Integrase strand transfer inhibitor treatment does not increase the incidence of immune reconstitution inflammatory syndrome in HIV-infected Koreans.

OBJECTIVES: Immune reconstitution inflammatory syndrome (IRIS) is a major concern when starting antiretroviral therapy (ART) in patients with advanced HIV infection. The aim of this study was to determine the incidence and risk factors of IRIS in HIV-infected Koreans initiating ART, and whether integrase strand transfer inhibitor (INSTI) treatment increases the risk of IRIS. METHODS: This retrospective analysis included adults living with HIV, seen at four university-affiliated hospitals in South Korea, who were naïve to ART and had a CD4 T-cell count < 200 cells/µL between January 2004 and May 2019. IRIS was determined through a medical record review within 6 months of ART initiation. Propensity score-matched case-control study between the non-INSTI and INSTI groups was performed. RESULTS: The study included 501 patients; 192 were assigned to the INSTI group, who started ART based on INSTIs as the initial treatment. There were opportunistic infections (OIs) in 253 (50.5%) cases before ART initiation. The three most common OIs were Pneumocystis jirovecii pneumonia, candidiasis and tuberculosis (TB). We identified 47 cases of IRIS; TB-IRIS was the most common type. The incidence of IRIS within 6 months of ART initiation was 9.4%, and there were no significant differences in baseline characteristics and incidence of IRIS between the matched groups. The risk factors for IRIS were pre-ART CD4 T-cell count (< 30 cells/µL), higher pre-ART viral load (≥ 75 000 copies/mL), and TB-OI. CONCLUSIONS: The incidence of IRIS was 9.4% in Korean HIV patients. The INSTI regimen was not related to IRIS occurrence.

Effects of transforming growth factor-ß1 on plasminogen activation in stem cells from the apical papilla: role of activating receptor-like kinase 5/Smad2 and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signalling.

AIM: To study the effects of TGF-ß1 on the plasminogen activation (PA) system of stem cells from the apical papilla (SCAP) and its signalling. METHODOLOGY: SCAP cells were isolated from the apical papilla of immature permanent teeth extracted for orthodontic reasons. They were exposed to various concentration of TGF-ß1 with/without pretreatment and coincubation by SB431542 (ALK/Smad2/3 inhibitor), or U0126 (MEK/ERK inhibitor). MTT assay, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to detect their effects on cell viability, and the protein expression of plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and their secretion. The paired Student's t-test was used for statistical analysis. RESULTS: TGF-ß1 significantly stimulated PAI-1 and soluble uPAR (suPAR) secretion of SCAP cells (P < 0.05), whereas uPA secretion was inhibited. Accordingly, TGF-ß1 induced both PAI-1 and uPAR protein expression of SCAP cells. SB431542 (an ALK5/Smad2/3 inhibitor) pretreatment and coincubation prevented the TGF-ß1-induced PAI-1 and uPAR of SCAP. U0126 attenuated the TGF-ß1-induced expression/secretion of uPAR, but not PAI-1 in SCAP. SB431542 reversed the TGF-ß1-induced decline of uPA. CONCLUSIONS: TGF-ß1 may affect the repair/regeneration activities of SCAP via differential increase or decrease of PAI-1, uPA and uPAR. These effects induced by TGF-ß1 are associated with ALK5/Smad2/3 and MEK/ERK activation. Elucidation the signalling pathways and effects of TGF-ß1 is useful for treatment of immature teeth with open apex by revascularization/revitalization procedures and tissue repair/regeneration.

Developing Multipollutant Exposure Indicators of Traffic Pollution: The Dorm Room Inhalation to Vehicle Emissions (DRIVE) Study.

