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Duodenal Villous Atrophy in a TTG - Negative Patient Taking Olmesartan: A Case Report and Review of the Literature Olmesartan, an angiotensin II receptor antagonist used to treat hypertension, is associated with few adverse effects. Here, a case of severe sprue-like enteropathy and acute kidney injury is described in a 68-year-old male taking olmesartan for 3-4 years. He presented to hospital with a five-week history of diarrhea, vomiting, and a 20 lb weight loss. Anti-TTG was negative with a normal IgA. Biopsies of the distal duodenum and duodenal cap revealed marked blunting of the villi with near complete villous atrophy of the biopsies from the bulb. There was an increase in intraepithelial lymphocytes as well as neutrophils in the surface epithelium. The patient's diarrhea improved upon discontinuation of olmesartan and he returned to his previous weight. Repeat endoscopy four months later demonstrated complete resolution of inflammatory change with normal villous architecture. Long-term olmesartan use is associated with severe sprue-like enteropathy. The mechanism of intestinal injury is unknown. Duodenal biopsy results may mimic other enteropathies such as celiac disease. Physicians should consider medications as potential etiologies of enteropathy.
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Personalized Medicine Approaches in Prostate Cancer Employing Patient Derived 3D Organoids and Humanized Mice Prostate cancer (PCa) is the most common malignancy and the second most common cause of cancer death in Western men. Despite its prevalence, PCa has proven very difficult to propagate in vitro. PCa represents a complex organ-like multicellular structure maintained by the dynamic interaction of tumoral cells with parenchymal stroma, endothelial and immune cells, and components of the extracellular matrix (ECM). The lack of PCa models that recapitulate this intricate system has hampered progress toward understanding disease progression and lackluster therapeutic responses. Tissue slices, monolayer cultures and genetically engineered mouse models (GEMM) fail to mimic the complexities of the PCa microenvironment or reproduce the diverse mechanisms of therapy resistance. Moreover, patient derived xenografts (PDXs) are expensive, time consuming, difficult to establish for prostate cancer, lack immune cell-tumor regulation, and often tumors undergo selective engraftments. Here, we describe an interdisciplinary approach using primary PCa and tumor initiating cells (TICs), three-dimensional (3D) tissue engineering, genetic and morphometric profiling, and humanized mice to generate patient - derived organoids for examining personalized therapeutic responses in vitro and in mice co-engrafted with a human immune system (HIS), employing adaptive T-cell- and chimeric antigen receptor- (CAR) immunotherapy. The development of patient specific therapies targeting the vulnerabilities of cancer, when combined with antiproliferative and immunotherapy approaches could help to achieve the full transformative power of cancer precision medicine.
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Effect of endodontic access cavity preparation on monolithic and ceramic veneered zirconia restorations Due to the high chipping rates observed in veneered zirconia ceramic restorations, the use of monolithic zirconia restorations has been recommended. This study tried to compare veneered and monolithic zirconia fixed dental prostheses (FDPs) with respect to the amount of damage induced by endodontic access preparation. Monolithic and ceramic veneered (n = 10) three-unit restorations (retainers: first premolar and first molar; pontic: second premolar) were subject to endodontic access cavity preparation in both retainers using a diamond rotary instrument under continuous water cooling. The number of chipping fractures and microfractures detected using the fluorescent penetrant method were recorded. Statistical analysis was based on Wilcoxon rank sum tests with Bonferroni correction (level of significance α = .05). Only one microfracture could be identified in the group of monolithic FDPs while a maximum of seven microfractures and three chipping fractures per retainer crown were recorded in the group of veneered restorations. At the premolar site, the veneered restorations showed significantly more microfractures (P = .0055) and chipping fractures (P = .0008). At the molar site, no significant difference with respect to microfractures could be detected (P = .0767), while significantly more chipping fractures occurred in the veneered samples (P = .0293). Monolithic zirconia restorations seem to be less susceptible to damage when endodontic access cavities have to be prepared as compared to veneered zirconia reconstructions. However, no conclusions can be drawn on the longterm performance of a specific restoration based on this study.
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The relationship between hemorheological parameters and mortality in critically ill patients with and without sepsis The prognostic scoring systems for mortality of intensive care patients estimate clinical outcome using several physiological and biochemical parameters. In altered hemodynamic conditions of critically ill patients, hemorheological variables may play a significant role in appropriate tissue perfusion. We investigated if hemorheological parameters are altered in critical status and if they could be markers of mortality. 112 patients (67.8 ± 12 years, 58 males, 54 females) treated in intensive care unit with different non-surgical diseases were investigated. Routine laboratory parameters and prognostic scores were determined and hemorheological variables (hematocrit, plasma and whole blood viscosity, red blood cell aggregation and deformability) were measured on the 1st and the 2nd day after admission. ICU scores predicted 35.2-41.3% mortality rate, real mortality in intensive care unit was 37.5%, while 30-day mortality was 46.6%. Whole blood viscosity (WBV) and red blood cell (RBC) deformability were lower, red blood cell aggregation was higher in septic than in nonseptic patients (p < 0.05). In septic patients calcium was increased, osmolality was decreased, while in nonseptic patients WBV and RBC aggregation were higher in nonsurvivors compared to survivors (p < 0.05). Worsening of RBC deformability from day 1 to day 2 predicted higher mortality (p < 0.05). Calcium and osmolality level were associated with outcome in sepsis. Whole blood viscosity, red blood cell aggregation and change in red blood cell deformability could predict mortality in nonseptic patients and they may add prognostic information over the ICU scores. Further investigations are needed to evaluate the benefit of our findings in clinical practice.
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Effect of Low - Dose MDCT and Iterative Reconstruction on Trabecular Bone Microstructure Assessment We investigated the effects of low - dose multi detector computed tomography (MDCT) in combination with statistical iterative reconstruction algorithms on trabecular bone microstructure parameters. Twelve donated vertebrae were scanned with the routine radiation exposure used in our department (standard-dose) and a low - dose protocol. Reconstructions were performed with filtered backprojection (FBP) and maximum-likelihood based statistical iterative reconstruction (SIR). Trabecular bone microstructure parameters were assessed and statistically compared for each reconstruction. Moreover, fracture loads of the vertebrae were biomechanically determined and correlated to the assessed microstructure parameters. Trabecular bone microstructure parameters based on low - dose MDCT and SIR significantly correlated with vertebral bone strength. There was no significant difference between microstructure parameters calculated on low - dose SIR and standard - dose FBP images. However, the results revealed a strong dependency on the regularization strength applied during SIR. It was observed that stronger regularization might corrupt the microstructure analysis, because the trabecular structure is a very small detail that might get lost during the regularization process. As a consequence, the introduction of SIR for trabecular bone microstructure analysis requires a specific optimization of the regularization parameters. Moreover, in comparison to other approaches, superior noise - resolution trade-offs can be found with the proposed methods.
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Fine - scale spatial genetic structure of a fungal parasite of coffee scale insects The entomopathogenic fungus Lecanicillium lecanii persists in a highly dynamic network of habitat patches (i.e., a metapopulation) formed by its primary host, the green coffee scale Coccus viridis. Lecanicillium lecanii is an important biological control of both C. viridis and the coffee rust, Hemileia vastatrix. Successfully managing this biocontrol agent will depend on an increased understanding of the characteristics of its dispersal, as migration between occupied and unoccupied patches is essential for the persistence of this metapopulation. In the present study, we employ a population genetics approach, and show that in our study system, a coffee farm in the Soconusco region of southern Mexico, L. lecanii is characterized by clear spatial genetic structure among plots within the farm but a lack of apparent structure at smaller scales. This is consistent with dispersal dominated by highly localized transport, such as by insects or rain splash, and less dependence on longer distance dispersal such as wind transport. The study site was dominated by a few multi-locus microsatellite genotypes, and their identities and large - scale locations persist across both study years, suggesting that local epizootics (outbreaks) are initiated each wet season by residual propagules from the previous wet season, and not by long - distance transport of propagules from other sites. The index of association, a measure of linkage disequilibrium, indicates that epizootics are primarily driven by asexual, clonal reproduction, which is consistent with the apparent lack of a teleomorph in the study site and the presence of only a single mating type across the site (MAT-1-2-1). Although the same predominant clonal genotypes were found across years, a drastic difference in genotypic diversity was witnessed across two sites between the two years, suggesting that interclonal selection was occurring. In light of the dispersal limitation of L. lecanii, spatial structure may be an essential axis of management to ensure the persistence of L. lecanii and preserve the ecosystem services provided by this versatile biocontrol agent in this and similar coffee farms.
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Externally Connected Zirconia Abutments with Standard Platform are Successful Long Term in Anterior Regions Performance of zirconia abutments for implant-supported single-tooth crowns in esthetic areas: a retrospective study up to 12-year follow-up. Passos SP, Linke B, Larjava H, French D. Clin Oral Implants Res 2016;27(1):47-54. Information not available Retrospective cohort study.
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Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of DAMGO, a selective agonist for μ-opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of DAMGO and ACPA in attenuating complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia in the rat hindpaw. DAMGO (1μg-1mg) or ACPA (1μg-2mg) was administered into the inflamed paw when mechanical hyperalgesia was fully developed. When administered individually, DAMGO and ACPA dose -dependently reversed the mechanical hyperalgesia. DAMGO displayed a lower ED50 value (57.4±2.49μg) than ACPA (111.6±2.18μg), but ACPA produced longer lasting antihyperalgesic effects. Combinations of DAMGO and ACPA also dose -dependently attenuated mechanical hyperalgesia, but the antihyperalgesic effects were partial and transient even at high doses. Using isobolographic analysis, we determined that combined treatment with DAMGO and ACPA produced antagonistic effects with the observed ED50 of 128.4±2.28μg. Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together. The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.
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Making use of longitudinal information in pattern recognition Longitudinal designs are widely used in medical studies as a means of observing within- subject changes over time in groups of subjects, thereby aiming to improve sensitivity for detecting disease effects. Paralleling an increased use of such studies in neuroimaging has been the adoption of pattern recognition algorithms for making individualized predictions of disease. However, at present few pattern recognition methods exist to make full use of neuroimaging data that have been collected longitudinally, with most methods relying instead on cross-sectional style analysis. This article presents a principal component analysis -based feature construction method that uses longitudinal high-dimensional data to improve predictive performance of pattern recognition algorithms. The method can be applied to data from a wide range of longitudinal study designs and permits an arbitrary number of time-points per subject. We apply the method to two longitudinal datasets, one containing subjects with mild cognitive impairment along with healthy controls, the other with early dementia subjects and healthy controls. Across both datasets, we show improvements in predictive accuracy relative to cross-sectional classifiers for discriminating disease subjects from healthy controls on the basis of whole- brain structural magnetic resonance image -based voxels. In addition, we can transfer longitudinal information from one set of subjects to make disease predictions in another set of subjects. The proposed method is simple and, as a feature construction method, flexible with respect to the choice of classifier and image registration algorithm. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
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Protective effect of epigallocatechin-3-gallate (EGCG) via Nrf2 pathway against oxalate -induced epithelial mesenchymal transition (EMT) of renal tubular cells This study evaluated effect of oxalate on epithelial mesenchymal transition (EMT) and potential anti-fibrotic property of epigallocatechin-3-gallate (EGCG). MDCK renal tubular cells were incubated with 0.5 mM sodium oxalate for 24-h with/without 1-h pretreatment with 25 μM EGCG. Microscopic examination, immunoblotting and immunofluorescence staining revealed that oxalate -treated cells gained mesenchymal phenotypes by fibroblast -like morphological change and increasing expression of vimentin and fibronectin, while levels of epithelial markers (E-cadherin, occludin, cytokeratin and ZO-1) were decreased. EGCG pretreatment could prevent all these changes and molecular mechanisms underlying the prevention by EGCG were most likely due to reduced production of intracellular ROS through activation of Nrf2 signaling and increased catalase anti-oxidant enzyme. Knockdown of Nrf2 by small interfering RNA (siRNA) abrogated all the effects of EGCG, confirming that the EGCG protection against oxalate -induced EMT was mediated via Nrf2. Taken together, our data indicate that oxalate turned on EMT of renal tubular cells that could be prevented by EGCG via Nrf2 pathway. These findings also shed light onto development of novel therapeutics or preventive strategies of renal fibrosis in the future.
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A review of risk factors for bovine tuberculosis infection in cattle in the UK and Ireland Bovine tuberculosis (bTB) is an important disease of cattle caused by infection with Mycobacterium bovis, a pathogen that may be extremely difficult to eradicate in the presence of a true wildlife reservoir. Our objective was to identify and review relevant literature and provide a succinct summary of current knowledge of risk factors for transmission of infection of cattle. Search strings were developed to identify publications from electronic databases to February 2015. Abstracts of 4255 papers identified were reviewed by three reviewers to determine whether the entire article was likely to contain relevant information. Risk factors could be broadly grouped as follows: animal (including nutrition and genetics), herd (including bTB and testing history), environment, wildlife and social factors. Many risk factors are inter-related and study designs often do not enable differentiation between cause and consequence of infection. Despite differences in study design and location, some risk factors are consistently identified, e.g. herd size, bTB history, presence of infected wildlife, whereas the evidence for others is less consistent and coherent, e.g. nutrition, local cattle movements. We have identified knowledge gaps where further research may result in an improved understanding of bTB transmission dynamics. The application of targeted, multifactorial disease control regimens that address a range of risk factors simultaneously is likely to be a key to effective, evidence -informed control strategies.
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Infectivity, effects on helper viruses and whitefly transmission of the deltasatellites associated with sweepoviruses (genus Begomovirus, family Geminiviridae) Begomoviruses (family Geminiviridae) are whitefly - transmitted viruses with single-stranded DNA genomes that are frequently associated with DNA satellites. These satellites include non-coding satellites, for which the name deltasatellites has been proposed. Although the first deltasatellite was identified in the late 1990s, little is known about the effects they have on infections of their helper begomoviruses. Recently a group of deltasatellites were identified associated with sweepoviruses, a group of phylogenetically distinct begomoviruses that infect plants of the family Convolvulaceae including sweet potato. In this work, the deltasatellites associated with sweepoviruses are shown to be transreplicated and maintained in plants by the virus with which they were identified, sweet potato leaf curl virus (SPLCV). These deltasatellites were shown generally to reduce symptom severity of the virus infection by reducing virus DNA levels. Additionally they were shown to be maintained in plants, and reduce the symptoms induced by two Old World monopartite begomoviruses, tomato yellow leaf curl virus and tomato yellow leaf curl Sardinia virus. Finally one of the satellites was shown to be transmitted plant -to- plant in the presence of SPLCV by the whitefly vector of the virus, Bemisia tabaci, being the first time a deltasatellite has been shown to be insect transmitted.
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Reintervention after endovascular repair for aortic dissection: A systematic review and meta-analysis Thoracic endovascular aortic repair has been chosen as a less-invasive alternative to open surgery for the treatment of aortic dissections; however, the advantages have been challenged by the postoperative reintervention during the follow-up period. This study aimed at evaluating the incidence, reasons, and potential risk factors for reintervention. Studies reporting reintervention after endovascular repair were identified by searching PubMed and Embase in accordance with preferred reporting items for systematic reviews and meta-analyses guidelines, and by reviewing the reference lists of retrieved articles. Sensitivity analysis and subgroup analyses were performed to determine the sources of heterogeneity. Funnel plot and Egger's test were used to determine the publication bias. A total of 27 studies encompassing 2403 patients with aortic dissection were identified. The pooled incidence of reintervention after endovascular repair was 15% (95% confidence interval, 12-19) during 33.7 months of follow-up. The 3 most common reasons for reintervention were endoleak (33.2%), false lumen perfusion and aortic dilation (19.8%), and new dissection (6.9%). The potential factors for reintervention were the mean age of onset and diabetes mellitus determined by performing a single meta-regression analysis (P < .001 and .044, respectively). Current data suggest that the incidence of reintervention after endovascular therapy is relatively high during midterm follow-up. Advanced age of onset is a risk factor and diabetes mellitus is a protective factor of reintervention after endovascular therapy. The possible mechanism that diabetes mellitus protects patients from reintervention should be explored further.
