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Chronic constipation is a functional gastrointestinal disease that is detrimental to the quality of patient life. Cassia obtusifolia L. (CO) and Foeniculum vulgare M. (FV) are commonly used as medicinal foods in many countries. We aimed to examine the laxative effect and their underlying mechanism of CO and FV mixture on loperamide (lop)-induced constipated rats. To determine the laxative effects of these compounds, Sprague-Dawley rats were divided into six groups: the control, lop-induced constipated (2mg/kg), and three doses (100, 300, and 500mg/kg) of CO and FV mixture-, and Bisacodyl (bis, 3.3mg/kg)-treated groups. The mixture of CO and FV and bis were orally administered once a day for 4 weeks. For induction of constipation, the lop were treated with a dose of 2 mg/kg twice a day on the 3rd week after treatments of CO and FV extracts and bis. The results were revealed that the CO and FV mixture has the laxative effects more than those in CO and FV-alone treatments on constipated rats by determining the stool parameters, including stool number and weight. Indeed, stool parameters, such as, stool number, weight, and water contents and colonic peristalsis from the intestinal transit length and ratio were dramatically improved by CO and FV mixture treatment. Histological study also revealed that CO and FV mixture enhanced the thicknesses of mucosa and muscular layers of the colon in constipated rats. For their underlying mechanism, the mRNAs and proteins expression of muscarinic acetylcholine receptors (mAchR) M2 and M3 and their downstream signaling were preserved by CO and FV mixture treatment in constipated rats. Therefore, this study suggests that treatment with CO and FV mixture has beneficial effects against constipation. We further suggest that CO and FV mixture may be utilized as an alternative therapeutic strategy for constipation. [ABSTRACT FROM AUTHOR]

Disruption of Wnt signaling often happens in tumorigenesis, but whether Wnt signaling affects the early stages of thyroid tumor, such as papillary thyroid carcinoma, is still a question, especially in the papillary thyroid carcinoma without genomic RET/PTC mutation. In this study, we demonstrated the important function of Wnt signaling in papillary thyroid carcinoma K1 cells, which have no RET/PTC mutation. We found that K1 cells have enhanced Wnt signaling in comparison to normal thyroid cells. We further demonstrated that K1 cells require the enhanced Wnt signaling for growth and survival. Interestingly, we identified that enhancing E2F activity by either knockdown of Rb or overexpression of Cyclin D1 induces cell death in K1 cells. And we further revealed that the cell death is caused by enhanced oxidative stress. Our studies present a novel cell model to support the key roles of Wnt signaling in early stage of thyroid tumor, and also provide an alternative way to limit thyroid cancer. [ABSTRACT FROM AUTHOR]

The brain is highly energy consuming, therefore is under strong selective pressure to achieve cost-efficiency in both cortical connectivities and activities. However, cost-efficiency as a design principle for cortical activities has been rarely studied. Especially it is not clear how cost-efficiency is related to ubiquitously observed multi-scale properties: irregular firing, oscillations and neuronal avalanches. Here we demonstrate that these prominent properties can be simultaneously observed in a generic, biologically plausible neural circuit model that captures excitation-inhibition balance and realistic dynamics of synaptic conductance. Their co-emergence achieves minimal energy cost as well as maximal energy efficiency on information capacity, when neuronal firing are coordinated and shaped by moderate synchrony to reduce otherwise redundant spikes, and the dynamical clusterings are maintained in the form of neuronal avalanches. Such cost-efficient neural dynamics can be employed as a foundation for further efficient information processing under energy constraint. [ABSTRACT FROM AUTHOR]

