bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron‐chelating agent, deferasirox, inhibits neutrophil activation and extracellular trap formation
Authors: Kono Mari , Saigo Katsuyasu , Yamamoto Shiori , Shirai Kohei , Iwamoto Shuta , Uematsu Tomoko , Takahashi Takayuki , Imoto Shion , Hashimoto Makoto , Minami Yosuke , Wada Atsushi , Takenokuchi Mariko , Kawano Seiji 
Published: June 2016

SummaryIron‐chelating agents, which are frequently prescribed to transfusion‐dependent patients, have various useful biological effects in addition to chelation. Reactive oxygen species (ROS) produced by neutrophils can cause pulmonary endothelial cell damage, which can lead to acute lung injury (ALI). We previously reported that deferasirox (DFS), an iron‐chelating agent, inhibits phorbol myristate acetate (PMA) or formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐induced ROS production in neutrophils, in vitro. Here, we investigate whether DFS inhibits vacuolization in neutrophils and neutrophil extracellular trap (NET) formation. Human neutrophils were incubated with DFS and stimulated with PMA or fMLP. Human neutrophils were separated from heparinized peripheral blood using density gradient centrifugation, and subsequently incubated with DFS. After 10 minutes, neutrophils were stimulated by PMA or fMLP. Vacuole formation was observed by electron microscopy. For observing NET formations using microscopes, immunohistological analyses using citrullinated histone H3 and myeloperoxidase antibodies, and SYTOX Green (an impermeable DNA detection dye) staining, were conducted. NET formation was measured as the quantity of double‐stranded DNA (dsDNA), using the AccuBlue Broad Range dsDNA Quantitation Kit. DFS (50 μmol/L) inhibited vacuole formation in the cytoplasm and NET formation. Additionally, 5–100 μmol/L concentration of DFS inhibited the release of dsDNA in a dose‐independent manner. We demonstrate that DFS inhibits not only ROS production but also vacuolization and NET formation in neutrophils. These results suggest the possibility of protective effects of DFS against NET‐related adverse effects, including ALI and thrombosis.
Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases
Authors: McDowell Lachlan J , Tan Tze‐Jian , Bressel Mathias , Estall Vanessa , Kleid Stephen , Corry June , Johnston Meredith L 
Published: June 2016

AbstractIntroductionCutaneous squamous cell carcinoma of the head and neck (cHNSCC) metastatic to the parotid has a moderate risk of recurrence despite multimodality treatment. Immunosuppression is associated with lower rates of long‐term cure. Our aim was to review outcomes of current management in a tertiary centre with a view to targeting future strategies.MethodsA retrospective review of clinico‐pathological data and outcomes for patients with metastatic cHNSCC involving the parotid gland, undergoing radical surgery and adjuvant radiotherapy during 2000–2014 was conducted. The Kaplan–Meier method was used to determine time‐to‐event outcomes.ResultsOne hundred and thirty‐two patients met the inclusion criteria. Median follow‐up was 5.0 years. Five‐year overall (OS), cancer‐specific (CSS) and progression free survival (PFS) were 44% (95% Confidence Interval (CI) 34–53%), 64% (95% CI 52–74%) and 37% (95% CI 28–47%) respectively. Locoregional control (LRC) was 68% (95% CI 55–77%) at 5 years. Immunosuppressed patients fared worse (compared with immune‐competent) with five‐year OS, CSS, and PFS of 14% versus 53% (HR = 3.19; 95% CI 1.91–5.34), 40% versus 71% (Hazard Ratio (HR) = 2.92; 95% CI 1.38–6.19) and 10% versus 46% (HR = 2.51; 95% CI 1.52–4.14) respectively. On multivariate analysis, immune status strongly predicted OS (P < 0.001), CSS (P = 0.003), DMFS (P < 0.001) and PFS (P < 0.001), but not LRC. Largest lymph node size was the only significant factor predictive for LRC on multivariate analysis (P = 0.02).ConclusionsDespite multimodality treatment metastatic cHNSCC involving the parotid shows moderate rates of recurrence. Immunosuppressed patients with this disease have a particularly poor prognosis, demonstrating lower rates of CSS with similar rates of LRC compared to their immunocompetent counterparts.
A randomized trial assessing the impact of three different glycoprotein IIb/IIIa antagonists on glycoprotein IIb/IIIa platelet receptor inhibition and clinical endpoints in patients with acute coronary syndromes
Authors: Holmes Lewis E. , Gupta Rohan , Rajendran Saissan , Luu John , French John K. , Juergens Craig P. 
Published: June 2016