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Optimizing Prone Cardiopulmonary Resuscitation: Identifying the Vertebral Level Correlating With the Largest Left Ventricle Cross-Sectional Area via Computed Tomography Scan Placing the patient in the prone position frequently is required for some surgical procedures. If cardiac arrest occurs and the patient cannot be safely turned supine, cardiopulmonary resuscitation (CPR) may need to be performed with the patient in the prone position. Although clear landmarks have been defined for supine CPR, the optimal hand position for CPR in the prone position has not been clearly determined. The purpose of this study was to determine anatomically the optimal hand position for CPR in the prone position. We reviewed retrospectively the chest computed tomography images of 100 patients taken in the prone position. The vertebral body levels crossing the medial angle of the scapula, the inferior angle of the scapula, and the spinous process of the vertebral body connected to the most inferior rib were identified, and we selected the image level at which the left ventricular (LV) cross-sectional area was the largest. This level was defined as the optimal compression level and correlated to surface anatomical landmarks. We calculated the ratio of the distance from the C7 spinous process to the level of the largest LV cross-sectional area divided by the distance from the C7 spinous process to the spinous process of the vertebral body connected with the most inferior rib. The level of the largest LV cross-sectional area in the prone position was 1 vertebral segment below the inferior angle of the scapula in 45% (99% confidence interval [CI], 33-58) of patients and 0 to 2 vertebral segments below that in 95% (99% CI, 86-98) of patients. The mean (SD) ratio of the distance from the C7 spinous process to the level of the largest LV cross-sectional area divided by the distance from the C7 spinous process to T12 spinous process was 67% ± 7% (99% CI, 65-69). When the patient is positioned prone, the largest LV cross-sectional area is 0 to 2 vertebral segments below the inferior angle of the scapula in at least 86% of patients. Further studies are needed to determine whether this position is optimal for chest compressions in the prone position.
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12-Lead electrocardiogram as a predictor of sudden cardiac death: from epidemiology to clinical practice Sudden cardiac death (SCD) causes a high burden of premature deaths in the population affecting subjects of all ages. The identification of subjects at high risk for SCD is of great importance as the prevention of many of these events would be possible with the treatment of underlying cardiac diseases and the use of implantable cardioverter-defibrillators (ICD). However, the current selection of patients for ICD therapy is based solely on left ventricular ejection fraction, and thus a substantial portion of patients at high risk does not qualify for the therapy. Role of the standard electrocardiogram (ECG) in SCD risk stratification has been under active research during the last decade and multiple abnormalities of depolarization and repolarization on the ECG associated with an increased risk of SCD have been identified. In this review, we describe the basic pathophysiological principles behind these changes. We also review the current knowledge of the prognostic significance of ECG predictors of SCD in the general population, and in patients with coronary heart disease (CHD), heart failure, cardiomyopathies, and in inheritable arrhythmia syndromes. Also, insights into the novel digital ECG signal processing techniques are provided.
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How Can We Estimate Sepsis Incidence and Mortality? Sepsis is one of the oldest and complex syndromes in medicine that has been in debate for over two millennia. Valid and comparable data on the population burden of sepsis constitute an essential resource for guiding health policy and resource allocation. Despite current epidemiological data suggesting that the global burden of sepsis is huge, the knowledge of its incidence, prevalence, mortality, and case-fatality rates is subject to several flaws. The objective of this narrative review is to assess how sepsis incidence and mortality can be estimated, providing examples on how it has been done so far in medical literature and discussing its possible biases. Results of recent studies suggest that sepsis incidence rates are increasing consistently during the last decades. Although estimates might be biased, this probably reflects a real increase in incidence over time. Nevertheless, case fatality rates have decreased, which is a probable reflex of advances in critical care provision to this very sick population at high risk of death. This conclusion can only be drawn with a reasonable degree of certainty for high-income countries. Conversely, adequately designed studies from middle - and low-income countries are urgently needed. In these countries, sepsis incidence and case-fatality rates could be disproportionally higher due to health care provision constraints and ineffective preventive measures.
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An Anechoic Space at the Carpal Tunnel Inlet is a Consistent Ultrasonographic Entity which Accommodates Tendon Displacement during Finger Flexion We consistently observed the presence of anechoic spaces on standard ultrasonographic imaging of the carpal tunnel inlet in normal subjects. These spaces change in size during finger flexion and have not been characterized in a large sample of normal individuals. Ultrasonographic quantification of these spaces may indicate the available space in the region of the carpal tunnel, which allows the normal motion of tendons and the median nerve. Transverse ultrasonographic images of the carpal tunnel inlet from 33 asymptomatic volunteers were obtained at Position A (fingers in extension) and B (fingers in flexion). Cross-sectional area (CSA), perimeter and position of anechoic space relative to median nerve were recorded. Analysis showed a 75.4% prevalence rate of a single anechoic space. Two discrete patterns were observed. 89.1% had a decrease in CSA and perimeter of anechoic space from Position A to B while 10.9% exhibited an increase. Mean position of the anechoic space is ulnar (7.49 ± 3.57 mm) and dorsal (2.18 ± 1.28 mm) to the median nerve. A consistent anechoic space at the carpal tunnel inlet is seen in 75.4% of normal hands and can be quantified (cross sectional area 11.75 ± 7.36 mm(2)). It allows for the accommodation of flexor tendons during finger flexion.
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Prognosis of Fibrolamellar Carcinoma Compared to Non-cirrhotic Conventional Hepatocellular Carcinoma Fibrolamellar carcinoma (FLC) and conventional hepatocellular carcinoma (HCC) share the same American Joint Committee on Cancer (AJCC) staging. The worse survival with HCC is attributed to the underlying cirrhosis .The aim of this study was to compare stage-matched prognosis after resection of FLC and non-cirrhotic HCC. Outcomes after resection of 65 consecutive patients with FLC and 158 non-cirrhotic patients with HCC were compared. Patients were staged according to the 7th edition AJCC staging. The AJCC stage distributions for FLC and HCC demonstrated a predominance of stage IV disease in FLC and stage I in HCC (FLC stage I-23 %, II-15 %, III-15 %, IV-46 % vs. HCC stage I-42 %, II-32 %, III-20 %, IV-6 %, p < 0.001). Among stage IV FLC patients, 81 % had isolated nodal metastases, which did not affect overall survival (OS) or recurrence-free survival (RFS). In FLC, OS was significantly affected by the number of tumors and vascular invasion (p < 0.05). Recurrent disease developed in 56 (86 %) FLC patients and was treated with repeat surgical resection in 25 (45 %) patients. Vascular invasion was associated with recurrent FLC, with 3-year RFS rates of 9 % and 35 %, with and without vascular invasion (p = 0.034). With respect to RFS, the AJCC staging did not stratify FLC patients, compared to non-cirrhotic HCC. When compared to non-cirrhotic HCC, patients with FLC are not adequately stratified by AJCC staging with respect to RFS. Our results support classifying lymph node metastases in FLC as regional disease, rather than systemic disease. Important prognostic factors in FLC are the number of tumors and vascular invasion.
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Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) adenovirus - associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes.
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Highly sensitive detection of influenza virus by boron-doped diamond electrode terminated with sialic acid-mimic peptide The progression of influenza varies according to age and the presence of an underlying disease; appropriate treatment is therefore required to prevent severe disease. Anti-influenza therapy, such as with neuraminidase inhibitors, is effective, but diagnosis at an early phase of infection before viral propagation is critical. Here, we show that several dozen plaque-forming units (pfu) of influenza virus (IFV) can be detected using a boron-doped diamond (BDD) electrode terminated with a sialic acid-mimic peptide. The peptide was used instead of the sialyloligosaccharide receptor, which is the common receptor of influenza A and B viruses required during the early phase of infection, to capture IFV particles. The peptide, which was previously identified by phage-display technology, was immobilized by click chemistry on the BDD electrode, which has excellent electrochemical characteristics such as low background current and weak adsorption of biomolecules. Electrochemical impedance spectroscopy revealed that H1N1 and H3N2 IFVs were detectable in the range of 20-500 pfu by using the peptide-terminated BDD electrode. Our results demonstrate that the BDD device integrated with the receptor-mimic peptide has high sensitivity for detection of a low number of virus particles in the early phase of infection.
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Identification of a peroxisomal -targeted aldolase involved in chlorophyll biosynthesis and sugar metabolism in rice Chlorophyll plays remarkable and critical roles in photosynthetic light-harvesting, energy transduction and plant development. In this study, we identified a rice Chl -deficient mutant, ygdl-1 (yellow green and droopy leaf-1), which showed yellow-green leaves throughout plant development with decreased content of Chls and carotene and an increased Chl a/b ratio. The ygdl-1 mutant also exhibited severe defects in chloroplast development, including disorganized grana stacks. Sequence analysis revealed that the mutant contained a T-DNA insertion within the promoter of a fructose-1,6-bisphosphate aldolase (OsAld-Y), which dramatically reduced the OsAld-Y mRNA level, and its identity was verified by transgenic complementation. Real-time PCR analysis showed that the expression levels of genes associated with chlorophyll biosynthesis and chloroplast development were concurrently altered in the ygdl-1 mutant. The expression of OsAld-Y - GFP fusion protein in tobacco epidermal cells showed that OsAld-Y was localized to the peroxisome. In addition, the analysis of primary carbon metabolites revealed the significantly reduced levels of sucrose and fructose in the mutant leaves, while the glucose content was similar to wild-type plants. Our results suggest that the OsAld-Y participates in Chl accumulation, chloroplast development and plant growth by influencing the photosynthetic rate of leaves and the sugar metabolism of rice.
[ "B-T103", "O", "B-T103", "I-T103", "O", "O", "O", "B-T038", "O", "B-T033", "O", "O", "B-T170", "O", "B-T038", "I-T038", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "O", "B-T103", "I-T103", "O", "O", "B-T103", "I-T103", "O", "B-T204", "O", "O", "O", "O", "B-T103", "B-T103", "I-T103", "O", "O", "O", "B-T103", "O", "O", "O", "O", "O", "O", "O", "O", "B-T103", "O", "B-T103", "I-T103" ]
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Brassinosteroid / Abscisic Acid Antagonism in Balancing Growth and Stress In this issue of Developmental Cell, Gui et al. (2016) show that an abscisic acid - inducible remorin protein in rice directly interacts with critical brassinosteroid signaling components to attenuate the brassinosteroid response, thus illuminating one aspect of the brassinosteroid / abscisic acid antagonism.
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Salvage surgery after head and neck squamous cell carcinoma treated with bioradiotherapy The purpose of this study was to describe the results and complications of primary site salvage surgery after head and neck squamous cell carcinoma (HNSCC) treated with bioradiotherapy. We conducted a retrospective chart review of 268 patients treated with bioradiotherapy between March 2006 and December 2013 at the Hospital Universitari de Bellvitge-ICO. Fifty-nine patients developed local recurrence or had residual disease with a 1- year and 3- year overall survival of 47% and 15.4%, respectively. Salvage surgery was feasible in 22 patients (37.3%). There were 16 complications in these 22 patients (72.7%), 11 (50%) of which were major. Bilateral neck dissection was identified as a risk factor for complications. Salvage surgery after bioradiotherapy is associated with a high rate of complications. Neck dissection seems to be related to an increased rate of complications with no survival improvement. © 2016 Wiley Periodicals, Inc. Head Neck 39: 116-121, 2017.
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Bioinformatic analysis of RNA-seq data unveiled critical genes in rectal adenocarcinoma RNA-seq data of rectal adenocarcinoma (READ) were analyzed with bioinformatics tools to unveil potential biomarkers in the disease. RNA-seq data of READ were downloaded from The Cancer Genome Atlas (TCGA) database. Differential analysis was performed with package edgeR. False discovery rate (FDR) < 0.05 and |log2 (fold change)|>1 were set as cut-off values to screen out differentially expressed genes (DEGs). Gene coexpression network was constructed with package Ebcoexpress. Gene Ontology enrichment analysis was performed for the DEGs in the gene coexpression network with DAVID online tool. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was also performed for the genes with KOBASS 2.0. A total of 620 DEGs, 3ated genes, and 231 down-regulated genes, were identified from 163 READ samples and 9 normal controls. A gene coexpression network consisting of 71 DEGs and 253 edges were constructed. Genes were associated with ribosome and focal adhesion functions. Three modules were identified, in which genes were involved in muscle contraction, negative regulation of glial cell proliferation and extracellular matrix organization functions, respectively. Several critical hub genes were disclosed, such as RPS2, MMP1, MMP11 and FAM83H. Thirteen relevant small molecule drugs were identified, such as scriptaid and spaglumic acid. A total of 8 TFs and 5 miRNAs were acquired, such as MYC, NFY, STAT5A, miR-29, miR-200 and miR-19. Several critical genes and relevant drugs, TFs and miRNAs were revealed in READ. These findings could advance the understanding about the disease and benefit therapy development.
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Regulation of bone homeostasis by glucose Synthesis of type Ⅰ collagen, a m ajor c omponent of the b one matrix, p recedes t he expression of R unt-related transcription factor 2(R unx2), a master regulator in osteoblast differentiation. Thus, a direct link between osteoblast differentiation and bone formation is seemingly absent, and how these are maintained in a coordinated matter remains unclear. It was recently demonstrated that osteoblasts depend on glucose, which glucose transporter type 1 (GLUT1)takes up as an energy source, and it was found that glucose uptake promotes osteoblast differentiation and bone formation via AMP-activated protein kinase. It was also shown that Runx2 upregulates GLUT1 expression, and this Runx2 - GLUT1 feedforward regulation integrates and coordinates osteoblast differentiation and bone formation throughout life. These previous findings revealed that the energy metabolism balance in osteoblasts integrates the differentiation and function of osteoblasts, and re-emphasized the importance of crosstalk between bone and sugar metabolism.
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Chelation competition induced polymerization (CCIP): construction of integrated hollow polydopamine nanocontainers with tailorable functionalities A novel ' chelation competition induced polymerization ' route was developed to construct hollow polydopamine nanocontainers with tailorable functionalities. The mechanism is systematically investigated and the nanocontainers constructed through this method show excellent chemo-thermo performance in vitro. This strategy is facile and is expected to be used for the construction of a series of hollow polymer nanostructures.
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Impaired autophagy in macrophages promotes inflammatory eye disease Autophagy is critical for maintaining cellular homeostasis. Organs such as the eye and brain are immunologically privileged. Here, we demonstrate that autophagy is essential for maintaining ocular immune privilege. Deletion of multiple autophagy genes in macrophages leads to an inflammation-mediated eye disease called uveitis that can cause blindness. Loss of autophagy activates inflammasome -mediated IL1B secretion that increases disease severity. Inhibition of caspase activity by gene deletion or pharmacological means completely reverses the disease phenotype. Of interest, experimental uveitis was also increased in a model of Crohn disease, a systemic autoimmune disease in which patients often develop uveitis, offering a potential mechanistic link between macrophage autophagy and systemic disease. These findings directly implicate the homeostatic process of autophagy in blinding eye disease and identify novel pathways for therapeutic intervention in uveitis.
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Objective Assessment of Vergence after Treatment of Concussion - Related CI: A Pilot Study To evaluate changes in objective measures of disparity vergence after office-based vision therapy (OBVT) for concussion - related convergence insufficiency (CI) and determine the feasibility of using this objective assessment as an outcome measure in a clinical trial. This was a prospective, observational trial. All participants were treated with weekly OBVT with home reinforcement. Participants included two adolescents and three young adults with concussion - related, symptomatic CI. The primary outcome measure was average peak velocity for 4° symmetrical convergence steps. Other objective outcome measures of disparity vergence included time to peak velocity, latency, accuracy, settling time, and main sequence. We also evaluated saccadic eye movements using the same outcome measures. Changes in clinical measures (near point of convergence, positive fusional vergence at near, Convergence Insufficiency Symptom Survey [CISS] score) were evaluated. There were statistically significant and clinically meaningful changes in all clinical measures for convergence. Four of the five subjects met clinical success criteria. For the objective measures, we found a statistically significant increase in peak velocity, response accuracy to 4° symmetrical convergence and divergence step stimuli, and the main sequence ratio for convergence step stimuli. Objective saccadic eye movements (5 and 10°) appeared normal pre- OBVT and did not show any significant change after treatment. This is the first report of the use of objective measures of disparity vergence as outcome measures for concussion - related convergence insufficiency. These measures provide additional information that is not accessible with clinical tests about underlying physiological mechanisms leading to changes in clinical findings and symptoms. The study results also demonstrate that patients with concussion can tolerate the visual demands (over 200 vergence and versional eye movements) during the 25-minute testing time and suggest that these measures could be used in a large-scale randomized clinical trial of concussion - related CI as outcome measures.
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Trends in traffic fatalities in Mexico: examining progress on the decade of action for road safety 2011-2020 We explore demographic, temporal and geographic patterns of 256,588 road traffic fatalities from 1998 to 2013 in Mexico, in context of UN´s decade of action for road safety 2010-2020 (DARS). Combined traffic mortality data and population counts were analyzed using mixed-effects logistic regression, distinguishing sex-age groups, vulnerable and protected road users, and municipal size. Rapid growth from 1998 to 2008 in traffic mortality rates has been reversed since 2009. Most deaths averted are among young male protected road users (reduction of 0.95 fatalities per 100,000 per year in males 12-49). In spite of a steady decrease over the full study period, mortality rates remain high in vulnerable road users over 50, with a high mortality rate of 26 per 100,000 males over 75 years in 2013. Progress on the reduction of deaths advances in Mexico, in line with DARS targets. National road safety efforts require strengthening. Initiatives should target vulnerable road users, specifically adults >50 years in urban areas. Strengthening of drink driving programs aimed at young drivers / occupants is promising.