Introduction: The Dorm Room Inhalation to Vehicle Emissions (DRIVE2) study was conducted to measure traditional single-pollutant and novel multipollutant traffic indicators along a complete emission-to-exposure pathway. The overarching goal of the study was to evaluate the suitability of these indicators for use as primary traffic exposure metrics in panel-based and small-cohort epidemiological studies. Methods: Intensive field sampling was conducted on the campus of the Georgia Institute of Technology (GIT) between September 2014 and January 2015 at 8 monitoring sites (2 indoors and 6 outdoors) ranging from 5 m to 2.3 km from the busiest and most congested highway artery in Atlanta. In addition, 54 GIT students living in one of two dormitories either near (20 m) or far (1.4 km) from the highway were recruited to conduct personal exposure sampling and weekly biomonitoring. The pollutants measured were selected to provide information about the heterogeneous particulate and gaseous composition of primary traffic emissions, including the traditional traffic-related species (e.g., carbon monoxide [CO], nitrogen dioxide [NO2], nitric oxide [NO], fine particulate matter [PM2.5], and black carbon [BC]), and of secondary species (e.g., ozone [O3] and sulfate as well as organic carbon [OC], which is both primary and secondary) from traffic and other sources. Along with these pollutants, we also measured two multipollutant traffic indicators: integrated mobile source indicators (IMSIs) and fine particulate matter oxidative potential (FPMOP). IMSIs are derived from elemental carbon (EC), CO, and nitrogen oxide (NOx) concentrations, along with the fractions of these species emitted by gasoline and diesel vehicles, to construct integrated estimates of gasoline and diesel vehicle impacts. Our FPMOP indicator was based on an acellular assay involving the depletion of dithiothreitol (DTT), considering both water-soluble and insoluble components (referred to as FPMOPtotal-DTT). In addition, a limited assessment of 18 low-cost sensors was added to the study to supplement the four original aims. Results: Pollutant levels measured during the study showed a low impact by this highway hotspot source on its surrounding vicinity. These findings are broadly consistent with results from other studies throughout North America showing decreased relative contributions to urban air pollution from primary traffic emissions. We view these reductions as an indication of a changing near-road environment, facilitated by the effectiveness of mobile source emission controls. Many of the primary pollutant species, including NO, CO, and BC, decreased to near background levels by 20 to 30 m from the highway source. Patterns of correlation among the sites also varied by pollutant and time of day. NO2 exhibited spatial trends that differed from those of the other single-pollutant primary traffic indicators. We believe this was caused by kinetic limitations in the photochemical chemistry, associated with primary emission reductions, required to convert the NO-dominant primary NOx, emitted from automobiles, to NO2. This finding provides some indication of limitations in the use of NO2 as a primary traffic exposure indicator in panel-based health effect studies. Roadside monitoring of NO, CO, and BC tended to be more strongly correlated with sites, both near and far from the road, during morning rush hour periods and often weakly to moderately correlated during other time periods of the day. This pattern was likely associated with diurnal changes in mixing and chemistry and their impact on spatial heterogeneity across the campus. Among our candidate multipollutant primary traffic indicators, we report several key findings related to the use of oxidative potential (OP)-based indicators. Although earlier studies have reported elevated levels of FPMOP in direct exhaust emissions, we found that atmospheric processing further enhanced FPMOPtotal-DTT, likely associated with the oxidation of primary polycyclic aromatic hydrocarbons (PAHs) to quinones and hydroxyquinones and with the oxidization and water solubility of metals. This has important implications in terms both of the utility of FPMOPtotal-DTT as a marker for exhaust emissions and of the importance of atmospheric processing of particulate matter (PM) being tied to potential health outcomes. The results from the personal exposure monitoring also point to the complexity and diversity of the spatiotemporal variability patterns among the study monitoring sites and the importance of accounting for location and spatial mobility when estimating exposures in panel-based and small-cohort studies. This was most clearly demonstrated with the personal BC measurements, where ambient roadside monitoring was shown to be a poor surrogate for exposures to BC. Alternative surrogates, including ambient and indoor BC at the participants' respective dorms, were more strongly associated with personal BC, and knowledge of the participants' mean proximity to the highway was also shown to explain a substantial level of the variability in corresponding personal exposures to both BC and NO2. In addition, untargeted metabolomic indicators measured in plasma and saliva, which represent emerging methods for measuring exposure, were used to extract approximately 20,000 and 30,000 features from plasma and saliva, respectively. Using hydrophilic interaction liquid chromatography (HILIC) in the positive ion mode, we identified 221 plasma features that differed significantly between the two dorm cohorts. The bimodal distribution of these features in the HILIC column was highly idiosyncratic; one peak consisted of features with elevated intensities for participants living in the near dorm; the other consisted of features with elevated intensities for participants in the far dorm. Both peaks were characterized by relatively short retention times, indicative of the hydrophobicity of the identified features. The results from the metabolomics analyses provide a strong basis for continuing this work toward specific chemical validation of putative biomarkers of traffic-related pollution. Finally, the study had a supplemental aim of examining the performance of 18 low-cost CO, NO, NO2, O3, and PM2.5 pollutant sensors. These were colocated alongside the other study monitors and assessed for their ability to capture temporal trends observed by the reference monitoring instrumentation. Generally, we found the performance of the low-cost gas-phase sensors to be promising after extensive calibration; the uncalibrated measurements alone, however, would likely not have led to reliable results. The low-cost PM sensors we evaluated had poor accuracy, although PM sensor technology is evolving quickly and warrants future attention. Conclusions: An immediate implication of the changing near-road environment is that future studies aimed at characterizing hotspots related to mobile sources and their impacts on health will need to consider multiple approaches for characterizing spatial gradients and exposures. Specifically and most directly, the mobile source contributions to ambient concentrations of single-pollutant indicators of traffic exposure are not as distinguishable to the degree that they have been in the past. Collectively, the study suggests that characterizing exposures to traffic-related pollutants, which is already difficult, will become more difficult because of the reduction in traffic-related emissions. Additional multi-tiered approaches should be considered along with traditional measurements, including the use of alternative OP measures beyond those based on DTT assays, metabolomics, low-cost sensors, and air quality modeling.

