Epigenetic Regulation of Cytochrome P450 Enzymes and Clinical Implication.
CYPs are a large and diverse group of drug-metabolizing enzymes, which govern the metabolism of the majority of xenobiotic substances as well as endogenous components. The high inter-subject variability of CYP bioactivity has been largely attributed to gene polymorphism until the rapid development in epigenetics in the last decade that revealed another aspect of regulatory mechanism of drug-related genes. Epigenetics is the study of changes in gene expression or cellular phenotype that are not caused by changes in the underlying DNA sequence. The modification of histone proteins, together with DNA methylation and miRNAs, is the most extensively studied epigenetic mechanism in mammals. Recently, it has been demonstrated that alterations in epigenetic regulation occur during multiple pathological processes, especially carcinogenesis. As CYPs play an important role in carcinogen and anti-cancer drug biotransformation, epigenetic changes in CYP genes would lead to interindividual differences in drug responses. In this review, we provide an up-to-date summary of epigenetic studies on human CYPs, and discuss how such information could be integrated with clinical application.


Treat-to-target in PsA: methods and necessity.
With increasing recognition of the high burden and impact of psoriatic arthritis (PsA) and the growing number of therapeutic options, there has been an intensifying focus on treatment strategy in recent years. In 2015, the Tight Control of Psoriatic Arthritis study confirmed the clinical benefit of using a treat-to-target approach in PsA. This randomised controlled trial found benefits in both arthritis and psoriasis disease activity as well as lower disease impact reported by patients, although participants allocated to tight control experienced a higher rate of serious adverse events. European and international recommendations support the use of a treat-to-target approach in PsA and have offered specific advice on how to do this using outcomes such as the minimal disease activity criteria. However, implementation of this approach in routine practice is low, with real-world data highlighting undertreatment as a result. Recent qualitative work with physicians in the UK has helped researchers to understand the barriers to implementation of treat-to-target in PsA. We now need to address these barriers, provide education and support to non-specialist clinicians in routine practice, and aid the translation of optimal care to the clinic.


Multiple-step melting in two-dimensional hexatic liquid-crystal films
An unexpected three-stage melting transition has been observed in two-dimensional (2D) free-standing liquid-crystal films by in situ electron-diffraction and optical-reflectivity measurements. These data suggest the existence of two phases between the 2D solid and liquid: a hexatic phase and, at a higher temperature, an intermediate liquid phase with hexatic-like positional correlations ( approximately 40 angstroms) but no long-range orientational order. Previous high-resolution heat-capacity measurements have revealed a divergent-like anomaly at the hexatic-liquid transition that sharply contradicts the predictions of 2D melting theories. The observation of an intermediate isotropic phase may alter our understanding of 2D melting and lead to reconciliation between current experiments and theories.


The role of psychological support in cardiac surgery: initial experience.
The scientific literature has pointed out several predictors of negative outcome after surgery such as pain and depression, negatively affecting the postoperative outcome in cardiac surgery. From January 2009 until June 2010, 15 patients scheduled for cardiac surgery were enrolled. The patients were assessed by psychological evaluation either in the hospital stay either in the rehabilitation period with the aim of identifying their emotional condition (sentiments about the onset of the disease, support received from family and friends) even by means of preformed tests for anxiety and depression (tests of Stay and Back). Thus, in our preliminary experience, the psychological evaluation failed to detect the occurrence of postoperative complications. Conversely, the psychological evaluation is very effective in detecting a poor emotional state and the psychological support decreases the degree of anxiety and depression with positive effects on postoperative outcome. In conclusion, a standardize test for anxiety and depression should be used for patients at hospital admission to detect who may benefits by psychological support.


Scopolin ameliorates high-fat diet induced hepatic steatosis in mice: potential involvement of SIRT1-mediated signaling cascades in the liver.
The present study aimed to investigate whether scopolin exhibits beneficial effects on high-fat diet (HFD)-induced hepatic steatosis in mice. The involvement of sirtuin 1 (SIRT1) as a molecular target for scopolin was also explored. Scopolin decreased the Km of SIRT1 for p53 and nicotinamide adenine dinucleotide without altering Vmax in a cell-free system. Scopolin alleviated oleic acid-induced lipid accumulation and downregulation of SIRT1 activity in HepG2 cells, and these beneficial effects of scopolin were abolished in the presence of SIRT1 inhibitor. Mice administered 0.02% scopolin for 8 weeks exhibited improved phenotypes of HFD-induced hepatic steatosis along with increased hepatic SIRT1 activity and protein expression. Scopolin resulted in increased deacetylation of sterol regulatory element-binding protein 1c with subsequent downregulation of lipogenic genes, and enhanced deacetylation of protein peroxisome proliferator-activated receptor-γ coactivator 1α with upregulation of fatty acid oxidation genes in livers. Scopolin also enhanced deacetylation of nuclear factor-kappa enhancer binding protein and liver kinase B1 (LKB1), facilitating LKB1/AMP-activated protein kinase signaling cascades. Scopolin attenuated hepatic steatosis through activation of SIRT1-mediated signaling cascades, a potent regulator of lipid homeostasis. Increased hepatic SIRT1 activity and protein expression appeared to be associated with these beneficial effects of scopolin.


[The peculiarities of calcium metabolism regulation in different periods of growth and development].
The review contains literature data about calcium metabolism regulation in different periods of growth and development. The analyses of retrospective and current sources of information about the regulation of calcium homeostasis under the theory of functional systems, the regulation of calcium metabolism in prenatal and postnatal periods of the development, the significance of calcium metabolism disturbances in the development of pathological conditions were showed.


Paraventricular nucleus Sim1 neuron ablation mediated obesity is resistant to high fat diet.
Single minded 1 (SIM1) is a transcription factor involved in brain patterning and control of energy balance. In humans, haploinsufficiency of SIM1 causes early-onset obesity. Mice deficient in the homologous gene, SIM1, also exhibit early onset obesity and increased sensitivity to a high fat diet. SIM1 is expressed in several areas of the brain implicated in control of energy balance including the paraventricular nucleus (PVN), the supraoptic nucleus (SON), the medial amygdala and nucleus of the lateral olfactory tract. We have previously shown that mice with global Sim1 neuron ablation exhibit obesity with hyperphagia as the primary defect. The PVN has a critical role in feeding and in high-fat appetite, thus, we sought to determine the effect of Sim1 neuron ablation limited to the PVN. We achieved PVN-SIM1 limited ablation through stereotactic injection of diphtheria toxin into the PVN of Sim1Cre-iDTR mice. The specificity of this ablation was confirmed by immunohistochemistry and quantitative real time PCR of the PVN, supraoptic nucleus and the amygdala. Mice with PVN Sim1 neuron ablation, similar to mice with global Sim1 neuron ablation, exhibit early onset obesity with hyperphagia as the primary defect. However, PVN-Sim1 neuron ablated mice have a decreased response to fasting-induced hyperphagia. Consistent with this decrement, PVN-Sim1 neuron ablated mice have a decreased hyperphagic response to PVN injection of agouti-related peptide (AgRP). When PVN-Sim1 neuron ablated mice are placed on a high fat diet, surprisingly, their intake decreases and they actually lose weight. When allowed ad lib access to high fat diet and normal chow simultaneously, PVN-Sim1 neuron ablated mice exhibit overall decreased intake. That is, in PVN-Sim1 neuron ablated mice, access to fat suppresses overall appetite.


The effects of thioredoxin peroxidase from Cysticercus cellulosae excretory-secretory antigens on TGF-β signaling pathway and Th17 cells differentiation in Jurkat cells by transcriptomics.
Thioredoxin peroxidase (TPx) protein from the excretory-secretory antigens (ESAs) of Cysticercus cellulosae (C. cellulosae) has been shown to regulate the differentiation of host Treg and Th17 cells, resulting in an immunosuppressive response dominated by Treg cells. However, the molecular mechanism by which TPx protein from the ESAs of C. cellulosae regulates the imbalance of host Treg/Th17 cell differentiation has not been reported. TPx protein from porcine C. cellulosae ESAs was used to stimulate Jurkat cells activated with PMA and ionomycin at 0, 24, 48, and 72 h. Transcriptomic analysis was performed to investigate the signaling pathways associated with Jurkat cells differentiation regulated by TPx protein from C. cellulosae ESAs. Gene Set Enrichment Analysis (GSEA) revealed that TPx protein from porcine C. cellulosae ESAs could induce upregulation of the TGF-β signaling pathway and downregulation of Th17 cell differentiation in Jurkat cells. TPx protein from porcine C. cellulosae ESAs can activate the TGF-β signaling pathway in Jurkat cells, thereby regulating the differentiation of Treg/Th17 cells and leading to an immunosuppressive response dominated by Treg cells, enabling evasion of the host immune attack. This study provides a foundation for further validation of these pathways and further elucidates the molecular mechanisms underlying immune evasion caused by porcine C. cellulosae.


