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  • Authors: Evangelos Terpos; Richard J. Cook; Robert E. Coleman; Allan Lipton; +1 Authors

    Abstract Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P < .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

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    Article . 2007
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      Article . 2007
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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Ren Na; Yanjie Luo; Haoyu Bo; Jian Zhang; +5 Authors

    Abstract Sunflower (Helianthus annuus) can be infected by the fungal pathogen Sclerotinia sclerotiorum, but its susceptibility varies depending on the cultivars. The aim of this study was to characterize and compare the biochemical responses between the R and the S sunflower cultivars after inoculation with S. sclerotiorum. The biochemical activities were detected by measuring necrotic cell, callose deposition, soluble protein content, as well as ROS accumulation at the infection site. Antioxidant enzymatic activities, the transcripts of ROS related genes and marker genes in pathways of salicylic acid (SA) and jasmonic acid (JA) were also quantified to characterize the responses. Results showed that compared to the S cultivar, the R cultivar was characterized having reduced number of necrotic cell, more callose deposition on the cell wall, increased soluble protein content, higher levels of H2O2 and ROS scavenger enzyme activities, and upregulated transcript profile of marker genes of both SA and JA pathways.

    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Physiological and Mo...arrow_drop_down
    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Physiological and Molecular Plant Pathology
    Article . 2018
    License: Elsevier TDM
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      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Physiological and Mo...arrow_drop_down
      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
      Physiological and Molecular Plant Pathology
      Article . 2018
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Vijaya M, Musini; Kendra Ak, Lawrence; Patricia M, Fortin; Ken, Bassett; +1 Authors

    Background Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II. Objectives To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension. To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema). Search methods The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work. Selection criteria We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension. Data collection and analysis This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available. Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs. Main results 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias. Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes. Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. Authors' conclusions Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Cochrane Database of...arrow_drop_down
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    Europe PubMed Central
    Other literature type . 2017
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      Europe PubMed Central
      Other literature type . 2017
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Alexander Aarvold; Ryan Lohre; Harpreet Chhina; Kishore Mulpuri; +1 Authors

    Aims Though the pathogenesis of Legg-Calve-Perthes disease (LCPD) is unknown, repetitive microtrauma resulting in deformity has been postulated. The purpose of this study is to trial a novel upright MRI scanner, to determine whether any deformation occurs in femoral heads affected by LCPD with weightbearing. Methods Children affected by LCPD were recruited for analysis. Children received both standing weightbearing and supine scans in the MROpen upright MRI scanner, for coronal T1 GFE sequences, both hips in field of view. Parameters of femoral head height, width, and lateral extrusion of affected and unaffected hips were assessed by two independent raters, repeated at a one month interval. Inter- and intraclass correlation coefficients were determined. Standing and supine measurements were compared for each femoral head. Results Following rigorous protocol development in healthy age-matched volunteers, successful scanning was performed in 11 LCPD-affected hips in nine children, with seven unaffected hips therefore available for comparison. Five hips were in early stage (1 and 2) and six were in late stage (3 and 4). The mean age was 5.3 years. All hips in early-stage LCPD demonstrated dynamic deformity on weightbearing. Femoral head height decreased (mean 1.2 mm, 12.4% decrease), width increased (mean 2.5 mm, 7.2% increase), and lateral extrusion increased (median 2.5 mm, 23% increase) on standing weightbearing MRI compared to supine scans. Negligible deformation was observed in contra-lateral unaffected hips, with less deformation observed in late-stage hips. Inter- and intraclass reliability for all measured parameters was good to excellent. Conclusion This pilot study has described an effective novel research investigation for children with LCPD. Femoral heads in early-stage LCPD demonstrated dynamic deformity on weightbearing not previously seen, while unaffected hips did not. Expansion of this protocol will allow further translational study into the effects of loading hips with LCPD. Cite this article: Bone Joint Open 2020;1-7:364–369.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Almoudaris, A; Mamidanna, R; Bottle, A; Aylin, P; +3 Authors

