice. Finally, an A. membranaceus water extract activated PPARγ activity in either human embryonic kidney 293 (HEK293) or A549 cells in a PPARγ-responsive element-containing luciferase reporter assay. These results indicate that A. membranaceus has an inhibitory effect on airway inflammation in a murine model of asthma through modulating the imbalanced relationship between Th1 and Th2 cytokines.

More than 20% of chronic hepatitis C (CHC) patients receiving interferon-alpha (IFN-α)-based anti-hepatitis C virus (HCV) therapy experienced significant depression, which was relieved by treatment with fluoxetine. However, whether and how fluoxetine affected directly the anti-HCV therapy remained unclear. Here, we demonstrated that fluoxetine inhibited HCV infection and blocked the production of reactive oxygen species (ROS) and lipid accumulation in Huh7.5 cells. Fluoxetine facilitated the IFN-α-mediated antiviral actions via activations of signal transducer and activator of transcription (STAT)-1 and c-Jun amino-terminal kinases (JNK). Alternatively, fluoxetine elevated peroxisome proliferator-activated receptor (PPAR) response element activity under HCV infection. The inhibitory effects of fluoxetine on HCV infection and lipid accumulation, but not production of ROS, were partially reversed by the PPAR-β, -γ, and JNK antagonists. Furthermore, fluoxetine intervention to the IFN-α-2b regimen facilitated to reduce HCV titer and alanine transaminase level for CHC patients. Therefore, fluoxetine intervention to the IFN-α-2b regimen improved the efficacy of anti-HCV treatment, which might be related to blockades of ROS generation and lipid accumulation and activation of host antiviral JNK/STAT-1 and PPARβ/γ signals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

An integrated approach was developed to assess exposure and health-risk from polycyclic aromatic hydrocarbons (PAHs) contained in oil mists in a fastener manufacturing industry. One previously developed model and one new model were adopted for predicting oil mist exposure concentrations emitted from metal work fluid (MWF) and PAHs contained in MWF by using the fastener production rate (Pr) and cumulative fastener production rate (CPr) as predictors, respectively. By applying the annual Pr and CPr records to the above two models, long-term workplace PAH exposure concentrations were predicted. In addition, true exposure data was also collected from the field. The predicted and measured concentrations respectively served as the prior and likelihood distributions in the Bayesian decision analysis (BDA), and the resultant posterior distributions were used to determine the long-term exposure and health-risks posed on workers. Results show that long term exposures to PAHs would result in a 3.1%, 96.7%, and 73.4% chance of exceeding the PEL-TWA (0.2 mg/m3), action level (0.1 mg/m3), and acceptable health risk (10-3), respectively. In conclusion, preventive measures should be taken immediately to reduce workers' PAH exposures.