SummaryAimsTo compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and coadministered P2Y12 agents.MethodsEighty‐three acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with planned GPI use were randomized to receive high‐dose bolus tirofiban, double‐bolus eptifibatide, or abciximab followed by a 12‐hour infusion. Glycoprotein IIb/IIIa platelet receptor inhibition was measured at baseline and at 10 minutes, 1 hour, and 24 hours postbolus dose. Major adverse cardiac events and bleeding complications at 30 days were documented. The incidence of MACEs and bleeding in patients receiving ticagrelor or prasugrel were compared to those given clopidogrel.ResultsThere were no statistically significant differences in platelet inhibition between GPIs at 10 minutes (P=.085) and 1 hour (P=.337). At 24 hours, abciximab achieved statistically significantly higher median [interquartile range] platelet inhibition (75 [65–88]%) compared to tirofiban (28 [3–56]%; P<.0001) and eptifibatide (44 [31–63]%; P=.007). There were no differences in bleeding or MACEs depending on GPI or P2Y12 inhibitor administered.ConclusionsGlycoprotein receptor inhibitors achieve similar levels of platelet inhibition at 10 minutes and 1 hour; however, abciximab maintains this benefit 24 hours after bolus dose. We did not witness an increased rate of bleeding in patients given new potent P2Y12 inhibitors and a GPI in the modern era.
Safety and efficacy of policosanol in patients with high on‐treatment platelet reactivity after drug‐eluting stent implantation: two‐year follow‐up results
Authors: Xu Kai , Liu Xinming , Li Yi , Wang Yunuo , Zang Hongyun , Guo Liang , Wang Yuan , Zhao Wei , Wang Xiaozeng , Han Yaling 
Published: June 2016

SummaryObjectivesTo investigate safety and efficacy of policosanol in patients with high on‐treatment platelet reactivity after drug‐eluting stent implantation.BackgroundCertain number of patients has high residual platelet reactivity on clopidogrel after coronary intervention, and their risk of thrombotic events is high.MethodIn this prospective, randomized trial conducted in four Chinese sites, 350 patients with high on‐treatment platelet reactivity (HPR, defined as platelet aggregation >65%) were randomized by the ratio of 1:3:3 to: group A, clopidogrel 75 mg/d for 1 year (n=50); group B, clopidogrel 150 mg/d for 30 days followed by 75 mg/d until 1 year (n=150); or group C, policosanol 40 mg/d for 6 month and clopidogrel 75 mg/d for 1 year (n=150). All of them were treated with aspirin. The primary endpoint was the reversion rate of HPR at 1 month (reversion was defined as platelet aggregation <65%). The secondary endpoints were 6‐month major adverse cardiac events (MACE), which included cardiac death, nonfatal myocardial infarction, or ischemic symptoms driven target vessel revascularization.ResultsAt 30 days, the reversion rate of HPR was 34.0%, 55.2%, and 48.7% in group A, group B, and group C, respectively (P=.029). Major adverse cardiac events occurred in 4 (8.0%), 6(4.0%), and 5(3.3%) patients (P=.342). There was 1 (0.7%) major bleeding and 1 (0.7%) minor bleeding event in high maintenance dose clopidogrel group, no major or moderate bleeding in the other two groups. The minimal bleeding in group B was significantly higher than group C (10.7% vs 2.7%, P=.022). At 2‐year follow‐up, the benefits of policosanol on bleedings persisted compared with group B.ConclusionsPolicosanol reduced platelet reactivity to a similar extent as high maintenance dose of clopidogrel without increasing bleeding rate.
Rho‐Kinase inhibitor fasudil suppresses high glucose‐induced H9c2 cell apoptosis through activation of autophagy
Authors: Gao Huikuan , Hou Fei , Dong Ruiqing , Wang Zefeng , Zhao Can , Tang Wurina , Wu Yongquan 
Published: June 2016