The ventromedial nucleus of the hypothalamus (VMH) is important for the regulation of whole body energy homeostasis and lesions in the VMH are reported to result in massive weight gain. The nuclear receptor steroidogenic factor 1 (SF-1) is a known VMH marker as it is exclusively expressed in the VMH region of the brain. SF-1 plays a critical role not only in the development of VMH but also in its physiological functions. In this study, we generated prenatal VMH-specific SF-1 KO mice and investigated age-dependent energy homeostasis regulation by SF-1. Deletion of SF-1 in the VMH resulted in dysregulated insulin and leptin homeostasis and late onset obesity due to increased food intake under normal chow and high fat diet conditions. In addition, SF-1 ablation was accompanied by a marked reduction in energy expenditure and physical activity and this effect was significantly pronounced in the aged mice. Taken together, our data indicates that SF-1 is a key component in the VMH-mediated regulation of energy homeostasis and implies that SF-1 plays a protective role against metabolic stressors including aging and high fat diet. [ABSTRACT FROM AUTHOR]

The slow growth of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), hinders development of new diagnostics, therapeutics and vaccines. Using non-invasive real-time imaging technologies to monitor the disease process in live animals would facilitate TB research in all areas. We developed fluorescent protein (FP) expressing Mycobacterium bovis BCG strains for in vivo imaging, which can be used to track bacterial location, and to quantify bacterial load in live animals. We selected an optimal FP for in vivo imaging, by first cloning six FPs: tdTomato, mCherry, mPlum, mKate, Katushka and mKeima, into mycobacteria under either a mycobacterial Hsp60 or L5 promoter, and compared their fluorescent signals in vitro and in vivo. Fluorescence from each FP-expressing strain was measured with a multimode reader using the optimal excitation and emission wavelengths for the FP. After normalizing bacterial numbers with optical density, the strain expressing L5-tdTomato displayed the highest fluorescence. We used the tdTomato-labeled M. bovis BCG to obtain real-time images of pulmonary infections in living mice and rapidly determined the number of bacteria present. Further comparison between L5-tdTomato and Hsp60-tdTomato revealed that L5-tdTomato carried four-fold more tdTomato gene copies than Hsp60-tdTomato, which eventually led to higher protein expression of tdTomato. Evaluating anti-TB efficacy of rifampicin and isoniazid therapy in vitro and in vivo using the L5-tdTomato strain demonstrated that this strain can be used to identify anti-TB therapeutic efficacy as quickly as 24 h post-treatment. These M. bovis BCG reporter strains represent a valuable new tool for evaluation of therapeutics, vaccines and virulence. [ABSTRACT FROM AUTHOR]

Cystic echinococcosis (CE) caused by the larval stage of Echinococcus granulosus sensu lato (s.l.) is one of the most important zoonotic parasitic diseases worldwide and 10 genotypes (G1–G10) have been reported. In China, almost all the epidemiological and genotyping studies of E. granulosus s.l. are from the west and northwest pasturing areas. However, in Heilongjiang Province of northeastern China, no molecular information is available on E. granulosus s.l. To understand and to speculate on possible transmission patterns of E. granulosus s.l., we molecularly identified and genotyped 10 hydatid cysts from hepatic CE patients in Heilongjiang Province based on mitochondrial cytochrome c oxidase subunit I (cox1), cytochrome b (cytb) and NADH dehydrogenase subunit 1 (nad1) genes. Two genotypes were identified, G1 genotype (n = 6) and G7 genotype (n = 4). All the six G1 genotype isolates were identical to each other at the cox1 locus; three and two different sequences were obtained at the cytb and nad1 loci, respectively, with two cytb gene sequences not being described previously. G7 genotype isolates were identical to each other at the cox1, cytb and nad1 loci; however, the cytb gene sequence was not described previously. This is the first report of G7 genotype in humans in China. Three new cytb gene sequences from G1 and G7 genotypes might reflect endemic genetic characterizations. Pigs might be the main intermediate hosts of G7 genotype in our investigated area by homology analysis. The results will aid in making more effective control strategies for the prevention of transmission of E. granulosus s.l. [ABSTRACT FROM AUTHOR]