Process modelling and techno-economic analysis of anaerobic digestion of sewage sludge integrated with wet oxidation using a gravity pressure vessel and thermal hydrolysis.
Anaerobic digestion (AD) of sewage sludge is used to biodegrade sewage sludge into biomethane and digestate. With the addition of thermal processes such as thermal hydrolysis (TH) and wet oxidation (WO), AD biodegradability generally improves. Implementation of additional treatment is challenging due to the limitation in the mass and energy balances. Hence, tools such as process simulation can be utilized to predict the input and output around the process. In addition, an economic analysis needs to be conducted to check the economic feasibility. The techno-economic analysis (TEA), an integrated method to evaluate a process scheme through simulation and subsequent economic analysis, is effective in providing a systematic understanding of economic implications and the feasibility of a process by identifying the bottlenecks and uncertainties that have a significant impact on the technology. TEA of AD, especially incorporating the TH or WO using gravity pressure vessel (GPV) technology, is limited in the literature. A comprehensive TEA of the AD and the pre- and post-treatment schemes can be utilized to determine the most feasible pathway for sludge treatment for implementation in the wastewater industry. In this study, TEA for four different scenarios of AD was conducted using Aspen Plus and economic analysis tools: (1) without any pre- or post-treatment, (2) with TH pre-treatment, (3) with 100 % WO post-treatment, and (4) with 20 % partial wet oxidation (PWO) and acid hydrolysis pre- or post-treatment. A simulation model (GPVM) was developed using Aspen Plus to mimic the GPV reactor. The study outcomes showed that Scenario 3 with 100 % WO post-treatment was the most suitable for processing parameters and sludge treatment cost. The sensitivity analysis concluded that operating cost and plant capacity are the dominant factors that impact the plant feasibility significantly.


Can Temperate-Water Immersion Effectively Reduce Rectal Temperature in Exertional Heat Stroke? A Critically Appraised Topic.
Clinical Scenario: Exertional heat stroke (EHS) is a medical emergency which, if left untreated, can result in death. The standard of care for EHS patients includes confirmation of hyperthermia via rectal temperature (Trec) and then immediate cold-water immersion (CWI). While CWI is the fastest way to reduce Trec, it may be difficult to lower and maintain water bath temperature in the recommended ranges (1.7°C-15°C [35°F-59°F]) because of limited access to ice and/or the bath being exposed to high ambient temperatures for long periods of time. Determining if Trec cooling rates are acceptable (ie, >0.08°C/min) when significantly hyperthermic humans are immersed in temperate water (ie, ≥20°C [68°F]) has applications for how EHS patients are treated in the field. Are Trec cooling rates acceptable (≥0.08°C/min) when significantly hyperthermic humans are immersed in temperate water? Trec cooling rates of hyperthermic humans immersed in temperate water (≥20°C [68°F]) ranged from 0.06°C/min to 0.19°C/min. The average Trec cooling rate for all examined studies was 0.11±0.06°C/min. Clinical Bottom Line: Temperature water immersion (TWI) provides acceptable (ie, >0.08°C/min) Trec cooling rates for hyperthermic humans post-exercise. However, CWI cooling rates are higher and should be used if feasible (eg, access to ice, shaded treatment areas). Strength of Recommendation: The majority of evidence (eg, Level 2 studies with PEDro scores ≥5) suggests TWI provides acceptable, though not ideal, Trec cooling. If possible, CWI should be used instead of TWI in EHS scenarios.


Association Between Computer Vision Syndrome, Insomnia, and Migraine Among Lebanese Adults: The Mediating Effect of Stress.
Objective: Computer vision syndrome (CVS) refers to a group of ocular and extraocular symptoms due to prolonged digital device screen use. The objective of this study was to assess the correlation between CVS, insomnia, and migraine, taking into consideration stress as a mediating factor between these 3 variables. Methods: This cross-sectional study was conducted between August 2020 and April 2021 using an online questionnaire filled out by 749 participants. Participants were enrolled using a snowball sampling technique. The link to the Arabic questionnaire was sent to the individuals by WhatsApp and by e-mail. Results: The prevalence of CVS among participants was 70.5%. The presence of CVS (β = 3.26) was significantly associated with higher insomnia. The presence of CVS (adjusted odds ratio [aOR] = 1.66) and higher stress (aOR = 1.09) was significantly associated with higher odds of having migraine. Stress fully mediated the association between CVS and migraine by 52.76% and between CVS and insomnia by 79.99%. Conclusion: CVS was significantly associated with insomnia and migraine. Stress mediated the relationship between CVS and insomnia, and between CVS and migraine. The precise mechanisms behind these associations were not evaluated in this study, with the hope that future research will provide more information on this topic.


The immune response to Prevotella bacteria in chronic inflammatory disease.
The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease-modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low-grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) -mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll-like receptor 2, leading to production of Th17-polarizing cytokines by antigen-presenting cells, including interleukin-23 (IL-23) and IL-1. Furthermore, Prevotella stimulate epithelial cells to produce IL-8, IL-6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella-mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.


[Hepatic involvement in a case of lysosomal glycogen storage disease with normal acid maltase].
A 19-year-old man, who could run only slowly since childhood and who walked on his toes since 12 years of age, noted difficulty in climbing upstairs at 17 years of age. He was admitted to Kyushu University Hospital because of elevated AST, ALT and CK levels. On admission, the liver was palpable two fingerbreadths beneath the right costal margin. A neurological examination revealed a low IQ on WAIS-R, a decreased muscle tonus in his four limbs, moderate weakness of the neck flexor and bilateral tibialis anterior muscles, contracture of the ankle joints, and bilateral pes cavus. The serum CK was elevated to 1,124U/l. Hepatic enzymes, such as AST, ALT, LDH and gamma-GTP were also moderately increased in the sera. A needle EMG disclosed myogenic patterns in the limb muscles. Biopsied biceps brachii muscle showed a mild variation in the fiber size and multiple tiny vacuoles in 5-10% of the muscle fibers. PAS and acid phosphatase were strongly positive in some vacuoles. On electron microscopy, numerous autophagic vacuoles containing glycogen granules were observed. The acid maltase activities were, however, normal in the peripheral blood lymphocytes, the biopsied muscle, and the cultured skin fibroblasts. He was thus diagnosed to have lysosomal glycogen storage disease with normal acid maltase. A histological examination of the biopsied liver revealed the portal and central veins to be slightly sclerotic. In addition, mild fatty changes and frequent nuclear vacuolization were present in the hepatocytes. On electron microscopy, enlarged mitochondria with irregular cristae were also observed. Due to the fact that the cardiac function was well preserved, these hepatic lesions were thought to result from the metabolic abnormalities underlying in this disorder.


VEGF rescues cigarette smoking-induced human RPE cell death by increasing autophagic flux: implications of the role of autophagy in advanced age-related macular degeneration.
Cigarette smoking (CS) is the most consistent risk factor for advanced age-related macular degeneration (AMD). To verify the molecular basis for CS-induced RPE alterations, RPE cell survival levels after being exposed to CS in relation with VEGF expression and autophagic flux were evaluated. Cigarette smoking extract (CSE) was added to ARPE-19 cells and hydrogen peroxide (HP) was used as a pure oxidant control. Cell survival was measured by flow cytometry with annexin V-fluorescein isothiocyanate. Cell survival analysis was performed after pretreatment with anti-VEGF or recombinant VEGF. The expression of VEGF-A, VEGF-R1/R2, and soluble VEGF-R1 was determined by semiquantitative RT-PCR. LC3B-I (microtubule-associated protein-1 inhibitors), LC3B-II, and phosphorylation of Akt or Erk were measured with Western blot. Autophagic flux was determined by increasing LC3B-II levels with inhibitors of lysosomal proteases. Incubation with 5% CSE for 16 hours induced approximately 30% cell death, which was similar to cell death levels when exposed to concentrations of 200 μM HP. Pretreatment with anti-VEGF did not decrease cell survival under CSE, unlike the decrease in cell survival shown with HP. However, supplementation with VEGF rescued CSE-induced RPE cell death. Interestingly, CSE caused an increase in autophagic flux, which was augmented with VEGF pretreatment. Cigarette smoking extract also degraded the total amounts of Akt levels, and VEGF blunted CSE-induced phosphorylation of Erk. Cigarette smoking extract, similar to HP, affects cell viability and induces expression of VEGF and its receptors. Increased autophagic flux accelerated by treatment of exogenous VEGF may have a role in rescuing CSE-induced RPE cell death.


Ventricular Recovery and Pump Explantation in Patients Supported by Left Ventricular Assist Devices: A Systematic Review.
Several studies have reported that a portion of patients who exhibit cardiac recovery during left ventricular assist device (LVAD) support can have their device explanted with reasonable long-term survival. The aim of this systematic review is to assess the survival and cardiac function in patients with explanted LVADs from the current literature. Electronic search was performed to identify all studies in English literature assessing LVAD explantation. All identified articles were systematically assessed using the inclusion and exclusion criteria. Selected studies were subjected to quantitative assessment. From 5 electronic databases, 11 studies (213 patients) were included. Pooled mean perioperative mortality rate of those explanted was 9.2% (95% CI, 5.0-14.5%; I = 0). Pooled mean late mortality rate was 15% (95% CI, 9.0-22.1%; I = 31%). The pooled 1, 5, and 10 year survival postexplant was 91, 76, and 65.7%, respectively. Pooled postweaning freedom from heart failure (HF) recurrence reached 81.3%. Subset analysis demonstrated that patients explanted from a continuous-flow LVAD versus pulsatile LVAD had a lower rate of HF recurrence (6.6 vs. 28.3%, p = 0.03) and LVAD reimplantation (7.5 vs. 37%, p = 0.001). Before LVAD explantation, overall mean left ventricular ejection fraction (LVEF) was 49%. Weighted pooled early and late postexplantation mean LVEF was 47.3 and 41.2%, respectively. Late postexplantation LVEF was significantly higher in the continuous-flow versus pulsatile LVAD subgroup (41.5 vs. 24%, p = 0.001). This review shows encouraging safety and 10 year survival outcomes after explantation of LVADs in carefully selected patients, with rates better than expected after a heart transplant. Recovery of the native heart is the most desirable clinical outcome in patients supported with LVADs and should be actively sought.