Background: Shipbreaking remains one of the most dangerous jobs worldwide. Shipbreaking workers are exposed to many hazardous chemicals, especially asbestos. Unfortunately, long-term follow-up studies of cancer incidence patterns in shipbreaking workers are lacking. This study examines whether there is an increased risk of cancer among male shipbreaking workers over a 24-year follow-up period., Methods: 4155 male shipbreaking worker's information was retrospectively collected from Kaohsiung's Shipbreaking Workers Union database from 1985. The study cohort was linked to the Taiwan Cancer Registry from 1985 to 2008 for new cancer cases. The expected number of cancers for shipbreaking workers was calculated by using the age (5-year intervals) and calendar time-specific annual rates of cancer incidence with reference to the general population of Taiwan from 1985 to 2008. Standardized incidence ratios (SIRs) were calculated as relative risk estimates. The hazard ratio (HR) for cancer was calculated for the shipbreaking workers with Total Exposure Potential Scores for asbestos., Results: After consideration of a 5-year latency period, an elevated incidence of overall cancer (N=368; SIR=1.13 (1.01-1.25)), oral cavity cancer (N=83; SIR=1.99 (1.58-2.46)), and trachea, bronchus, and lung cancers (N=53; SIR=1.36 (1.02-1.78)) was found among male shipbreaking employees. Moreover, mesothelioma cases were found in those who had the occupation of flame cutter. The high asbestos exposure group was associated with an increased SIR of developing overall cancer and oral cancer, whether we considered a 5-year or 10-year latency period., Conclusion: Asbestos-related diseases, including lung cancer and mesothelioma, were seen in excess in these shipbreaking workers and some cases appeared to have a dose-dependent relationship. Preventative measures among male shipbreaking workers should be researched further., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aeromonas dhakensis, often phenotypically identified as Aeromonas hydrophila, is an important human pathogen. The present study aimed to compare the clinical and biological features of A. dhakensis and A. hydrophila isolates from human wounds. A total of 80 Aeromonas wound isolates collected between January 2004 and April 2011 were analysed. The species was identified by the DNA sequence matching of rpoD and gyrB (or rpoB if necessary). Most of the Aeromonas isolates were identified as A. dhakensis (37, 46.3%), and 13 (16.3%) as A. hydrophila. Both species alone can cause severe skin and soft-tissue infections. More A. dhakensis isolates were found in wounds exposed to environmental water (32.4% vs 0%, p 0.042). More biofilm formation was noted among A. dhakensis isolates (mean optical density at 570 nm, 1.23 ± 0.09 vs 0.78 ± 0.21, p 0.03). The MICs of ceftriaxone, imipenem and gentamicin for A. dhakensis isolates were higher (p <0.0001, <0.04, and <0.01, respectively). The survival rates of Caenorhabditis elegans co-incubated with A. dhakensis from day 1 to day 3 were lower than those of worms infected with A. hydrophila in liquid toxicity assays (all p values <0.01). Isolates of A. dhakensis exhibited more cytotoxicity, as measured by the released leucocyte lactate dehydrogenase levels in human normal skin fibroblast cell lines (29.6 ± 1.2% vs 20.6 ± 0.6%, p <0.0001). The cytotoxin gene ast was primarily present in A. hydrophila isolates (100% vs 2.7%, p <0.0001). In summary, A. dhakensis is the predominant species among Aeromonas wound isolates, and more virulent than A. hydrophila., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

We present an experimental study of the coherence properties of amplified slow light by four-wave mixing (FWM) in a three-level electromagnetically induced transparency (EIT) system driven by one additional pump field. High energy gain (up to 19) is obtained with a weak pump field (a few mW/cm2) using optically dense cold atomic gases. A large fraction of the amplified light is found to be phase incoherent to the input signal field. The dependence of the incoherent fraction on pump field intensity and detuning and the control field intensity is systematically studied. With the classical input pulses, our results support a recent theoretical study by Lauk et al. [Phys. Rev. A88, 013823 (2013)], showing that the noise resulting from the atomic dipole fluctuations associated with spontaneous decay is significant in the high gain regime. This effect has to be taken into consideration in EIT-based applications in the presence of FWM.

Clustered regularly interspaced short palindromic repeats (CRISPR) are composed of numerous repeat-spacer units and are considered a prokaryotic defence system against foreign nucleic acids. Since antibiotic-resistant genes are frequently encoded in foreign nucleic acids, the aim of this study was to test whether erythromycin susceptibility in group A streptococcus (Streptococcus pyogenes) is associated with characteristics of CRISPR elements. Erythromycin susceptibility of 330 isolates collected between 1997 and 2003 was analysed. Among 29 emm types, emm12, emm75 and emm92 showed significant changes in erythromycin-resistance rates. By sequencing the spacers from two CRISPR loci, spacer contents in emm12, emm75 and emm92 strains were associated with erythromycin susceptibility. Strains with fewer spacers were more resistant to erythromycin. Moreover, in emm4 strains, which showed no significant change in their annual erythromycin-resistance rate, CRISPR type and number of spacers were not correlated with erythromycin susceptibility. These results highlight a novel association between CRISPR spacer content and erythromycin susceptibility in group A streptococcus., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