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Diagnostic Yield of Routine Stress Testing in Low and Intermediate Risk Chest Pain Patients Under 40 Years: A Systematic Review Chest pain is one of the most frequent causes for presentation to emergency departments (EDs). The majority of patients will undergo diagnostic workup including stress testing to rule out an acute coronary syndrome, but very few patients will be diagnosed with a cardiac cause for their pain. Patients under 40 years represent a lower risk group in which routine stress testing may be of little benefit. This systematic review sought to determine the diagnostic yield of routine stress testing in low - and intermediate-risk chest pain patients under 40 years. Electronic databases were searched for relevant studies. The quality of the included primary studies was assessed using the National Health and Medical Research Council evidence hierarchy and the McMaster Critical Appraisal Tool for Quantitative Studies. Descriptive statistics summarized the findings. Five primary studies were included in the review (all level III-3 evidence); 7 additional sources of relevant data were also included. Diagnostic yield of routine stress testing in low - and intermediate-risk patients under 40 years is reported between 0% and 1.1%. Combined data from included primary studies demonstrated just 4 out of 1683 true positive stress tests (0.24%), only one of which was definitively confirmed by coronary angiogram; additional data sources identified just 1 out of 310 true positive stress tests (0.32%). Diagnostic yield of routine stress testing in low - and intermediate-risk chest pain patients under 40 years is low. However, better quality studies are required to be able to draw definitive conclusions.
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"debates", "that", "have", "arisen", "from", "past", "research", ".", "The", "innovative", "techniques", "and", "experiments", "that", "were", "performed", "to", "answer", "particular", "research", "questions", "are", "emphasised", ".", "The", "features", "that", "are", "outlined", "here", "concern", "the", "arrangement", "of", "the", "airways", ",", "the", "path", "followed", "by", "the", "inspired", "air", ",", "structural", "features", "of", "the", "lung", "and", "the", "air", "and", "blood", "capillaries", ",", "and", "the", "level", "of", "cellular", "defence", "in", "the", "avian", "respiratory", "system", ".", "Hitherto", ",", "based", "on", "association", "with", "the", "proven", "efficiency", "of", "naturally", "evolved", "and", "human", "-", "made", "counter", "-", "current", "exchange", "systems", "rather", "than", "on", "definite", "experimental", "evidence", ",", "a", "counter", "-", "current", "gas", "exchange", "system", "was", "suggested", "to", "exist", "in", "the", "avian", "respiratory", "system", "and", "was", "used", "to", "explain", "its", "exceptional", "efficiency", ".", "However", ",", "by", "means", "of", "an", "elegant", "experiment", "in", "which", "the", "direction", "of", "the", "air", "-", "flow", "in", "the", "lung", "was", "reversed", ",", "a", "cross", "-", "current", "system", "was", "shown", "to", "be", "in", "operation", "instead", ".", "Studies", "of", "the", "arrangement", "of", "the", "airways", "and", "the", "blood", "vessels", "corroborated", "the", "existence", "of", "a", "cross", "-", "current", "system", "in", "the", "avian", "lung", ".", "While", "the", "avian", "respiratory", "system", "is", "ventilated", "tidally", ",", "like", "most", "other", "invaginated", "gas", "exchangers", ",", "the", "lung", ",", "specifically", "the", "paleopulmonic", "parabronchi", ",", "is", "ventilated", "unidirectionally", "and", "continuously", "in", "a", "caudocranial", "(", "back", "-", "to", "-", "front", ")", "direction", "by", "synchronized", "actions", "of", "the", "air", "sacs", ".", "The", "path", "followed", "by", "the", "inspired", "air", "in", "the", "lung", "-", "air", "sac", "system", "is", "now", "known", "to", "be", "controlled", "by", "a", "mechanism", "of", "aerodynamic", "valving", "and", "not", "by", "anatomical", "valves", "or", "sphincters", ",", "as", "was", "previously", "supposed", ".", "The", "structural", "strength", "of", "the", "air", "and", "blood", "capillaries", "is", "derived", "from", ":", "the", "interdependence", "between", "the", "air", "and", "blood", "capillaries", ";", "a", "tethering", "effect", "between", "the", "closely", "entwined", "respiratory", "units", ";", "the", "presence", "of", "epithelial", "-", "epithelial", "cell", "connections", "(", "retinacula", "or", "cross", "-", "bridges", ")", "that", "join", "the", "blood", "capillaries", "while", "separating", "the", "air", "capillaries", ";", "the", "abundance", "and", "intricate", "arrangement", "of", "the", "connective", "tissue", "elements", ",", "i", ".", "e", ".", "collagen", ",", "elastin", ",", "and", "smooth", "muscle", "fibres", ";", "the", "presence", "of", "type", "-", "IV", "collagen", ",", "especially", "in", "the", "basement", "membranes", "of", "the", "blood", "-", "gas", "barrier", "and", "the", "epithelial", "-", "epithelial", "cell", "connections", ";", "and", "a", "putative", "tensegrity", "state", "in", "the", "lung", ".", "Notwithstanding", "the", "paucity", "of", "free", "surface", "pulmonary", "macrophages", ",", "the", "respiratory", "surface", "of", "the", "avian", "lung", "is", "well", "protected", "from", "pathogens", "and", "particulates", "by", "an", "assortment", "of", "highly", "efficient", "phagocytic", "cells", ".", "In", "commercial", "poultry", "production", ",", "instead", "of", "weak", "pulmonary", "cellular", "defence", ",", "stressful", "husbandry", "practices", "such", "as", "overcrowding", ",", "force", "-", "feeding", ",", "and", "intense", "genetic", "manipulation", "for", "rapid", "weight", "gain", "and", "egg", "production", "may", "account", "for", "the", "reported", "susceptibility", "of", "birds", "to", "aerosol", "-", "transmitted", "diseases" ]
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Pivotal debates and controversies on the structure and function of the avian respiratory system: setting the record straight Among the extant air-breathing vertebrates, the avian respiratory system is structurally the most complex and functionally the most efficient gas exchanger. Having been investigated for over four centuries, some aspects of its biology have been extremely challenging and highly contentious and others still remain unresolved. Here, while assessing the most recent findings, four notable aspects of the structure and function of the avian respiratory system are examined critically to highlight the questions, speculations, controversies and debates that have arisen from past research. The innovative techniques and experiments that were performed to answer particular research questions are emphasised. The features that are outlined here concern the arrangement of the airways, the path followed by the inspired air, structural features of the lung and the air and blood capillaries, and the level of cellular defence in the avian respiratory system. Hitherto, based on association with the proven efficiency of naturally evolved and human-made counter-current exchange systems rather than on definite experimental evidence, a counter-current gas exchange system was suggested to exist in the avian respiratory system and was used to explain its exceptional efficiency. However, by means of an elegant experiment in which the direction of the air - flow in the lung was reversed, a cross-current system was shown to be in operation instead. Studies of the arrangement of the airways and the blood vessels corroborated the existence of a cross-current system in the avian lung. While the avian respiratory system is ventilated tidally, like most other invaginated gas exchangers, the lung, specifically the paleopulmonic parabronchi, is ventilated unidirectionally and continuously in a caudocranial (back-to-front) direction by synchronized actions of the air sacs. The path followed by the inspired air in the lung - air sac system is now known to be controlled by a mechanism of aerodynamic valving and not by anatomical valves or sphincters, as was previously supposed. The structural strength of the air and blood capillaries is derived from: the interdependence between the air and blood capillaries; a tethering effect between the closely entwined respiratory units; the presence of epithelial - epithelial cell connections (retinacula or cross-bridges) that join the blood capillaries while separating the air capillaries; the abundance and intricate arrangement of the connective tissue elements, i.e. collagen, elastin, and smooth muscle fibres; the presence of type-IV collagen, especially in the basement membranes of the blood-gas barrier and the epithelial - epithelial cell connections; and a putative tensegrity state in the lung. Notwithstanding the paucity of free surface pulmonary macrophages, the respiratory surface of the avian lung is well protected from pathogens and particulates by an assortment of highly efficient phagocytic cells. In commercial poultry production, instead of weak pulmonary cellular defence, stressful husbandry practices such as overcrowding, force-feeding, and intense genetic manipulation for rapid weight gain and egg production may account for the reported susceptibility of birds to aerosol - transmitted diseases.
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microRNA-145 Mediates the Inhibitory Effect of Adipose Tissue -Derived Stromal Cells on Prostate Cancer Adipose-derived stromal cell (ASC), known as one of the mesenchymal stem cells (MSCs), is a promising tool for regenerative medicine; however, the effect of ASCs on tumor growth has not been studied sufficiently. We investigated the hypothesis that ASCs have an inhibitory effect on metastatic tumor progression. To evaluate the in vitro inhibitory effect of ASCs on metastatic prostate cancer (PCa), direct coculture and indirect separate culture experiments with PC3M-luc2 cells and human ASCs were performed, and ASCs were administered to PC3M-luc2 cell -derived tumor -bearing nude mice for in vivo experiment. We also performed exosome microRNA (miRNA) array analysis to explore a mechanistic insight into the effect of ASCs on PCa cell proliferation / apoptosis. Both in vitro and in vivo experiments exhibited the inhibitory effect of ASCs on PC3M-luc2 cell proliferation, inducing apoptosis and PCa growth, respectively. Among upregulated miRNAs in ASCs compared with fibroblasts, we focused on miR-145, which was known as a tumor suppressor. ASC -derived conditioned medium (CM) significantly inhibited PC3M-luc2 cell proliferation, inducing apoptosis, but the effect was canceled by miR-145 knockdown in ASCs. ASC miR-145 knockdown CM also reduced the expression of Caspase 3 / 7 with increased antiapoptotic protein, BclxL, expression in PC3M-luc2 cells. This study provides preclinical data that ASCs inhibit PCa growth, inducing PCa cell apoptosis with reduced activity of BclxL, at least in part, by miR-145, including exosomes released from ASCs, suggesting that ASC administration could be a novel and promising therapeutic strategy in patients with PCa.
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Initial experience using a femtosecond laser cataract surgery system at a UK National Health Service cataract surgery day care centre To describe the initial outcomes following installation of a cataract surgery laser system. National Health Service cataract surgery day care unit in North London, UK. 158 eyes of 150 patients undergoing laser-assisted cataract surgery. Laser cataract surgery using the AMO Catalys femtosecond laser platform. intraoperative complications including anterior and posterior capsule tears. docking to the laser platform, successful treatment delivery, postoperative visual acuities. Mean case age was 67.7±10.8 years (range 29-88 years). Docking was successful in 94% (148/158 cases), and in 4% (6/148 cases) of these, the laser delivery was aborted part way during delivery due to patient movement. A total of 32 surgeons, of grades from junior trainee to consultant, performed the surgeries. Median case number per surgeon was 3 (range from 1-20). The anterior capsulotomy was complete in 99.3% of cases, there were no anterior capsule tears (0%). There were 3 cases with posterior capsule rupture requiring anterior vitrectomy, and 1 with zonular dialysis requiring anterior vitrectomy (4/148 eyes, 2.7%). These 4 cases were performed by trainee surgeons, and were either their first laser cataract surgery (2 surgeons) or their first and second laser cataract surgeries (1 surgeon). Despite the learning curve, docking and laser delivery were successfully performed in almost all cases, and surgical complication rates and visual outcomes were similar to those expected based on national data. Complications were predominately confined to trainee surgeons, and with the exception of intraoperative pupil constriction appeared unrelated to the laser-performed steps.
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Gene Expression Profile in the Liver of Sheep Infected with Cystic Echinococcosis Cystic Echinococcosis (CE), caused by infection with the Echinococcus granulosus (E. granulosus), represents considerable health problems in both humans and livestock. Nevertheless, the genetic program that regulates the host response to E. granulosus infection is largely unknown. Previously, using microarray analysis, we found that the innate immunity played a vital role in the E. granulosus defense of the intestine tissue where E. granulosus first invaded. Subsequently, we turned our attention to investigating the molecular immune mechanism in its organ target, the liver, which is where the E. granulosus metacestodes are established and live for very long periods. In this work, the microarray-based methodology was used to study gene expression profiles in the liver of sheep infected with E. granulosus at 8 weeks post infection, corresponding to the early cystic established phase. A total of 6 female -1- year -old healthy Kazakh sheep were used for the experiments. Three Kazakh sheep were orally infected with E. granulosus eggs, and the others remained untreated and served as controls. Sheep were humanely euthanized and necropsized at 8 weeks post - infection (the early stage of cyst established). The microarray was used to detect differential hepatic gene expression between CE infection sheep and healthy controls at this time point. Real-time PCR was used to validate the microarray data. We found that E. granulosus infection induces 153 differentially expressed genes in the livers of infected sheep compared with healthy controls. Among them, 87 genes were up-regulated, and 66 genes were notably down-regulated. Functional analysis showed that these genes were associated with three major functional categories: (a) metabolism, (b) the immune system and (c) signaling and transport. Deeper analysis indicated that complement together with other genes associated with metabolism, played important roles in the defense of E. granulosus infection. The present study identified genes profiling in the liver tissue of E. granulosus infection in sheep. The expression pattern obtained here could be helpful for understanding the molecular immunity mechanisms of host responses to E. granulosus infection. However, it is necessary to carry out further studies to evalute the role of these genes.
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An Encapsulation of Gene Signatures for Hepatocellular Carcinoma, MicroRNA-132 Predicted Target Genes and the Corresponding Overlaps Previous studies have demonstrated that microRNA-132 plays a vital part in and is actively associated with several cancers, with its tumor-suppressive role in hepatocellular carcinoma confirmed. The current study employed multiple bioinformatics techniques to establish gene signatures for hepatocellular carcinoma, microRNA-132 predicted target genes and the corresponding overlaps. Various assays were performed to explore the role and cellular functions of miR-132 in HCC and a successive panel of tasks was completed, including NLP analysis, miR-132 target genes prediction, comprehensive analyses (gene ontology analysis, pathway analysis, network analysis and connectivity analysis), and analytical integration. Later, HCC - related and miR-132 - related potential targets, pathways, networks and highlighted hub genes were revealed as well as those of the overlapped section. MiR-132 was effective in both impeding cell growth and boosting apoptosis in HCC cell lines. A total of fifty-nine genes were obtained from the analytical integration, which were considered to be both HCC - and miR-132 - related. Moreover, four specific pathways were unveiled in the network analysis of the overlaps, i.e. adherens junction, VEGF signaling pathway, neurotrophin signaling pathway, and MAPK signaling pathway. The tumor-suppressive role of miR-132 in HCC has been further confirmed by in vitro experiments. Gene signatures in the study identified the potential molecular mechanisms of HCC, miR-132 and their established associations, which might be effective for diagnosis, individualized treatments and prognosis of HCC patients. However, combined detections of miR-132 with other bio-indicators in clinical practice and further in vitro experiments are needed.
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[ 1891, 1901 ] ]
Prevalence and Hospital Management of Amphotericin B Deoxycholate -Related Toxicities during Treatment of HIV - Associated Cryptococcal Meningitis in South Africa We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd -related toxicities. Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 -February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). AmBd -related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies.
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[ 1575, 1582 ] ]
Recent blood pressure trends in adolescents from China, Korea, Seychelles and the United States of America, 1997-2012 Although the prevalence of obesity is increasing worldwide, secular trends in elevated blood pressure (BP) differ across populations. We aimed to compare recent BP and obesity trends in adolescents aged 10-19 years in China, Korea, Seychelles and the United States of America. Data in adolescents aged 10-19 years came from China (1997-2011, n = 8025), Korea (1998-2012, n = 10 119), Seychelles (1998-2012, n = 27 569) and the United States of America (1999-2012, n = 14 580). Elevated BP was defined as SBP or DBP equal to or above the referent sex, age and height-specific 95th percentile of the US Fourth Report. Overweight and obesity were defined using criteria of the International Obesity Task Force. Between 1997-2000 and 2011-2012, the prevalence of elevated BP decreased in Korea and did not change substantially in China and in the United States of America. The prevalence of elevated BP increased in Seychelles. In 2011-2012, the prevalence of elevated BP was 1.7% in the United States of America, 3.8% in China, 3.7% in Korea and 14.3% in Seychelles. The prevalence of overweight and obesity increased over time and reached in 2011-2012 41.2% in the United States of America, 18.6% in China, 25.2% in Korea and 27.4% in Seychelles. Elevated BP was strongly associated with obesity in all countries. Although the prevalence of obesity increased markedly in the four countries, secular BP trends in adolescents differed in countries of different regions.