Impacts of Regulations on Air Quality and Emergency Department Visits in the Atlanta Metropolitan Area, 1999-2013.

INTRODUCTION: The United States and Western Europe have seen great improvements in air quality, presumably in response to various regulations curtailing emissions from the broad range of sources that have contributed to local, regional, and global pollution. Such regulations, and the ensuing controls, however, have not come without costs, which are estimated at tens of billions of dollars per year. These costs motivate accountability-related questions such as, to what extent do regulations lead to emissions changes? More important, to what degree have the regulations provided the expected human health benefits?Here, the impacts of specific regulations on both electricity generating unit (EGU) and on-road mobile sources are examined through the classical accountability process laid out in the 2003 Health Effects Institute report linking regulations to emissions to air quality to health effects, with a focus on the 1999-2013 period. This analysis centers on regulatory actions in the southeastern United States and their effects on health outcomes in the 5-county Atlanta metropolitan area. The regulations examined are largely driven by the 1990 Clean Air Act Amendments (C). This work investigates regulatory actions and controls promulgated on EGUs: the Acid Rain Program (ARP), the NOx Budget Trading Program (NBP), and the Clean Air Interstate Rule (CAIR) - and mobile sources: Tier 2 Gasoline Vehicle Standards and the 2007 Heavy Duty Diesel Rule. METHODS: Each step in the classic accountability process was addressed using one or more methods. Linking regulations to emissions was accomplished by identifying major federal regulations and the associated state regulations, along with analysis of individual facility emissions and control technologies and emissions modeling (e.g., using the U.S. Environmental Protection Agency's [U.S. EPA's] MOtor Vehicle Emissions Simulator [MOVES] mobile-source model). Regulators, including those from state environmental and transportation agencies, along with the public service commissions, play an important role in implementing federal rules and were involved along with other regional stakeholders in the study. We used trend analysis, air quality modeling, satellite data, and a ratio-of-ratios technique to investigate a critical current issue, a potential large bias in mobile-source oxides of nitrogen (NOx) emissions estimates.The second link, emissions-air quality relationships, was addressed using both empirical analyses as well as chemical transport modeling employing the Community Multiscale Air Quality (CMAQ) model. Kolmogorov-Zurbenko filtering accounting for day of the year was used to separate the air quality signal into long-term, seasonal, weekday-holiday, and short-term meteorological signals. Regression modeling was then used to link emissions and meteorology to ambient concentrations for each of the species examined (ozone [O3], particulate matter ≤ 2.5 µm in aerodynamic diameter [PM2.5], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], sulfate [SO4-2], nitrate [NO3-], ammonium [NH4+], organic carbon [OC], and elemental carbon [EC]). CMAQ modeling was likewise used to link emissions changes to air quality changes, as well as to further establish the relative roles of meteorology versus emissions change impacts on air quality trends. CMAQ and empirical modeling were used to investigate aerosol acidity trends, employing the ISORROPIA II thermodynamic equilibrium model to calculate pH based on aerosol composition. The relationships between emissions and meteorology were then used to construct estimated counterfactual air quality time series of daily pollutant concentrations that would have occurred in the absence of the regulations. Uncertainties in counterfactual air quality were captured by the construction of 5,000 pollutant time series using a Monte Carlo sampling technique, accounting for uncertainties in emissions and model parameters.Health impacts of the regulatory actions were assessed using data on cardiorespiratory emergency department (ED) visits, using patient-level data in the Atlanta area for the 1999-2013 period. Four outcome groups were chosen based on previous studies identifying associations with ambient air pollution: a combined respiratory disease (RD) category; the subgroup of RD presenting with asthma; a combined cardiovascular disease (CVD) category; and the subgroup of CVD presenting with congestive heart failure (CHF).Models were fit to estimate the joint effects of multiple pollutants on ED visits in a time-series framework, using Poisson generalized linear models accounting for overdispersion, with a priori model formulations for temporal and meteorological covariates and lag structures. Several parameterizations were considered for the joint-effects models, including different sets of pollutants and models with nonlinear pollutant terms and first-order interactions