tbuckley/cabot-search huggingface dataset:
Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II–Induced Hypertension via Regulatory T Cells
Authors: Xiao-Hui Chen, Cheng-Chao Ruan, Qian Ge, Yu Ma, Jian-Zhong Xu, Ze-Bei Zhang, Jing-Rong Lin, Dong-Rui Chen, Ding-Liang Zhu, Ping-Jin Gao
Journal: Circulation Research (2018)

Rationale: Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear. Objective: We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs). Methods and Results: We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR−/−), or C5aR-deficient (C5aR−/−) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals. Conclusions: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.
Electrocardiographic Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome—Reply
Authors: Ashwin Prakash, Leslie Smoot
Journal: JAMA Cardiology (2018)

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Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice
Authors: Scott A. LeMaire, Lin Zhang, Wei Luo, Pingping Ren, Alon R. Azares, Yidan Wang, Chen Zhang, Joseph S. Coselli, Ying H. Shen
Journal: JAMA Surgery (2018)

Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD.
Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex–Mediated Activation of the NLRP3 Inflammasome
Authors: Min Sun Shin, Youna Kang, Elizabeth R. Wahl, Hong‐Jai Park, Rossitza Lazova, Lin Leng, Mark Mamula, Smita Krishnaswamy, Richard Bucala, Insoo Kang
Journal: Arthritis & Rheumatology (2018)

Objective High‐expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to the severity of systemic lupus erythematosus (SLE). The U1 small nuclear RNP (snRNP) immune complex containing U1 snRNP and anti–U1 snRNP antibodies, which are found in patients with SLE, activates the NLRP3 inflammasome, comprising NLRP3, ASC, and procaspase 1, in human monocytes, leading to the production of interleukin‐1β (IL‐1β). This study was undertaken to investigate the role of the snRNP immune complex in up‐regulating the expression of MIF and its interface with the NLRP3 inflammasome. Methods MIF, IL‐1β, NLRP3, caspase 1, ASC, and MIF receptors were analyzed by enzyme‐linked immunosorbent assay, Western blotting, quantitative polymerase chain reaction, and cytometry by time‐of‐flight mass spectrometry (CytoF) in human monocytes incubated with or without the snRNP immune complex. MIF pathway responses were probed with the novel small molecule antagonist MIF098. Results The snRNP immune complex induced the production of MIF and IL‐1β from human monocytes. High‐dimensional, single‐cell CytoF analysis established that MIF regulates activation of the NLRP3 inflammasome, including findings of a quantitative relationship between MIF and its receptors and IL‐1β levels in the monocytes. MIF098, which blocks MIF binding to its cognate receptor, suppressed the production of IL‐1β, the up‐regulation of NLRP3, which is a rate‐limiting step in NLRP3 inflammasome activation, and the activation of caspase 1 in snRNP immune complex–stimulated human monocytes. Conclusion The U1 snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL‐1β production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as those classified as high genotypic MIF expressers or those with anti‐snRNP antibodies.
Predictors of acute care utilization and acute pain treatment outcomes in adults with sickle cell disease: The role of non‐hematologic characteristics and baseline chronic opioid dose
Authors: C. Patrick Carroll, Cody Cichowitz, Tiffany Yu, Yetunde O. Olagbaju, Julie Anne Nelson, Timothy Campbell, Sophie Lanzkron
Journal: American Journal of Hematology (2018)

Despite its rarity in the United States, sickle cell disease accounts for a disproportionate amount of healthcare utilization and costs. The majority of this is due to acute care for painful crises. A small subpopulation of patients accounts for most these costs due to frequent visits to emergency departments and acute care facilities. Previous investigations have found that these high utilizing patients are distinguished by both a more severe disease course and certain non‐hematologic characteristics, which may include higher socioeconomic status and some psychiatric and psychological characteristics. This prospective observational cohort study was undertaken to test the ability of these characteristics to prospectively predict acute pain care outcomes, including visit frequency, total opioid doses, and pain improvement at the Johns Hopkins Sickle Cell Infusion Center (SCIC). Seventy‐three participants were followed for 12 months and SCIC utilization and treatment outcomes were tabulated for 378 visits. Participants who visited the SCIC most frequently had markedly worse pain improvement despite higher within‐visit opioid doses. Higher utilization was associated with indicators of greater illness severity, more aggressive treatment for sickle cell disease, higher baseline opioid doses, higher socioeconomic status, greater pain‐related anxiety, and a history of psychiatric treatment. Overall, poor acute pain treatment response was associated with higher utilization and higher baseline opioid doses. The pattern of association between high utilization, poor acute care outcomes, and higher baseline opioid doses is discussed in terms of prior research and future directions.
Effectiveness and Safety of Standard- and Low-Dose Rivaroxaban in Asians With Atrial Fibrillation
Authors: Yi-Cheng Lin, Shu-Chen Chien, Yi-Chen Hsieh, Chun-Ming Shih, Feng-Yen Lin, Nai-Wen Tsao, Chih-Wei Chen, Yung-Ta Kao, Kuang-Hsing Chiang, Wan-Ting Chen, Li-Nien Chien, Chun-Yao Huang
Journal: Journal of the American College of Cardiology (2018)