Fatty acid synthetase activity in the liver and adipose tissue of rats fed with various carbohydrates.
1. The inclusion of sucrose in the diet of rats led to an increase in hepatic fatty acid synthetase activity compared with that of rats fed with starch as the sole carbohydrate. The higher activity occurred within 18h of the introduction of sucrose and persisted with fluctuations for the 30 days of the experiment. Reversal of the diets in some rats after 21 days led to changes in the enzyme activity to values appropriate to the second diet. The plasma triglyceride concentration followed a similar pattern. 2. A comparison of the effects of diets with starch, glucose, maltose, sucrose or fructose showed that fructose gave the highest values of triglyceride content and of fatty acid synthetase activity in liver, but the lowest values of the synthetase activity in adipose tissue and the lowest values of plasma insulin concentration. These effects may perhaps be attributed to the low insulin response to fructose and to the high affinity of the liver for this sugar. 3. When the diet contained fructose or sucrose there was a correlation between hepatic synthetase activity and plasma triglyceride concentration. Neither of these, however, was related to plasma insulin concentration. On the other hand, there was a correlation between plasma insulin concentration and fatty acid synthetase activity in adipose tissue. 4. When rats were starved and then re-fed the differences in enzyme activities induced by fructose or glucose were minimized. This, together with the varying degree of difference during the course of the experiments, may explain why other workers, using the starvation-re-feeding technique and making measurements on one day only, have failed to observe differences in the activities of lipogenic enzymes in animals fed with either fructose or glucose.


Examining the correlation between quantifiable SVOCs and organic carbon content or particulate size in benthic sediments as a function of ocean stratum.
The raw analytical concentration values of semi-volatile organic compounds (SVOCs) in ocean sediments do not necessarily reflect the bioavailable fractions of SVOCs in the sediments due to factors such as the total organic carbon content of sediments (TOC) and the percentage of fine particles in sediments (% fines) as they are believed to affect the extraction efficiency of SVOCs from sediments. Corrective actions are therefore taken to minimize their influence on measurements. In doing so, a broad and uniform correlation is assumed to exist between the 'native' levels of SVOCs and TOC or % fines across ocean strata. However, the validity of this blanket assumption is not yet verified. In this study, we examined the strength of the assumption using DDTs, PAHs and PCBs levels in sediments from Santa Monica Bay (SMB), California, USA. (The distribution patterns of these SVOCs in SMB are known and reproducible for quality assurance.) As our results show, a uniform correlation between SVOC levels and TOC or % fines across strata is mostly absent. For example, PAH and PCB levels show negative correlation with TOC or % fines, and only in canyon sediments, DDT levels correlate positively with both TOC and % fines across at least three strata. Furthermore, the distribution of PAH molecules appears to be controlled by molecular size with smaller PAHs being found almost exclusively in the canyons. Our finding here, being the first of its kind, suggests that more work is needed to clarify the reporting of SVOC levels in ocean sediments.


Potential energy surfaces for chemical reactions at solid surfaces.
Many-body potential energy surfaces (PESs) for describing atomic interactions in gas-solid and surface reaction dynamics are reviewed in this work. Initial PESs from the 1960s-1970s were restricted to a diatomic molecule interacting with a solid surface. Since the 1980s, a multitude of many-body reactive PESs, their parameterization, and their applications have been reported in the literature. Although we mention most of the PESs in general, we have chosen to describe only those that either have had general utility or have had staying power, i.e. they have been used widely by other research groups. The potentials discussed in the most detail are the Stillinger-Weber and Tersoff Si PESs, the Brenner hydrocarbon PES, and the embedded-atom method (EAM) style potentials for metals. We conclude that although these PESs have been used successfully in large-scale computer simulations, further development is needed in many-body PESs. In particular, the development of new functional forms for multicomponent reactive systems is required.


Selectable mutant phenotypes of the extremely thermophilic archaebacterium Sulfolobus acidocaldarius.
As a first step toward developing the genetic potential of extremely thermophilic archaebacteria, mutant strains of Sulfolobus acidocaldarius were selected by plating cells directly on solid medium containing one of several growth inhibitors. Three spontaneous resistance phenotypes were observed (5-fluorouracil resistance, novobiocin resistance, and L-ethionine resistance), each at a different average frequency. Characterization of representative strains showed each of the three mutant phenotypes to provide a potentially useful genetic marker.


[Transperineal ultrasonic therapy for chronic prostatitis].
To evaluate the clinical efficacy and safety of transperineal ultrasonic therapy for chronic prostatitis (CP) by analyzing the scores of NIH-CPSI and the results of prostate fluid routine examination. We conducted a randomized, double-blind, multi-centered trial on 96 CP patients that met the inclusion criteria. We divided the patients into groups A (trial) and B (control) of equal number, the former treated by transperineal ultrasound, while the latter with the same machine but no ultrasound waves, 10 min a time qd alt for 2 weeks. Then we evaluated the therapeutic effect and safety by comparing the scores of NIH-CP-SI and counts of white blood cells (WBC) and lecithin corpuscles (LC) in the prostate fluid between the two groups before and after treatment. The total effectiveness rate was 70.83% in group A and 25% in group B (P < 0.01). The scores on prostate pain, urinary symptoms and quality of life as well as the total NIH-CPSI score were significantly improved in group A as compared with pretreatment (P < 0.05), and so were the prostate pain score and total NIH-CPSI score in group B (P < 0.05). Statistically significant differences were observed between the two groups in the scores on prostate pain and urinary symptoms and total NIH-CPSI score after treatment (P < 0.05), but not in any of the NIH-CPSI scores before treatment (P > 0.05), nor were there any significant differences in the counts of WBCs and LC either between the two groups or within each group before and after treatment (P > 0.05). Two patients experienced adverse events in group A, and 1 in group B (P > 0.05). Transperineal ultrasonic therapy is highly effective for CP, especially in relieving prostate pain. With its advantages of safety, easy operation and high acceptability, it deserves a wider clinical application.


Macroscopic role of microparticles in cardiovascular disease.
Microparticles, also termed extracellular vesicles (EVs) are novel candidate markers of platelet activation and ongoing inflammation in vivo. Different subtypes of EVs are released from platelets, endothelial cells and leukocytes. Blood concentration of EV subtypes in patients with acute myocardial infarction, stroke and peripheral artery disease correlated with the severity of the disease. Accumulating data indicate that EVs may contribute to the development of atherosclerosis and its complications. Measurement of EV concentrations might become an element of minimally-invasive diagnostic tests, allowing for early diagnosis of cardiovascular disease (CVD), risk stratification and monitoring of therapy in patients with high cardiovascular risk. It also may allow to monitor the response to antiplatelet therapy with acetylsalicylic acid or P2Y12 antagonists. Isolation and detection of EVs have been recently standardized, allowing for further development of research on these promising biomarkers. EV-based tests might eventually be implemented into every-day clinical practice as well as in multicenter clinical trials.


Application of Dexmedetomidine in Epidural Labor Analgesia: A Systematic Review and Meta-Analysis on Randomized Controlled Trials.
To summarize and appraise the use of dexmedetomidine in epidural labor analgesia, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We conducted the literature search about the RCTs of epidural labor analgesia with or without dexmedetomidine from inception until November 1, 2022, in the following databases: PubMed, Cochrane Library, and Embase. The primary outcome was visual analog scale (VAS) within 2 hours after epidural intubation. The secondary outcomes included the duration of the first and second labor stages, Apgar score, umbilical blood pH, dosage of analgesics, and side effects. Eight RCTs including 846 parturients were included. The VAS score of the dexmedetomidine group was significantly lower than that of the control group at the time of 15 minutes (mean difference [MD] -1.41, 95% confidence interval [CI] -2.23, -0.59), 30 minutes (MD -1.02, 95% CI -1.70, -0.33), 60 minutes (MD -0.90, 95% CI -1.36, -0.44), and 90 minutes (MD -0.70, 95% CI -1.16, -0.23). The incidence of pruritus in the dexmedetomidine group was lower than that of the control group (MD 0.28, 95% CI 0.11, 0.74), but the incidence of maternal bradycardia was higher (MD 6.41, 95% CI 1.64, 25.04). There were no significant difference in other outcomes. Dexmedetomidine combined with local anesthetic for epidural labor analgesia can improve the VAS score of parturients. Except for the increased incidence of maternal bradycardia, it seems to be safe for the parturients and fetuses.


Silica nanoparticles based on an AIE-active molecule for ratiometric detection of RNS in vitro.
Nitric oxide (NO), known as a reactive nitrogen species (RNS), has been considered to be a significant factor in many cell-related biological processes. There is a great desire to develop fluorescent probes that can highly sensitively and selectively detect NO in living cells. Herein, a fluorescent probe, a tetraphenylethene (TPE) derivative TPE-2NH2, with aggregation induced emission (AIE) properties was designed and synthesized. Then silica nanoparticles based on TPE-2NH2 were fabricated for ratiometric detection of NO in vitro with high sensitivity and selectivity. In the presence of NO, the fluorescence of the silica nanoparticles changes from 519 nm (green) to 655 nm (red) because of the chemical reaction between NO and o-phenylenediamine in TPE-2NH2. The silica nanoparticles exhibited very high sensitivity and selectivity towards NO in aqueous buffer, and the response time was as short as 5 minutes. Moreover, the silica nanoparticles can also highly sensitively and selectively respond to NO produced in living cells. When MCF-7 cancer cells were activated by lipopolysaccharides (LPS), which can effectively induce the production of NO, the red emission signal of the silica nanoparticles obviously increased. This demonstrated that the silica nanoparticles showed fine imaging contrast towards NO in MCF-7 cancer cells, which provides a facile tool to detect intracellular NO.