Background: Universal Zero-Markup Drug Policy (UZMDP) mandates no price mark-ups on any drug dispensed by a healthcare institution, and covers the medicines not included in the China’s National Essential Medicine System. Five tertiary hospitals in Beijing, China implemented UZMDP in 2012. Its impacts on these hospitals are unknown. We described the effects of UZMDP on a participating hospital, Jishuitan Hospital, Beijing, China (JST). Methods: This retrospective longitudinal study examined the hospital-level data of JST and city-level data of tertiary hospitals of Beijing, China (BJT) 2009–2015. Rank-sum tests and join-point regression analyses were used to assess absolute changes and differences in trends, respectively. Results: In absolute terms, after the UZDMP implementation, there were increased annual patient-visits and decreased ratios of medicine-to-healthcare-charges (RMOH) in JST outpatient and inpatient services; however, in outpatient service, physician work-days decreased and physician-workload and inflation-adjusted per-visit healthcare charges increased, while the inpatient physician work-days increased and inpatient mortality-rate reduced. Interestingly, the decreasing trend in inpatient mortality-rate was neutralized after UZDMP implementation. Compared with BJT and under influence of UZDMP, JST outpatient and inpatient services both had increasing trends in annual patient-visits (annual percentage changes[APC] = 8.1% and 6.5%, respectively) and decreasing trends in RMOH (APC = -4.3% and -5.4%, respectively), while JST outpatient services had increasing trend in inflation-adjusted per-visit healthcare charges (APC = 3.4%) and JST inpatient service had decreasing trend in inflation-adjusted per-visit medicine-charges (APC = -5.2%). Conclusion: Implementation of UZMDP seems to increase annual patient-visits, reduce RMOH and have different impacts on outpatient and inpatient services in a Chinese urban tertiary hospital. [ABSTRACT FROM AUTHOR]

Background: Invasive fractional flow reserve (FFR) is a standard tool for identifying ischemia-producing coronary stenosis. However, in clinical practice, over 70% of treatment decisions still rely on visual estimation of angiographic stenosis, which has limited accuracy (about 60%-65%) for the prediction of FFR < 0.80. One of the reasons for the visual-functional mismatch is that myocardial ischemia can be affected by the supplied myocardial size, which is not always evident by coronary angiography. The aims of this study were to develop an angiography-based machine learning (ML) algorithm for predicting the supplied myocardial volume for a stenosis, as measured using coronary computed tomography angiography (CCTA), and then to build an angiography-based classifier for the lesions with an FFR < 0.80 versus ≥ 0.80.Methods and Findings: A retrospective study was conducted using data from 1,132 stable and unstable angina patients with 1,132 intermediate lesions who underwent invasive coronary angiography, FFR, and CCTA at the Asan Medical Center, Seoul, Korea, between 1 May 2012 and 30 November 2015. The mean age was 63 ± 10 years, 76% were men, and 72% of the patients presented with stable angina. Of these, 932 patients (assessed before 31 January 2015) constituted the training set for the algorithm, and 200 patients (assessed after 1 February 2015) served as a test cohort to validate its diagnostic performance. Additionally, external validation with 79 patients from two centers (CHA University, Seongnam, Korea, and Ajou University, Suwon, Korea) was conducted. After automatic contour calibration using the caliber of guiding catheter, quantitative coronary angiography was performed using the edge-detection algorithms (CAAS-5, Pie-Medical). Clinical information was provided by the Asan BiomedicaL Research Environment (ABLE) system. The CCTA-based myocardial segmentation (CAMS)-derived myocardial volume supplied by each vessel (right coronary artery [RCA], left anterior descending [LAD], left circumflex [LCX]) and the myocardial volume subtended to a stenotic segment (CAMS-%Vsub) were measured for labeling. The ML for (1) predicting vessel territories (CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA) and CAMS-%Vsub and (2) identifying the lesions with an FFR < 0.80 was constructed. Angiography-based ML, employing a light gradient boosting machine (GBM), showed mean absolute errors (MAEs) of 5.42%, 8.57%, and 4.54% for predicting CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA, respectively. The percent myocardial volumes predicted by ML were used to predict the CAMS-%Vsub. With 5-fold cross validation, the MAEs between ML-predicted percent myocardial volume subtended to a stenotic segment (ML-%Vsub) and CAMS-%Vsub were minimized by the elastic net (6.26% ± 0.55% for LAD, 5.79% ± 0.68% for LCX, and 2.95% ± 0.14% for RCA lesions). Using all attributes (age, sex, involved vessel segment, and angiographic features affecting the myocardial territory and stenosis degree), the ML classifiers (L2 penalized logistic regression, support vector machine, and random forest) predicted an FFR < 0.80 with an accuracy of approximately 80% (area under the curve [AUC] = 0.84-0.87, 95% confidence intervals 0.71-0.94) in the test set, which was greater than that of diameter stenosis (DS) > 53% (66%, AUC = 0.71, 95% confidence intervals 0.65-0.78). The external validation showed 84% accuracy (AUC = 0.89, 95% confidence intervals 0.83-0.95). The retrospective design, single ethnicity, and the lack of clinical outcomes may limit this prediction model's generalized application.Conclusion: We found that angiography-based ML is useful to predict subtended myocardial territories and ischemia-producing lesions by mitigating the visual-functional mismatch between angiographic and FFR. Assessment of clinical utility requires further validation in a large, prospective cohort study. [ABSTRACT FROM AUTHOR]