    IMPORTANCE: Gastroesophageal cancer resections are associated with significant reintervention and perioperative mortality rates. OBJECTIVE: To compare outcomes following operative and nonoperative reinterventions between high- and low-mortality gastroesophageal cancer surgical units in England. DESIGN: All elective esophageal and gastric resections for cancer between 2000 and 2010 in English public hospitals were identified from a national administrative database. Units were divided into low- and high-mortality units (LMUs and HMUs, respectively) using a threshold of 5% or less for 30-day adjusted mortality. The groups were compared for reoperations and nonoperative reinterventions following complications. SETTING: Both LMUs and HMUs. PARTICIPANTS: Patients who underwent esophageal and gastric resections for cancer. EXPOSURE: Elective esophageal and gastric resections for cancer, with reoperations and nonoperative reinterventions following complications. MAIN OUTCOMES AND MEASURES: Failure to rescue is defined as the death of a patient following a complication; failure to rescue-surgical is defined as the death of a patient following reoperation for a surgical complication. RESULTS: There were 14 955 esophagectomies and 10 671 gastrectomies performed in 141 units. For gastroesophageal resections combined, adjusted mortality rates were 3.0% and 8.3% (P < .001) for LMUs and HMUs, respectively. Complications rates preceding reoperation were similar (5.4% for LMUs vs. 4.9% for HMUs; P = .11). The failure to rescue-surgical rates were lower in LMUs than in HMUs (15.3% vs. 24.1%; P < .001). The LMUs performed more nonoperative reinterventions than the HMUs did (6.7% vs. 4.7%; P < .001), with more patients surviving in LMUs than in HMUs (failure to rescue rate, 7.0% vs. 12.5%; P < .001). Overall, LMUs reintervened more than HMUs did (12.2% vs 9.6%; P < .001), and LMUs had lower failure to rescue rates following reintervention than HMUs did (9.0% vs. 18.3%; P = .001). All P values stated refer to 2-sided values. CONCLUSIONS AND RELEVANCE: Overall, LMUs were more likely to reintervene and rescue patients following gastroesophageal cancer resections in England. Patients were more likely to survive following both reoperations and nonsurgical interventions in LMUs.

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    JAMA Surgery
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  • Authors: Winau, L.; Baydes, R.H.; Braner, A.; Drott, U.; +12 Authors

    BackgroundCardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR).Methods and resultsThis is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement.ConclusionsPatients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement.Trial registration numerNCT02407197; Results.

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    Authors: P, Marcato; G, Mulvey; R J, Read; , Vander Helm K; +2 Authors

    The Shiga toxins Stx1 and Stx2 contribute to the development of enterohemorrhagic O157: H7 Escherichia coli‐mediated colitis and hemolytic-uremic syndrome in humans. The Stx2 B subunit, which binds to globotriaosylceramide (GB3) receptors on target cells, was cloned. This involved replacing the Stx2 B subunit leader peptide nucleotide sequences with those from the Stx1 B subunit. The construct was expressed in the TOPP3 E. coli strain. The Stx2 B subunits from this strain assembled into a pentamer and bound to a GB3 receptor analogue. The cloned Stx2 B subunit was not cytotoxic to Vero cells or apoptogenic in Burkitt’s lymphoma cells. Although their immune response to the Stx2 B subunit was variable, rabbits that developed Stx2 B subunit‐specific antibodies, as determined by immunoblot and in vitro cytotoxicity neutralization assays, survived a challenge with Stx2 holotoxin. This is thought to be the first demonstration of the immunoprophylactic potential of the Stx2 B subunit.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: David, Tweats; David A, Eastmond; Anthony M, Lynch; Azeddine, Elhajouji; +6 Authors

    Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.

