bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tie2 Activation Promotes Protection and Reconstitution of the Endothelial Glycocalyx in Human Sepsis
Authors: Drost Carolin Christina , Rovas Alexandros , Kusche-Vihrog Kristina , Van Slyke Paul , Kim Harold , Hoang Van C , Maynes Jason T. , Wennmann Dirk Oliver , Pavenstädt Hermann , Linke Wolfgang , Lukasz Alexander , Hesse Bettina , Kümpers Philipp 
Published: September 2019

AbstractThe endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage in sepsis. We hypothesized that angiopoietin-2 (Angpt-2), antagonist of the endothelium-stabilizing receptor Tie2, induces a rapid loss of the eGC in human sepsis. Using intravital microscopy, we measured the perfused boundary region (PBR), an inverse parameter of eGC dimensions in sublingual microvessels, in patients with sepsis and age-matched nonseptic subjects. Median PBR values were significantly higher in patients compared with controls and correlated with serum Angpt-2 levels. To transfer and further explore these findings in a cell culture system, we exposed endothelial cells (ECs) to serum (5%) from a subgroup of septic patients and nonseptic controls. Confocal and atomic force microscopy revealed that sepsis serum, but not control serum, induced thinning of the eGC on human ECs in vitro, which correlated with paired PBR values obtained in vivo (r = 0.96, p < 0.01). Inhibition of Angpt-2 or Tie2 activation completely abolished eGC damage. Mechanistically, sepsis-induced eGC breakdown required the loss of its main constituent heparan sulfate; a result of heparan sulfate-specific enzyme heparanase, which was suppressed by Tie2 activation. Finally, Tie2 activation, but not Angpt-2 inhibition, initiated after septic or enzymatic damage provoked rapid refurbishment of the eGC. Our data indicate that eGC breakdown in human sepsis is mediated via Tie2 deactivation by Angpt-2. Activation of Tie2 seems to accelerate recovery of the eGC and might hold promise as a therapeutic target in human sepsis.
Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery
Authors: Salomon Ophira , Budnik Ivan , Avishai Einat , Tamarin Ilia , Bashari Dalia , Dardik Rima , Livnat Tami 
Published: September 2019

Abstract
Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products.
Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity.
Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration.
Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic.
Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.
Apolipoprotein B100/Low-Density Lipoprotein Regulates Proteolysis and Functions of von Willebrand Factor under Arterial Shear
Authors: Cao Wenjing , Abdelgawwad Mohammad S. , Li Jingzhi , Zheng X. Long 
Published: September 2019

Abstract
Background Proteolytic cleavage of von Willebrand factor (VWF) by a plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motifs, member 13 (ADAMTS13) is regulated by shear stress and binding of coagulation factor VIII, platelets or platelet glycoprotein 1b, and ristocetin to VWF.
Objective Current study aims to identify novel VWF binding partners that may modulate VWF functions under physiological conditions.
Methods A deoxyribonucleic acid aptamer-based affinity purification of VWF, followed by tandem mass spectrometry, functional, and binding assays was employed.
Results Apolipoprotein B100/low-density lipoprotein (apoB100/LDL) was identified as a novel VWF-binding partner. Purified apoB100/LDL was able to accelerate the proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. This rate-enhancing activity was dramatically reduced when apoB100/LDL was oxidized. More interestingly, the oxidized apoB100/LDL appeared to compete with native apoB100/LDL for its enhancing activity on VWF proteolysis under shear. As a control, a purified apoA1/high-density lipoprotein (apoA1/HDL) or apoB48 exhibited a minimal or no activity enhancing VWF proteolysis by ADAMTS13 under the same conditions. Both VWF and ADAMTS13 were able to bind native or oxidized apoB100/LDL with high affinities. No binding interaction was detected between VWF (or ADAMTS13) and apoA1/HDL (or apoB48). Moreover, apoB100/LDL but not its oxidized products inhibited the adhesion of platelets to ultra large VWF released from endothelial cells under flow. Finally, significantly reduced ratios of high to low molecular weight of VWF multimers with increased levels of plasma VWF antigen were detected in LDLR−/−
mice fed with high cholesterol diet.
Conclusion These results indicate that apoB100/LDL may be a novel physiological regulator for ADAMTS13-VWF functions.
Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin
Authors: He Long , Fei Dennis Liang , Nagiec Michal J. , Mutvei Anders P. , Lamprakis Andreas , Kim Bo Yeon , Blenis John 
Published: September 2019