Low-dose rivaroxaban (10 mg/day) has been widely used in Asia for patients with atrial fibrillation (AF), although there is a lack of evidence regarding its effectiveness. In Asians, it is unclear whether low-dose rivaroxaban is equally effective as that of the standard dose or is associated with less bleeding risk.The aim of this study was to evaluate the effectiveness and safety of standard-dose (15 or 20 mg/day) and low-dose (10 mg/day) rivaroxaban in Asians with AF.Using data files from the National Health Insurance Research Database between May 1, 2014, and September 30, 2015, a retrospective population-based cohort study was conducted in patients diagnosed with AF or atrial flutter and treated with low- or standard-dose rivaroxaban. Patients were followed up until the first occurrence of the study outcome or the end of the observation period (December 31, 2015).Among 6,558 eligible patients, a total of 2,373 and 4,185 patients took low- and standard-dose rivaroxaban, respectively. Compared to standard-dose rivaroxaban, low-dose rivaroxaban was associated with a significantly higher risk of myocardial infarction (subdistribution hazard ratio: 2.26; 95% confidence interval: 1.13 to 4.52), with similar risk of ischemic stroke, systemic embolism, major bleeding, and nonmajor clinically relevant bleeding.Compared to standard-dose rivaroxaban, low-dose rivaroxaban in Asian patients with AF was associated with similar risks of thromboembolism and bleeding except myocardial infarction.
Abstract 11722: Excellent Preclinical Results of Honeycomb Microporous Covered Stents for the Treatment of Large and Wide-Necked Cerebral Aneurysms
Authors: Yasuhide Nakayama, Tetsu Satow, Marina Funayama, Takeshi Moriwaki, Tsutomu Tajikawa, Maya Furukoshi, Eika Hamano, Daizo Ishii, Masataka Hayashi, Sei Sugata, Hatsue Ishibashi-Ueda, Jun C Takahashi
Journal: Circulation (2015)

Background: We developed covered stents with a microhoneycomb mesh for the treatment of large or giant wide-necked cerebral aneurysms. These aneurysms are extremely difficult to treat and carry high risks, even with the use of clinically available surgical methods or the endovascular technique using coils with the assistance of bare stents. This preclinical study confirmed the excellent performance of our stents in three animal experimental models. Methods and Results: The covered stents were prepared by using balloon-expandable stents (CoCr; diameter, 3.5-5.0 mm; length, 16-28 mm) and by dip coating to cover their struts completely with a polyurethane membrane (thickness, 20 μm), followed by laser microprocessing (pore size, approximately 100 μm; opening ratio, approximately 30%). Model 1: In prepared tortuous canine arteries (n = 12) that simulated the shape of the human internal carotid artery, all stent-mounted delivery catheters could smoothly navigate with little arterial damage. Model 2: In a prepared canine model (n = 10) of large (over 7 mm), wide-necked (over 4 mm) outer-sidewall aneurysms, at 3 months after stenting, completely endothelialized neointima was formed at the aneurysm openings and the aneurysm sacs were entirely organized. Model 3: In rabbit branching abdominal aortas, the vascular flow pattern at all the branching arteries remained unchanged for over 1 year, even after performing overlap stenting (n = 5) in addition to single stenting (n = 5). On all the stented luminal surfaces, complete thin neointimal formation with complete endothelialization was observed. Conclusion: Our newly developed novel covered stents exhibited excellent preclinical performance in three animal experimental models in terms of stent delivery, aneurysm embolization, and flow maintenance in branching arteries. We highly expect that the stents will be useful as endovascular embolization devices for large and wide-necked aneurysms in humans.
Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue
Authors: Guo-Hui Wu, Hui-Juan Shi, Ming-Tian Che, Meng-Yao Huang, Qing-Shuai Wei, Bo Feng, Yuan-Huan Ma, Lai-Jian Wang, Bin Jiang, Ya-Qiong Wang, Inbo Han, Eng-Ang Ling, Xiang Zeng, Yuan-Shan Zeng
Journal: Biomaterials (2018)