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CT -guided fine-needle aspiration of abdominal and retroperitoneal small lesions with the coaxial technique using MPR images To demonstrate the advantages of CT -guided fine-needle aspiration (FNA) of abdominal and retroperitoneal small lesions with the coaxial technique using MPR images. The study included retrospectively 50 patients who underwent CT -guided FNA of abdominal and/or retroperitoneal small lesion (<30 mm). Patients with suspected lymphomas or sarcomas were excluded. Cytology reports were the reference standard. The cytology was diagnostic in 48/50 biopsies (96%): out of 41 neoplastic lesions (85%), 37 were malignant (90.2%) and 4 were benign (9.8%); 7 out of 48 were non-neoplastic (14.6%). No procedural complications were observed (0%). By using MPR images there is an effective improvement in coaxial CT -guided FNA of abdominal and retroperitoneal small lesions.
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A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults The aim of the study was to investigate the efficacy and safety of St John's wort extract and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Databases were searched for studies comparing efficacy and/or safety of St John's wort extract with SSRIs in depression from 1966 to April 2015. Stata software was used for statistical analysis. Twenty-seven studies met the study entry criteria. A total of 3,126 patients with depression were included. St John's wort extract did not differ from SSRIs in clinical response, remission, and mean reduction in Hamilton Rating Scale for Depression score. St John's wort extract had a significantly lower rate of adverse events compared to SSRIs (summary relative risk: 0.77; 95% confidence interval: 0.70, 0.84, P=0.00) and had fewer withdrawals due to adverse events. St John's wort extract had superior safety in the management of patients with depression. Both St John's wort extract and SSRIs are effective in treating mild-to-moderate depression. St John's wort extract is safer than SSRIs.
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Redistribution of Cav2.1 channels and calcium ions in nerve terminals following end-to-side neurorrhaphy: ionic imaging analysis by TOF-SIMS The P/Q-type voltage-dependent calcium channel (Cav2.1) in the presynaptic membranes of motor nerve terminals plays an important role in regulating Ca(2+) transport, resulting in transmitter release within the nervous system. The recovery of Ca(2+) -dependent signal transduction on motor end plates (MEPs) and innervated muscle may directly reflect nerve regeneration following peripheral nerve injury. Although the functional significance of calcium channels and the levels of Ca(2+) signalling in nerve regeneration are well documented, little is known about calcium channel expression and its relation with the dynamic Ca(2+) ion distribution at regenerating MEPs. In the present study, end-to-side neurorrhaphy (ESN) was performed as an in vivo model of peripheral nerve injury. The distribution of Ca(2+) at regenerating MEPs following ESN was first detected by time-of-flight secondary ion mass spectrometry, and the specific localization and expression of Cav2.1 channels were examined by confocal microscopy and western blotting. Compared with other fundamental ions, such as Na(+) and K(+), dramatic changes in the Ca(2+) distribution were detected along with the progression of MEP regeneration. The re-establishment of Ca(2+) distribution and intensity were correlated with the functional recovery of muscle in ESN rats. Furthermore, the re-clustering of Cav2.1 channels after ESN at the nerve terminals corresponded with changes in the Ca(2+) distribution. These results indicated that renewal of the Cav2.1 distribution within the presynaptic nerve terminals may be necessary for initiating a proper Ca(2+) influx and shortening the latency of muscle contraction during nerve regeneration.
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Chitinibacter fontanus sp. nov., isolated from a spring A bacterial strain, designated STM-7T, was isolated from a spring in Taiwan and characterized using a polyphasic taxonomy approach. Cells of strain STM-7T were Gram-staining-negative, aerobic, poly--hydroxybutyrate -accumulating, motile by a single polar flagellum, rod-shaped that were surrounded by a thick capsule and forming milky white colored colonies. Growth occurred at 15-37 oC (optimum, 25-30 °C), at pH 6-8 (optimum, pH 6-7) and with 0-2 % NaCl (optimum, 0-1 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain STM-7T belonged to the genus Chitinibacter and was most closely related to Chitinibacter tainanensis S1T with sequence similarity of 97.3 %. Strain STM-7T contained summed feature 3 (comprising C16:17c and/or C16:16c) and C 16:0 as the predominant f atty acids. The major h ydroxyl fatty acids were C12:0 3-OH and C16:0 3-OH. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized aminophospholipid, an uncharacterized glycolipid and an uncharacterized phospholipid. The major isoprenoid quinone was Q-8. The DNA G+C content of the genomic DNA was 52.4 mol%. The DNA-DNA hybridization value for strain STM-7T with Chitinibacter tainanensis S1T was less than 47 %. On the basis of the phylogenetic inference and phenotypic data, strain STM-7T should be classified as a novel species, for which the name Chitinibacter fontanus sp. nov. is proposed. The type strain is STM-7T (=BCRC 80923T =LMG 29289T =KCTC 42982T).
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The role of sub-hippocampal versus hippocampal regions in bitemporal lobe epilepsies We aimed at better delineating the functional anatomical organization of bitemporal lobe epilepsy. We studied the epileptogenic zone (EZ) by quantifying the epileptogenicity of brain structures explored by depth electrodes in patients investigated by stereoelectroencephalography (SEEG). We compared 15 patients with bilateral mesial temporal lobe epilepsy (BTLE) and 15 patients with unilateral mesial temporal lobe epilepsy (UTLE). This quantification was performed using the ' Epileptogenicity Index ' (EI). Age at epilepsy onset, and epilepsy duration, were not statistically different in both groups. UTLE patients more frequently displayed maximal epileptogenicity in hippocampal structures, whereas BTLE patients had maximal values in subhippocampal areas (entorhinal cortex, temporal pole, parahippocampal cortex). Our results suggest different organization of the EZ in the two groups. BTLE was associated with more involvement of subhippocampal regions, a result in agreement with known anatomical connections between the two temporal lobes.
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Health-Related Quality of Life in Patients With α1 Antitrypsin Deficency: A Cross Sectional Study Measures of health related quality of life (HRQoL) in patients with α1-antitrypsin deficiency (AATD) can help to determine the impact of the disease and provide an important insight into the intervention outcomes. There is few data regarding this issue in the literature. The aim of this study is to assess the relationship between HRQoL and gender, functional parameters and history of hospitalizations in patients with AATD. This is a cross-sectional study of 26 patients with severe AATD recruited in the pulmonology outpatient clinic at a tertiary care medical center. Social-demographic, clinical and functional parameters were recorded and HRQoL was assessed with the Portuguese version of the medical outcome study short form-36 (SF-36) self-administered questionnaire. Older patients, females and patients with at least one hospitalization in the previous year due to respiratory disease had statistical lower scores in some dimensions of the SF-36 questionnaire. Superior FEV1 and higher distance mark in the 6-min walking test distance influenced positively several dimensions of the questionnaire. Higher scores in the mMRC scale influenced negatively the HRQoL. These data suggests that older and female patients with AATD have worse HRQoL. Hospitalizations and functional markers of respiratory disease progression influenced negatively the HRQoL, suggesting that the SF-36 questionnaire could be useful as an outcome for AATD patients with lung involvement.
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Disparities in treatment and survival for women with endometrial cancer: A contemporary national cancer database registry analysis The study aim was to identify contemporary socioeconomic, racial, ethnic, and facility-related factors associated with stage at diagnosis, receipt of cancer treatment, and survival in women with endometrial cancer (EC). Women diagnosed with EC between 1998 and 2010 were identified from the National Cancer Database. Variables associated with the outcomes of interest were assessed using multivariable Cox proportional hazards and logistic regression. Among 228,511 women identified, the percentage of blacks with stage IIIC/IV disease at diagnosis was nearly twice that of non-Hispanic whites (17.8% vs 9.8%; P<0.001). Patients with advanced disease who were insured with Medicare were less likely to receive standard-of-care postoperative radiotherapy and/or chemotherapy than those with private insurance (odds ratio: OR 0.80, P<0.001), as were those residing in the South (reference) in comparison to the Northeast, Atlantic, Great Lakes, and Midwest regions (OR 1.3-1.7, all P<0.001). Those residing in the Mountain region were even less likely to receive appropriate treatment (OR 0.7, P<0.001). Five-year stage IIIC/IV survival was 42.8% for non-Hispanic whites vs 24.6% for blacks (hazard ratio 1.3, P<0.001). Other factors associated with inferior 5-year survival included payer status (not insured, Medicaid, Medicare, vs private, ORs 1.2-1.3, all P<0.01), and treatment at low-volume centers (<5 vs ≥30cases/year, HR 1.3, P<0.001). Socioeconomic, geographic and facility-related factors predict advanced endometrial cancer stage, failure to receive cancer care, and shorter survival. Black women had especially poor survival. Nationwide standardization and concentration of treatment at high-volume centers may improve outcomes.
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Readily Accessible and Predictable Naphthalene -Based Two-Photon Fluorophore with Full Visible - Color Coverage Herein we report 22 acedan -derived, two-photon fluorophores with synthetic feasibility and full coverage of visible wavelength emission. The emission wavelengths were predicted by computational analysis, which enabled us to visualize multicolor images by two-photon excitation with single wavelength, and to design a turn-on, two-photon fluorescence sensor for endogenous H2 O2 in Raw 264.7 macrophage and rat brain hippocampus ex vivo.
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Association of β-blocker therapy with long-term clinical outcomes in patients with coronary chronic total occlusion There are limited data regarding the efficacy of β-blockers for secondary prevention in patients with coronary chronic total occlusion (CTO). Therefore, we investigated the association of β-blocker therapy with long-term clinical outcomes in CTO patients. From March 2003 to February 2012, a total of 2024 CTO patients treated with either medical therapy alone or revascularization were enrolled in the study. We assessed 1596 patients with stable ischemic heart disease and divided them into the β-blocker group (n = 932) and the no - β-blocker group (n = 664). The primary outcome was all-cause death. The median follow-up duration was 3.9 (interquartile range: 2.0-6.2) years. All-cause death occurred in 11.6% patients in the β-blocker group and 13.6% patients in the no - β-blocker group (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.61-1.08; P = 0.15). In the propensity score - matched population (570 pairs), all-cause death occurred in 12.3% patients in the β-blocker group and 12.8% patients in the no - β-blocker group (HR: 0.93, 95% CI: 0.67-1.29; P = 0.66). In subgroup analysis, β-blocker therapy was associated with better outcome, in terms of all-cause death, in patients with CTO of the left anterior descending coronary artery and Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX) score ≥23 (P for interaction = 0.01 and 0.02, respectively). In conclusion, β-blocker therapy was not associated with favorable long-term clinical outcomes in stable CTO patients, regardless of treatment strategy. However, β-blocker therapy might be beneficial in a highly selective group of CTO patients with a high ischemic burden.
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S-Nitrosylation Induces Structural and Dynamical Changes in a Rhodanese Family Protein S-Nitrosylation is well established as an important post-translational regulator in protein function and signaling. However, relatively little is known about its structural and dynamical consequences. We have investigated the effects of S-nitrosylation on the rhodanese domain of the Escherichia coli integral membrane protein YgaP by NMR, X-ray crystallography, and mass spectrometry. The results show that the active cysteine in the rhodanese domain of YgaP is subjected to two competing modifications: S-nitrosylation and S-sulfhydration, which are naturally occurring in vivo. It has been observed that in addition to inhibition of the sulfur transfer activity, S-nitrosylation of the active site residue Cys63 causes an increase in slow motion and a displacement of helix 5 due to a weakening of the interaction between the active site and the helix dipole. These findings provide an example of how nitrosative stress can exert action at the atomic level.
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Combination of diagnostic laparoscopy and intraoperative indocyanine green fluorescence angiography for the early detection of intestinal ischemia not detectable at CT scan Acute mesenteric ischemia is the most severe gastrointestinal complication of acute aortic dissection. The timing of diagnosis is of major importance, in fact the recognition of acute mesenteric ischemia often occurs too late due to the presence of unspecific symptoms and lack of reliable exams. Recently, indocyanine green fluorescence angiography has been adopted in order to measure blood perfusion and microcirculation. We decided to perform a diagnostic laparoscopy with the support of intra-operative near-infrared indocyanine green fluorescence angiography, in order to detect an initial intestinal ischemia in a 68-year-old patient previously treated with a TEVAR procedure for a type-B aortic dissection. The fluorescence system demonstrated an hypoperfused area in the ascending colon, therefore an ileocholic resection was thus performed. Opening the operatory specimen, the mucosa of the colon appeared totally ischemic, whilst the serosa was normal. When ischemia occurs, the oxygen supply is interrupted, hence the necrosis of the enteral mucosa occurs within 3h, whilst the necrosis of the full thickness of the bowel wall occurs within 6h. A diagnosis during these " golden hours " is of major importance for a successful treatment. The combination of laparoscopy and UV light and fluorescein dye should be considered as an invaluable diagnostic procedure for the diagnosis of early stage acute bowel ischemia which is not visible at instrumental examinations nor with diagnostic laparoscopy.
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Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic / NMDAR activity via different mechanisms. In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway. An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse -the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour. Our results show that relapse -like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048. Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic / NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.
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Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo-controlled clinical trial Preemptive analgesia is considered an alternative for treating the postsurgical pain of third molar removal. The aim of this study was to evaluate the preemptive analgesic efficacy of oral ketorolac versus intramuscular tramadol after a mandibular third molar surgery. A parallel, double-blind, randomized, placebo-controlled clinical trial was carried out. Thirty patients were randomized into two treatment groups using a series of random numbers: Group A, oral ketorolac 10 mg plus intramuscular placebo (1 mL saline solution); or Group B, oral placebo (similar tablet to oral ketorolac) plus intramuscular tramadol 50 mg diluted in 1 mL saline solution. These treatments were given 30 min before the surgery. We evaluated the time of first analgesic rescue medication, pain intensity, total analgesic consumption and adverse effects. Patients taking oral ketorolac had longer time of analgesic covering and less postoperative pain when compared with patients receiving intramuscular tramadol. According to the VAS and UAC results, this study suggests that 10 mg of oral ketorolac had superior analgesic effect than 50 mg of tramadol when administered before a mandibular third molar surgery.
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Homeostasis of chosen bioelements in organs of rats receiving lithium and/or selenium Lithium is an essential trace element, widely used in medicine and its application is often long-term. Despite beneficial effects, its administration can lead to severe side effects including hyperparathyroidism, renal and thyroid disorders. The aim of the current study was to evaluate the influence of lithium and/or selenium treatment on magnesium, calcium and silicon levels in rats ' organs as well as the possibility of using selenium as an adjuvant in lithium therapy. The study was performed on rats divided into four groups (six animals each): control - treated with saline; Li - treated with Li2CO3 (2.7 mg Li /kg b.w.); Se - treated with Na2SeO3·H2O (0.5 mg Se /kg b.w.); Se + Li - treated simultaneously with Li2CO3 and Na2SeO3·H2O (2.7 mg Li /kg b.w. and of 0.5 mg Se /kg b.w., respectively). The administration was performed in form of water solutions by stomach tube once a day for 3 weeks. In the organs (liver, kidney, brain, spleen, heart, lung and femoral muscle) the concentrations of magnesium, calcium and silicon were determined. Magnesium was increased in liver of Se and Se + Li given rats. Lithium decreased tissue Ca and co-administration of selenium reversed this effect. Silicon was not affected by any treatment. The beneficial effect of selenium on disturbances of calcium homeostasis let suggest that further research on selenium application as an adjuvant in lithium therapy is worth being performed.
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Substance use and sexual function in juvenile idiopathic arthritis To evaluate alcohol / tobacco / illicit drug use and sexual function in adolescent juvenile idiopathic arthritis (JIA) and healthy controls. 174 adolescents with pediatric rheumatic diseases were selected. A cross-sectional study with 54 JIA patients and 35 controls included demographic / anthropometric data and puberty markers assessments, physician -conducted CRAFFT (car / relax / alone / forget / friends / trouble) screen tool for substance abuse / dependence high risk and a questionnaire that evaluated sexual function, bullying and alcohol / tobacco / illicit drug use. Clinical / laboratorial data and treatment were also assessed in JIA. The median current age was similar between JIA patients and controls [15(10-19) vs. 15(12-18) years, p=0.506]. Frequencies of alcohol / tobacco / illicit drug use were high and similar in both JIA and controls (43% vs. 46%, p=0.829). However, age at alcohol onset was significantly higher in those with JIA [15(11-18) vs. 14(7-18) years, p=0.032], particularly in polyarticular onset (p=0.040). High risk for substance abuse / dependence (CRAFFT score ≥2) was found in both groups (13% vs. 15%, p=1.000), likewise bullying (p=0.088). Further analysis of JIA patients regarding alcohol / tobacco / illicit drug use showed that the median current age [17(14-19) vs. 13(10-19) years, p<0.001] and education years [11(6-13) vs. 7(3-12) years, p<0.001] were significant higher in those that used substances. Sexual activity was significantly higher in the former group (48% vs. 7%, p<0.001). A positive correlation was evidenced between CRAFFT score and current age in JIA patients (p=0.032, r=+0.296). A high risk for substance abuse / dependence was observed in both JIA and controls. JIA substance users were more likely to have sexual intercourse. Therefore, routine screening is suggested in all visits of JIA adolescents.