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    ENEA Open Archive
    Article . 2019
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    ENEA Open Archive
    Article . 2019
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      ENEA Open Archive
      Article . 2019
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      ENEA Open Archive
      Article . 2019
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Peige Song; Manli Wang; Xinlei Chang; Jiawen Wang; +2 Authors

    ABSTRACTAimTo assess the prevalence of impaired renal function and its associated factors in Chinese children.MethodsChildren aged 7–18 years in China Health and Nutrition Survey (CHNS) 2009 were included as participants, and their anthropometric measurements, blood pressure (BP) and biochemical parameters were taken for analysis. The estimated glomerular filtration rate (eGFR) was calculated by using the Schwartz ‘original’ formula.ResultsThe prevalence of estimated glomerular filtration rate (eGFR) < 90 mL/min per 1.73 m2 and <75 mL/min per 1.73 m2 was 10.09% (95% CI: 8.03–12.11) and 1.01% (95% CI: 0.38–1.77), respectively. The prevalence of impaired renal function (eGFR <60 mL/min per 1.73 m2) was 0.25%. Age was detected as a negative associated factor whereas hyperuricemia and elevated total cholesterol (TC) were positively associated factors for subjects with eGFR <90 mL/min per 1.73 m2. In the group of eGFR <75 mL/min per 1.73 m2, only elevated TC was related to the increased odds of decreased eGFR.ConclusionOur findings underscore the need for large‐scale programs to detect and treat the early‐stage impaired renal function in the paediatric population in China.

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    Europe PubMed Central
    Other literature type . 2019
    Data sources: PubMed Central
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    Nephrology
    Article
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    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Nephrology
    Article . 2019
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      Other literature type . 2019
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      Nephrology
      Article
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      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
      Nephrology
      Article . 2019
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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Zhen-Wang, Zhao; Min, Zhang; Ling-Yan, Chen; Duo, Gong; +8 Authors

    Abstract Background and aims Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE−/− mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. Methods HSP70 was overexpressed in apoE−/− mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE−/− mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Results Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE−/− mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE−/− mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE−/− mice. Conclusions HSP70 promotes the progression of atherosclerosis in apoE−/− mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.

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  • Authors: Evangelos Terpos; Richard J. Cook; Robert E. Coleman; Allan Lipton; +1 Authors

    Abstract Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P &lt; .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

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    Blood
    Article . 2007
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      Article . 2007
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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Ren Na; Yanjie Luo; Haoyu Bo; Jian Zhang; +5 Authors

    Abstract Sunflower (Helianthus annuus) can be infected by the fungal pathogen Sclerotinia sclerotiorum, but its susceptibility varies depending on the cultivars. The aim of this study was to characterize and compare the biochemical responses between the R and the S sunflower cultivars after inoculation with S. sclerotiorum. The biochemical activities were detected by measuring necrotic cell, callose deposition, soluble protein content, as well as ROS accumulation at the infection site. Antioxidant enzymatic activities, the transcripts of ROS related genes and marker genes in pathways of salicylic acid (SA) and jasmonic acid (JA) were also quantified to characterize the responses. Results showed that compared to the S cultivar, the R cultivar was characterized having reduced number of necrotic cell, more callose deposition on the cell wall, increased soluble protein content, higher levels of H2O2 and ROS scavenger enzyme activities, and upregulated transcript profile of marker genes of both SA and JA pathways.

    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Physiological and Mo...arrow_drop_down
    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Physiological and Molecular Plant Pathology
    Article . 2018
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      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
      Physiological and Molecular Plant Pathology
      Article . 2018
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Vijaya M, Musini; Kendra Ak, Lawrence; Patricia M, Fortin; Ken, Bassett; +1 Authors

    Background Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II. Objectives To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension. To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema). Search methods The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work. Selection criteria We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension. Data collection and analysis This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available. Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs. Main results 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias. Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes. Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. Authors' conclusions Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