Significance
The clinical effectiveness of FDA-approved anticancer rapalogs is limited because resistance is observed in multiple-tumor settings. In order to improve the efficacy of rapalogs, there is a need to improve our ability to predict and overcome rapamycin resistance. Here we report that high FRAT1/2 expression confers rapamycin resistance by excluding GSK3 from the nucleus in multiple-cancer cell lines. FRAT1 expression is frequently high in multiple cancers, and our observations provide evidence for using FRAT1/2 expression as a biomarker for rapamycin sensitivity. Moreover, our findings reveal a major mechanism for how mTORC1 regulates nuclear protein phosphorylation and signaling, and uncover a potential therapeutic approach for targeting mTORC1-driven cancers.
Preserved capacity for learning statistical regularities and directing selective attention after hippocampal lesions
Authors: Rungratsameetaweemana Nuttida , Squire Larry R. , Serences John T. 
Published: September 2019

Significance
The hippocampus is important for many kinds of learning and memory. We explored the role of the hippocampus in the learning of statistical regularities. We administered a motion discrimination task where expectation about stimulus regularities, the degree of attention afforded to the relevant stimulus, and the amount of available sensory information were manipulated. Although modestly slower overall, patients with bilateral damage to the hippocampus performed similar to controls, exhibiting a normal tendency to respond faster and more accurately when the motion direction was more probable, when the stimulus was better attended, and when more sensory evidence was present. These findings show that the ability to acquire expectations based on regularities of a sensory environment can be independent of the hippocampus.
Perseverative Behavior on Verbal Fluency Task in Patients with Huntington’s Disease: a Retrospective Study on a Large Patient Sample
Authors: De Lucia Natascia , Peluso Silvio , Roca Alessandro , De Michele Giuseppe , Trojano Luigi , Salvatore Elena 
Published: September 2019

Abstract

Objective
Patients with Huntington’s disease (HD) may show impairments of frontal cortical–subcortical circuits with difficulties on cognitive flexibility tasks. One marker of poor flexibility is “perseveration” behavior, which refers to inappropriate and involuntary production of iterative responses not adequate to the current task demands. This study explored frequency, type, and possible cognitive mechanisms of verbal perseverations in a large sample of HD patients.

Method
A sample of 128 patients with HD underwent phonological and category verbal fluency tests to assess perseverative errors, within a wide neuropsychological, psychopathological, motor, and functional assessment.

Results
Perseverative errors in verbal fluency task occurred in 89 (69.5%) patients. Patients showing perseverations scored significantly lower than patients without perseverations on tasks tapping executive and motor functions and on functional independence scales. Logistic regression analysis revealed a significant independent association of verbal perseverations with scores on Trail Making Test only.
Conclusions: Verbal perseverations are frequent in HD patients and are likely related with impairments of attentional switching and working memory, hampering tracking of verbal responses already produced. Perseverative behavior may serve as a useful clinical marker of cognitive and functional impairment in patients with HD.
Comparative Analysis of Cytokines of Tumor Cell Lines, Malignant and Benign Effusions Around Breast Implants
Authors: Kadin Marshall E , Morgan John , Kouttab Nick , Xu Haiying , Adams William P , Glicksman Caroline , McGuire Patricia , Sieber David , Epstein Alan L , Miranda Roberto N , Clemens Mark W 
Published: September 2019

Abstract

Background
More than 700 women have developed an anaplastic large T cell lymphoma (ALCL) surrounding textured surface breast implants, termed breast implant–associated ALCL (BIA-ALCL). Most patients with BIA-ALCL present with an accumulation of fluid (delayed seroma) around the implant. However, benign seromas without malignant cells complicating scar contracture, implant rupture, trauma, infection, and other causes are more common. For proper patient management and to avoid unnecessary surgery, a simple diagnostic test to identify malignant seromas is desirable.

Objectives
The aim of this study was to develop an ancillary test for the diagnosis of malignant seromas and to gain insight into the nature of the malignant cells and their microenvironment.

Methods
We employed an immunologic assay on only 50 µL of aspirated seroma fluid. The assay measures 13 cytokines simultaneously by flow cytometry. To establish a baseline for clinical studies we measured cytokines secreted by BIA-ALCL and cutaneous ALCL lines.