among pollutants. Use of different periods for parameter estimates was assessed, as associations between pollutant levels and ED visits varied over the study period. A 7-pollutant, nonlinear model with pollutant interaction terms was chosen as the baseline model and fitted using pollutant and outcome data from 1999-2005 before regulations might have substantially changed the toxicity of pollutant mixtures. In separate analyses, these models were fitted using pollutant and outcome data from the entire 1999-2013 study period. Daily counterfactual time series of pollutant concentrations were then input into the health models, and the differences between the observed and counterfactual concentrations were used to estimate the impacts of the regulations on daily counts of ED visits. To account for the uncertainty in both the estimation of the counterfactual time series of ambient pollutant levels and the estimation of the health model parameters, we simulated 5,000 sets of parameter estimates using a multivariate normal distribution based on the observed variance-covariance matrix, allowing for uncertainty at each step of the chain of accountability. Sensitivity tests were conducted to assess the robustness of the results. RESULTS: EGU NOx and SO2 emissions in the Southeast decreased by 82% and 83%, respectively, between 1999 and 2013, while mobile-source emissions controls led to estimated decreases in Atlanta-area pollutant emissions of between 61% and 93%, depending on pollutant. While EGU emissions were measured, mobile-source emissions were modeled. Our results are supportive of a potential high bias in mobile-source NOx and CO emissions estimates. Air quality benefits from regulatory actions have increased as programs have been fully implemented and have had varying impacts over different seasons. In a scenario that accounted for all emissions reductions across the period, observed Atlanta central monitoring site maximum daily 8-hour (MDA8h) O3 was estimated to have been reduced by controls in the summertime and increased in the wintertime, with a change in mean annual MDA8h O3 from 39.7 ppb (counterfactual) to 38.4 ppb (observed). PM2.5 reductions were observed year-round, with average 2013 values at 8.9 µg/m3 (observed) versus 19.1 µg/m3 (counterfactual). Empirical and CMAQ analyses found that long-term meteorological trends across the Southeast over the period examined played little role in the distribution of species concentrations, while emissions changes explained the decreases observed. Aerosol pH, which plays a key role in aerosol formation and dynamics and may have health implications, was typically very low (on the order of 1-2, but sometimes much lower), with little trend over time despite the stringent SO2 controls and SO42- reductions.Using health models fit from 1999-2005, emissions reductions from all selected pollution-control policies led to an estimated 55,794 cardiorespiratory disease ED visits prevented (i.e., fewer observed ED visits than would have been expected under counterfactual scenarios) - 52,717 RD visits, of which 38,038 were for asthma, and 3,057 CVD visits, of which 2,104 were for CHF - among the residents of the 5-county area over the 1999-2013 period, an area with approximately 3.5 million people in 2013. During the final two years of the study (2012-2013), when pollution-control policies were most fully implemented and the associated benefits realized, these policies were estimated to prevent 5.9% of the RD ED visits that would have occurred in the absence of the policies (95% interval estimate: -0.4% to 12.3%); 16.5% of the asthma ED visits (95% interval estimate: 7.5% to 25.1%); 2.3% of the CVD ED visits (95% interval estimate: -1.8% to 6.2%); and -.6% of the CHF ED visits (95% interval estimate: 26.3% to 10.4%). Estimates of ED visits prevented were generally lower when using health models fit for the entire 1999-2013 study period.Sensitivity analyses were conducted to show the impact of the choice of parameterization of the health models and to assess alternative definitions of the study area. When impacts were assessed for separate policy interventions, policies affecting emissions from EGUs, especially the ARP and the NBP, appeared to have had the greatest effect on prevention of RD and asthma ED visits. CONCLUSIONS: This study demonstrates the effectiveness of regulations on improving air quality and health in the southeastern United States. It also demonstrates the complexities of accountability assessments as uncertainties are introduced in each step of the classic accountability process. While accounting for uncertainties in emissions, air quality-emissions relationships, and health models does lead to relatively large uncertainties in the estimated outcomes due to specific regulations, overall the benefits of regulations have been substantial.

A longitudinal study of the association between the GNB3 C825T polymorphism and metabolic disturbance in bipolar II patients treated with valproate.