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NLRP3 protects alveolar barrier integrity by an inflammasome - independent increase of epithelial cell adherence Bacterial pneumonia is a major cause of acute lung injury and acute respiratory distress syndrome, characterized by alveolar barrier disruption. NLRP3 is best known for its ability to form inflammasomes and to regulate IL-1β and IL-18 production in myeloid cells. Here we show that NLRP3 protects the integrity of the alveolar barrier in a mouse model of Streptococcus pneumoniae - induced pneumonia, and ex vivo upon treatment of isolated perfused and ventilated lungs with the purified bacterial toxin, pneumolysin. We reveal that the preserving effect of NLRP3 on the lung barrier is independent of inflammasomes, IL-1β and IL-18. NLRP3 improves the integrity of alveolar epithelial cell monolayers by enhancing cellular adherence. Collectively, our study uncovers a novel function of NLRP3 by demonstrating that it protects epithelial barrier function independently of inflammasomes.
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Regulation of the host immune system by helminth parasites Helminth parasite infections are associated with a battery of immunomodulatory mechanisms, which impact all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host may benefit from suppression of collateral damage during parasite infection, and from reduced allergic, autoimmune and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to co-infection, and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research.
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Observation of Network Dynamics of Ryanodine Receptors on Skeletal Muscle Sarcoplasmic Reticulum Membranes Rabbit muscle vesicles derived from sarcoplasmic reticulum were used as a material in studying networks of ryanodine receptors by cryo electron tomography. Three-dimensional analysis reveals the dynamical features of these networks. It was found that the connection angles were rotated along the transmembrane axis of ryanodine receptors. Majority of the connections was observed at domains 6/6 of ryanodine receptors while a small group of connections were showed at domains 9/10. The flexible rotation and connection shift seem to facilitate the extension of an annular network on the wall of the sarcoplasmic reticulum in a triad.
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[ 1803, 1804 ], [ 1805, 1809 ], [ 1810, 1813 ], [ 1814, 1822 ], [ 1823, 1833 ] ]
Effects of Montelukast in an Experimental Model of Acute Pancreatitis BACKGROUND We evaluated the hematological, biochemical, and histopathological effects of Montelukast on pancreatic damage in an experimental acute pancreatitis model created by cerulein in rats before and after the induction of pancreatitis. MATERIAL AND METHODS Forty rats were divided into 4 groups with 10 rats each. The study groups were: the Cerulein (C) group, the Cerulein + early Montelukast (CMe) group, the Cerulein + late Montelukast (CMl) group, and the Control group. The pH, pO2, pCO2, HCO3, leukocyte, hematocrit, pancreatic amylase, and lipase values were measured in the arterial blood samples taken immediately before rats were killed. RESULTS There were statistically significant differences between the C group and the Control group in the values of pancreatic amylase, lipase, blood leukocyte, hematocrit, pH, pO2, pCO2, HCO3, and pancreatic water content, and also in each of the values of edema, inflammation, vacuolization, necrosis, and total histopathological score (P<0.05). When the CMl group and C group were compared, no statistically significant differences were found in any parameter analyzed. When the CMe group was compared with the C group, pancreatic amylase, lipase, pH, PO2, pCO2, HCO3, pancreatic water content, histopathological edema, inflammation, and total histopathological score values were significantly different between the groups (P<0.05). Finally, when the CMe group and the Control group were compared, significant differences were found in all except 2 (leukocyte and pO2) parameters (P<0.05). CONCLUSIONS Leukotriene receptor antagonists used in the late phases of pancreatitis might not result in any benefit; however, when they are given in the early phases or prophylactically, they may decrease pancreatic damage.
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Functional characterization of the Aspergillus nidulans glucosylceramide pathway reveals that LCB Δ8-desaturation and C9-methylation are relevant to filamentous growth, lipid raft localization and Psd1 defensin activity C8-desaturated and C9-methylated glucosylceramide (GlcCer) is a fungal -specific sphingolipid that plays an important role in the growth and virulence of many species. In this work, we investigated the contribution of Aspergillus nidulans sphingolipid Δ8-desaturase (SdeA), sphingolipid C9-methyltransferases (SmtA / SmtB) and glucosylceramide synthase (GcsA) to fungal phenotypes, sensitivity to Psd1 defensin and Galleria mellonella virulence. We showed that ΔsdeA accumulated C8-saturated and unmethylated GlcCer, while gcsA deletion impaired GlcCer synthesis. Although increased levels of unmethylated GlcCer were observed in smtA and smtB mutants, ΔsmtA and wild-type cells showed a similar 9,Me-GlcCer content, reduced by 50% in the smtB disruptant. The compromised 9,Me-GlcCer production in the ΔsmtB strain was not accompanied by reduced filamentation or defects in cell polarity. When combined with the smtA deletion, smtB repression significantly increased unmethylated GlcCer levels and compromised filamentous growth. Furthermore, sdeA and gcsA mutants displayed growth defects and raft mislocalization, which were accompanied by reduced neutral lipids levels and attenuated G. mellonella virulence in the ΔgcsA strain. Finally, ΔsdeA and ΔgcsA showed increased resistance to Psd1, suggesting that GlcCer synthesis and fungal sphingoid base structure specificities are relevant not only to differentiation but also to proper recognition by this antifungal defensin.
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Subepidermal Calcified Nodules of the Eyelid Differ in Children and Adults Subepidermal calcified nodule of the eyelid is considered as one of the types of calcinosis cutis. It generally occurs in children, and is not known to be associated with systemic disease. The authors report histopathological and clinical findings in 14 cases of subepidermal calcified nodule of the eyelid, including 3 older patients with unique microscopic features. Clinical records and pathological materials were critically reviewed in each case, including von kossa, CD3, CD20, and CD68 stains. The 14 cases presented clinically as nodular eyelid lesions. All were treated with surgical excision. The authors found 2 distinct histopathological patterns which correlated with the patients ' age. In young patients, the authors observed multiple, small calcified bodies within the dermis surrounded by chronic inflammation and granulomatous foreign body reaction. On the other hand, in elderly patients, lesions were characterized by a single, large, well-demarcated amorphous calcified deposit surrounded by fibrous tissue, without chronic inflammation or foreign body reaction. One of these patients, a 70- year-old man, also suffered from gout. The presence of subepidermal calcified nodule was not documented as a preoperative diagnostic possibility in any of the cases. Subepidermal calcified nodule of the eyelid is a rare condition, but should be considered in any patient presenting with a painless white to yellowish colored nodule of the ocular adnexa, particularly during the teenage years. Clinicians and pathologists should be aware that this entity has a distinct appearance and could be associated with systemic conditions in elderly patients.
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Cover Image, Volume 117, Number 10, October 2016 Cover: The cover image, by Jacqueline May Bentel et al., is based on the Article Activity of ABCG2 Is Regulated by Its Expression and Localization in DHT and Cyclopamine - Treated Breast Cancer Cells, DOI: 10.1002/jcb.25523.
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What kind of processing is survival processing?: Effects of different types of dual-task load on the survival processing effect Words judged for their relevance in a survival context are remembered better than words processed in non-survival contexts. This phenomenon is known as the survival processing effect. Recently, inconsistent results were reported on whether the size of the survival processing effect is affected by cognitive load. Whereas Kroneisen, Rummel, and Erdfelder (Memory 22: 92-102, 2014) observed that the survival processing effect vanishes under dual-task conditions, Stillman, Coane, Profaci, Howard, and Howard (Memory & Cognition 42: 175-185, 2014, Experiment 1) found that the size of survival processing effect is essentially unaffected by a cognitively demanding secondary task. In three experiments, we investigated the differences between these studies to achieve a better understanding of dual-task effects on the survival-processing advantage. In the first experiment, we replicated Stillman et al.'s results using their dual-task conditions combined with a sample more than twice as large as theirs. In the second experiment, we compared dual-task conditions that differed regarding how strongly the secondary task taxed (a) working memory load (maintenance of one vs. several items) and (b) processing demands (switching vs. time-sharing between tasks). A third experiment focussed on low (i.e., single-item) load under time-sharing processing conditions. Results consistently showed that the survival processing effect persisted under low load but vanished when the number of items held in working memory increased beyond one, irrespective of processing demands. Implications of these findings for explanations of the survival-processing advantage are discussed.
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Impact of systemic alitretinoin treatment on skin barrier gene and protein expression in patients with chronic hand eczema Chronic hand eczema (CHE) is a common inflammatory skin disease that affects approximately 10% of the population. Systemic alitretinoin has been shown to be effective in patients with CHE who are refractory to topical corticosteroids. To analyse the impact of alitretinoin on the skin barrier genes and protein expression in the skin lesions of patients with CHE. Fifteen patients with CHE were treated with 30 mg daily of alitretinoin for up to 27 weeks. Disease severity was assessed using a clinical score. Skin biopsies from all the patients were evaluated before and after therapy for the expression of Ki-67, various skin barrier genes and thymic stromal lymphopoietin (TSLP) by real-time quantitative polymerase chain reaction and immunohistochemistry. After alitretinoin application, an improvement in the clinical severity of CHE was observed in the majority of patients. Analysis of skin biopsies before treatment showed a significant increase in Ki-67 - positive cells in the suprabasal layer and a dysregulated expression of various skin barrier genes, such as claudin 1, loricrin, filaggrin and cytokeratin 10, which were normalized after treatment. TSLP was significantly upregulated in patients with CHE and also normalized after alitretinoin treatment and negatively correlated with filaggrin. Our data indicate that the expression of barrier genes and proteins was normalized following treatment with alitretinoin in patients with CHE. The change in expression levels of these genes correlated with the clinical efficacy, suggesting that alitretinoin exhibits a disease - modifying activity. TSLP is upregulated in CHE and seems to counteract filaggrin expression in the skin.
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Patient adoption of an internet based diabetes medication tool to improve adherence: A pilot study To investigate the effect of a video intervention, Managing Your Diabetes Medicines, on patient self-efficacy, problems with using medication, and medication adherence in a rural, mostly African American population. Patients selected their problem areas in medication use and watched one of nine 2-min videos with a research assistant at a clinic or pharmacy and were given an access code to watch all the videos at their convenience. Outcomes were measured at baseline and 3-month follow-up. Fifty-one patients were enrolled; 84% were African American and 80% were female (mean age: 54 years). Seventy-three percent watched at least one module after the initial visit. Improve d self-efficacy was associated with a decrease in concerns about medications (r=-0.64). Low literate patients experienced greater improvement in self-efficacy than more literate patients (t=2.54, p=0.02). Patients ' mean number of problems declined from 6.14 to 5.03. The number of patients with high or medium adherence rose from 33% at baseline to 43% at 3-month follow-up. A practical, customized video intervention may help improve patient self-efficacy, reduce problems with medication use, and improve medication adherence in diabetes patients. Providers should consider implementing technology - based interventions in the clinic to address common problems that patients have with self-management.
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Reduced susceptibilities to biocides and resistance to antibiotics in food - associated bacteria following exposure to quaternary ammonium compounds Our aim was to assess the effects of step-wise exposure to didecyl dimethyl ammonium chloride (DDAC) on the antimicrobial (antibiotics and biocides) susceptibilities of food - associated bacterial strains. Adaptive responses of bacterial strains were investigated by exposing the strains daily to increasing subinhibitory concentrations of DDAC for 7 days. Following adaptation to DDAC, a threefold increase in the minimum inhibitory concentration (MIC) values for this biocide was observed in 48% of the Escherichia coli and Listeria monocytogenes strains, and 3% of the Salmonella strains. Reduced susceptibility to other biocides was found with the most important increase in MIC for benzalkonium chloride (BC) and a commercial biocide formulation (Galox Horizon) containing DDAC and glutaraldehyde, for all species except Salmonella. Increase in antibiotic MIC values was more pronounced in E. coli in terms of antibiotic numbers and of magnitude (from 4- to 32-fold increase) and, to a lesser extent, in Salmonella strains. Most of these strains had acquired resistance to ampicillin, cefotaxime, ceftazidime, chloramphenicol and ciprofloxacin. The effects of exposure to DDAC on biocides and antibiotics susceptibilities depend upon the bacteria species. Extensive use of DDAC at subinhibitory concentrations may lead to the development of antibiotic - resistant bacteria and may represent a public health issue.
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Analgesic and anti-inflammatory actions on bradykinin route of a polysulfated fraction from alga Ulva lactuca We investigated structural features of polysaccharides from Ulva lactuca and their effects on the classical models of nociception and inflammation. Crude extract was obtained by enzymatic digestion and isolated by ion exchange chromatography on DEAE-cellulose. The fraction with higher yield was used in the tests (SP-Ul). Swiss mice received SP-Ul (1, 3 or 9mg/kg; i.v.), 30min prior to injection of 0.8%- acetic acid or 1%- formalin or prior to a thermal stimulus. At same doses, SP-Ul was tested on Wistar rats on paw edema elicited by different irritants (carrageenan, dextran, bradykinin, histamine or serotonin). The results of infrared characterization indicated the presence of hydroxyl groups, sulfate, uronic acid and glycosidic linkages in all SP fractions spectrums. SP-Ul decreased significantly the antinociception in response to acetic acid or formalin (second phase), but not in the hot-plate test, suggesting that its analgesia occurs through a peripheral mechanism. SP-Ul did not reduce carrageenan - induced paw edema as supported by both histological and myeloperoxidase activity assessments. However, SP-Ul (1mg/kg; s.c.) reduced dextran -elicited edema, showing vascular anti-inflammatory effect, with bradykinin as major target because it did not reduce histamine - and serotonin - induced paw edemas. Therefore, SP-Ul acts on bradykinin pathway in its antinociceptive and anti-inflammatory responses.
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Challenges Caring for Adults With Congenital Heart Disease in Pediatric Settings: How Nurses Can Aid in the Transition As surgery for complex congenital heart disease is becoming more advanced, an increasing number of patients are surviving into adulthood, yet many of these adult patients remain in the pediatric hospital system. Caring for adult patients is often a challenge for pediatric nurses, because the nurses have less experience and comfort with adult care, medications, comorbid conditions, and rehabilitation techniques. As these patients age, the increased risk of complications and comorbid conditions from their heart disease may complicate their care further. Although these patients are admitted on a pediatric unit, nurses can aid in promoting their independence and help prepare them to transition into the adult medical system. Nurses, the comprehensive medical teams, and patients ' families can all effectively influence the process of preparing these patients for transition to adult care.
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Coffee - Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine - containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration - diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.
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Elevated Serum Krebs von den Lungen-6 in Early Disease Predicts Subsequent Deterioration of Pulmonary Function in Patients with Systemic Sclerosis and Interstitial Lung Disease To identify predictors of poor prognosis in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD). Fifty patients with early-stage SSc - ILD who had never received disease - modifying drugs and were either observed for ≥ 10 years or died from ILD -related causes were enrolled. The baseline variables of patients who developed endstage lung disease (ESLD) were compared with those of patients who remained ESLD - free, and the Cox proportional hazard model was used to identify initial factors that correlated with ESLD development. Sixteen patients (32%) developed ESLD during 173.5 ± 64.7 months of followup. Elevated serum Krebs von den Lungen-6 (KL-6) at initial assessment was highly correlated with ESLD development (p = 0.0002). Receiver-operating characteristic curve analysis revealed that a KL-6 value of 1273 U/ml effectively discriminated patients who developed ESLD from those who did not. Patients with KL-6 > 1273 U/ml were less likely to remain ESLD - free compared with those with lower KL-6 levels (p < 0.0001). Multivariate analysis showed that KL-6 > 1273 U/ml was the most reliable predictor of ESLD development (OR 51.2, 95% CI 7.6-343, p < 0.0001). Finally, the initial KL-6 level correlated with the forced vital capacity (FVC) decline rate (r = 0.58, p < 0.0001). The natural course of SSc - ILD is highly variable. Baseline serum KL-6 is a biomarker potentially useful for predicting FVC decline.