Identification of virulence factors and antibiotic resistance in Salmonella enterica subsp. enterica serovar Javiana (FARPER-220) isolated from broiler chickens.
Genome sequencing of highly virulent Salmonella enterica subsp. enterica serovar Javiana strain FARPER-220 (ST-1674) isolated from broiler chickens in Peru revealed multiple virulence factors, antibiotic resistance genes, and invasion-related subcategories. The results provide insights into the potential importance of this strain in causing infections in various animals.


Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices.
An important but poorly understood event associated with ischemia is anoxic depolarization (AD), a sudden and profound depolarization of neurons and glia in cortical and subcortical gray matter. Leao first measured the AD as a wave of electrical silence moving across the cerebral cortex in 1947 and noted its similarity to spreading depression (SD). SD is harmless when coursing through normoxic cortical tissue as during migraine aura. However for 3-4 h following focal ischemia, the additional metabolic stress arising from recurring SD in the penumbra expands the ischemic core, so SD blockade is potentially beneficial therapeutically. In the present study, we measured intrinsic optical signals (IOSs) to monitor anoxic depolarization in submerged rat neocortical slices during O2/glucose deprivation (OGD). After approximately 6 min of OGD, the AD was imaged as a focal increase in light transmittance which then propagated across neocortical gray at approximately 2 mm/min. Although the slice was globally stressed, the AD always initiated focally, sometimes at multiple sites. Its propagation was coincident with a transient negative shift in the extracellular potential, the electrical signature of AD. Acute damage to neocortex (measured as a delayed decrease in LT and as a loss of the evoked field potential) followed only where the AD had propagated, so it is the combined metabolic demands of AD and OGD that acutely damages all layers of the neocortex. Glutamate receptor antagonists (2 mM kynurenate or 25 microM AP-5/10 microM CNQX) did not block AD initiation, slow its propagation or prevent post-AD damage. This study shows that acute ischemic damage is greatly exacerberated by AD during metabolic stress and that glutamate receptor antagonists are not protective. Using this slice model, therapeutically tolerable drugs that block the AD and SD can be investigated.


Electrospun bioresorbable heart valve scaffold for tissue engineering.
Currently marketed mechanical or biological prosthetic heart valves are regarded as valid substitutes for native heart valves suffering from degenerative pathologies. These devices require strict follow-up due to dysfunctions or post-surgical complications. Potential drawbacks of these medical devices are calcification, tearing of the cusps, thromboembolism and hemolysis. In this context, a tissue engineering approach offers a promising alternative scenario. In this paper, a trileaflet poly(epsilon-caprolactone) (PCL) heart valve scaffold prototype has been manufactured by electrospinning technique using a custom-made rotating target. Process parameters were selected in order to achieve suitable microstructure and mechanical performance. The electrospun heart valve prototype was functionally characterized by means of a pulse duplicator in order to evaluate the mechanical/hydraulic response to the imposed testing conditions. Leaflets synchronously opened in the ejection phase and the proper apposition of the leaflets prevented high leakage volumes in the diastolic phase. This preliminary study suggests a successful perspective for the proposed approach in designing a novel tissue engineered bioresorbable heart valve.


[Endovascular treatment for acute ischemic stroke].
The benefit of endovascular treatment (ET) after acute ischemic stroke has long been debated. Recent studies have demonstrated the clinical benefit of ET up to approximately 8 hours after stroke onset, mainly in association with intranenous thrombolysis. The positive effect is higher if ET is initiated early and performed by an experienced team. Current ET techniques include thrombectomy with clot removal using stentretriever technques or local thromboaspiration of the clot. ET seems to be so efficient that stroke care networks have to be organised to offer ET as quickly as possible in all patients who could benefit from this therapy.


INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells.
In diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A-maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells. DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay. We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A-induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A-expressing cells, but not DN-HNF1A-expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V-positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A-induced cells by stimulating cell proliferation and increasing insulin gene expression. Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY.


A 12-Month Prospective Cohort Study of Symptoms of Common Mental Disorders Among European Professional Footballers.
To determine the 12-month incidence and comorbidity of symptoms of common mental disorders (CMD) among European professional footballers and to explore the association of potential stressors with the health conditions under study among those European professional footballers. Observational prospective cohort study with a follow-up period of 12 months. Male professional footballers from 5 European countries (n = 384 at baseline). Adverse life events, conflicts with trainer/coach, and career dissatisfaction were explored by using validated questionnaires. Symptoms of distress, anxiety/depression, sleep disturbance, and adverse alcohol use were assessed using validated questionnaires. A total of 384 players (mean age of 27 years old; mean career duration of 8 years) were enrolled, of which 262 completed the follow-up period. The incidence of symptoms of CMD were 12% for distress, 37% for anxiety/depression, 19% for sleep disturbance, and 14% for adverse alcohol use. Over the follow-up period of 12 months, approximately 13% of the participants reported 2 symptoms, 5% three symptoms, and 3% four symptoms. Professional footballers reporting recent adverse life events, a conflict with trainer/coach, or career dissatisfaction were more likely to report symptoms of CMD, but statistically significant associations were not found. The 12-month incidence of symptoms of CMD among European professional footballers ranged from 12% for symptoms of distress to 37% for symptoms of anxiety/depression. A professional football team typically drawn from a squad of 25 players can expect symptoms of CMD to occur among at least 3 players in one season.


Forced alignment of mesenchymal stem cells undergoing cardiomyogenic differentiation affects functional integration with cardiomyocyte cultures.
Alignment of cardiomyocytes (CMCs) contributes to the anisotropic (direction-related) tissue structure of the heart, thereby facilitating efficient electrical and mechanical activation of the ventricles. This study aimed to investigate the effects of forced alignment of stem cells during cardiomyogenic differentiation on their functional integration with CMC cultures. Labeled neonatal rat (nr) mesenchymal stem cells (nrMSCs) were allowed to differentiate into functional heart muscle cells in different cell-alignment patterns during 10 days of coculture with nrCMCs. Development of functional cellular properties was assessed by measuring impulse transmission across these stem cells between 2 adjacent nrCMC fields, cultured onto microelectrode arrays and previously separated by a laser-dissected channel (230+/-10 microm) for nrMSC transplantation. Coatings in these channels were microabraded in a direction (1) parallel or (2) perpendicular to the channel or were (3) left unabraded to establish different cell patterns. Application of cells onto microabraded coatings resulted in anisotropic cell alignment within the channel. Application on unabraded coatings resulted in isotropic (random) alignment. After coculture, conduction across seeded nrMSCs occurred from day 1 (perpendicular and isotropic) or day 6 (parallel) onward. Conduction velocity across nrMSCs at day 10 was highest in the perpendicular (11+/-0.9 cm/sec; n=12), intermediate in the isotropic (7.1+/-1 cm/sec; n=11) and lowest in the parallel configuration (4.9+/-1 cm/sec; n=11) (P<0.01). nrCMCs and fibroblasts served as positive and negative control, respectively. Also, immunocytochemical analysis showed alignment-dependent increases in connexin 43 expression. In conclusion, forced alignment of nrMSCs undergoing cardiomyogenic differentiation affects the time course and degree of functional integration with surrounding cardiac tissue.


Rasch analysis of the Burke Lateropulsion Scale (BLS).
Lateropulsion is a common problem following stroke. Whilst the Burke Lateropulsion Scale (BLS) is recommended in the literature as the outcome measure of choice for measuring lateropulsion, the internal validity of the BLS has not been investigated. To evaluate the internal validity of the BLS for use in evaluating the effectiveness of therapies aimed at reducing lateropulsion. Rasch analysis procedures were undertaken including assessment of overall model fit, item, and person fit, threshold ordering, differential item functioning, internal consistency, targeting, and dimensionality. Data from 132 participants were utilized to perform Rasch analysis of the BLS. In this preliminary study, overall model fit and individual item and person fit were found to be good using fit residual statistics and chi-square probability values. The BLS was found to be unidimensional and have good internal consistency (Person Separation Index 0.867). Thresholds for four of the five items were found to be only marginally disordered and were subsequently not modified. Non-uniform differential item functioning was detected for age for the transfers item; however, this item did not display item misfit and was therefore not removed. This study identified good psychometric properties of the BLS using Rasch analysis and supports the use of the BLS as a measure of lateropulsion following stroke. Further use of Rasch analysis on the BLS using a larger sample is recommended to confirm these preliminary findings and allow transformation into an interval-level scale.


Preferential inhibition of 5-trifluoromethyl-2'-deoxyuridine phosphorylation by 5'-amino-5'-deoxythymidine in uninfected versus herpes simplex virus-infected cells.
The cytotoxic effects of 5-trifluoromethyl-2'-deoxyuridine (CF3dUrd) were effectively antagonized by 5'-amino-5'-deoxythymidine (5'-AdThd). The antiproliferative actions of CF3dUrd were reduced in a dose-dependent manner by 5'-AdThd in both HeLa and Vero cells. In addition, the ability of CF3dUrd to kill HeLa cells (95% at 1 microM and 99% at 3 microM), as measured by cloning efficiency, was ablated entirely by 5'-AdThd (300 microM). In contrast, the inhibition of herpes simplex virus Type 2 (HSV-2) replication in HeLa cells was not antagonized by 5'-AdThd. In Vero cells, the combination of CF3dUrd and 5'-AdThd produced a greater antiviral effect than either agent alone. The reduction in CF3dUrd cytotoxicity caused by 5'-AdThd in uninfected HeLa and Vero cells was associated with decreased intracellular levels of CF3dUrd nucleotides. In contrast, in HSV-2-infected Vero cells the intracellular levels of CF3dUrd nucleotides were slightly elevated by 5'-AdThd and, in virally infected HeLa cells, a 300-fold excess of 5'-AdThd reduced CF3dUrd uptake only marginally. Since the relative abundance of these phosphorylated derivatives of CF3dUrd was not markedly changed by 5'-AdThd, preferential inhibition of the mammalian thymidine kinase (EC 18.104.22.168) was suggested. Using CF3dUrd as the substrate, the ability of 5'-AdThd to inhibit thymidine kinase activity in extracts prepared from parallel cultures of mock-infected or HSV-2 infected HeLa cells was compared. CF3dUrd was phosphorylated to a lesser extent and the reaction was more potently inhibited by 5'-AdThd in the extracts prepared from the uninfected cells. The HeLa cell and HSV-2 thymidine kinases were purified by affinity column chromatography, and kinetic analyses were then done. Using CF3dUrd as the variable substrate, the Ki values for 5'-AdThd were 2.2 microM for the HeLa enzyme and 36 microM for the viral enzyme. Km values for CF3dUrd were 2.6 microM and 4 microM for the viral and mammalian enzymes, respectively. These data account for the ability of 5'-AdThd to inhibit preferentially the phosphorylation of CF3dUrd in uninfected host cells. The presence of 5'-AdThd substantially increased the therapeutic index of CF3dUrd, indicating that this drug combination, an example of specific inhibition, warrants investigation in vivo.