This longitudinal study aimed to investigate the associations between the polymorphisms of guanine nucleotide-binding protein subunit ß-3 (GNB3) C825T and metabolic disturbance in bipolar II disorder (BP-II) patients being treated with valproate (VPA). A 100 BP-II patients received a 12-week course of VPA treatment, and their body weight and metabolic indices were measured. At baseline, the GNB3 C825T polymorphisms were associated with the triglyceride level (P=0.032) in BP-II patients. During the VPA treatment course, the polymorphisms were not only associated with body mass index (BMI) and waist circumference (P-values=0.009 and 0.001, respectively), but also with total cholesterol, triglyceride, low-density lipoprotein and leptin levels (P-values=0.004, 0.002, 0.031 and 0.015, respectively). Patients with the TT genotype had a lower BMI, smaller waist circumference, and lower levels of lipids and leptin than those with the CT or CC genotypes undergoing the VPA treatment course.

Methyl gallate limits infection in mice challenged with Brucella abortus while enhancing the inflammatory response.

AIMS: To investigate the effects of methyl gallate (MG) on murine macrophages, cytokine production and treatment of Brucella abortus infection using a mouse model. METHODS AND RESULTS: MG-treated cells displayed increased F-actin polymerization and modest increase in ERK, JNK and p38α phosphorylation levels. The mice were intraperitoneally infected with Br. abortus and were orally treated with PBS or MG for 14 days. The weight and bacterial number from each spleen were monitored, and the serum was evaluated for cytokine production. The spleen proliferation and bacterial burden were lower in the MG-treated group than in the MG-untreated control. The noninfected MG-treated mice displayed increased production of TNF, IFN-γ, and the chemokine MCP-1, whereas the Br. abortus-infected MG-treated mice revealed enhanced induction of IL-12p70, TNF and IL-10 compared to the MG-untreated control. CONCLUSIONS: MG induced F-actin polymerization and modest upregulation of MAPKs. Furthermore, oral treatment with MG induced an immune response and decreased bacterial proliferation in Br. abortus-infected mice, suggesting that MG may be an alternative treatment for brucellosis. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study demonstrates the therapeutic effects of MG against Brucella infection through induction of cytokine production and protection from bacterial proliferation in the spleens of mice.

Renal depletion of myo-inositol is associated with its increased degradation in animal models of metabolic disease.

Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.

A clinically applicable molecular-based classification for endometrial cancers.

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. METHODS: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. RESULTS: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Detection of DNA mismatch repair (MMR) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (MSI) phenotype in endometrial carcinomas.

BACKGROUND: A proportion of endometrial carcinomas (ECs) are associated with deficient DNA mismatch repair (MMR). These tumors are characterized by high levels of microsatellite instability (MSI). Identification of MSI is important in identifying women who should be tested for Lynch syndrome and identifying a phenotype that may have specific prognostic and predictive implications. Genomic characterization of ECs has shown that MSI tumors form a distinct subgroup. The two most common methodologies for MSI assessment have not been compared in EC. METHODS: Pentaplex mono and di-nucleotide PCR for MSI testing was compared to MMR IHC (presence/absence of MLH1, MSH2, MSH6, PMS2) in a cohort of patients with EC. Concordance, Kappa statistic, sensitivity, specificity, positive and negative predictive values were obtained on the cross-tabulation of results. RESULTS: Comparison of both MSI and MMR status was complete for 89 cases. Overall agreement between methods (concordance) was 93.3% (95% CI[85.9%-97.5%]). A one-sided test to determine whether the accuracy is better than the "no information rate," which is taken to be the largest class percentage in the data, is significant (p<0.00001). Unweighted Kappa was 0.84, along with the sensitivity (88.5%), specificity (95.2%), PPV (88.5%), and NPV (95.2%). The balanced accuracy (i.e. the average between sensitivity and specificity) was 92%. DISCUSSION: We show the equivalence of MSI testing and MMR IHC. We advocate the implementation of MMR IHC in future EC classification schemes, enabling stratification of cases for future clinical trials as well as assisting identification of Lynch syndrome, so that screening and risk reducing interventions can be undertaken.

Quantifying midbrain serotonin transporter in depression: a preliminary study of diagnosis and naturalistic treatment outcome.

INTRODUCTION: Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain. METHODS: In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment. RESULTS: A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT. DISCUSSION: The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.

Packaging modifications for protecting flavor of extended-shelf-life milk from light.