SummaryIntroductionCardiac cell apoptosis plays a crucial role in the progression of diabetic cardiomyopathy. Recent studies have shown that fasudil, a Rho‐kinase (ROCK) inhibitor, inhibits cardiac cell apoptosis; however, the underlying mechanism remains unclear.AimThis study aimed to investigate whether fasudil protects H9c2 cells from high glucose‐induced apoptosis via activation of autophagy.MethodsRat cardiomyocyte H9c2 cells were treated with high glucose and used as a diabetic cardiomyopathy model. Cell survival rate, apoptosis, and subcellular morphology were examined using the MTT assay, flow cytometry, and electron microscopy, respectively. ROCK1 and ROCK2 mRNA levels were determined using quantitative real‐time PCR. Bcl‐2 and Bax, myosin phosphatase target subunit‐1 (MYPT‐1), phosphorylated (p)‐MYPT1, LC3‐II/LC3‐I, Beclin‐1, soluble and insoluble P62 protein levels were determined by Western blot analysis.ResultsFasudil reversed the high glucose‐induced inhibition of cell proliferation and suppressed high glucose‐induced early apoptosis. Fasudil also reversed the high glucose‐suppressed Bcl‐2 levels and decreased the high glucose‐induced Bax levels. Further, Fasudil suppressed ROCK levels, expression, promoted autophagy via increasing the LC3‐II/LC3‐I ratio, Beclin‐1 expression, and the number of autophagosomes in H9c2 cells treated with high glucose. These effects of fasudil were abrogated by 3‐methyladenine (3‐MA), an autophagy inhibitor.ConclusionFasudil inhibited high glucose‐induced apoptosis in rat H9c2 cells through activating autophagy.
Are there subtypes of bipolar depression?
Authors: Perich T. , Hadzi‐Pavlovic D. , Frankland A. , Breakspear M. , Loo C. , Roberts G. , Holmes‐Preston E. , Mitchell P. B. 
Published: June 2016

ObjectiveTo investigate for subtypes of bipolar depression using latent class analysis (LCA).MethodParticipants were recruited through a bipolar disorder (BD) clinic. LCA was undertaken using: (i) symptoms reported on the SCID‐IV for the most severe lifetime depressive episode; (ii) lifetime illness features such as age at first depressive and hypo/manic episodes; and (iii) family history of BD and unipolar depression. To explore the validity of any demonstrated ‘classes’, clinical, demographic and treatment correlates were investigated.ResultsA total of 243 BD subjects (170 with BD‐I and 73 with BD‐II) were included. For the combined sample, we found two robust LCA solutions, with two and three classes respectively. There were no consistent solutions when the BD‐I and BD‐II samples were considered separately. Subjects in class 2 of the three‐class solution (characterised by anxiety, insomnia, reduced appetite/weight loss, irritability, psychomotor retardation, suicidal ideation, guilt, worthlessness and evening worsening) were significantly more likely to be in receipt of government financial support, suggesting a particularly malign pattern of symptoms.ConclusionOur study suggests the existence of two or three distinct classes of bipolar depression and a strong association with functional outcome.
The canine era: the rise of a biomedical model
Authors: van Steenbeek F. G. , Hytönen M. K. , Leegwater P. A. J. , Lohi H. 
Published: June 2016

SummarySince the annotation of its genome a decade ago, the dog has proven to be an excellent model for the study of inherited diseases. A large variety of spontaneous simple and complex phenotypes occur in dogs, providing physiologically relevant models to corresponding human conditions. In addition, gene discovery is facilitated in clinically less heterogeneous purebred dogs with closed population structures because smaller study cohorts and fewer markers are often sufficient to expose causal variants. Here, we review the development of genomic resources from microsatellites to whole‐genome sequencing and give examples of successful findings that have followed the technological progress. The increasing amount of whole‐genome sequence data warrants better functional annotation of the canine genome to more effectively utilise this unique model to understand genetic contributions in morphological, behavioural and other complex traits.
Laparoscopic subtotal proctocolectomy for synchronous triple colorectal cancers: a case report
Authors: Okoshi Kae , Mizumoto Masaki , Kinoshita Koichi 
Published: June 2016

AbstractA 42‐year‐old woman presented with abdominal pain. On the basis of CT results, we diagnosed her condition as bowel obstruction caused by advanced transverse colon cancer. Colonoscopy findings showed three lesions: (i) an advanced tumor in the transverse colon; (ii) a laterally spreading descending colon tumor; and (iii) a rectal polyp. The tumors and the polyp were all pathologically diagnosed as adenocarcinoma. After inserting a self‐expanding metallic stent into the main tumor of the transverse colon to decompress the bowel, we performed endoscopic submucosal dissection of the laterally spreading descending colon tumor. Pathological examination results showed submucosal invasion and a positive margin. Because we endoscopically identified that the rectal polyp was invading the submucosa, we performed laparoscopic subtotal proctocolectomy and ileorectal anastomosis with lymph node dissection along the surgical trunk; we also performed central vascular ligation of the ileocolic artery, right and left branches of the middle colic artery, and inferior mesenteric artery. The patient's postoperative course was uneventful. We present this case because there have been few reports on laparoscopic subtotal or total proctocolectomy for synchronous multiple colorectal cancers.
Glycogen synthase kinase‐3β in patients with bipolar I disorder: results from a prospective study
Authors: Jacoby Anne S , Munkholm Klaus , Vinberg Maj , Joaquim Helena GP , Talib Leda L , Gattaz Wagner F , Kessing Lars V 
Published: June 2016