Although hemodynamic influence of the subprosthetic tissue, termed as pannus, may contribute to prosthetic aortic valve dysfunction, the relationship between pannus extent and hemodynamics in the prosthetic valve has rarely been reported. We investigated the fluid dynamics of pannus formation using in vitro experiments with particle image velocimetry. Subvalvular pannus formation caused substantial changes in prosthetic valve transvalvular peak velocity, transvalvular pressure gradient (TPG) and opening angle. Maximum flow velocity and corresponding TPG were mostly affected by pannus width. When the pannus width was 25% of the valve diameter, pannus formation elevated TPG to >2.5 times higher than that without pannus formation. Opening dysfunction was observed only for a pannus involvement angle of 360°. Although circumferential pannus with an involvement angle of 360° decreased the opening angle of the valve from approximately 82° to 58°, eccentric pannus with an involvement angle of 180° did not induce valve opening dysfunction. The pannus involvement angle largely influenced the velocity flow field at the aortic sinus and corresponding hemodynamic indices, including wall shear stress, principal shear stress and viscous energy loss distributions. Substantial discrepancy between the velocity-based TPG estimation and direct pressure measurements was observed for prosthetic valve flow with pannus formation. [ABSTRACT FROM AUTHOR]

Background: Rabies is a major public health problem with a fatality rate close to 100%; however, complete prevention can be achieved through pre- or post-exposure prophylaxis. The rapid fluorescent focus inhibition test (RFFIT) is one of the recommended testing methods to determine the production of neutralizing antibodies after vaccination. Here, we report the development of a new monoclonal antibody (mAb) designed to react specifically with Rabies virus (RABV) phosphoprotein (P protein), and the evaluation of its applicability to the RFFIT and its effectiveness as a diagnostic reagent for human rabies. Methodology/principal findings: The mAb KGH P 16B8 was produced to target the P protein of the Korean KGH RABV strain. An indirect immunofluorescence assay (IFA) was conducted to detect various strains of RABV in various cell lines. Alexa-conjugated KGH P 16B8 (16B8-Alexa) was developed for the RFFIT. The IFA test could detect RABV up to a 1:2,500 dilution, with a detection limit comparable to that of a commercial diagnostic reagent. The sensitivity, specificity, positive predictive value, and negative predictive value of the RFFIT using 16B8-Alexa in 414 clinical specimens were 98.67%, 99.47%, 99.55%, and 98.42%, respectively. The results of the RFFIT with 16B8-Alexa were strongly correlated with those obtained using an existing commercial diagnostic reagent (r = 0.995, p<0.001). Conclusions/significance: The mAb developed in this study shows high sensitivity and specificity, confirming its clinical utility with the RFFIT to measure the rabies neutralizing antibody titer and establish a diagnosis in human. Thus, 16B8-Alexa is expected to serve as an alternative diagnostic reagent that is widely accessible, with potentially broad applications beyond those of the RFFIT in Korea. Further studies with 16B8-Alexa should provide insight into the immunological mechanism of the P protein of Korean RABV. [ABSTRACT FROM AUTHOR]