The effectiveness of titanium dioxide (TiO2)-loaded high-density polyethylene (HDPE) to reduce light-induced oxidation of extended-shelf-life milk (2% total fat) was studied. The objective was to determine differences over time in sensory quality, vitamin retention, and oxidative chemistry as a function of packaging and retail light exposure duration. Effectiveness of packaging for protecting milk quality was assessed by sensory evaluation (triangle tests, untrained panel), changes in volatile compounds, thiobarbituric reactive substances (TBARS), and riboflavin concentration. Milk (2%) was stored in HDPE packages consisting of TiO2 at 3 levels (low: 0.6%; medium: 1.3%; high: 4.3%) at 3 °C for up to 43 d. Light-protected (translucent, foil-wrapped) and light-exposed (translucent) HDPE packages served as controls. The high TiO2-HDPE package provided protection similar to light-protected control package through d 22 of light exposure, with less consistent performance by the medium TiO2 package. The TBARS increased in all treatments during storage. Under the experimental conditions used, a TBARS value of 1.3mg/L could be considered the limiting sensory threshold for differentiating oxidized milk from light-protected milk. Riboflavin concentration decreased 10.5% in the light-protected control and 28.5% in the high TiO2 packaged milk past 29 d of light exposure, but losses were greater than 40% for all other packages. The high TiO2 package protected riboflavin concentration from degradation and controlled aldehyde concentration throughout the test period.

Predictors of uropathogens other than Escherichia coli in patients with community-onset acute pyelonephritis.

AIM: A constant reduction in the incidence of community-onset acute pyelonephritis (CO-APN) caused by Escherichia coli has been shown with a parallel increase incidence caused by other organisms. Therefore, we evaluated the risk factors and outcome of non-E. coli as uropathogens in patients with community-onset APN. METHODS: As a part of a nationwide multicentre surveillance study conducted in Korea, a total of 416 patients with CO-APN were collected with their epidemiological, antibiotic treatment and outcome data. RESULTS: The risk factors and outcomes of non-E. coli as uropathogens were evaluated in a total of 416 patients with culture-confirmed CO-APN. Non-E. coli caused 127 cases (30.5%) of CO-APN. CO-APN caused by non-E. coli resulted in higher inappropriate empirical therapy (38.6% vs. 20.1%, p < 0.001), longer hospital stay (12.6 days vs. 6.7 days, p = 0.005) and higher 30-day mortality (9.4% vs. 3.8% p = 0.020) compared with CO-APN caused by E. coli. Multivariate analyses showed that male gender (OR, 3.48; CI, 2.13-5.67; p < 0.001), underlying haematological disease (OR, 5.32; CI, 1.17-24.254; p = 0.031), underlying benign prostate hyperplasia (OR, 2.61; CI, 1.02-6.74; p = 0.046), chronic indwelling urethral catheter (OR, 6.34; CI, 1.26-31.84; p = 0.025) and admission history in the previous 6 months (OR, 2.12; CI, 1.23-3.58; p = 0.005) were predictors for CO-APN caused by a non-E. coli isolate. CONCLUSIONS: Community-onset APN caused by non-E. coli represents a distinct subset of urinary tract infections with worse outcomes. The defined risk factors related with non-E. coli should be taken into consideration when empirical antibiotic therapy is prescribed in patients with community-onset APN.

Predicting inhaled corticosteroid response in asthma with two associated SNPs.

Inhaled corticosteroids (ICS) are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in corticotrophin releasing hormone receptor 1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics, who received ICS and had lung function measured by forced expiratory volume in 1 s (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (P=0.039 vs random) area under the receiver-operator characteristic curve in the training population and 65.9% (P=0.025 vs random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.

Characteristics of traditional Chinese medicine use in children with asthma: a nationwide population-based study.

Asthma is a chronic inflammatory airway disease accounting for severe morbidity and mortality in children. To determine the characteristics of traditional Chinese medicine (TCM) used to treat pediatric asthma, we conducted a nationwide population-based study by analyzing a cohort of one million randomly sampled patients from the beneficiaries of the National Health Insurance Program in Taiwan from 2002 to 2010. Children under 18 years of age with newly diagnosed asthma (ICD-9-CM code: 493, N = 45 833) were enrolled, and 57.95% (N = 26 585) of them had used TCM. The number of TCM users was significantly more than that of non-TCM users in school-age children. The most commonly prescribed TCM formula is Ding-chuan-tang, or Xing-ren (Semen Armeniacae Amarum) for the single herb. Our study is the first to reveal characteristics and prescription patterns of the use of TCM in children with asthma. Further research is needed to elucidate the efficacy and safety of these Chinese herbal products.