Δ7-Eicosatrienoic acid (Δ7-ETrA; Δ7,11,14-20:3), an elongation metabolite of pinolenic acid (PNA; Δ5,9,12-18:3), is a rare polyunsaturated fatty acid (PUFA) originally from pine seeds. Incorporation of PNA and Δ7-ETrA into murine macrophages inhibited lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) production. Due to the lack of availability of the naturally-occurring fatty acid, we synthesized Δ7-ETrA and demonstrated it was capable of suppressing PGE2 production. Using laboratory synthetic techniques involving 2-carbon elongation and argentated column chromatography, Δ7-ETrA was synthesized and isolated. Its identity and purity (>98%) were confirmed by gas chromatography (GC)/GC-mass spectroscopy. Incubation of murine RAW264.7 cells or rat primary peritoneal macrophages with Δ7-ETrA reduced PGE2 production by up to 84%, but slightly down-regulated type-2 cyclooxygenase (COX-2) expression. Δ7-ETrA blocked nuclear factor-kappa B (NF-κB) translocation into nucleus and inactivated mitogen-activated protein kinases (MAPK), however, these results might not directly account for its inhibitory effect. Furthermore, PGE2 production reduced by Δ7-ETrA was highly correlated with the extent of Δ7-ETrA incorporation into cellular phospholipids and appeared to be the result of competition between this unusual fatty acid and arachidonic acid (AA) for COX-2. In conclusion, Δ7-ETrA incorporation suppresses PGE2 production by macrophages through competition between Δ7-ETrA and AA for COX-2., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Propionibacterium acnes (P. acnes) is a commensal bacterium which is possibly involved in acne inflammation. The saturated fatty acid, lauric acid (C12:0) has been shown to possess antibacterial and anti-inflammatory properties against P. acnes. Little is known concerning the potential effects of its decanoic counterpart, capric acid (C10:0)., Objective: To examine the antibacterial and anti-inflammatory activities of capric acid against P. acnes and to investigate the mechanism of the anti-inflammatory action., Methods: The antimicrobial activity of fatty acids was detected using the broth dilution method. An evaluation of P. acnes-induced ear edema in mice was conducted to evaluate the in vivo anti-inflammatory effect. To elucidate the in vitro anti-inflammatory effect, human SZ95 sebocytes and monocytic THP-1 cells were treated with P. acnes alone or in the presence of a fatty acid. The mRNA levels and secretion of pro-inflammatory cytokines were measured by qRT-PCR and enzyme immunoassay, respectively. NF-κB activation and MAPK expression were analyzed by ELISA and Western blot, respectively., Results: Lauric acid had stronger antimicrobial activity against P. acnes than capric acid in vitro and in vivo. However, both fatty acids attenuated P. acnes-induced ear swelling in mice along with microabscess and significantly reduced interleukin (IL)-6 and CXCL8 (also known as IL-8) production in P. acnes-stimulated SZ95 sebocytes. P. acnes-induced mRNA levels and secretion of IL-8 and TNF-α in THP-1 cells were suppressed by both fatty acids, which inhibited NF-κB activation and the phosphorylation of MAP kinases., Conclusion: Our data demonstrate that both capric acid and lauric acid exert bactericidal and anti-inflammatory activities against P. acnes. The anti-inflammatory effect may partially occur through the inhibition of NF-κB activation and the phosphorylation of MAP kinases., (Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Hyaluronic acid capsule is one of the most important virulence factors of group A Streptococcus (GAS). Over-production of capsule has been thought to enhance GAS virulence during infections. However, although the increased of capsule expression associates with increased bacterial virulence and invasive ability, over-production of capsule has not often been observed among clinical isolates. In the present study, we identified two mucoid emm12 type isolates that can convert to the hypermucoid morphology under both in vitro and in vivo conditions. Consistent with previous studies, hypermucoid variants are more invasive in the mouse air-pouch infection model. However, one of the hypermucoid variants showed a growth-defective phenotype in regular broth culture conditions and is significantly more susceptible to various DNA-damaging treatments when compared with the mucoid variant. These properties of the hypermucoid variant may be adverse factors inhibiting its adaptation to the host environment during infections., (© 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