ObjectivesThe enzyme glycogen synthase kinase‐3β (GSK3β) is involved in the mechanisms of action of lithium and may play a role in relation to affective states in bipolar disorder. The objectives of the present study were to compare the activity of GSK‐3β (measured as levels of phosphorylated GSK‐3β [p‐GSK‐3β]) between patients with bipolar disorder in the euthymic state and healthy control subjects, and to investigate whether GSK‐3β activity varies with affective states in patients with bipolar I disorder.MethodsIn a prospective 6–12‐month follow‐up study, we investigated state‐specific, intraindividual alterations in the activity of GSK‐3β in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic, depressive and manic states and compared this with repeated measurements in healthy control subjects. Data were analyzed using linear mixed‐effects models.ResultsFrom baseline to the end of follow‐up, blood samples were drawn from the 60 patients during 181 affective states, comprising 60 manic, 11 mixed, 23 depressive, and 87 states of euthymia. A total of 69 blood samples were drawn from 35 healthy control subjects, with two samples from the same subject taken three months apart. In mixed‐model analysis, p‐GSK‐3β was decreased in the euthymic state of subjects with bipolar disorder compared with healthy control subjects (b=0.63, 95% confidence interval [CI]: 0.42–0.96, P=.03). In addition, p‐GSK‐3β varied with affective states, being increased in depressive (b=1.68, 95% CI: 1.08–2.62, P=.02) and mixed (b=2.07, 95% CI: 1.12–3.84, P=.02) states but not in mania compared with euthymia.ConclusionsThe activity of GSK‐3β is altered in euthymic bipolar disorder compared with healthy control subjects and varies with affective states.
Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective
Authors: Shokouhi Sepideh , Campbell Desmond , Brill Aaron B. , Gwirtsman Harry E. ,   The Alzheimer's Disease Neuroimaging Initiative
Published: June 2016

AbstractRecent Alzheimer's trials have recruited cognitively normal people at risk for Alzheimer's dementia. Due to the lack of clinical symptoms in normal population, conventional clinical outcome measures are not suitable for these early trials. While several groups are developing new composite cognitive tests that could serve as potential outcome measures by detecting subtle cognitive changes in normal people, there is a need for longitudinal brain imaging techniques that can correlate with temporal changes in these new tests and provide additional objective measures of neuropathological changes in brain. Positron emission tomography (PET) is a nuclear medicine imaging procedure based on the measurement of annihilation photons after positron emission from radiolabeled molecules that allow tracking of biological processes in body, including the brain. PET is a well‐established in vivo imaging modality in Alzheimer's disease diagnosis and research due to its capability of detecting abnormalities in three major hallmarks of this disease. These include (1) amyloid beta plaques; (2) neurofibrillary tau tangles and (3) decrease in neuronal activity due to loss of nerve cell connection and death. While semiquantitative PET imaging techniques are commonly used to set discrete cut‐points to stratify abnormal levels of amyloid accumulation and neurodegeneration, they are suboptimal for detecting subtle longitudinal changes. In this study, we have identified and discussed four critical barriers in conventional longitudinal PET imaging that may be particularly relevant for early Alzheimer's disease studies. These include within and across subject heterogeneity of AD‐affected brain regions, PET intensity normalization, neuronal compensations in early disease stages and cerebrovascular amyloid deposition.
Direct modulation of TRPM4 and TRPM3 channels by the phospholipase C inhibitor U73122
Authors: Leitner Michael G , Michel Niklas , Behrendt Marc , Dierich Marlen , Dembla Sandeep , Wilke Bettina U , Konrad Maik , Lindner Moritz , Oberwinkler Johannes , Oliver Dominik 
Published: June 2016