Differential regulation of collagen, lysyl oxidase and MMP-2 in human periodontal ligament cells by low- and high-level mechanical stretching.

BACKGROUND AND OBJECTIVE: Mechanical stretching modulates extracellular matrix (ECM) protein synthesis by periodontal ligament (PDL) cells. However, the mechanoregulation of lysyl oxidase (LOX), a key enzyme for collagen cross-linking, is not fully understood. In the present study, we hypothesized that low-level and high-level mechanical stretching differentially regulates collagen deposition and the expression of LOX and the enzymes responsible for ECM degradation, such as MMP-2 in PDL cells. MATERIAL AND METHODS: Human PDL cells were cultured on flexible-bottom culture plates and subjected to cyclic mechanical stretching (3% and 10% elongation at 0.1 Hz) for 24 and 48 h in a Flexercell FX-4000 strain unit. The levels of expression of type I collagen alpha 1 (COL1A1), type III collagen alpha 1 (COL3A1), lysyl oxidase (LOX), MMP2 and TIMP2 mRNAs were analyzed using an RT-PCR technique. The cell layer and the culture medium were separately collected and processed for detection of the following ECM-related molecules: (i) total collagen content using a Sircol dye-binding method; (ii) LOX protein expression by western blotting; (iii) LOX activity using a fluorometric assay; and (iv) MMP-2 enzyme activity by gelatin zymography. RESULTS: Low-level (3%) mechanical stretching of PDL cells upregulated the expression of COL1A1, COL3A1 and LOX mRNAs, enhanced the production of collagen and increased the LOX activity but did not change the level of expression of MMP2 or TIMP2 mRNA. The collagen content and LOX activity showed obvious elevation in the medium, but not in the cell layer. High-level (10%) mechanical stretching downregulated COL1A1 mRNA but upregulated COL3A1 mRNA; however, the effect on COL3A1 was smaller, and occurred earlier, compared with the effect on the COL1A1 gene. High-level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNAs but did not change collagen production or LOX activity. Moreover, high-level mechanical stretching increased the level of pro-MMP-2, especially in the cell layer. CONCLUSIONS: This study substantiates the mechanoregulation of the expression of ECM-related molecules in PDL cells. High-level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNAs, but did not affect collagen production or LOX activity. In addition to increasing the transcription of COL1A1, COL3A1 and LOX genes, low-level mechanical stretching enhanced total collagen production and LOX activity, which should favor ECM stabilization. As an effective regulator of ECM remodeling, mechanical stretching can be exploited in periodontal regeneration and ligament tissue engineering via application of appropriate mechanical stimulation.

Cardiac iron measurement and iron chelation therapy in patients with ß thalassaemia major: experience from Taiwan.

BACKGROUND: The aims of our study were to evaluate (i) the relationship between cardiac T2* values and cardiac complications in Asian ß-thalassaemia major (TM) patients, and (ii) the association between cardiac T2* values and other parameters currently used to predict cardiac complications as a result of transfusion iron overload. METHODS: We examined the myocardial iron loads of 88 TM patients from Taiwan with cardiac T2* magnetic resonance imaging (MRI) and assessed the correlation between cardiac T2* values and serum ferritin levels, liver iron concentration and left ventricular ejection fraction (LVEF). We also determined the predictive value of these measurements for the development of arrhythmia. RESULTS AND CONCLUSION: In our group of Taiwanese patients, the relative risk for arrhythmia was 10·36 when cardiac T2* values were less than 10 ms (compared with ≥10 ms) and 1·98 when serum ferritin levels increased >2500 ng mL(-1) (compared with ≤2500 ng mL(-1) ). Serum ferritin levels correlated with cardiac T2* values in patients with abnormal myocardial iron loads (T2* < 20 ms, r = -0·48, P = 0·004, n = 34), but LVEF (measured by echocardiography) gave no indication of excess myocardial iron deposition (r = -0·07, P = 0·52) or of the risk of developing arrhythmia.

Arecoline-stimulated placenta growth factor production in gingival epithelial cells: modulation by curcumin.