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    Europe PubMed Central
    Other literature type . 2017
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      Europe PubMed Central
      Other literature type . 2017
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    Authors: Alexander Aarvold; Ryan Lohre; Harpreet Chhina; Kishore Mulpuri; +1 Authors

    Aims Though the pathogenesis of Legg-Calve-Perthes disease (LCPD) is unknown, repetitive microtrauma resulting in deformity has been postulated. The purpose of this study is to trial a novel upright MRI scanner, to determine whether any deformation occurs in femoral heads affected by LCPD with weightbearing. Methods Children affected by LCPD were recruited for analysis. Children received both standing weightbearing and supine scans in the MROpen upright MRI scanner, for coronal T1 GFE sequences, both hips in field of view. Parameters of femoral head height, width, and lateral extrusion of affected and unaffected hips were assessed by two independent raters, repeated at a one month interval. Inter- and intraclass correlation coefficients were determined. Standing and supine measurements were compared for each femoral head. Results Following rigorous protocol development in healthy age-matched volunteers, successful scanning was performed in 11 LCPD-affected hips in nine children, with seven unaffected hips therefore available for comparison. Five hips were in early stage (1 and 2) and six were in late stage (3 and 4). The mean age was 5.3 years. All hips in early-stage LCPD demonstrated dynamic deformity on weightbearing. Femoral head height decreased (mean 1.2 mm, 12.4% decrease), width increased (mean 2.5 mm, 7.2% increase), and lateral extrusion increased (median 2.5 mm, 23% increase) on standing weightbearing MRI compared to supine scans. Negligible deformation was observed in contra-lateral unaffected hips, with less deformation observed in late-stage hips. Inter- and intraclass reliability for all measured parameters was good to excellent. Conclusion This pilot study has described an effective novel research investigation for children with LCPD. Femoral heads in early-stage LCPD demonstrated dynamic deformity on weightbearing not previously seen, while unaffected hips did not. Expansion of this protocol will allow further translational study into the effects of loading hips with LCPD. Cite this article: Bone Joint Open 2020;1-7:364–369.

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    Authors: Almoudaris, A; Mamidanna, R; Bottle, A; Aylin, P; +3 Authors

    IMPORTANCE: Gastroesophageal cancer resections are associated with significant reintervention and perioperative mortality rates. OBJECTIVE: To compare outcomes following operative and nonoperative reinterventions between high- and low-mortality gastroesophageal cancer surgical units in England. DESIGN: All elective esophageal and gastric resections for cancer between 2000 and 2010 in English public hospitals were identified from a national administrative database. Units were divided into low- and high-mortality units (LMUs and HMUs, respectively) using a threshold of 5% or less for 30-day adjusted mortality. The groups were compared for reoperations and nonoperative reinterventions following complications. SETTING: Both LMUs and HMUs. PARTICIPANTS: Patients who underwent esophageal and gastric resections for cancer. EXPOSURE: Elective esophageal and gastric resections for cancer, with reoperations and nonoperative reinterventions following complications. MAIN OUTCOMES AND MEASURES: Failure to rescue is defined as the death of a patient following a complication; failure to rescue-surgical is defined as the death of a patient following reoperation for a surgical complication. RESULTS: There were 14 955 esophagectomies and 10 671 gastrectomies performed in 141 units. For gastroesophageal resections combined, adjusted mortality rates were 3.0% and 8.3% (P < .001) for LMUs and HMUs, respectively. Complications rates preceding reoperation were similar (5.4% for LMUs vs. 4.9% for HMUs; P = .11). The failure to rescue-surgical rates were lower in LMUs than in HMUs (15.3% vs. 24.1%; P < .001). The LMUs performed more nonoperative reinterventions than the HMUs did (6.7% vs. 4.7%; P < .001), with more patients surviving in LMUs than in HMUs (failure to rescue rate, 7.0% vs. 12.5%; P < .001). Overall, LMUs reintervened more than HMUs did (12.2% vs 9.6%; P < .001), and LMUs had lower failure to rescue rates following reintervention than HMUs did (9.0% vs. 18.3%; P = .001). All P values stated refer to 2-sided values. CONCLUSIONS AND RELEVANCE: Overall, LMUs were more likely to reintervene and rescue patients following gastroesophageal cancer resections in England. Patients were more likely to survive following both reoperations and nonsurgical interventions in LMUs.