Results
Our study of cell line culture supernatants, and 8 malignant compared with 9 benign seromas indicates that interleukin 9 (IL-9), IL-10, IL-13, IL-22, and/or interferon γ concentrations &gt;1000 pg/mL distinguish malignant seromas from benign seromas. IL-6, known to be a driver of malignant cells, is also elevated in benign seromas and does not distinguish them from malignant seromas.

Conclusions
The cytokine assay introduced in this study can be used together with levels of soluble CD30 to identify malignant seromas. Validation of these findings in a larger prospective patient cohort is warranted. The unique pattern of cytokine expression in malignant effusions surrounding breast implants gives further insight into the pathogenesis and cells of origin of BIA-ALCL.

Level of Evidence: 5
Hybridization and polyploidy in the weeping lizard Liolaemus chiliensis (Squamata: Liolaemidae)
Authors: Araya-Donoso Raúl , Torres-Pérez Fernando , Véliz David , Lamborot Madeleine 
Published: September 2019

Abstract
In reptiles, polyploidy is an unusual phenomenon that can originate from interspecific hybridization. In Chile, the lizard Liolaemus chiliensis provides a unique model with which to study the origin of polyploidy because it occurs in populations of diploid individuals and a few populations that also contain triploid and diploid–triploid mosaic lizards. To test whether L. chiliensis polyploids were hybrids between lineages within the species, we analysed the karyotype, the mitochondrial gene Cytb, seven microsatellite loci, and the linear and geometric morphometry of individuals throughout the species distribution. We found polyploidy at different localities throughout the distribution. Hybrids were detected with the microsatellite loci and morphological data. A clear relationship between hybridization and polyploidy could not be established because triploid and mosaic lizards were hybrids and purebreds. However, our results support the occurrence of both phenomena, and further research is needed to clarify how hybridization could be involved in the origin of polyploidy.
Geographical isolation and restricted gene flow drive speciation of Aegla singularis (Decapoda: Anomura: Aeglidae) in southern South America
Authors: Loretán Gisela , Rueda Eva Carolina , Cabrera Juan Manuel , Pérez-Losada Marcos , Collins Pablo Agustín , Giri Federico 
Published: September 2019

AbstractGeographical isolation is a key element in allopatric speciation. If gene flow is interrupted for long enough by geographical barriers, populations can evolve independently and eventually form distinct species. Aegla singularis provides an ideal model to study this process due to the characteristics of the geographical area that it occupies and its limited dispersal ability. Aegla singularis inhabits streams of the Uruguay and Paraná River basins in the Neotropical region of South America. The basins are separated by the Sierra Central Mountains. Here we studied the speciation of A. singularis resulting from geographical isolation by using molecular and morphometric data. Individuals of A. singularis were analysed using geometric morphometrics and genetic data (COII and EFα1). We found significant differences in shape and genetics between A. singularis populations from the two basins. These differences suggest ongoing divergence due to restricted gene flow caused by the geographical barrier of the Sierra Central Mountains, indicating that the populations of the Parana and Uruguay River slopes are undergoing divergence.
The Relationship Between Axon Density, Myelination, and Fractional Anisotropy in the Human Corpus Callosum
Authors: Friedrich Patrick , Fraenz Christoph , Schlüter Caroline , Ocklenburg Sebastian , Mädler Burkhard , Güntürkün Onur , Genç Erhan 
Published: September 2019

Abstract
The corpus callosum serves the functional integration and interaction between the two hemispheres. Many studies investigate callosal microstructure via diffusion tensor imaging (DTI) fractional anisotropy (FA) in geometrically parcellated segments. However, FA is influenced by several different microstructural properties such as myelination and axon density, hindering a neurobiological interpretation. This study explores the relationship between FA and more specific measures of microstructure within the corpus callosum in a sample of 271 healthy participants. DTI tractography was used to assess 11 callosal segments and gain estimates of FA. We quantified axon density and myelination via neurite orientation dispersion and density imaging (NODDI) to assess intra-neurite volume fraction and a multiecho gradient spin-echo sequence estimating myelin water fraction. The results indicate three common factors in the distribution of FA, myelin content and axon density, indicating potentially shared rules of topographical distribution. Moreover, the relationship between measures varied across the corpus callosum, suggesting that FA should not be interpreted uniformly. More specific magnetic resonance imaging-based quantification techniques, such as NODDI and multiecho myelin water imaging, may thus play a key role in future studies of clinical trials and individual differences.
Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy
Authors: Kumar Ashwani , Ramachandran Raja , Rawat Amit , Das Reena , Rayat Charan S , Kenwar Deepesh B , Sharma Ashish , Gupta Krishan L , Nada Ritambhra 
Published: September 2019

Abstract

Background
Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia.