Long-range surface plasmon polariton mode cutoff and radiation in slab waveguides.
The normal-mode-analysis method is used to model the radiative spreading of long-range surface plasmon polariton modes injected into regions where the bound surface mode is cutoff or radiative. Mode cutoff is induced by an asymmetry between the index of refraction of the top cladding layer and that of the bottom. The analysis was performed at lambda(0)=1.55 microm for infinite-width (slab) metal waveguides where the metal was Au and the bounding dielectrics were SiO(2). Results show that a change in insertion loss of > 20 dB is possible for an appropriate waveguide geometry and dielectric asymmetry.


Intramammary pressure and udder firmness during a 72-h interruption of milking to simulate dry-off, with and without feed restriction.
The goal of the present study was to quantify the increase of intramammary pressure (IMP) in dry-off during an extended milking interval of 72 h. In particular, we tested the hypothesis that feed restriction (no concentrate and roughage with reduced energy) causes earlier cessation of milk secretion and a lower IMP than continued feeding of the lactational diet. In addition to repeated IMP measurements, we tested a noninvasive method that records udder firmness (UF) via external application of pressure on the udder. Two experimental groups consisted of 10 Holstein cows each, with a daily milk yield of 20 to 25 kg. The restricted group (RG) was changed to restricted feeding on the afternoon of the final milking (0 h), whereas late-lactation feeding was continued in the control group (CG). Both IMP and UF were measured before and after the final milking immediately before milking was stopped for 72 h. These measurements represented IMP and UF levels at 10 h and 0 h milking intervals, respectively. Further measurements were performed at 18, 24, 30, 36, 42, 48, and 72 h after final milking. Milk samples (2 mL) were taken through the IMP catheter at each sampling event, for analysis of somatic cell count (SCC) and serum albumin (SA). Both IMP and UF increased with time, and both parameters peaked at 30 h in CG and at 24 h in RG. The mean IMP from 18 to 72 h, compared with the 10-h IMP (normal milking interval) was higher in CG than in RG. The duration of elevated IMP and UF was prolonged in CG compared with RG (>36 h vs. 12 h). The Pearson correlation between IMP and UF was r = 0.67. Thus, the noninvasive measurement of UF is suitable to replace invasive IMP measurements. However, due to individual differences in udder shape, the correlation between UF and IMP was too low to predict exact IMP levels using UF. Both SCC (presented as logSCC) and SA increased after the final milking until the end of the experiment. The mean increase from 18 to 72 h, compared with levels immediately after final milking, was higher in CG than in RG for SCC but did not differ between treatments for SA. In conclusion, feed restriction causes a faster cessation of milk secretion and therefore limits the increase of IMP at dry-off.


[Diagnosis and treatment of acute intestinal obstruction in cancer of the large intestine].
A complex program of treatment of acute intestinal obstruction in carcinoma of the large bowel has been developed on the basis of an analysis of 71 patients. Urgent operations were performed in 70% of the patients with acute intestinal obstruction after a short preoperative preparing. Due to substantial metabolic and immunologic shifts the complex parenteral immunostimulating therapeutic measures are necessary in the postoperative period for all the patients.


Meta-analysis of cardiovascular superiority trials published in the New England Journal of Medicine to elucidate the concept of superiority margin.
To show that overpowered trials claim statistical significance detouring clinical relevance and warrant the need of superiority margin to avoid such misinterpretation. Selective review of articles published in the New England Journal of Medicine between 1 January 2015 and 31 December 2018 and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Published superiority trials evaluating cardiovascular diseases and diabetes mellitus with positive efficacy outcome were eligible. Fixed effects meta-analysis was performed using RevMan V.5.3 to calculate overall effect estimate, pooled HR and it was compared with mean clinically significant difference. Thirteen eligible trials with 164 721 participants provided the quantitative data for this review. Largely, the primary efficacy endpoint in these trials was the composite of cardiovascular death, non-fatal myocardial infarction, unstable angina requiring rehospitalisation, coronary revascularisation and fatal or non-fatal stroke. The pooled HR was 0.86 (95% CI 0.84 to 0.89, I2=45%) which was lower than the mean clinically significant difference of 0.196 (19.6%, range: 0.09375-0.35) of these studies. There was a wide 95% CI in these studies from 0.56 to 0.99. The upper margin of CI in most of the studies was close to the line of no difference. Absolute risk reduction was small (1.19% to 2.3%) translating to a high median number needed to treat of 63 (range: 43 to 84) over a follow-up duration of 2.95 years. The results of this meta-analysis indicate that overpowered trials give statistically significant results undermining clinical relevance. To avoid such misuse of current statistical tools, there is a need to derive superiority margin. We hope to generate debate on considering clinically significant difference, used to calculate sample size, as superiority margin.


Diagnostic Accuracy of Capillary Blood Glucometer Testing for Gestational Diabetes.
Few pregnant women in low-resource settings are screened for gestational diabetes mellitus (GDM) using the gold standard oral glucose tolerance test (OGTT). This study compared capillary blood glucose testing with 2-h plasma glucose measurements obtained using the 75-g OGTT to screen for GDM at primary healthcare clinics in Mexico. Pregnant women who participated in a previous prospective multicenter longitudinal cohort study and who had not been previously diagnosed with diabetes were included. Participants were evaluated using the plasmatic 2-h 75-g OGTT with simultaneous capillary blood glucose measurements using a glucometer. The study endpoint was the comparability of the glucometer results to the gold standard OGTT when collected simultaneously. Sensitivity, specificity, and area under the curve of the glucose measurements obtained for capillary blood compared with venous plasma (gold standard) were calculated to determine diagnostic accuracy. The study included 947 pregnant women who had simultaneous glucose measurements available (blood capillary [glucometer] and venous blood OGTT). Overall, capillary blood glucose testing was very sensitive (89.47%); the specificity was 66.58% and the area under the curve (95% confidence interval) was 0.78 (0.74-0.81). The sensitivity, specificity and area under the curve of each capillary measurement were: 89.47%, 66.58% and 0.78 (0.74-0.82) for the fasting measurement, 91.53%, 93.24% and 0.92 (0.88-0.96) for the one-hour measurement, and 89.80%, 93.32%, 0.91 (0.87-0.95) for the second-hour measurement, respectively. No adverse events were reported. Capillary OGTT is a valid alternative to the gold standard OGTT for screening of GDM in low-resource situations or in situations where there are other limitations to performing the OGTT as part of primary healthcare services.


Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.
Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.


A Review of the Use of GPEs in Zinc-Based Batteries. A Step Closer to Wearable Electronic Gadgets and Smart Textiles.
With the flourish of flexible and wearable electronics gadgets, the need for flexible power sources has become essential. The growth of this increasingly diverse range of devices boosted the necessity to develop materials for such flexible power sources such as secondary batteries, fuel cells, supercapacitors, sensors, dye-sensitized solar cells, etc. In that context, comprehensives studies on flexible conversion and energy storage devices have been released for other technologies such Li-ion standing out the importance of the research done lately in GPEs (gel polymer electrolytes) for energy conversion and storage. However, flexible zinc batteries have not received the attention they deserve within the flexible batteries field, which are destined to be one of the high rank players in the wearable devices future market. This review presents an extensive overview of the most notable or prominent gel polymeric materials, including biobased polymers, and zinc chemistries as well as its practical or functional implementation in flexible wearable devices. The ultimate aim is to highlight zinc-based batteries as power sources to fill a segment of the world flexible batteries future market.


Liver transplantation and autoimmune hepatitis.
Liver Transplantation (LT) is an effective treatment for patients with end-stage liver disease including autoimmune hepatitis (AIH). Indication for LT for AIH does not differ basically from other liver diseases including both acute and chronic types of disease progression, although it is reported to be an infrequent indication for LT worldwide due to the therapeutic advances of immunosuppression. The outcome following LT is feasible, with current patient and graft survival exceeding 75% at 5 years. Recurrent and de-novo AIH posttranslant has also been reported; and this seems to have important clinical implications because its management differs from the standard treatment for allograft rejection. In this review, we discuss the characteristics of AIH, focusing on the indication for LT and issues raised following LT.


Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury.
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.


Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention.
Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI).