Background and objective: Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer’s disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs. Methods: Three hundred patients with mild to moderate AD were enrolled in this multicenter prospective open-label study and divided into two groups. Group 1 comprised patients with AD with minimal WMHs and group 2 comprised those with moderate WMHs. The patients were treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline and after 24 weeks. The primary endpoint was the change in the AD Assessment Scale-Cognitive subscale (ADAS-Cog) from the baseline to the end of the study. Results: Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the 24-week study period. Demographic factors did not differ between group 1 and group 2. There were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery, while group 2 had a 0.16-point decline compared to baseline at the end of the study (p = 0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs (10.3% vs. 4.3%) did not differ between the groups. Conclusions: Although the efficacy and tolerability of rivastigmine patch therapy were not associated with WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Intestinal inflammation and mucosal damage in Crohn’s disease (CD) are believed to progress even during clinical remission. We investigated the long-term prognosis of CD patients in clinical remission according to serum C-reactive protein (CRP) levels. This study included 339 CD patients in clinical remission (Crohn’s disease activity index < 150) for more than 6 months between January 2008 and December 2010. Clinical outcomes were compared between patients with normal and elevated CRP levels during clinical remission. During clinical remission, 150 patients had normal CRP consistently and 189 had elevated CRP at least once. During follow-up (median, 7.9 years [interquartile range, 6.8–8.0]), the Kaplan–Meier analysis with the log-rank test showed that normal CRP group had a longer CD-related hospitalization-free survival (P = 0.007) and a longer CD-related intestinal resection-free survival (P = 0.046) than elevated CRP group. In multivariate analysis, elevated CRP was significantly and independently associated with an increased risk of subsequent CD-related hospitalization (adjusted hazard ratio [aHR] 1.787, 95% confidence interval [CI]: 1.245–2.565, P = 0.002) and of subsequent CD-related intestinal resection (aHR 1.726, 95% CI: 1.003–2.969, P = 0.049). The most common reason for CD-related hospitalization was penetrating complications (35.6%). Even when CD patients are in clinical remission, elevated CRP is significantly associated with subsequent CD-related hospitalization and CD-related intestinal resection during follow-up. CD patients in clinical remission but elevated CRP should receive more careful attention and timely interventions to improve long-term outcomes. [ABSTRACT FROM AUTHOR]

Although early treatment of Crohn’s disease (CD) patients with anti-tumor necrosis factor (TNF) agents or immunomodulators (IMs) may improve long-term outcomes, especially those with poor prognostic factors, their effectiveness in Asians remains unclear. In this study, Korean patients with CD naïve to both intestinal surgery and intestinal complications, and with at least two risk factors for progression (diagnosis at age <40 years, systemic corticosteroid treatment <3 months after diagnosis, and perianal fistula at diagnosis) were retrospectively analyzed. Patients were classified into those who started anti-TNFs, or IMs but not anti-TNFs, within 2 years of diagnosis, and those who started anti-TNFs and/or IMs later. Their probabilities of intestinal surgery and intestinal complications were compared. A total of 670 patients were enrolled, 79 in the early anti-TNF, 286 in the early IM, and 305 in the late treatment group. Kaplan-Meier analysis with the log-rank test showed that from starting anti-TNFs/IMs, times to intestinal surgery (P < 0.001), stricturing complications (P = 0.002), and penetrating complications (P < 0.001) were significantly longer in the early anti-TNF/IM groups than in the late treatment group. Multivariate Cox regression analysis showed that, from starting anti-TNFs/IMs, late anti-TNF/IM treatment was independently associated with higher risks of intestinal surgery (adjusted hazard ratio [aHR] 2.321, 95% confidence interval [CI] 1.503–3.584, P < 0.001), behavioral progression (aHR 2.001, 95% CI 1.449–2.763, P < 0.001), stricturing complications (aHR 1.736, 95% CI 1.209–2.493, P = 0.003), and penetrating complications (aHR 3.315, 95% CI 2.094–5.249, P < 0.001) than early treatment. In conclusion, treatment of Asian CD patients having poor prognostic factors with anti-TNFs/IMs within 2 years of diagnosis is associated with better clinical outcomes than later treatment. [ABSTRACT FROM AUTHOR]