Severe perineal injury (third and fourth degree laceration) at the time of vaginal delivery increases the risk of fecal incontinence, chronic perineal pain, and dyspareunia.1-5 Studies suggest the prevalence of severe perineal injury may vary by racial group.6 The purpose of the current study was to examine rates of severe perineal injury in different Asian and Pacific Islander subgroups. A retrospective cohort study was performed among all patients who had a vaginal delivery at Queens Medical Center in Honolulu, Hawai'i between January 1, 2002 and December 31, 2003. Demographic and health related variables were obtained for each participant. Maternal race/ethnicity (Japanese, Filipino, Chinese, other Asian, Part-Hawaiian/Hawaiian, Micronesian, other Pacific Islander, Caucasian, multiracial [non-Hawaiian], and other) was self-reported by the patient at the time admission. The significance of associations between racial/ethnic groups and demographic and health related variables was determined using chi-square tests for categorical variables and analysis of variance for continuous factors. Multiple logistic regression was performed to adjust for potential confounders when examining severe laceration rates. A total of 1842 subjects met inclusion criteria. The proportion of severe perineal lacerations did not differ significantly between racial groups. In the multiple logistic regression analysis, operative vaginal delivery was related to both race and severe perineal laceration. However, despite adjusting for this variable, race was not associated with an increased risk of having a severe laceration (P = .70). The results of this study indicate the risk of severe perineal laceration does not differ based on maternal race/ethnicity.

The response surface methodology (RSM) including polynomial equations has been used to design an optimal patch formulation with appropriate adhesion and flux. The patch formulations were composed of different polymers, including Eudragit RS 100 (ERS), Eudragit RL 100 (ERL) and polyvinylpyrrolidone K30 (PVP), plasticizers (PEG 400), and drug. In addition, using terpenes as enhancers could increase the flux of the drug. Menthol showed the highest enhancement effect on the flux of arecoline.

Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We studied the process of trans-differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) into insulin-producing cells. Streptozotocin (STZ)-induced diabetic rat model was used to study the effect of portal vein transplantation of these insulin-producing cells on blood sugar levels. The BM-MSCs were differentiated into insulin-producing cells under defined conditions. Real-time PCR, immunocytochemistry and glucose challenge were used to evaluate in vitro differentiation. Flow cytometry showed that hBM-MSCs were strongly positive for CD44, CD105 and CD73 and negative for hematopoietic markers CD34, CD38 and CD45. Differentiated cells expressed C-peptide as well as β-cells specific genes and hormones. Glucose stimulation increased C-peptide secretion in these cells. The insulin-producing, differentiated cells were transplanted into the portal vein of STZ-induced diabetic rats using a Port-A catheter. The insulin-producing cells were localized in the liver of the recipient rat and expressed human C-peptide. Blood glucose levels were reduced in diabetic rats transplanted with insulin-producing cells. We concluded that hBM-MSCs could be trans-differentiated into insulin-producing cells in vitro. Portal vein transplantation of insulin-producing cells alleviated hyperglycemia in diabetic rats.

Objectives: The aims of this study were to develop approaches for monitoring and prioritizing factors associated with thermal stresses imposed on workers in iron and steel casting industries, and to eventually purpose effective control strategies., Methods: The whole study was completed in the furnace areas of two steel casting and two iron casting plants, where the air temperature (Ta), radiant temperature (Tr), air velocity (Va) and partial water vapor pressure (Pa) were measured continuously during two consecutive work cycles. Simultaneously, the metabolic rates (M) of all workers in the furnace area were also measured., Results: Using the WBGT as an index for screening purposes, our results suggest that all furnace area workers in both types of casting plants might experience severe heat stress. The predicted heat strain (PHS) model proposed by ISO 7933 was further adopted for detailed analysis from the physiological aspect. Through use of the Monte Carlo simulation and sensitivity analysis, both M and Tr were found to be the two most important factors associated with workers' thermal hazard. Therefore, two effective control strategies were suggested, including reducing workloads of workers and reducing radiant heat transmitting from furnaces to workplace environments., Conclusions: The approach developed in the present study would be beneficial to many other industries for initiating strategies to avert the thermal hazard imposed on workers.