Functional evaluation of an artificial anal sphincter using shape memory alloys.
This article describes an implantable artificial anal sphincter using shape memory alloys and its in vivo assessment in porcine models. The new design was developed as a low invasive prosthesis with a simple structure to solve the problem of severe fecal incontinence in patients with hypoplastic sphincters or without anal sphincters and especially for ostomates. The artificial anal sphincter consists of two shape memory alloy (SMA) plates as the main functional parts to perform two basic functions when the SMA artificial sphincter is fitted around intestines (i.e., an occlusion at body temperature and an opening function on heating). Our previous assessments with short-term animal experiments revealed promising properties with the occlusion function of the device, although some complications, such as overpressure induced ischemia, heat burn, and infections, remained. This article addresses the concerns related to the practical use of the device, the power supplement to drive the actuator, and overheating protection of the device inside bodies. Results of chronic animal experiments of up to 4 weeks suggested great potential for the improved device.


Program-specific reports: implications and impact on program behavior.
Measuring and monitoring transplant center performance is vital to ongoing quality assessment and performance improvement initiatives geared toward ensuring optimal care for patients with end-stage organ failure. The impact of regulatory oversight on transplant center behavior and programmatic decision-making is complex. Program-specific reports (PSRs) are published by the Scientific Registry for Transplant Recipients (SRTR) and are publically available for use by a variety of stakeholders, including patients, regulators, insurers, and care providers. PSRs have been both groundbreaking and controversial. The principal areas of concern relate to potential unintended consequences of PSRs, limitations in both the data collected by the registry and the currently used statistical methodology employed by the SRTR for risk adjustment, and the subsequent impact on transplant program behavior. PSRs, which serve the purposes of fueling ongoing performance improvement initiatives and informing consumers and payers by fostering transparency in the communication of risk, also involve trade-offs because of their unintended use for regulatory oversight and subsequent impact on transplant center behavior. Future research is necessary to improve data integrity and risk-adjustment methodologies which will enhance regulation and preserve access to transplantation among vulnerable patient populations.


Y14 governs p53 expression and modulates DNA damage sensitivity.
Y14 is a core component of the exon junction complex (EJC), while it also exerts cellular functions independent of the EJC. Depletion of Y14 causes G2/M arrest, DNA damage and apoptosis. Here we show that knockdown of Y14 induces the expression of an alternative spliced isoform of p53, namely p53β, in human cells. Y14, in the context of the EJC, inhibited aberrant exon inclusion during the splicing of p53 pre-mRNA, and thus prevent p53β expression. The anti-cancer agent camptothecin specifically suppressed p53β induction. Intriguingly, both depletion and overexpression of Y14 increased overall p53 protein levels, suggesting that Y14 governs the quality and quantity control of p53. Moreover, Y14 depletion unexpectedly reduced p21 protein levels, which in conjunction with aberrant p53 expression accordingly increased cell sensitivity to genotoxic agents. This study establishes a direct link between Y14 and p53 expression and suggests a function for Y14 in DNA damage signaling.


A novel porcine model for chemically inducible Crohn's-like reaction.
New animal models provide insights into the pathogenesis of different types of inflammatory bowel disease as well as novel pathways for new therapeutic options. However, the scarcity of large animal models hinders the research and development of new surgical procedures and technological devices in inflammatory bowel disease surgery. Common small animal inducible models involve chemical agents that result in the development of acute intestinal inflammation. To assess a novel method for the induction of Crohn's-like colitis using intramural injection of sclerosants in a porcine model. Seven domestic pigs underwent several experimental protocols to assess the efficacy of intramural colonic injections of two different compounds (lauromacrogol, and phenol in almond oil).Twenty-five different large bowel segments were treated with intramural injections of the compounds. The animals were followed for 6 weeks, and treated colonic segments were resected for histopathological examination. Intramural injection of lauromacrogol resulted in non-specific, mild reactive foreign body changes only. Injection of various dosages of 5% phenol in almond oil caused a range of histopathological changes varying from focal fibrosis to Crohn's-like reactions com rising acute and chronic infiltrates, mucosal ulceration and focal necrosis with enteric and lymphoid non-caseating granulomas. Intramural colonic phenol in almond oil injection in pigs induces inflammatory reactions that histologically resemble Crohn's disease in humans.


A correlation analysis between pulse transit time and instantaneous blood pressure measured indirectly by the vascular unloading method.
Linear correlation coefficients (r) between pulse transit time (PTT) and blood pressure (BP) were evaluated on within-subject by within-condition level. Beat-to-beat systolic and diastolic BP was measured noninvasively using the vascular unloading technique (Yamakoshi, Shimazu and Togawa, 1980). PTT was determined from the time interval between the R-wave of ECG and the peak of the finger pulse wave. Five male subjects underwent a 2 min resting (RE), a 1 min cold pressor test (CP), eight 15 sec anagram tests (AN), and another 1 min CP. Significant r values were most frequently obtained for systolic BP and PTT in the RE condition. Under the CP or AN conditions, no consistent tendencies were observed. It was suggested that none of the r values are sufficiently high to warrant the use of PTT as an alternative index of BP. Some factors lowering the r values were discussed.


Cardiovascular changes in sepsis.
The hyperdynamic circulation characteristic of severe sepsis is not likely due to peripheral arteriovenous shunts since in skeletal muscle, at least, capillary blood flow is increased and varies directly with cardiac index. The finding that flow is normal in some septic patients who are severely ill and close to death suggests that blood flow can no longer be considered the critical factor explaining the death of the septic patient. Clearly, the commonly accepted sequence of low blood flow, tissue hypoxia, lactacidosis, and death does not apply to all patients dying from shock. The hyperdynamic circulatory state and the metabolic changes associated with severe sepsis may be related. Skeletal muscle capillary blood flow was increased in fasting normal subjects and septic postoperative patients, both of whom were catabolic. Therefore, elevated blood flow, which is characteristic of severe sepsis, may be a response to the catabolism of body protein required for energy production. If this concept of sepsis is accepted, it follows that treatment which heretofore has been aimed at increasing blood flow and blood pressure should be redirected to therapy which provides energy substrates and alters hormonal patterns to favor anabolism.


Model Microbial Consortia as Tools for Understanding Complex Microbial Communities.
A major biological challenge in the postgenomic era has been untangling the composition and functions of microbes that inhabit complex communities or microbiomes. Multi-omics and modern bioinformatics have provided the tools to assay molecules across different cellular and community scales; however, mechanistic knowledge over microbial interactions often remains elusive. This is due to the immense diversity and the essentially undiminished volume of not-yet-cultured microbes. Simplified model communities hold some promise in enabling researchers to manage complexity so that they can mechanistically understand the emergent properties of microbial community interactions. In this review, we surveyed several approaches that have effectively used tractable model consortia to elucidate the complex behavior of microbial communities. We go further to provide some perspectives on the limitations and new opportunities with these approaches and highlight where these efforts are likely to lead as advances are made in molecular ecology and systems biology.


HEV seroprevalence in blood donors in Turkey by two commercial total anti-HEV Ab ELISA kits.
Previous hepatitis E virus (HEV) seroprevalence studies in Turkey have shown high variabilities, leading to conflicting results. We aimed to re-evaluate HEV seroprevalence among blood donors in Turkey using the Wantai (Beijing, China) and the Dia.Pro (Milan, Italy) total anti-HEV antibody (Ab) enzyme-linked immunosorbent assay (ELISA) kits and compare their performances and to investigate the presence of HEV RNA in blood donors. Serum total anti-HEV antibodies were determined in a total of 2011 volunteer blood donor samples collected from different regions of Turkey (807 from Ankara, 243 from Kayseri, 284 from İzmir, 200 from Malatya, 200 from Kahramanmaraş, and 277 from Van). HEV RNA was evaluated by a real-time polymerase chain reaction in a total of 272 anti-HEV seropositive samples. The country-wide HEV seroprevalence was calculated as 11.5% (Dia.Pro) and 12.2% (Wantai) with seropositivity rates of 12.0%-12.5% in Ankara, 7.4%-8.2% in Kayseri, 14.5%-15.5% in Malatya, 8.1%-8.8% in İzmir, 15.0%-16.0% in Kahramanmaraş, and 12.6%-13.4% in Van by Dia.Pro and Wantai kits, respectively. The lowest detectable Ab concentrations were 0.16 and 0.14 units/mL WHO, for the Dia.Pro and the Wantai assays, respectively, showing no significant difference between assays. HEV RNA was not detected in any of the anti-HEV seropositive samples. Compared with previous studies, HEV was shown to have a higher overall seroprevalence in Turkey. Despite its limitation, the current study represents the most comprehensive HEV seroprevalence study in Turkey performed with two different commercial ELISA assays with high sensitivities so far. Further investigation is required to determine HEV genotypes in Turkey.


Clinical significance of delta neutrophil index in the differential diagnosis between septic arthritis and acute gout attack within 24 hours after hospitalization.
The most important differential diagnoses of acute monoarticular arthritis are septic arthritis and acute gout attack. Identifying infection is crucial in preventing the devastating outcome of septic arthritis. The delta neutrophil index (DNI) is a value that corresponds to the fraction of circulating immature granulocytes. As DNI reflects the burden of infection, we evaluated this index as a differentiating marker between septic arthritis and acute gout attack.The medical records of 149 patients with septic arthritis and 194 patients with acute gout attack were reviewed. A specific cell analyzer, ADVIA 2120, was used to measure DNI. Clinical and laboratory markers associated with predicting septic arthritis were assessed by using logistic regression.Patients with septic arthritis showed higher levels of DNI than those with acute gout attack (3.3 vs 0.6%, P < .001). Similar results were observed in patients without monosodium urate (MSU) crystal confirmation or those with normouricemia (3.3 vs 0.5 and 3.1 vs 0.7%, respectively; P < .001 for both). A DNI level of 1.9% was determined as the cutoff value for predicting septic arthritis. In the multivariate analysis, DNI was the most powerful independent value for predicting septic arthritis (odds ratio 14.003).This study showed the possibility of using DNI as a differentiating marker between septic arthritis and acute gout attack at the crucial early phase. DNI showed its relevance regardless of confirmation of MSU crystal deposition or serum level of uric acid.