Background and PurposeSignalling through phospholipase C (PLC) controls many cellular processes. Much information on the relevance of this important pathway has been derived from pharmacological inhibition of the enzymatic activity of PLC. We found that the most frequently employed PLC inhibitor, U73122, activates endogenous ionic currents in widely used cell lines. Given the extensive use of U73122 in research, we set out to identify these U73122‐sensitive ion channels.Experimental ApproachWe performed detailed biophysical analysis of the U73122‐induced currents in frequently used cell lines.Key ResultsAt concentrations required to inhibit PLC, U73122 modulated the activity of transient receptor potential melastatin (TRPM) channels through covalent modification. U73122 was shown to be a potent agonist of ubiquitously expressed TRPM4 channels and activated endogenous TRPM4 channels in CHO cells independently of PLC and of the downstream second messengers PI(4,5)P2 and Ca2+. U73122 also potentiated Ca2+‐dependent TRPM4 currents in human Jurkat T‐cells, endogenous TRPM4 in HEK293T cells and recombinant human TRPM4. In contrast to TRPM4, TRPM3 channels were inhibited whereas the closely related TRPM5 channels were insensitive to U73122, showing that U73122 exhibits high specificity within the TRPM channel family.Conclusions and ImplicationsGiven the widespread expression of TRPM4 and TRPM3 channels, these actions of U73122 must be considered when interpreting its effects on cell function. U73122 may also be useful for identifying and characterizing TRPM channels in native tissue, thus facilitating the analysis of their physiology.
Effect of pretreatment with antifungal agents on clinical outcomes in fungal keratitis
Authors: Sun Catherine Q , Prajna N Venkatesh , Krishnan Tiruvengada , Rajaraman Revathi , Srinivasan Muthiah , Raghavan Anita , O'Brien Kieran S , McLeod Stephen D , Acharya Nisha R , Rose‐Nussbaumer Jennifer ,   Mycotic Ulcer Treatment Trial Group
Published: June 2016

AbstractBackgroundTo determine if pretreatment with antifungal agents is predictive of worse clinical outcome in a fungal keratitis clinical trial.DesignNon‐pre‐specified subgroup analysis of a randomized controlled trial in a tertiary hospital.ParticipantsThree hundred twenty‐three fungal ulcer cases with an enrolment visual acuity of 20/40 to 20/400.MethodsThe Mycotic Ulcer Treatment Trial I was a randomized, double‐masked trial to determine the optimal treatment for filamentous fungal keratitis at the Aravind Eye Care System, India. Enrolled cases were randomized to receive topical natamycin or voriconazole. Prior antifungal medication use, dose and duration were collected at enrolment. A subgroup analysis was performed to determine if patients using natamycin or azoles at presentation have worse clinical outcomes compared with those who were not pretreated.Main Outcome MeasuresThree‐month visual acuity (primary), 3‐month infiltrate or scar size, corneal perforation and/or transplant and re‐epithelialization time.ResultsOf the 323 patients enrolled, 44% presented on an antifungal agent. Pretreated patients had larger mean baseline infiltrate size (P < 0.001) and epithelial defect size (P = 0.02). Multivariate regression analysis demonstrated that pretreatment was associated with significantly worse 3‐month visual acuity (P = 0.006), larger 3‐month scar size (P < 0.001) and increased odds of corneal perforation and/or transplant (P = 0.001).ConclusionsFungal keratitis that is smear‐positive despite being pretreated with appropriate antifungal agents appears to be a risk factor for worse outcomes, likely a result of initial ulcer severity and treatment failure. These patients may benefit from more aggressive multimodal therapy at a tertiary centre.
EF1A1/HSC70 Cooperatively Suppress Brain Endothelial Cell Apoptosis via Regulating JNK Activity
Authors: Liu Ying , Jiang Shu , Yang Peng‐Yuan , Zhang Yue‐Fan , Li Tie‐Jun , Rui Yao‐Cheng 
Published: June 2016

SummaryAimsIn our previous study, eEF1A1 was identified to be a new target for protecting brain ischemia injury, but the mechanism remains largely unknown. In this study, we screened the downstream cellular protein molecules interacted with eEF1A1 and found mechanism of eEF1A1 in brain ischemia protection.Methods and resultsThrough co‐immunoprecipitation and mass spectrometry for searching the interaction of proteins with eEF1A1 in bEnd3 cells, HSC70 was identified to be a binding protein of eEF1A1, which was further validated by Western blot and immunofluorescence. eEF1A1 or HSC70 knockdown, respectively, increased OGD‐induced apoptosis of brain vascular endothelial cells, which was detected by Annexin V‐FITC/PI staining. HSC70 or eEF1A1 knockdown enhances phosphorylated JNK, phosphorylation of c‐JUN (Ser63, Ser73), cleaved caspase‐9, and cleaved caspase‐3 expression, which could be rescued by JNK inhibitor.ConclusionIn summary, our data suggest that the presence of chaperone forms of interaction between eEF1A1 and HSC70 in brain vascular endothelial cells, eEF1A1 and HSC70 can play a protective role in the process of ischemic stroke by inhibiting the JNK signaling pathway activation.