Cardiolipin (CL) is a class of phospholipid tightly associated with the mitochondria functions and a prime target of oxidative stress. Peroxidation of CL dissociates its bound cytochrome C, a phenomenon that reflects oxidative stress sustained by the organ and a trigger for the intrinsic apoptotic pathway. However, CL distribution in normal organ tissues has yet to be documented. Fresh rat organs were snap-frozen, cut into cryosections that were subsequently desalted with ammonium acetate solution, and vacuum-dried. CL distribution in situ was determined using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique on sections sublimed with 2,5-dihydroxybenzoic acid. CL images in rat cardiac ventricular section showed a homogeneous distribution of a single m/z 1447.9 ion species that was confirmed as the (18:2)4 CL by tandem mass spectrometry. The presence of low abundant (18:2)3(18:1) CL with the bulk (18:2)4 CL in quadriceps femoris rendered the muscle CL exhibiting a slightly deviated isotopic pattern from that of cardiac muscle. In rat liver, MALDI-MSI unveiled three CL-containing mass ranges, each with a unique in situ distribution pattern. Co-registration of the CL ion images with its stained liver section image further revealed the association of CLs in each mass range with the functional zones in the liver parenchyma and suggests the participation of in situ CLs with localized hepatic functions such as oxidation, conjugation, and detoxification. The advances in CL imaging offer an approach with molecular accuracy to reveal potentially dysregulated metabolic machineries in acute and chronic diseased states.

The peroxide regulator (PerR) is a ferric uptake repressor-like protein, which is involved in adaptation to oxidative stress and iron homeostasis in group A streptococcus. A perR mutant is attenuated in surviving in human blood, colonization of the pharynx, and resistance to phagocytic clearance, indicating that the PerR regulon affects both host environment adaptation and immune escape. Sda1 is a phage-associated DNase which promotes M1T1 group A streptococcus escaping from phagocytic cells by degrading DNA-based neutrophil extracellular traps. In the present study, we found that the expression of sda1 is up-regulated under oxidative conditions in the wild-type strain but not in the perR mutant. A gel mobility shift assay showed that the recombinant PerR protein binds the sda1 promoter. In addition, mutation of the conserved histidine residue in the metal binding site of PerR abolished sda1 expression under hydrogen peroxide treatment conditions, suggesting that PerR is directly responsible for the sda1 expression under oxidative stress. Our results reveal PerR-dependent sda1 expression under oxidative stress, which may aid innate immune escape of group A streptococcus.

Background: Gestational diabetes (GDM) has been shown to have long-term sequelae for both the mother and infant. Women with GDM are at increased risk of macrosomia, which predisposes the infant to birth injuries. Previous studies noted increased rates of GDM in Asian and Pacific Islander (API) women; however, the rate of macrosomia in API women with GDM is unclear. The objective of this study was to examine the relationship between ethnicity, gestational diabetes (GDM), and macrosomia in Hawaii., Methods: A retrospective cohort study was performed using Hawaii Pregnancy Risk Assessment Monitoring System (PRAMS) data. Data from 2009-2011, linked with selected items from birth certificates, were used to examine GDM and macrosomia by ethnicity. SAS-callable SUDAAN 10.0 was used to generate odds ratios, point estimates and standard errors., Results: Data from 4735 respondents were weighted to represent all pregnancies resulting in live births in Hawaii from 2009-2011. The overall prevalence of GDM in Hawaii was 10.9%. The highest prevalence of GDM was in Filipina (13.1%) and Hawaiian/Pacific Islander (12.1%) women. The lowest prevalence was in white women (7.4%). Hawaiian/Pacific Islander, Filipina, and other Asian women all had an increased risk of GDM compared to white women using bivariate analysis. Adjusting for obesity, age, maternal nativity, and smoking, Asian Pacific Islander (API) women, which includes Hawaiian/Pacific Islander, Filipina, and other Asian women, had a 50% increased odds of having GDM compared to white women when compared using multivariate analysis. Among women with GDM, the highest prevalence of macrosomia was in white women (14.5%) while the lowest was in Filipina (5.3%) women., Conclusions: API women in Hawaii have increased rates of GDM compared to white women. Paradoxically, this elevated GDM risk in API women is not associated with an increased rate of macrosomia. This suggests the relationship between GDM and macrosomia is more complex in this population.