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1677 ], [ 1678, 1688 ], [ 1689, 1695 ], [ 1696, 1711 ] ]
Preoperative ultrasonographic findings of internal jugular veins and carotid arteries in kidney transplant recipients Hemodialysis via the internal jugular vein (IJV) has been widely used for patients with end stage renal disease (ESRD) patients, as they have a higher risk of arterial diseases. We investigated the ultrasonographic findings of the IJV and carotid artery (CA) in recipients of kidney transplantation (KT) and identified factors influencing IJV / CA abnormalities. We enrolled 120 adult KT recipients. Patients in group A (n = 57) had a history of IJV hemodialysis, while those in group B (n = 63) were not yet on dialysis or undergoing dialysis methods not involving the IJV. The day before surgery, we evaluated the state of the IJV and CA using ultrasonography. We followed patients with IJV stenosis for six months after KT. Ultrasonography revealed that four patients (7%) in group A had IJV abnormalities, while no patients in group B had abnormalities (P = 0.118). Of the four patients with abnormalities, one with 57.4% stenosis normalized during follow- up. However, another patient with 90.1% stenosis progressed to occlusion, while the two patients with total occlusion remained the same. Twenty patients in group A (n = 11) and B (n = 9) had several CA abnormalities (P = 0.462). Upon multivariate analysis with stepwise selection, height and age were significantly correlated with IJV stenosis (P = 0.043, odds ratio = 0.9) and CA abnormality (P = 0.012, odds ratio = 1.1), respectively. IJV abnormalities (especially with a history of IJV hemodialysis) and CA abnormalities may be present in ESRD patients. Therefore, we recommend ultrasonographic evaluation before catheterization.
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Lipid digestibility and energy content of distillers' corn oil in swine and poultry Two experiments were conducted to determine the DE and ME and apparent total tract digestibility of ether extract of 3 distillers' corn oil (DCO; 4.9, 12.8, or 13.9% free fatty acids [FFA]) samplescompared with a sample of refined corn oil (CO; 0.04% FFA) and an industrially hydrolyzed high-FFA DCO (93.8% FFA) in young pigs and growing broilers. In Exp. 1, 54 barrows (initial age = 28 d) were fed a common diet for 7 d and then fed their allotted dietary treatment (either 100% basal diet or 1 of 5 test diets consisting of 90% basal diet plus 10% test lipid) for the next 7 d in group pens (9 pigs / pen). For the next 10 d, pigs were moved to individual metabolism crates for continued diet and crate adaptation and to a twice-daily feeding regimen. Pigs remained on their respective diets for a 4-d total fecal and urine collection period. For Exp. 2, 567 male broilers were obtained from a commercial hatchery (1 d of age) and reared in grower battery cages that contained 9 chicks per cage. Broilers were fed a common corn - soybean meal starter diet from placement until the beginning of the trial (19 d of age). Birds were then randomly assigned to 1 of 6 dietary treatments (94% basal diet plus 6% dextrose or 94% basal diet plus 6% test lipid substituted for dextrose) on d 19 and were allowed an 8-d dietary acclimation period followed by a 48-h energy balance assay. In Exp. 1, the DCO sample with 12.8% FFA contained the lowest (< 0.05) DE (8,036 kcal/kg) content compared with the 0.04% refined CO sample and the 4.9 or 93.8% FFA DCO samples (8,814, 8,828, and 8,921 kcal/kg, respectively), with the DCO source containing 13.9% FFA having intermediate DE (8,465 kcal/kg) content. The ME content of these lipid sources also differed among treatments (< 0.01), following trends similar to their DE values, with no differences noted for ME as a percentage of DE (> 0.35) content among the lipids evaluated. In Exp. 2, lipids containing 0.04, 4.9, 12.8, and 13.9% FFA had similar nitrogen corrected apparent ME (AME) values (8,072, 7,936, 8,036, and 7,694 respectively), except for the industrially hydrolyzed DCO sample containing 93.8% FFA, which contained 6,276 kcal/kg (< 0.01). Using published prediction equations, the predicted DE of these lipids for swine was 3.5% greater than the values determined in Exp. 1 for all lipid sources, except for the DCO sample containing 93.8% FFA, which the predicted DE was underestimated. Likewise, the predicted AME of these lipids for broilers was 7.4% greater than the determined AMEn (Exp. 2) for all lipid sources.
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Hierarchical Address Event Routing for Reconfigurable Large-Scale Neuromorphic Systems We present a hierarchical address-event routing (HiAER) architecture for scalable communication of neural and synaptic spike events between neuromorphic processors, implemented with five Xilinx Spartan-6 field-programmable gate arrays and four custom analog neuromophic integrated circuits serving 262k neurons and 262M synapses. The architecture extends the single-bus address-event representation protocol to a hierarchy of multiple nested buses, routing events across increasing scales of spatial distance. The HiAER protocol provides individually programmable axonal delay in addition to strength for each synapse, lending itself toward biologically plausible neural network architectures, and scales across a range of hierarchies suitable for multichip and multiboard systems in reconfigurable large-scale neuromorphic systems. We show approximately linear scaling of net global synaptic event throughput with number of routing nodes in the network, at $3.6x10^7$ synaptic events per second per 16k- neuron node in the hierarchy.
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Prevalence of depression in patients of type 2 diabetes mellitus: A cross sectional study in a tertiary care centre The present study aims to study the prevalence of depression in patients with uncomplicated type II diabetes mellitus and to find its association with various socio-demographic factors in the same. A cross-sectional, single interview study was performed in an outpatient department of an endocrinology institute. Total 80 type II DM patients without any associated complications of diabetes were included in this study. To diagnose Depressive Episode, structured clinical interview for DSM V was applied. Severity of depression was assessed by Hamilton Rating Scale for Depression (HAM-D). To assess socio-demographic characteristics of the patients, all of them were evaluated with a semi-structured socio-demographic performa. 38.75% patients (N=31) were found to be suffering from depression. Among them 48.38% were moderately depressed and none were suffering from very severe depression. Significant association was not found between depression and socio-demographic factors of age (p=0.920), gender (p=0.251), economic profile (p=0.583), local background of the patient (p=0.646), educational qualification (p=0.935) and marital status (p=0.644). Similarly no association was found with duration of diabetes, HbA1c and BMI. Exclusion of complicated cases didn't seem to influence overall prevalence of depression, although reduction in severity was apparent. Thus even in those diabetic patients who are leading a complication free life, a detailed psychiatric analysis to rule out depression is mandatory.
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Scar Assessment After Breast Augmentation Surgery with Axillary Incision versus Inframammary Fold Incision: Long-Term Follow-Up in Chinese Patients The inframammary fold (IMF) incision is widely used in Western countries for breast augmentation surgery, whereas the axillary incision is the dominant approach used in China, because many Chinese surgeons believe that the Asian population has a higher risk of developing hypertrophic scars. However, comparative data of scar assessment through different incisions in Chinese patients are scarce. The aims of the study were as follows: (1) to evaluate the outcomes of scar assessment using the Vancouver scar scale (VSS), combined with patient satisfaction scoring, in the scar assessment after breast augmentation surgery; (2) to compare the long-term cosmetic effects of surgical scars between axillary and IMF incisions. Consecutive patients coming to our department for follow-up care at least 1 year after primary breast augmentation surgeries with axillary and IMF incisions between January 1, 2014 and December 31, 2014 were included in the research. Internal consistency, inter-rater reliability, and convergent validity were examined for the VSS and patient satisfaction scoring. The baseline characteristics and scar scores were tested using the Mann-Whitney U-test and Student's t test between the two groups. Sixty-one patients underwent implantation surgeries through the axillary incisions, and 17 patients through the IMF incisions. There were no significant differences in age, follow-up time, body mass index, implant volume, or implant projection between groups. Reliability and validity of the VSS and patient satisfaction scoring were satisfactory. The scores of pigmentation were higher in the IMF group than those in the axilla group with statistical significance (P < 0.05). The scores of other subscales, overall VSS scores, and patient satisfaction were not statistically significant. The scars were significantly longer in the axilla group compared with the IMF group (P < 0.05). The VSS combined with patient satisfaction scoring constitutes an effective tool to evaluate incision scars after augmentation mammaplasty. Scars in the axilla and IMF can achieve comparable cosmetic effects and patient satisfaction in Chinese women. Chinese patients with proper indications can receive breast augmentation surgery through the IMF incision, with fewer risks and less trauma, and get satisfactory scar appearance as through the axillary incision. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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MicroRNA-26a protects against cardiac hypertrophy via inhibiting GATA4 in rat model and cultured cardiomyocytes. Pathological cardiac hypertrophy is characterized by deleterious changes developed in cardiovascular diseases, whereas microRNAs (miRNAs) are involved in the mediation of cardiac hypertrophy. To investigate the role of microRNA-26a (miR-26a) in regulating cardiac hypertrophy and its functioning mechanisms, overexpression and suppression of miR-26a via its mimic and inhibitor in a transverse abdominal aortic constriction (TAAC)- induced rat model and in angiotensin II (Ang II)- induced cardiomyocytes (CMs) was performed. In the rat model, the heart weight (HW) compared with the body weight (BW), the CM area, and expression of the hypertrophy - associated factors, atrial natriuretic factor (ANF) and ß-myosin heavy chain (ß-MHC), were assessed. In CMs, the protein synthesis rate was determined using a leucine incorporation assay. Mutation of the GATA-binding protein 4 (GATA4) 3'-untranslated region (UTR) and overexpression of GATA4 were performed to confirm whether GATA4 is the target of miR-26a. The results indicated that miR-26a was significantly downregulated in the heart tissue of the rat model, as well as in Ang II - induced CMs (P<0.05). The TAAC - induced rat model exhibited a higher HW / BW ratio, a larger CM area, and higher expression levels of ANF and ß-MHC. CMs, upon Ang II treatment, also demonstrated a larger CM area, higher levels of ANF and ß-MHC, as well as accelerated protein synthesis. miR-26a was not able to regulate GATA4 with mutations in the 3'-UTR, indicating that GATA4 was the direct target of miR-26a. Overexpression of GATA4 abrogated the inhibitory functions of miR-26a in cardiac hypertrophy. Taken together, the present study suggested an anti-hypertrophic role of miR-26a in cardiac hypertrophy, possibly via inhibition of GATA4. These findings may be useful in terms of facilitating cardiac treatment, with potential therapeutic targets and strategies.
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Systematic Quantification of GPCR / cAMP - Controlled Protein Kinase A Interactions The diffusible second messenger cyclic AMP (cAMP) originates from multiple G protein-coupled receptor (GPCR) cascades activating the intracellular key effector protein kinase A (PKA). Spatially and temporally restricted cAMP - fluxes are directly sensed by macromolecular PKA complexes. The consequences are alterations of molecular interactions, which lead to activation of compartmentalized PKA phosphotransferase activities, regulating a vast array of cellular functions. To decode cell-type and cell-compartment specific PKA functions, the spatio-temporal dynamics of small molecule:protein interactions, protein:protein interactions (PPIs), cAMP - mobilization, and phosphotransferase activities need to be determined directly in the appropriate cellular context. A collection of cell-based reporters has been developed to either visualize or quantitatively measure kinase activities or PKA complex formation / dissociation. In this review, we list a collection of unimolecular and bimolecular PKA biosensors, followed by the specification of the modular design of a Renilla luciferase based protein-fragment complementation assay (PCA) platform for measuring PKA network interactions. We discuss the application spectrum of the PCA reporter to identify, quantify, and dissect dynamic and transient PKA complexes downstream of specific GPCR activities. We specify the implementation of a PCA PKA platform to systematically quantify the concurrent involvement of receptor - cAMP signaling, post-translational modifications, and kinase subunit mutations / perturbations in PKA activation. The systematic quantification of transient PKA network interactions will contribute to a better understanding how GPCR -recognized input signals are streamlined through the compartmentalized and cAMP - interacting PKA signalosome.
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The role of IGF-1 and the distribution of body fat in decreasing the number of prostate rebiopsies To assess the usefulness of IGF-1 and internal organ fat measured by bioelectrical impedance audiometry to avoid rebiopsies in patients with persistently high prostate-specific antigen (PSA) levels. A prospective study was conducted with 92 patients who underwent prostate rebiopsy due to high PSA levels with negative results in the rectal examination and a lack of preneoplastic lesions. The patients previously had their IGF-1 levels measured and had undergone an impedance audiometry test using the abdominal Fat Analyser AB-140 TANITA system. We calculated the receiver operating characteristic (ROC) curves for the PSA levels, % PSA, internal organ fat and IGF-1 and PSA density. Twenty-five patients were diagnosed with prostate cancer. These patients had significantly higher PSA, PSAd and IGF-1 values and a tendency towards higher internal organ fat levels and lower % PSA readings (p=.001, p=.003, p=.001, p=.24 and P=0.28, respectively). The ROC curve showed an area under the curve for IGF-1 and PSA of .82 and .81, respectively. Using the cutoff points for 95% sensitivity and using the 3 criteria as an indication of rebiopsy, 74% of the biopsies would have been spared, leaving undiagnosed only 1 patient with clinically significant cancer - Gleason score >7 (4+3)-. The positive and negative predictive values for the set of variables were higher than for each one separately (PPV: 66/NPV: 63). The cost of both determinations was 82 euros. Our results suggest that measuring IGF-1 could significantly decrease the number of unnecessary rebiopsies in an inexpensive and safe manner.
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Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents.
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Geometric morphometrics reveals restrictions on the shape of the female os coxae The methodology for sex determination in human skeletal remains depends on the different bone morphologies presented by men and women. Due to their direct implications in reproduction, the whole pelvis, particularly the os coxae, shows different characteristics in either sex. The sacrum and the os coxae constitute the birth cana l. In this research study, the os coxae shape is analyzed using geometric morphometrics, providing information on morphology, regardless of size or any other factor beyond the geometry itself. A total of 46 adult ossa coxae from a Spanish archaeological collection were studied using geometric morphometrics. The results show that there is a restriction on the shape of female os coxae. In contrast, male os coxae presents a greater range of variation. The biological reason for this difference is the obstetrical dilemma; a concept defined as the anatomical conflict between bipedalism and the full-term birth of a neonate whose large head requires greater dimensions in the pelvic cavity. Our experimental data reinforce the validity of the obstetrical dilemma as source of the restriction on the shape of female ossa coxae. Additionally, according to the results obtained, size itself does not represent a condition for belonging to one sex or another.
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Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation Pluripotency, differentiation, and X Chromosome inactivation (XCI) are key aspects of embryonic development. However, the underlying relationship and mechanisms among these processes remain unclear. Here, we systematically dissected these features along developmental progression using mouse embryonic stem cells (mESCs) and single-cell RNA sequencing with allelic resolution. We found that mESCs grown in a ground state 2i condition displayed transcriptomic profiles diffused from preimplantation mouse embryonic cells, whereas EpiStem cells closely resembled the post-implantation epiblast. Sex -related gene expression varied greatly across distinct developmental states. We also identified novel markers that were highly enriched in each developmental state. Moreover, we revealed that several novel pathways, including PluriNetWork and Focal Adhesion, were responsible for the delayed progression of female EpiStem cells. Importantly, we " digitalized " XCI progression using allelic expression of active and inactive X Chromosomes and surprisingly found that XCI states exhibited profound variability in each developmental state, including the 2i condition. XCI progression was not tightly synchronized with loss of pluripotency and increase of differentiation at the single-cell level, although these processes were globally correlated. In addition, highly expressed genes, including core pluripotency factors, were in general biallelically expressed. Taken together, our study sheds light on the dynamics of XCI progression and the asynchronicity between pluripotency, differentiation, and XCI.
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Prevalence of Psychoactive Substance Consumption in People With Obesity The aim of this study was to evaluate the prevalence and the kind of psychoactive substances consumed by people with obesity. Patients were included at their first visit for bariatric surgery. Socio-demographic characteristics, anxiety, depressive disorders and psychoactive substance consumption were assessed. The prevalence of psychoactive substance consumption was compared to that of the general population reported by the French National Institute of Prevention and Health Education. One hundred (100) patients were consecutively recruited: 60 women (mean age 41 ± 14 years) and 40 men (mean age 46 ± 13 years). Sixty-seven percent of subjects consumed alcohol. Consumption rates of cannabis (21% vs. 10%), cocaine (7.0% vs. 0.8%) and amphetamine (6.0% vs. 0.3%) were significantly (p < .0001) higher in people with obesity than in the general population. People with obesity have an excess risk of amphetamine, cocaine and cannabis consumption. This consumption may increase the risk of cardiovascular and psychiatric morbidity and should therefore be detected before surgery.