Streptococcus suis serotype 2 (SS2) is a major porcine and human pathogen which causes arthritis, meningitis, and septicemia. Streptococcus suis nuclease A (SsnA) is a recently discovered deoxyribonuclease (DNase), which has been demonstrated to contribute to escape killing in neutrophil extracellular traps (NETs). To further determine the effects of ssnA on virulence, the ssnA deletion mutant (ΔssnA) and its complemented strain (C-ΔssnA) were constructed. The ability of ΔssnA mutant to interact with human laryngeal epithelial cell (Hep-2) was evaluated and it exhibited dramatically decreased ability to adhere to and invade Hep-2 cells. This mutation was found to exhibit significant attenuation of virulence when evaluated in CD1 mice, suggesting ssnA plays a critical role in the pathogenesis of SS2. Finally, we found that immunization with the ΔssnA mutant triggered both antibody responses and cell-mediated immunity, and conferred 80% protection against virulent SS2 challenge in mice. Taken together, our results suggest that ΔssnA represents an attractive candidate for designing an attenuated live vaccine against SS2. [ABSTRACT FROM AUTHOR]

Background: Although the measurement of turbulence kinetic energy (TKE) by using magnetic resonance imaging (MRI) has been introduced as an alternative index for quantifying energy loss through the cardiac valve, experimental verification and clinical application of this parameter are still required. Objectives: The goal of this study is to verify MRI measurements of TKE by using a phantom stenosis with particle image velocimetry (PIV) as the reference standard. In addition, the feasibility of measuring TKE with MRI is explored. Methods: MRI measurements of TKE through a phantom stenosis was performed by using clinical 3T MRI scanner. The MRI measurements were verified experimentally by using PIV as the reference standard. In vivo application of MRI-driven TKE was explored in seven patients with aortic valve disease and one healthy volunteer. Transvalvular gradients measured by MRI and echocardiography were compared. Results: MRI and PIV measurements of TKE are consistent for turbulent flow (0.666 < R2 < 0.738) with a mean difference of −11.13 J/m3 (SD = 4.34 J/m3). Results of MRI and PIV measurements differ by 2.76 ± 0.82 cm/s (velocity) and −11.13 ± 4.34 J/m3 (TKE) for turbulent flow (Re > 400). The turbulence pressure drop correlates strongly with total TKE (R2 = 0.986). However, in vivo measurements of TKE are not consistent with the transvalvular pressure gradient estimated by echocardiography. Conclusions: These results suggest that TKE measurement via MRI may provide a potential benefit as an energy-loss index to characterize blood flow through the aortic valve. However, further clinical studies are necessary to reach definitive conclusions regarding this technique. [ABSTRACT FROM AUTHOR]

This paper reports on studies of the effect of temperature step-change (between a cool and a neutral environment) on human thermal sensation and skin temperature. Experiments with three temperature conditions were carried out in a climate chamber during the period in winter. Twelve subjects participated in the experiments simulating moving inside and outside of rooms or cabins with air conditioning. Skin temperatures and thermal sensation were recorded. Results showed overshoot and asymmetry of TSV due to the step-change. Skin temperature changed immediately when subjects entered a new environment. When moving into a neutral environment from cool, dynamic thermal sensation was in the thermal comfort zone and overshoot was not obvious. Air-conditioning in a transitional area should be considered to limit temperature difference to not more than 5°C to decrease the unacceptability of temperature step-change. The linear relationship between thermal sensation and skin temperature or gradient of skin temperature does not apply in a step-change environment. There is a significant linear correlation between TSV and Qloss in the transient environment. Heat loss from the human skin surface can be used to predict dynamic thermal sensation instead of the heat transfer of the whole human body. [ABSTRACT FROM AUTHOR]