OBJECTIVE: Placenta growth factor (PlGF) is associated with the progression and prognosis of oral cancer. MATERIALS AND METHODS: This study used ELISA, quantitative polymerase chain reaction, and Western blotting to study the arecoline-stimulated (PlGF) protein or mRNA expression in human gingival epithelial S-G cells. RESULTS: Arecoline, a major areca nut alkaloid and an oral carcinogen, could stimulate PlGF protein synthesis in S-G cells in a dose- and time-dependent manner. The levels of PlGF protein secretion increased about 3.1- and 3.8-fold after 24-h exposure to 0.4 and 0.8 mM arecoline, respectively. Pretreatment with antioxidant N-acetyl-l-cysteine (NAC) and ERK inhibitor PD98059, but not NF-κB inhibitor Bay 11-7082, JNK inhibitor SP600125, p38 MAPK inhibitor SB203580, and PI3-K inhibitor LY294002, significantly reduced arecoline-induced PlGF protein synthesis. ELISA analyses demonstrated that NAC and PD98059 reduced about 43% and 38% of the arecoline-induced PlGF protein secretion, respectively. However, combined treatment with NAC and PD98059 did not show additive effect. Moreover, 10 µM curcumin and 4 mM NAC significantly inhibited arecoline-induced ERK activation. Furthermore, 10 µM curcumin completely blocked arecoline-induced PlGF mRNA expression. CONCLUSION: Arecoline-induced PlGF synthesis is probably mediated by reactive oxygen species/ERK pathways, and curcumin may be an useful agent in controlling oral carcinogenesis.

Automatic Detection of Cow's Oestrus in Audio Surveillance System.

Early detection of anomalies is an important issue in the management of group-housed livestock. In particular, failure to detect oestrus in a timely and accurate way can become a limiting factor in achieving efficient reproductive performance. Although a rich variety of methods has been introduced for the detection of oestrus, a more accurate and practical method is still required. In this paper, we propose an efficient data mining solution for the detection of oestrus, using the sound data of Korean native cows (Bos taurus coreanea). In this method, we extracted the mel frequency cepstrum coefficients from sound data with a feature dimension reduction, and use the support vector data description as an early anomaly detector. Our experimental results show that this method can be used to detect oestrus both economically (even a cheap microphone) and accurately (over 94% accuracy), either as a standalone solution or to complement known methods.

Long-term exposure to traffic-related air pollution and non-accidental mortality: A systematic review and meta-analysis.

BACKGROUND: The health effects of traffic-related air pollution (TRAP) continue to be of important public health interest across the globe. Following its 2010 review, the Health Effects Institute appointed a new expert Panel to systematically evaluate the epidemiological evidence regarding the associations between long-term exposure to TRAP and selected health outcomes. This paper describes the main findings of the systematic review on non-accidental mortality. METHODS: The Panel used a systematic approach to conduct the review. An extensive search was conducted of literature published between 1980 and 2019. A new exposure framework was developed to determine whether a study was sufficiently specific to TRAP, which included studies beyond the near-roadway environment. We performed random-effects meta-analysis when at least three estimates were available of an association between a specific exposure and outcome. We evaluated confidence in the evidence using a modified Office of Health Assessment and Translation (OHAT) approach, supplemented with a broader narrative synthesis. RESULTS: Thirty-six cohort studies were included. Virtually all studies adjusted for a large number of individual and area-level covariates-including smoking, body mass index, and individual and area-level socioeconomic status-and were judged at a low or moderate risk for bias. Most studies were conducted in North America and Europe, and a few were based in Asia and Australia. The meta-analytic summary estimates for nitrogen dioxide, elemental carbon and fine particulate matter-pollutants with more than 10 studies-were 1.04 (95% CI 1.01, 1.06), 1.02 (1.00, 1.04) and 1.03 (1.01, 1.05) per 10, 1 and 5 µg/m3, respectively. Effect estimates are interpreted as the relative risk of mortality when the exposure differs with the selected increment. The confidence in the evidence for these pollutants was judged as high, because of upgrades for monotonic exposure-response and consistency across populations. The consistent findings across geographical regions, exposure assessment methods and confounder adjustment resulted in a high confidence rating using a narrative approach as well. CONCLUSIONS: The overall confidence in the evidence for a positive association between long-term exposure to TRAP and non-accidental mortality was high.

Gap opening and orbital modification of superconducting FeSe above the structural distortion.

We utilize steady-state and transient optical spectroscopies to examine the responses of nonthermal quasiparticles with respect to orbital modifications in normal-state iron-chalcogenide superconductors. The dynamics shows the emergence of gaplike quasiparticles (associated with a ~36 meV energy gap) with a coincident transfer of the optical spectral weight in the visible range, at temperatures above the structural distortion. Our observations suggest that opening of the high-temperature gap and the lattice symmetry breaking are possibly driven by short-range orbital and/or charge orders, implicating a close correlation between electronic nematicity and precursor order in iron-based superconductors.