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Comparison of semiologies between tilt-induced psychogenic nonsyncopal collapse and psychogenic nonepileptic seizures We sought to characterize the clinical features of tilt-induced psychogenic nonsyncopal collapse (PNSC) from a cohort of young patients and to compare the semiologies between PNSC and EEG -confirmed psychogenic nonepileptic seizures (PNES). A PNSC diagnosis was made if a clinical event occurred during tilt-table testing that the patient regarded as fainting, but neither hypotension nor EEG changes were present. A diagnosis of PNSC was made in 17.6% of all patients referred during the 15-month study period. Cohorts with psychogenic nonsyncopal collapse (n=40) and PNES (n=40) did not differ in age (15.5±2.2 versus 14.6±2.7, p=.11) or female gender (80% versus 72.5%, p=.43). Psychogenic nonsyncopal collapse events were briefer than PNES events (median: 45 versus 201.5s, p<.001). Negative motor signs (head drop, body limpness) predominated in PNSC (85% versus 20%, p<.001), while the positive motor signs of convulsion occurred more often with PNES (90% versus 30%, p<.001). Behavioral arrest (25% versus 32.5%, p=.46) and eye closure (85% versus 72.5%, p=.21) did not differ between PNSC and PNES. Patients with PNSC were more likely to be tearful before (30% versus 7.5%, p=.02) and after (62.5% versus 7.5%, p<.001) an event. In conclusion, although overlap exists, the features of PNSC generally appear similar to neurally mediated syncope, while the features of PNES generally appear similar to epileptic seizures. Psychogenic nonsyncopal collapse and PNES likely represent similar disorders that differ primarily by clinical semiologies and referral patterns.
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Mediation Analysis for Health Disparities Research Social epidemiologists often seek to determine the mechanisms that underlie health disparities. This work is typically based on mediation procedures that may not be justified with exposures of common interest in social epidemiology. In this analysis, we explored the consequences of using standard approaches, referred to as the difference and generalized product methods, when mediator-outcome confounders are associated with the exposure. We compared these with inverse probability -weighted marginal structural models, the structural transformation method, doubly robust g-estimation of a structural nested model, and doubly robust targeted minimum loss -based estimation. We used data on 900,726 births from 2003 to 2007 in the Penn Moms study, conducted in Pennsylvania, to assess the extent to which breastfeeding prior to hospital discharge explained the racial disparity in infant mortality. Overall, for every 1,000 births, 3.36 more infant deaths occurred among non-Hispanic black women relative to all other women (95% confidence interva l: 2.78, 3.93). Using the difference and generalized product methods to assess the disparity that would remain if everyone breastfed prior to discharge suggested a complete elimination of the disparity (risk difference = -0.87 per 1,000 births; 95% confidence interval: -1.39, -0.35). In contrast, doubly robust methods suggested a reduction in the disparity to 2.45 (95% confidence interva l: 2.20, 2.71) more infant deaths per 1,000 births among non-Hispanic black women. Standard approaches for mediation analysis in health disparities research can yield misleading results.
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Integrating Evidence From Systematic Reviews, Qualitative Research, and Expert Knowledge Using Co-Design Techniques to Develop a Web -Based Intervention for People in the Retirement Transition Integrating stakeholder involvement in complex health intervention design maximizes acceptability and potential effectiveness. However, there is little methodological guidance about how to integrate evidence systematically from various sources in this process. Scientific evidence derived from different approaches can be difficult to integrate and the problem is compounded when attempting to include diverse, subjective input from stakeholders. The intent of the study was to describe and appraise a systematic, sequential approach to integrate scientific evidence, expert knowledge and experience, and stakeholder involvement in the co-design and development of a complex health intervention. The development of a Web -based lifestyle intervention for people in retirement is used as an example. Evidence from three systematic reviews, qualitative research findings, and expert knowledge was compiled to produce evidence statements (stage 1). Face validity of these statements was assessed by key stakeholders in a co-design workshop resulting in a set of intervention principles (stage 2). These principles were assessed for face validity in a second workshop, resulting in core intervention concepts and hand-drawn prototypes (stage 3). The outputs from stages 1-3 were translated into a design brief and specification (stage 4), which guided the building of a functioning prototype, Web -based intervention (stage 5). This prototype was de-risked resulting in an optimized functioning prototype (stage 6), which was subject to iterative testing and optimization (stage 7), prior to formal pilot evaluation. The evidence statements (stage 1) highlighted the effectiveness of physical activity, dietary and social role interventions in retirement; the idiosyncratic nature of retirement and well-being; the value of using specific behavior change techniques including those derived from the Health Action Process Approach; and the need for signposting to local resources. The intervention principles (stage 2) included the need to facilitate self-reflection on available resources, personalization, and promotion of links between key lifestyle behaviors. The core concepts and hand-drawn prototypes (stage 3) had embedded in them the importance of time use and work exit planning, personalized goal setting, and acceptance of a Web -based intervention. The design brief detailed the features and modules required (stage 4), guiding the development of wireframes, module content and functionality, virtual mentors, and intervention branding (stage 5). Following an iterative process of intervention testing and optimization (stage 6), the final Web -based intervention prototype of LEAP (Living, Eating, Activity, and Planning in retirement) was produced (stage 7). The approach was resource intensive and required a multidisciplinary team. The design expert made an invaluable contribution throughout the process. Our sequential approach fills an important methodological gap in the literature, describing the stages and techniques useful in developing an evidence -based complex health intervention. The systematic and rigorous integration of scientific evidence, expert knowledge and experience, and stakeholder input has resulted in an intervention likely to be acceptable and feasible.
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Transcriptome profiling of the green alga Spirogyra pratensis (Charophyta) suggests an ancestral It is well known that ethylene regulates a diverse set of developmental and stress-related processes in angiosperms, yet its roles in early diverging embryophytes and algae are poorly understood. Recently, it was shown that ethylene functions as a hormone in the charophyte green alga Spirogyra pratensis. Since land plants evolved from Charophytes, this implies conservation of ethylene as a hormone in green plants for at least 450 million of years. However, the physiological role of ethylene in charophyte algae remained unknown. In order to gain insight into ethylene responses in Spirogyra, we used mRNA sequencing to measure changes in gene expression over time in Spirogyra filaments in response to an ethylene treatment. Our analyses show that at the transcriptional level, ethylene predominantly regulates three processes in Spirogyra: (1) modification of the cell wall matrix by expansins and xyloglucan endotransglucosylases / hydrolases, (2) down-regulation of chlorophyll biosynthesis and photosynthesis and (3) activation of abiotic stress responses. We confirmed that the photosynthetic capacity and chlorophyll content was reduced by an ethylene treatment and that several abiotic stress conditions could stimulate cell elongation in an ethylene -dependent manner. We also found that the Spirogyra transcriptome only harbors 10 ethylene responsive transcription factor (ERF) homologs, several of which are regulated by ethylene. These results provide an initial understanding of the hormonal responses induced by ethylene in Spirogyra, and help to reconstruct the role of ethylene in ancestral charophytes prior to the origin of land plants.
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[ [ 0, 11 ], [ 12, 16 ], [ 17, 26 ], [ 27, 29 ], [ 30, 43 ], [ 44, 54 ], [ 55, 57 ], [ 58, 67 ], [ 68, 82 ], [ 83, 92 ], [ 93, 95 ], [ 96, 97 ], [ 98, 102 ], [ 103, 104 ], [ 105, 110 ], [ 111, 126 ], [ 127, 134 ], [ 135, 137 ], [ 138, 147 ], [ 148, 149 ], [ 150, 154 ], [ 155, 159 ], [ 160, 162 ], [ 163, 172 ], [ 173, 187 ], [ 188, 197 ], [ 198, 203 ], [ 204, 209 ], [ 210, 220 ], [ 221, 231 ], [ 232, 234 ], [ 235, 237 ], [ 238, 246 ], [ 247, 258 ], [ 259, 263 ], [ 263, 264 ], [ 265, 266 ], [ 267, 269 ], [ 269, 270 ], [ 271, 275 ], [ 276, 277 ], [ 278, 281 ], [ 282, 285 ], [ 286, 289 ], [ 290, 298 ], [ 299, 302 ], [ 303, 313 ], [ 314, 316 ], [ 317, 325 ], [ 326, 331 ], [ 332, 336 ], [ 337, 340 ], [ 341, 349 ], [ 350, 357 ], [ 358, 360 ], [ 361, 362 ], [ 363, 371 ], [ 372, 382 ], [ 383, 385 ], [ 386, 389 ], [ 390, 395 ], [ 395, 396 ], [ 397, 399 ], [ 400, 403 ], [ 404, 411 ], [ 412, 414 ], [ 415, 422 ], [ 423, 432 ], [ 433, 434 ], [ 435, 440 ], [ 441, 450 ], [ 451, 454 ], [ 455, 469 ], [ 470, 479 ], [ 480, 489 ], [ 490, 500 ], [ 501, 506 ], [ 507, 517 ], [ 518, 520 ], [ 521, 522 ], [ 523, 531 ], [ 532, 541 ], [ 542, 547 ], [ 548, 553 ], [ 554, 561 ], [ 561, 562 ], [ 563, 566 ], [ 567, 575 ], [ 576, 586 ], [ 587, 589 ], [ 590, 593 ], [ 594, 599 ], [ 600, 612 ], [ 613, 625 ], [ 626, 637 ], [ 638, 653 ], [ 653, 654 ], [ 655, 657 ], [ 658, 670 ], [ 671, 680 ], [ 681, 694 ], [ 695, 705 ], [ 706, 710 ], [ 711, 725 ], [ 726, 732 ], [ 733, 743 ], [ 744, 745 ], [ 745, 749 ], [ 749, 750 ], [ 750, 754 ], [ 754, 755 ], [ 755, 756 ], [ 757, 760 ], [ 761, 766 ], [ 767, 779 ], [ 780, 785 ], [ 786, 790 ], [ 791, 798 ], [ 799, 801 ], [ 802, 805 ], [ 806, 813 ], [ 813, 814 ], [ 815, 820 ], [ 821, 823 ], [ 823, 824 ], [ 824, 828 ], [ 829, 837 ], [ 838, 848 ], [ 849, 861 ], [ 862, 871 ], [ 872, 882 ], [ 883, 897 ], [ 898, 907 ], [ 907, 908 ], [ 909, 922 ], [ 923, 929 ], [ 930, 932 ], [ 933, 942 ], [ 943, 945 ], [ 946, 956 ], [ 957, 964 ], [ 965, 967 ], [ 968, 972 ], [ 972, 973 ], [ 973, 977 ], [ 978, 980 ], [ 981, 985 ], [ 986, 994 ], [ 995, 1002 ], [ 1003, 1005 ], [ 1006, 1010 ], [ 1011, 1021 ], [ 1022, 1030 ], [ 1031, 1033 ], [ 1034, 1051 ], [ 1052, 1063 ], [ 1064, 1068 ], [ 1069, 1077 ], [ 1078, 1089 ], [ 1090, 1105 ], [ 1106, 1108 ], [ 1109, 1116 ], [ 1117, 1123 ], [ 1124, 1128 ], [ 1129, 1131 ], [ 1132, 1140 ], [ 1141, 1144 ], [ 1145, 1152 ] ]
Mediastinal mass diagnosed by endobronchial ultrasound as recurrent hepatocellular carcinoma in a post - liver transplantation patient We presented a rare case of recurrent hepatocellular carcinoma after liver transplant manifested as an isolated mediastinal mass. A 62- year - old man was referred for evaluation of atypical chest pain and abnormal finding of a computed tomography of the chest. He had history of chronic hepatitis C liver cirrhosis and hepatocellular carcinoma underwent orthotopic liver transplant as a curative treatment three years earlier. The computed tomography of the chest demonstrated paratracheal mediastinal lymphadenopathy. He subsequently underwent endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA). The right paratracheal lymph node station 4R was sampled. Rapid on-site cytology evaluation demonstrated recurrent metastatic hepatocellular carcinoma. Pulmonologist should be cognizant of diagnostic utility of EBUS-TBNA in this clinical setting as more transplant patients on immunosuppressive medications with enlarged mediastinal lymphadenopathy of unknown origin will be referred for further evaluation.
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Phosphodiesterase type 5 inhibitors: Irrational use in Saudi Arabia To identify the criteria of phosphodiesterase type 5 inhibitor (PDE5i) users and to analyse the knowledge, attitude, and practices of PDE5i use amongst Saudi men. A web - based, cross-sectional survey was conducted in Saudi Arabia between January and April 2015. Sexually active adult men were interviewed using a website questionnaire designed by the authors. Descriptive statistics were used to analyse the data. In all, 1008 men participated in the survey with 378 (37.5%) reporting use of PDE5i. Of those using PDE5i, 144 (38.1%) reported erectile dysfunction and 234 (61.9%) reported normal erection (recreational users). We found several demographic features, including high education level, health field occupation, high income, smoking, and increased frequency of sexual intercourse amongst the PDE5i users. Most of the PDE5i users (92.3%) had knowledge about PDE5i and 84.1% of them bought it without medical prescription. The most commonly used PDE5i was tadalafil (46.1%) and most of the users (79.9%) reported improvement in their sexual activity after PDE5i usage. Amongst the recreational users, the main reasons for PDE5i usage were curiosity (38.5%) and improving self-confidence (25.6%). Of them, 69.2% reported benefits from PDE5i usage, mainly in the form of enhancement of erection (36.7%) and increasing erection duration (31.2%). PDE5i use appears to be frequent in Saudi Arabia. Most of the users had knowledge about PDE5i and claimed to get benefits from it, even if used as a recreational drug.
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Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome Methylation -based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy -specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta β>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta β<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to the T18 differentially methylated CpGs was highly enriched for GO terms related to" DNA binding " and " transcription factor binding " coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments.
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Assessment of Early Treatment Response With DWI After CT -Guided Radiofrequency Ablation of Functioning Adrenal Adenomas The objective of this study was to establish the suitability of the apparent diffusion coefficient (ADC) as a parameter for evaluating early treatment response after percutaneous ablation of functional adrenal adenomas. Seventeen adult patients with functioning adrenal adenomas underwent radiofrequency ablation. Serum hormone levels were analyzed before and up to 6 months after ablation. MRI findings (nodule size in cm, signal intensity index, ADC maps, and nodule-to-muscle ADC ratio) were analyzed before and up to 30 days after ablation. A consensus review of all scans was performed by two attending abdominal imaging radiologists. The procedure was considered successful if serum hormone levels normalized and no contrast enhancement of the adrenal lesion was seen on follow-up MRI. Of 17 patients who underwent radiofrequency ablation, complete response was achieved in 16 patients with partial response in one patient. Of the four parameters of interest, only ADC maps and nodule-to-muscle ADC ratio showed statistically significant differences (p < 0.05). This prospective study suggests that apparent diffusion coefficient values may help radiologists monitor early treatment response after CT -guided radiofrequency ablation of functioning adrenal adenomas.
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TLR and NLRP3 inflammasome - dependent innate immune responses to tumor-derived autophagosomes (DRibbles) Autophagosomes derived from tumor cells, also referred to as defective ribosomal products in blebs (DRibbles), have been previously shown to stimulate potent T-cell responses and mediate tumor regression when used as therapeutic cancer vaccines in multiple preclinical cancer models. In this report, we investigated the underlining mechanisms by which DRibbles induced T-cell activation, particularly how DRibbles activated antigen-presenting cells (APCs). We found that DRibbles could induce a rapid differentiation of monocytes and DC precursor (pre-DC) cells into functional APCs. DRibbles triggered innate receptor signaling via Toll-like Receptors (TLR)-2, TLR4, TLR7, TLR8, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2), but not TLR3, TLR5, or TLR9. DRibbles induced PBMCs to produce pro-inflammatory cytokines, such as IL-6, IL-10, TNF-α, and IL-1β. DRibbles induced IL-1β release from PBMC or THP-1 cells without LPS priming, but required the core machinery of NLRP3 inflammasomes. Active endocytosis was required for inflammasome activation and cross presentation, and blocking endosome acidification or the ER-associated degradation (ERAD) pathway resulted in opposite effects on these two processes. Our data show that DRibbles could induce strong innate immune responses via multiple pattern recognition receptors, and explain why DRibbles could function as excellent antigen carriers to induce adaptive immune responses to both tumor cells and viruses. In contrast to the well-established inhibitory effect of autophagy on the inflammasome activation of APCs, our study demonstrates that isolated autophagosomes (DRibbles) from antigen donor cells activate inflammasomes by providing first and second signals required for IL-1β production by PMBC.