The Effect of Exercise Training Intensity on Quality of Life in Heart Failure Patients: A Systematic Review and Meta-Analysis.
To establish if exercise training intensity produces different effect sizes for quality of life in heart failure. Exercise intensity is the primary stimulus for physical and mental adaptation. We conducted a MEDLINE search (1985 to February 2016) for exercise-based rehabilitation trials in heart failure using the search terms 'exercise training', 'left ventricular dysfunction', 'peak VO2', 'cardiomyopathy', and 'systolic heart dysfunction'. Twenty-five studies were included; 4 (16%) comprised high-, 10 (40%) vigorous-, 9 (36%) moderate- and 0 (0%) low-intensity groups; two studies were unclassified. The 25 studies provided a total of 2,385 participants, 1,223 exercising and 1,162 controls (36,056 patient-hours of training). Analyses reported significant improvement in total Minnesota living with heart failure (MLWHF) total score [mean difference (MD) -8.24, 95% CI -11.55 to -4.92, p < 0.00001]. Physical MLWHF scorewas significantly improved in all studies (MD -2.89, 95% CI -4.27 to -1.50, p < 0.00001). MLWHF total score was significantly reduced after high- (MD -13.74, 95% CI -21.34 to -6.14, p = 0.0004) and vigorous-intensity training (MD -8.56, 95% CI -12.77 to -4.35, p < 0.0001) but not moderate-intensity training. A significant improvement in the total MLWHF score was seen after aerobic training (MD -3.87, 95% CI -6.97 to -0.78, p = 0.01), and combined aerobic and resistance training (MD -9.82, 95% CI -15.71 to -3.92, p = 0.001), but not resistance training. As exercise training intensity rises, so may the magnitude of improvement in quality of life in exercising patients. Aerobic-only or combined aerobic and resistance training may offer the greatest improvements in quality of life.


Evaluation of uniform crt display scales with visual threshold data.
Luminance, chromatic, and color visual threshold contrast data are found along the heated object scale at two mean luminance levels using a high resolution graphics monitor. Data from ideal stimulus characteristics (no or little noise and sharp contrast edges) and test stimulus sizes of 1.00( degrees ), 0.50( degrees ), and 0.25( degrees ) were obtained along with data for linearly stepwise blurred contrast edge stimuli in a noise pattern with test stimulus sizes of 0.50( degrees ) and 0.25( degrees ). All data were collected using an adaptive staircase with a spatial two alternative forced choice paradigm. The results suggest that uniform CRT display scales that have been perceptually optimized for ideal viewing conditions will remain uniform even though the contrast step sizes of the display scale will no longer be perceptually optimized in nonideal viewing conditions.


Increasing process understanding by analyzing complex interactions in experimental data.
There is a recognized need for new approaches to understand unit operations with pharmaceutical relevance. A method for analyzing complex interactions in experimental data is introduced. Higher-order interactions do exist between process parameters, which complicate the interpretation of experimental results. In this study, experiments based on mixed factorial design of coating process were performed. Drug release was analyzed by traditional analysis of variance (ANOVA) and generalized multiplicative ANOVA (GEMANOVA). GEMANOVA modeling is introduced in this study as a new tool for increased understanding of a coating process. It was possible to model the response, that is, the amount of drug released, using both mentioned techniques. However, the ANOVA model was difficult to interpret as several interactions between process parameters existed. In contrast to ANOVA, GEMANOVA is especially suited for modeling complex interactions and making easily understandable models of these. GEMANOVA modeling allowed a simple visualization of the entire experimental space. Furthermore, information was obtained on how relative changes in the settings of process parameters influence the film quality and thereby drug release.


ALDH1 is an immunohistochemical diagnostic marker for solitary fibrous tumours and haemangiopericytomas of the meninges emerging from gene profiling study.
Solitary Fibrous Tumours (SFT) and haemangiopericytomas (HPC) are rare meningeal tumours that have to be distinguished from meningiomas and more rarely from synovial sarcomas. We recently found that ALDH1A1 was overexpressed in SFT and HPC as compared to soft tissue sarcomas. Using whole-genome DNA microarrays, we defined the gene expression profiles of 16 SFT/HPC (9 HPC and 7 SFT). Expression profiles were compared to publicly available expression profiles of additional SFT or HPC, meningiomas and synovial sarcomas. We also performed an immunohistochemical (IHC) study with anti-ALDH1 and anti-CD34 antibodies on Tissue Micro-Arrays including 38 SFT (25 meningeal and 13 extrameningeal), 55 meningeal haemangiopericytomas (24 grade II, 31 grade III), 163 meningiomas (86 grade I, 62 grade II, 15 grade III) and 98 genetically confirmed synovial sarcomas. ALDH1A1 gene was overexpressed in SFT/HPC, as compared to meningiomas and synovial sarcomas. These findings were confirmed at the protein level. 84% of the SFT and 85.4% of the HPC were positive with anti-ALDH1 antibody, while only 7.1% of synovial sarcomas and 1.2% of meningiomas showed consistent expression. Positivity was usually more diffuse in SFT/HPC compared to other tumours with more than 50% of tumour cells immunostained in 32% of SFT and 50.8% of HPC. ALDH1 was a sensitive and specific marker for the diagnosis of SFT (SE = 84%, SP = 98.8%) and HPC (SE = 84.5%, SP = 98.7%) of the meninges. In association with CD34, ALDH1 expression had a specificity and positive predictive value of 100%. We show that ALDH1, a stem cell marker, is an accurate diagnostic marker for SFT and HPC, which improves the diagnostic value of CD34. ALDH1 could also be a new therapeutic target for these tumours which are not sensitive to conventional chemotherapy.


Contribution of oxygen to attenuation in the solar blind UV spectral region.
The solar blind ultraviolet (SBUV) spectral region covers the interval between 230 and 290 nm. The lower limit of this interval is given by the edge of the Schumann-Runge band and the upper limit is determined by solar radiation penetrating the stratospheric ozone shield. The SBUV region is interesting from the experimental point of view, since the lack of solar background is favorable in such applications as lidar, atmospheric communications, and remote sensing. The present models (LOWTRAN-6) include as atmospheric attenuators in this region ozone absorption and aerosol and molecular scattering. New theoretical calculations of the Herzberg I oxygen band predict significant absorption by O(2). This prediction is confirmed experimentally in this study. Field measurements at 252, 255, and 264 nm are reported over optical paths of up to 2750 m. Results show that LOWTRAN-6 is inadequate in the SBUV region, as indicated by the present extinction measurements.


Which type of valve should we use in tricuspid position? Long-term comparison between mechanical and biological valves.
Nowadays, tricuspid valve replacement (TVR) is much less common than aortic or mitral valve replacement, since repair is almost always preferable. Prosthetic tricuspid valves are associated with high mortality and morbidity, mostly due to thrombotic or hemorrhagic events. Nevertheless, there is lack of evidence of which is the optimal type of valve (biological versus mechanical) in tricuspid position. We analyzed all the patients who underwent TVR in our Institution, from 2005 to 2015. Patient baseline characteristics were recorded (such as functional class, previous cardiac surgery, right ventricular dysfunction or pulmonary hypertension), and a clinical long-term follow-up was conducted. We compared the outcomes between mechanical and biological prostheses: in-hospital mortality, long-term mortality, need for reintervention and adverse events (such as stroke or valve thrombosis). During the study period 120 tricuspid prosthetic valves were implanted in 111 patients. 81 of them (67.5%) were bioprostheses, and 39 (32.5%) mechanical valves. 73 patients (60.8%) had undergone a previous cardiac surgery (28.4% had previous tricuspid surgery). Most of the patients (87.1%) were in high functional class (grade III-IV of the NYHA classification), and 85% had moderate to severe pulmonary hypertension. Mean logistic EuroSCORE I was 14.80%. Only 37 cases were isolated TVR (30.6%), as most of the cases were TVR concomitant to mitral valve replacement. In-hospital mortality was 21.7%, and during the follow-up (mean follow-up of 7 years) reached 37.5%. Three mechanical tricuspid valves (7.7%) had to be replaced due to thrombosis, while 7 biological valves (8.6%) had to be replaced due to valve deterioration. The incidence of stroke was 7.5%. Tricuspid valve replacement is an infrequent procedure with a high incidence of perioperative morbidity and mortality. Biological or mechanical valves have similar mortality, and a reasonably low incidence of need for reintervention due to thrombosis or valve deterioration.


Decrease in CD14++CD16+ Monocytes in Low-Immunological-Risk Kidney Transplant Patients with Subclinical Borderline Inflammation.
We determined the association between CD14++CD16+ monocytes and subclinical infiltrates that do not reach the histological threshold for rejection (≥Banff IA). We studied low-immunological-risk kidney-transplant recipients in a clinical trial (NCT02284464; EudraCT 2012-003298-24) whose protocol biopsy in the third month showed no significant changes or borderline lesions (BL). Flow cytometry was used to analyze the percentage of CD14++CD16+ monocytes in peripheral blood (PB) and blood from a fine-needle-aspiration biopsy (FNAB). A protocol biopsy was performed in 81 low-immunological-risk patients, of whom 15 were excluded (BK polyomavirus and rejection). The 28 (42.4%) with borderline lesions had significantly low levels of CD14++CD16+ in PB compared to patients with normal biopsies (7.9 ± 5.4 vs. 13.0 ± 12.8; p = 0.047). Patients without significant changes had similar percentages of CD14++CD16+ monocytes in the graft blood (GB) and FNAB blood. The percentage of these monocytes in the patients with an interstitial infiltrate, however, increased significantly in the FNAB blood compared to the GB: 16.9 ± 16.6 vs. 7.9 ± 5.4; p = 0.006. A difference of 50% in CD14++CD16+ in the GB versus the PB was a significant risk factor (p = 0.002) for BL, increasing the risk seven times. A decrease in CD14++CD16+ in the PB could be associated with the recruitment of these cells to the graft tissue in cases of subclinical BL inflammatory infiltrates below the threshold for rejection.