Impacts of maternal Cd(2+) exposure on female zebrafish (Danio rerio) were observed in females as well as their offspring. In females, Cd disturbed fecundity and other reproductive functions. In their offspring, it retarded gamete development and growth and influenced gene expression. There was a positive relationship between Cd(2+) contents in ovaries of females and treatment doses of 0-8.9 μM of Cd(2+). The mating rate decreased by 60 % when females were exposed to 8.9-35.6 μM of Cd(2+) for 72 h compared with the control group. It was observed that growth is delayed by one somite stage in maternal-Cd(2+) embryos compared with control embryos, which grew at the sixth-somite stage. The ceratohyal angles of larvae of Cd-exposed adults (maternal Cd(2+)) at 72 h postfertilization (hpf) appeared to have a positive response after doses of maternal Cd. In addition, approximately 30 % of 96-hpf larvae that were treated with a dose of 35.6 μM of maternal Cd(2+) appeared to have pericardial edema. At the 5-hpf stage of maternal Cd(2+) exposure, embryos showed 33 and 37 target genes, respectively, that were significantly downregulated and upregulated as shown by cDNA microarray analysis. A major effect of maternal Cd(2+) exposure on zebrafish embryo genes is that 18.9% of transcription functions were upregulated. In addition, 33.3% of transcripts relative to the function of protein biosynthesis were downregulated. These results showed that maternal Cd(2+) exposure influenced the reproduction ability of females and also caused their embryos to develop with abnormal gene expression.

The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X₁), hydrogenated coconut oil (X₂), and soybean oil (X₃). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X₁X₂, X₁X₃, and X₂X₃) showed more potential influence than that of the main factors (X₁, X₂, and X₃). An optimal predicted formulation with Y(10 min), Y(30 min), Y(60 min), and Y(90 min) release values of 12.3%, 36.7%, 73.6%, and 92.7% at X₁, X₂, and X₃ of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f₂ was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile.

Executive dysfunction is one of the core symptoms of schizophrenia. Functional neuro-imaging studies have suggested an association between deficits in activating the dorsolateral prefrontal cortex (DLPFC) and executive dysfunction, but neuro-integration from the DLPFC to the whole brain remains unclear. Studies investigating the neuro-integration from the DLPFC to the whole brain in unaffected but genetically liable family members are scant. In this study, we report DLPFC neuro-integrative deficits correlated with executive dysfunction and family history of schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Using seed regions in DLPFC, we examined resting-state functional connectivity in 25 patients with schizophrenia, 25 unaffected first-degree relatives (UR), and 25 healthy control (HC) persons. Schizophrenia patients and UR have impaired connectivity from DLPFC to its coordinated regions (ANOVA: F=7.316-10.974, p<0.001). These coordinated brain regions are distributed in the bilateral caudate, left middle/inferior frontal gyrus, left precentral gyrus, and right cerebellum. The individual functional connectivity strength between the left DLPFC and its coordinated regions was correlated with individual executive function performance among whole persons. (Pearson's r=0.244-0.366, p=0.035-0.008) Our findings support that distributed neuro-integrative DLPFC deficits reflect a genetic risk for schizophrenia and that these deficits are present, to a lesser degree, in unaffected first-degree relatives. Our findings also support that neuro-integration might correlate with a patient's executive function performance., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In this study, a semi-quantitative occupational chemical exposure risk prediction model, based on the calculation of exposure hazard indexes, was proposed, corrected, and applied to a national chemical exposure databank. The model comprises one factor used to describe toxicity (i.e., the toxicity index), and two factors used to reflect the exposure potential (i.e., the exposure index and protection deficiency index) of workers exposed to chemicals. An expert system was used to correct the above proposed model. By applying the corrected model to data obtained from a national occupational chemical hazard survey program, chemical exposure risks of various manufacturing industries were determined and a national control strategy for the abatement of occupational chemical exposures was proposed. The results of the present study would provide useful information for governmental agencies to allocate their limited resources effectively for reducing chemical exposures of workers.