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[ [ 0, 4 ], [ 4, 5 ], [ 5, 14 ], [ 15, 19 ], [ 19, 20 ], [ 20, 28 ], [ 29, 39 ], [ 40, 45 ], [ 46, 49 ], [ 50, 58 ], [ 59, 65 ], [ 65, 66 ], [ 66, 70 ], [ 71, 78 ], [ 78, 79 ], [ 80, 82 ], [ 83, 90 ], [ 91, 101 ], [ 102, 103 ], [ 103, 105 ], [ 105, 106 ], [ 107, 111 ], [ 112, 122 ], [ 123, 125 ], [ 126, 130 ], [ 131, 132 ], [ 132, 140 ], [ 141, 149 ], [ 150, 153 ], [ 154, 161 ], [ 162, 164 ], [ 165, 174 ], [ 175, 181 ], [ 182, 189 ], [ 190, 200 ], [ 201, 211 ], [ 212, 217 ], [ 218, 226 ], [ 227, 236 ], [ 236, 237 ], [ 238, 242 ], [ 242, 243 ], [ 243, 251 ], [ 252, 254 ], [ 254, 255 ], [ 255, 257 ], [ 257, 258 ], [ 258, 259 ], [ 260, 270 ], [ 271, 274 ], [ 275, 277 ], [ 277, 278 ], [ 278, 280 ], [ 280, 281 ], [ 281, 282 ], [ 283, 288 ], [ 289, 294 ], [ 295, 299 ], [ 300, 304 ], [ 305, 314 ], [ 315, 317 ], [ 318, 326 ], [ 327, 333 ], [ 333, 334 ], [ 334, 338 ], [ 339, 346 ], [ 347, 351 ], [ 352, 364 ], [ 365, 367 ], [ 368, 370 ], [ 370, 371 ], [ 371, 373 ], [ 373, 374 ], [ 374, 377 ], [ 377, 378 ], [ 379, 393 ], [ 394, 403 ], [ 403, 404 ], [ 405, 407 ], [ 408, 418 ], [ 418, 419 ], [ 420, 423 ], [ 424, 437 ], [ 438, 442 ], [ 443, 444 ], [ 445, 447 ], [ 447, 448 ], [ 448, 451 ], [ 451, 452 ], [ 453, 454 ], [ 454, 459 ], [ 460, 464 ], [ 464, 465 ], [ 465, 473 ], [ 474, 476 ], [ 476, 477 ], [ 477, 480 ], [ 480, 481 ], [ 481, 482 ], [ 483, 493 ], [ 494, 496 ], [ 497, 499 ], [ 499, 500 ], [ 500, 502 ], [ 502, 503 ], [ 503, 504 ] ]
Self-assembled half-sandwich polyhedral cages via flexible Schiff-base ligands: an unusual macrocycle -to- cage conversion An edge -directed strategy was adopted to construct highly ordered polyhedral structures using flexible functions. Half-sandwich M6(L1)4 octahedral and M8(L2)4 cubic cages have been assembled by flexible Schiff-base ligands upon coordination to Cp*Rh(iii) organometallic acceptors. In particular, the rearrangement from a Rh(iii) -based half-sandwich M2(HL1)2 macrocycle to M6(L1)4 cage was found to occur in a solution.
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[ 1933, 1936 ], [ 1937, 1949 ], [ 1950, 1953 ], [ 1954, 1961 ], [ 1962, 1969 ], [ 1970, 1974 ] ]
Dysplasia discrimination in intestinal - type neoplasia of the esophagus and colon via digital image analysis Determining gastrointestinal tract dysplasia level is clinically important but can be difficult, and given this challenge, we investigated colonic and esophageal dysplastic progression using digital image analysis (IA). Whole slide images were obtained for colonic normal mucosa (NCM), hyperplastic polyps (HP), conventional tubular adenomas (TA), and adenomas with high-grade dysplasia (HGD), and esophageal intestinal metaplasia negative for dysplasia (IM), indefinite for dysplasia (IFD), low-grade dysplasia (LGD), and HGD. Characteristic nuclei were circumscribed, and parameters discriminating groups included nuclear circumference (μm), area (μm(2)), and 15 positive pixel count (PPC) algorithm IA measurements. In colon polyps and esophageal lesions, average nuclear area and circumference ranged 30-108.6 μm(2) and 27.5-48.9 μm, respectively. Differences for average nuclear area and circumference met statistical significance (p < 0.05) between diagnostic groups in the esophagus and colon, except for IM versus IFD nuclear area. Pixel intensity (brightness) separated lesions within both groups with statistical significance except for colonic TAs versus HPs and esophageal LGD versus IM. HGD nuclei in both groups demonstrated more pixel staining heterogeneity than other lesions. Hierarchical clustering and principal component analysis demonstrated that lesions with similar diagnoses tended to cluster together on a low- to high-grade spectrum. Our results confirm that quantitative IA is an effective adjunct reflecting dysplasia in colon polyps and Barrett esophagus lesions. Nuclear area, circumference, and PPC algorithm findings distinguished lesions in a statistically significant manner. This suggests utility for future studies on similar methods, which may provide an adjunctive ancillary technique for pathologists and enhance patient care.
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Aeromonas salmonicida subsp. salmonicida strains isolated from Chinese freshwater fish contain a novel genomic island and possible regional-specific mobile genetic elements profiles Two strains of Aeromonas salmonicida, YK and BG, were isolated from largemouth bronze gudgeon and northern whitefish in China, and identified as A. salmonicida subsp. salmonicida based on phylogenetic analysis of vapA and 16S rRNA gene sequences. YK and BG originated from freshwater fish, one of which belonged to the cyprinid family, and the strains showed a difference in virulence. Subsequently, we performed whole genome sequencing of the strains, and comparison of their genomic sequences to the genome of the A449 reference strain revealed various genomic rearrangements, including a new variant of the genomic island AsaGEI in BG, designated as AsaGEI2c This is the first report on a GEI of A. salmonicida strain from China. Furthermore, both YK and BG strains contained a Tn7 transposon inserted at the same position in the chromosome. Finally, IS-dependent rearrangements on pAsa5 are deemed likely to have occurred, with omission of the resD gene in both strains as well as omission of genes related to the IncF conjugal transfer system in the YK isolate. This study demonstrates that A. salmonicida subsp. salmonicida can infect non-salmonids (cyprinids) in addition to salmonids, and that AsaGEI2c might be useful as a geographical indicator of Chinese A. salmonicida subsp. salmonicida isolates.
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Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. δ-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of δ-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (Cmax). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto -based tocotrienols in healthy fed subjects. All four isomers (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-tocotrienol in 6 healthy fed subjects. All subjects (3/ dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of α-, β-, γ-, δ-tocotrienols, and tocopherols in plasmas were quantified by HPLC. Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUC t0-t8 6621, 7450; AUC t0-∞ 8688, 9633; AUMC t0-∞ 52497, 57199; MRT 6.04, 5.93; Cmax 1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax 3.33-4 h; elimination half-life (t1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h(-1)) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease.
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The effect of green tea extract supplementation on sputum smear conversion and weight changes in pulmonary TB patients: A randomized controlled trial Acceleration in sputum smear conversion helps faster improvement and decreased probability of the transfer of TB. In this study, we aimed to investigate the effect of green tea extract supplementation on sputum smear conversion and weight changes in smear positive pulmonary TB patients in Iran. In this double blind clinical study, TB patients were divided into intervention, (n=43) receiving 500 mg green tea extract (GTE), and control groups (n=40) receiving placebo for two months, using balanced randomization. Random allocation and allocation concealment were observed. Height and weight were measured at the beginning, and two and six months post-treatment. Evaluations were performed on three slides, using the ZiehlNeelsen method. Independent and paired t test, McNemar's, Wilcoxon, Kaplan-Meier, Cox regression model and Log-Rank test were utilized. Statistical significance was set at p<0.05. This trial was registered under IRCT201212232602N11. The interventional changes and the interactive effect of intervention on weight were not significant (p>0.05). In terms of shortening the duration of conversion, the case to control proportion showed a significant difference (p=0.032). Based on the Cox regression model, the hazard ratio of the relative risk of delay in sputum smear conversion was 3.7 (p=0.002) in the higher microbial load group compared to the placebo group and 0.54 (95% CI: 0.31-0.94) in the intervention compared to the placebo group. GTE decreases the risk of delay in sputum smear conversion, but has no effect on weight gain. Moreover, it may be used as an adjuvant therapy for faster rehabilitation for pulmonary TB patients.
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Novel antibody probes for the characterization of endosialin / TEM-1 Endosialin (Tumor Endothelial Marker-1 (TEM-1), CD248) is primarily expressed on pericytes of tumor - associated microvasculature, tumor - associated stromal cells and directly on tumors of mesenchymal origin, including sarcoma and melanoma. While the function of endosialin/TEM-1 is incompletely understood, studies have suggested a role in supporting tumor growth and invasion thus making it an attractive therapeutic target. In an effort to further understand its role in cancer, we previously developed a humanized anti-endosialin/TEM-1 monoclonal antibody (mAb), called ontuxizumab (MORAb-004) for testing in preclinical and clinical studies. We herein report on the generation of an extensive panel of recombinant endosialin/TEM-1 protein extracellular domain (ECD) fragments and novel mAbs against ECD motifs. The domain-specific epitopes were mapped against ECD sub-domains to identify those that can detect distinct structural motifs and can be potentially formatted as probes suitable for diagnostic and functional studies. A number of mAbS were shown to cross-react with the murine and human protein, potentially allowing their use in human animal models and corresponding clinical trials. In addition, pairing of several mAbs supported their use in immunoassays that can detect soluble endosialin/TEM-1 (sEND) in the serum of healthy subjects and cancer patients.
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Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN - augmenting activity in airway epithelium Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC 50 = 5-11 μM) of rhinovirus - induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN - stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.
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Impact of AAC(6')-Ib-cr in combination with chromosomal -mediated mechanisms on clinical quinolone resistance in Escherichia coli aac(6')-Ib-cr is the most prevalent plasmid -mediated fluoroquinolone (FQ) resistance mechanism in Enterobacteriaceae. We aimed to analyse the interplay between this plasmid -mediated gene and chromosomal -mediated quinolone resistance mechanisms on both FQ resistance and bacterial fitness in Escherichia coli. E. coli ATCC 25922 and derived isogenic strains carrying chromosomal -mediated quinolone resistance modifications (Ser83Leu-Asp87Asn in GyrA, Ser80Arg in ParC and/or a marR gene deletion) were electroporated with a pBK-CMV vector encoding AAC(6')-Ib-cr. The MICs of FQs were determined by microdilution and bactericidal activity was determined using time-kill curves. A peritoneal sepsis murine model was used to evaluate the in vivo impact. Bacterial fitness was analysed using growth curves and competition assays. The presence of the aac(6')-Ib-cr gene increased the MICs of ciprofloxacin and norfloxacin 4-8-fold for all E. coli genotypes, independently of the initial resistance level. Combination of the aac(6')-Ib-cr gene with three or four chromosomal mechanisms was necessary to reach MIC values above the susceptible category. Killing curve assays showed a clear selective advantage for survival in strains harbouring the aac(6')-Ib-cr gene (up to 7 log10 cfu/mL after 24 h). AAC(6')-Ib-cr significantly reduced the ciprofloxacin efficacy in vivo. In terms of bacterial fitness cost, maximal OD was significantly lower for all strains harbouring the aac(6')-Ib-cr gene, independently of chromosomal mutations associated. The aac(6')-Ib-cr gene, in spite of producing low-level resistance by itself, plays a relevant role in acquisition of a clinical level of ciprofloxacin and norfloxacin resistance, when combined with three or four chromosomal mutations, both in vitro and in vivo.
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1777 ], [ 1778, 1788 ] ]
Cluster - dependent colistin hetero-resistance in Enterobacter cloacae complex Aims of this study were to: (i) evaluate whether the cluster membership could have an impact on hetero-resistance phenotype to colistin in the Enterobacter cloacae complex (ECC); and (ii) determine the genetic mechanism of colistin hetero-resistance in ECC. A collection of 124 clinical isolates belonging to 13 clusters were used to analyse the hetero-resistance phenotype (MICs were determined using the broth microdilution method, Etest and population analysis profiling). Different mutants (ΔphoP, ΔphoQ, ΔphoPQ, ΔpmrA, ΔpmrB, ΔpmrAB, ΔarnE, ΔarnF and ΔarnBCADTEF) were constructed and tested for their colistin hetero-resistance phenotype. Based on broth microdilution and Etest results, it was shown that the hetero-resistance to colistin depended on the cluster: strains from clusters I, II, IV, VII, IX, X, XI and XII were usually hetero-resistant, whereas those from clusters III, V, VI, VIII and XIII were categorized as susceptible. However, for some cluster V and VIII strains, a small proportion (<10(-7)) of cells appeared resistant when tested by population analysis profiling. From a mechanistic point of view, analysis of mutants revealed that the mechanism of hetero-resistance was mainly due to the expression of the arn operon and the phoP / phoQ two-component regulatory system. Because the colistin hetero-resistance appeared cluster - dependent in the ECC, it should be advocated to determine the cluster of the strain associated with the infection in parallel with the MIC of colistin. The resistance mechanism may not be similar to other Enterobacteriaceae since only the two-component regulatory system PhoP / PhoQ (and not PmrA / PmrB) seemed to play a role in resistance regulation.
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Levels of bone markers in a population of infants exposed in utero and during breastfeeding to tenofovir within an Option B+ programme in Malawi No data are available on bone metabolism in infants exposed to tenofovir during breastfeeding. We investigated bone metabolism markers in the first year of life in infants from mothers who received tenofovir, lamivudine and efavirenz during pregnancy and 12 months of breastfeeding in a national Option B+ programme in Malawi. Serum samples collected at 6 and 12 months in tenofovir - exposed infants and in a small sample of tenofovir - unexposed infants from the same clinical centre were analysed in batches for levels of bone-specific alkaline phosphatase (BAP; marker of bone formation) and of C-terminal telopeptide of type I collagen (CTX; marker of bone resorption). Overall, 136 tenofovir - exposed infants were evaluated. No infant had at either timepoint CTX values above the upper normal limit, while most of them had at 6 and 12 months levels of BAP above the upper normal limit for the age range. Levels of bone markers showed no differences by gender and no association with growth parameters. Tenofovir - unexposed and - exposed children had similar mean levels of bone markers at 6 months (CTX: 0.62 versus 0.55 ng/mL, P = 0.122; BAP: 384 versus 362 U/L, P = 0.631). No significant association between treatment with tenofovir and CTX or BAP levels was found. The high levels of BAP, coupled to the normal levels observed for CTX, might reflect primarily skeletal growth. Potential negative effects of prolonged exposure to tenofovir through breastfeeding cannot however be excluded and longitudinal studies that evaluate bone mineralization status in children enrolled in Option B+ programmes are warranted.
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Enforcement of the Emergency Medical Treatment and Labor Act, 2005 to 2014 We determine the incidence of and trends in enforcement of the Emergency Medical Treatment and Labor Act (EMTALA) during the past decade. We obtained a comprehensive list of all EMTALA investigations conducted between 2005 and 2014 directly from the Centers for Medicare & Medicaid Services (CMS) through a Freedom of Information Act request. Characteristics of EMTALA investigations and resulting citation for violations during the study period are described. Between 2005 and 2014, there were 4,772 investigations, of which 2,118 (44%) resulted in citations for EMTALA deficiencies at 1,498 (62%) of 2,417 hospitals investigated. Investigations were conducted at 43% of hospitals with CMS provider agreements, and citations issued at 27%. On average, 9% of hospitals were investigated and 4.3% were cited for EMTALA violation annually. The proportion of hospitals subject to EMTALA investigation decreased from 10.8% to 7.2%, and citations from 5.3% to 3.2%, between 2005 and 2014. There were 3.9 EMTALA investigations and 1.7 citations per million emergency department (ED) visits during the study period. We report the first national estimates of EMTALA enforcement activities in more than a decade. Although EMTALA investigations and citations were common at the hospital level, they were rare at the ED - visit level. CMS actively pursued EMTALA investigations and issued citations throughout the study period, with half of hospitals subject to EMTALA investigations and a quarter receiving a citation for EMTALA violation, although there was a declining trend in enforcement. Further investigation is needed to determine the effect of EMTALA on access to or quality of emergency care.
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A new and consistent parameter for measuring the quality of multivariate analytical methods: Generalized analytical sensitivity Generalized analytical sensitivity (γ) is proposed as a new figure of merit, which can be estimated from a multivariate calibration data set. It can be confidently applied to compare different calibration methodologies, and helps to solve literature inconsistencies on the relationship between classical sensitivity and prediction error. In contrast to the classical plain sensitivity, γ incorporates the noise properties in its definition, and its inverse is well correlated with root mean square errors of prediction in the presence of general noise structures. The proposal is supported by studying simulated and experimental first-order multivariate calibration systems with various models, namely multiple linear regression, principal component regression (PCR) and maximum likelihood PCR (MLPCR). The simulations included instrumental noise of different types: independently and identically distributed (iid), correlated (pink) and proportional noise, while the experimental data carried noise which is clearly non-iid.