Methods
In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up.

Results
A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (&lt;1 month) was noted in six patients, whereas recurrence in five patients occurred within 8–17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died.

Conclusion
Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.
The Influence of Microscopic Inflammation at Resection Margins on Early Postoperative Endoscopic Recurrence After Ileocaecal Resection for Crohn’s Disease
Authors: Poredska Karolina , Kunovsky Lumir , Marek Filip , Kala Zdenek , Prochazka Vladimir , Dolina Jiri , Zboril Vladimir , Kovalcikova Petra , Pavlik Tomas , Jabandziev Petr , Pavlovsky Zdenek , Vlazny Jakub , Mitas Ladislav 
Published: September 2019

Abstract

Background and Aims
The pathogenesis and risk factors for early postoperative endoscopic recurrence of Crohn’s disease [CD] remain unclear. Thus, this study aimed to identify whether histological inflammation at the resection margins after an ileocaecal resection influences endoscopic recurrence.

Methods
We have prospectively followed up patients with CD who underwent ileocaecal resection at our hospital between January 2012 and January 2018. The specimens were histologically analysed for inflammation at both of the resection margins [ileal and colonic]. We evaluated whether histological results of the resection margins are correlated with endoscopic recurrence of CD based on colonoscopy 6 months after ileocaecal resection. Second, we assessed the influence of known risk factors and preoperative therapy on endoscopic recurrence of CD.

Results
A total of 107 patients were included in our study. Six months after ileocaecal resection, 23 patients [21.5%] had an endoscopic recurrence of CD. The histological signs of CD at the resection margins were associated with a higher endoscopic recurrence [56.5% versus 4.8%, p &lt; 0.001]. Disease duration from diagnosis to surgery [p = 0.006] and the length of the resected bowel [p = 0.019] were significantly longer in patients with endoscopic recurrence. Smoking was also proved to be a risk factor for endoscopic recurrence [p = 0.028].

Conclusions
Histological inflammation at the resection margins was significantly associated with a higher risk of early postoperative endoscopic recurrence after an ileocaecal resection for CD.
Carotid arterial stiffness is increased and related to left ventricular function in patients with hypertrophic cardiomyopathy
Authors: Roşca Monica , Mandeş Leonard , Ciupercă Daniela , Călin Andreea , Beladan Carmen C , Enache Roxana , Jurcuţ Ruxandra , Coman Ioan M , Ginghină Carmen , Popescu Bogdan A 
Published: September 2019

Abstract

Aims
To assess the carotid mechanical properties in patients with hypertrophic cardiomyopathy and the relation between arterial stiffness and left ventricular function in this setting.

Methods and results
We have prospectively enrolled 71 patients (52 ± 16 years, 34 men) with hypertrophic cardiomyopathy, divided into two groups depending on the presence (46 patients) or absence (25 patients) of cardiovascular risk factors associated with increased arterial stiffness. Twenty-five normal subjects similar by age and gender with hypertrophic cardiomyopathy patients without risk factors formed the control group. A comprehensive echocardiography was performed in all subjects. Carotid arterial stiffness index (β index), pressure–strain elastic modulus, arterial compliance, and pulse wave velocity were also obtained using an echo-tracking system. β index, pulse wave velocity, and pressure–strain elastic modulus were significantly higher in hypertrophic cardiomyopathy patients without risk factors compared to controls. After linear regression analysis, the increase in carotid β index was independently correlated with the presence of hypertrophic cardiomyopathy [beta = 0.49, 95% confidence interval (CI) = 1.04–3.02; P &lt; 0.001]. In the entire hypertrophic cardiomyopathy population arterial stiffness parameters correlated with age, gender, hypertension degree, presence of hypercholesterolaemia, and the E/e′ ratio. In multivariable analysis, β index (beta = 0.36, 95% CI = 0.32–1.25; P = 0.001), global left ventricular longitudinal strain, and the presence of left ventricular outflow tract obstruction were independently correlated with the E/e′ ratio.

Conclusion
In patients with hypertrophic cardiomyopathy arterial stiffness is increased independently of age or presence of cardiovascular risk factors. Carotid artery stiffness is independently related to left ventricular filling pressure, increased arterial stiffness representing a possible marker of a more severe phenotype.