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  • Authors: Winau, L.; Baydes, R.H.; Braner, A.; Drott, U.; +12 Authors

    BackgroundCardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR).Methods and resultsThis is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement.ConclusionsPatients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement.Trial registration numerNCT02407197; Results.

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    Authors: P, Marcato; G, Mulvey; R J, Read; , Vander Helm K; +2 Authors

    The Shiga toxins Stx1 and Stx2 contribute to the development of enterohemorrhagic O157: H7 Escherichia coli‐mediated colitis and hemolytic-uremic syndrome in humans. The Stx2 B subunit, which binds to globotriaosylceramide (GB3) receptors on target cells, was cloned. This involved replacing the Stx2 B subunit leader peptide nucleotide sequences with those from the Stx1 B subunit. The construct was expressed in the TOPP3 E. coli strain. The Stx2 B subunits from this strain assembled into a pentamer and bound to a GB3 receptor analogue. The cloned Stx2 B subunit was not cytotoxic to Vero cells or apoptogenic in Burkitt’s lymphoma cells. Although their immune response to the Stx2 B subunit was variable, rabbits that developed Stx2 B subunit‐specific antibodies, as determined by immunoblot and in vitro cytotoxicity neutralization assays, survived a challenge with Stx2 holotoxin. This is thought to be the first demonstration of the immunoprophylactic potential of the Stx2 B subunit.

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    Authors: David, Tweats; David A, Eastmond; Anthony M, Lynch; Azeddine, Elhajouji; +6 Authors

    Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms. Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process. Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence. The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.

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    Authors: Peige Song; Manli Wang; Xinlei Chang; Jiawen Wang; +2 Authors

    ABSTRACTAimTo assess the prevalence of impaired renal function and its associated factors in Chinese children.MethodsChildren aged 7–18 years in China Health and Nutrition Survey (CHNS) 2009 were included as participants, and their anthropometric measurements, blood pressure (BP) and biochemical parameters were taken for analysis. The estimated glomerular filtration rate (eGFR) was calculated by using the Schwartz ‘original’ formula.ResultsThe prevalence of estimated glomerular filtration rate (eGFR) < 90 mL/min per 1.73 m2 and <75 mL/min per 1.73 m2 was 10.09% (95% CI: 8.03–12.11) and 1.01% (95% CI: 0.38–1.77), respectively. The prevalence of impaired renal function (eGFR <60 mL/min per 1.73 m2) was 0.25%. Age was detected as a negative associated factor whereas hyperuricemia and elevated total cholesterol (TC) were positively associated factors for subjects with eGFR <90 mL/min per 1.73 m2. In the group of eGFR <75 mL/min per 1.73 m2, only elevated TC was related to the increased odds of decreased eGFR.ConclusionOur findings underscore the need for large‐scale programs to detect and treat the early‐stage impaired renal function in the paediatric population in China.

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    Nephrology
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    Nephrology
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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Zhen-Wang, Zhao; Min, Zhang; Ling-Yan, Chen; Duo, Gong; +8 Authors

    Abstract Background and aims Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE−/− mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. Methods HSP70 was overexpressed in apoE−/− mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE−/− mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Results Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE−/− mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE−/− mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE−/− mice. Conclusions HSP70 promotes the progression of atherosclerosis in apoE−/− mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.

    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Biochimica et Biophy...arrow_drop_down
    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
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      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Biochimica et Biophy...arrow_drop_down
      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
      addClaim

      This Research product is the result of merged Research products in OpenAIRE.

      You have already added works in your ORCID record related to the merged Research product.