Using a Fluorescent PCR-capillary Gel Electrophoresis Technique to Genotype CRISPR/Cas9-mediated Knockout Mutants in a High-throughput Format.
The development of programmable genome-editing tools has facilitated the use of reverse genetics to understand the roles specific genomic sequences play in the functioning of cells and whole organisms. This cause has been tremendously aided by the recent introduction of the CRISPR/Cas9 system-a versatile tool that allows researchers to manipulate the genome and transcriptome in order to, among other things, knock out, knock down, or knock in genes in a targeted manner. For the purpose of knocking out a gene, CRISPR/Cas9-mediated double-strand breaks recruit the non-homologous end-joining DNA repair pathway to introduce the frameshift-causing insertion or deletion of nucleotides at the break site. However, an individual guide RNA may cause undesirable off-target effects, and to rule these out, the use of multiple guide RNAs is necessary. This multiplicity of targets also means that a high-volume screening of clones is required, which in turn begs the use of an efficient high-throughput technique to genotype the knockout clones. Current genotyping techniques either suffer from inherent limitations or incur high cost, hence rendering them unsuitable for high-throughput purposes. Here, we detail the protocol for using fluorescent PCR, which uses genomic DNA from crude cell lysate as a template, and then resolving the PCR fragments via capillary gel electrophoresis. This technique is accurate enough to differentiate one base-pair difference between fragments and hence is adequate in indicating the presence or absence of a frameshift in the coding sequence of the targeted gene. This precise knowledge effectively precludes the need for a confirmatory sequencing step and allows users to save time and cost in the process. Moreover, this technique has proven to be versatile in genotyping various mammalian cells of various tissue origins targeted by guide RNAs against numerous genes, as shown here and elsewhere.


Chemical substances and their activities in sea cucumber Apostichopus japonicus: A review.
Apostichopus japonicus, also known as Stichopus japonicus, with medicinal and food homologous figures, is a globally recognized precious ingredient with extremely high nutritional value. There is no relevant review available through literature search, so this article selects the research articles through the keywords "sea cucumber" and "Apostichopus japonicus (Stichopus japonicus)" in six professional databases, such as Wiley, PubMed, ScienceDirect, ACS, Springer, and Web of Science, from 2000 to the present, summarizing the extraction, isolation, and purification methods for the four major categories (polysaccharides, proteins and peptides, saponins, and other components) of the A. japonicus chemical substances and 10 effective biological activities of A. japonicus. Included are anticoagulation, anticancer/antitumor activities, hematopoiesis, regulation of gut microbiota, and immune regulatory activities that correspond to traditional efficacy. Literature support is provided for the development of medicines and functional foods and related aspects that play a leading role in future directions.


10-GHz clock differential phase shift quantum key distribution experiment.
This paper reports the first quantum key distribution experiment implemented with a 10-GHz clock frequency. We used a 10-GHz actively mode-locked fiber laser as a source of short coherent pulses and single photon detectors based on frequency up-conversion in periodically poled lithium niobate waveguides. The use of short pulses and low-jitter upconversion detectors significantly reduced the bit errors caused by detector dark counts even after long-distance transmission of a weak coherent state pulse. We employed the differential phase shift quantum key distribution protocol, and generated sifted keys at a rate of 3.7 kbit/s over a 105 km fiber with a bit error rate of 9.7%.


Pantoea alhagi, a novel endophytic bacterium with ability to improve growth and drought tolerance in wheat.
A novel strain LTYR-11ZT that exhibited multiple plant growth promoting (PGP) traits was isolated from the surface-sterilized leaves of Alhagi sparsifolia Shap. (Leguminosae), which reprsents one of the top drought tolerant plants in north-west China. Phylogenetic analysis of 16S rRNA gene sequences and multilocus sequence analysis based on partial sequences of atpD, gyrB, infB and rpoB genes revealed that strain LTYR-11ZT was a member of the genus Pantoea, with Pantoea theicola NBRC 110557T and Pantoea intestinalis DSM 28113T as the closest phylogenetic relatives. The results of DNA-DNA hybridization, phenotypic tests and fatty acid analysis confirmed that strain LTYR-11ZT represents a novel species of the genus Pantoea, for which we propose the name Pantoea alhagi sp. nov. Confocal microscopy observation revealed that strain LTYR-11ZT effectively colonizes the rhizoplane of both Arabidopsis and wheat. Strain LTYR-11ZT was able to promote the growth of wheat enhancing its resistance to drought stress. Strain LTYR-11ZT led to increased accumulation of soluble sugars, decreased accumulation of proline and malondialdehyde (MDA), and decreased degradation of chlorophyll in leaves of drought-stressed wheat. Our findings will contribute to the development of a novel biotechnological agent to improve the adaptation of crop plants to drought in arid ecosystems.


Conjugate of Thiol and Guanidyl Units with Oligoethylene Glycol Linkage for Manipulation of Oxidative Protein Folding.
Oxidative protein folding is a biological process to obtain a native conformation of a protein through disulfide-bond formation between cysteine residues. In a cell, disulfide-catalysts such as protein disulfide isomerase promote the oxidative protein folding. Inspired by the active sites of the disulfide-catalysts, synthetic redox-active thiol compounds have been developed, which have shown significant promotion of the folding processes. In our previous study, coupling effects of a thiol group and guanidyl unit on the folding promotion were reported. Herein, we investigated the influences of a spacer between the thiol group and guanidyl unit. A conjugate between thiol and guanidyl units with a diethylene glycol spacer (GdnDEG-SH) showed lower folding promotion effect compared to the thiol-guanidyl conjugate without the spacer (GdnSH). Lower acidity and a more reductive property of the thiol group of GdnDEG-SH compared to those of GdnSH likely resulted in the reduced efficiency of the folding promotion. Thus, the spacer between the thiol and guanidyl groups is critical for the promotion of oxidative protein folding.


An Examination of an Interviewer-Respondent Matching Protocol in a Longitudinal CATI Study.
This article presents results from an experimental study in Germany designed to test the effectiveness of a novel protocol for matching participants in a national panel survey with interviewers employing computer-assisted telephone interviewing (CATI) on selected sociodemographic features, including sex, age, and education. We specifically focus on the ability of the protocol to engender close matches between respondents and interviewers in terms of these features, using both theory and empirical evidence to suggest that this type of matching will improve cooperation rates in surveys employing CATI. We also focus on indicators of "success" at first contact (defined as a successful interview or establishment of an appointment for an interview) as a function of whether the matching protocol was in use on a given day and whether specific types of matches generated higher rates of success overall. We find strong evidence of the protocol effectively establishing close matches, and we also observe that matches based on education proved especially effective for rates of "success" in a panel survey that focused primarily on labor market topics. We conclude with thoughts on practical implementation of this approach in other settings and suggested directions for future work in this area.


Isolation and Characterization of a Chinese Hamster Ovary Heparan Sulfate Cell Mutant Defective in Both Met Receptor Binding and Hepatocyte Growth Factor NK1/Met Signaling.
The up-regulation of hepatocyte growth factor/receptor, HGF/Met, signal transduction is observed in most of human cancers. Specific heparan sulfate structures enhance the HGF/Met signaling at both cell and animal-based model systems. Biochemical studies indicate that heparan sulfate interacts with HGF and a natural occurring splicing variant NK1 of HGF with similar affinity. However, it is currently unknown if cell surface heparan sulfate binds to Met at physiological conditions and if specific cell surface heparan sulfate structures are required for effective HGF/Met or NK1/Met signaling. An established flow sorting strategy was used to isolate a soluble Met recombinant protein-binding positive or negative CHO cell clones different only in specific heparan sulfate structures. The cell surface bindings were imaged by confocal microscopy and flow cytometry analysis. Glucosamine vs. galactosamine contents from media-, cell surface-, and cell association glycosaminoglycans were quantified by HPLC. 35S-sulfate labeled glycosaminoglycans were characterized by anion exchange and size-exclusion HPLC. Heparan sulfate disaccharide compositions were determined by HPLC-MS analysis. Western blot analyses of MAPK-p42/44 were used to monitor HGF- and NK1-facillated Met signaling. CHO-Positive but not CHO-Negative cell surface heparan sulfate bound to Met recombinant protein and HGF/NK1 further promoted the binding. Overall glycosaminoglycan analysis results indicated that the CHO-Negative cells had reduced amount of heparan sulfate, shorter chain length, and less 6-O-sulfated disaccharides compared to that of CHO-Positive cells. Moreover, CHO-Negative cells were defective in NK1/Met but not HGF/Met signaling. This study demonstrated that soluble Met recombinant protein bound to cell surface HS at physiological conditions and a Met /HGF or NK1/HS ternary signaling complex might be involved in Met signaling. Shorter HS chains and reduced 6-O-sulfation might be responsible for reduced Met binding and the diminished NK1-initiated signaling in the CHO-Negative cells. The unique CHO-Positive and CHO-Negative cell clones established in current study should be effective tools for studying the role of specific glycosaminoglycan structures in regulating Met signaling. Such knowledge should be useful in developing glycosaminoglycan-based compounds that target HGF/Met signaling.