We have reported previously that bone marrow mesenchymal stem cell (MSC)-derived neural network scaffold not only survived in the injury/graft site of spinal cord but also served as a "neuronal relay" that was capable of improving the limb motor function in a complete spinal cord injury (SCI) rat model. It remained to be explored whether such a strategy was effective for repairing the large spinal cord tissue loss as well as restoring motor function in larger animals. We have therefore extended in this study to construct a canine MSC-derived neural network tissue in vitro with the aim to evaluate its efficacy in treating adult beagle dog subjected to a complete transection of the spinal cord. The results showed that after co-culturing with neurotropin-3 overexpressing Schwann cells in a gelatin sponge scaffold for 14 days, TrkC overexpressing MSCs differentiated into neuron-like cells. In the latter, some cells appeared to make contacts with each other through synapse-like structures with trans-synaptic electrical activities. Remarkably, the SCI canines receiving the transplantation of the MSC-derived neural network tissue demonstrated a gradual restoration of paralyzed limb motor function, along with improved electrophysiological presentation when compared with the control group. Magnetic resonance imaging and diffusion tensor imaging showed that the canines receiving the MSC-derived neural network tissue exhibited robust nerve tract regeneration in the injury/graft site. Histological analysis showed that some of the MSC-derived neuron-like cells had survived in the injury/graft site up to 6.5 months. Implantation of MSC-derived neural network tissue significantly improved the microenvironment of the injury/graft site. It is noteworthy that a variable number of them had integrated with the regenerating corticospinal tract nerve fibers and 5-HT nerve fibers through formation of synapse-like contacts. The results suggest that the transplanted MSC-derived neural network tissue may serve as a structural and functional "neuronal relay" to restore the paralyzed limb motor function in the canine with complete SCI.
Is the NHS really “based on need?”
Authors: Iain S Fraser
Journal: BMJ (2018)

Readers of The BMJ voted “providing care based on need and free at the point of delivery” as the NHS’s greatest achievement in its 70 years.1 Equity is the foundation stone of the NHS, and by international comparisons it is one of the fairest health systems in the world. But how far have we managed to ensure that the resources available are matched to need? The major determinants …
Dopamine Triggers the Maturation of Striatal Spiny Projection Neuron Excitability during a Critical Period
Authors: Ori J. Lieberman, Avery F. McGuirt, Eugene V. Mosharov, Irena Pigulevskiy, Benjamin D. Hobson, Sejoon Choi, Micah D. Frier, Emanuela Santini, Anders Borgkvist, David Sulzer
Journal: Neuron (2018)
Transcriptional signature primes human oral mucosa for rapid wound healing
Authors: Ramiro Iglesias-Bartolome, Akihiko Uchiyama, Alfredo A. Molinolo, Loreto Abusleme, Stephen R. Brooks, Juan Luis Callejas-Valera, Dean Edwards, Colleen Doci, Marie-Liesse Asselin-Labat, Mark W. Onaitis, Niki M. Moutsopoulos, J. Silvio Gutkind, Maria I. Morasso
Journal: Science Translational Medicine (2018)

Transcriptional profiling of human cutaneous and oral wound healing reveals pathways involved in rapid wound resolution.
Functional Deletion Mutation of the 5′-Flanking Region of Type A Human Natriuretic Peptide Receptor Gene and Its Association With Essential Hypertension and Left Ventricular Hypertrophy in the Japanese
Authors: TomohiroNakayama, MasayoshiSoma, YukieTakahashi, DuolikunRehemudula, KatsuoKanmatsuse, KiyohideFuruya
Journal: Circulation Research (2000)

Abstract—The natriuretic peptide (NP) family is involved in the regulation of blood pressure and fluid volume. We isolated the 5′-flanking region of the type A human NP receptor gene and identified an insertion/deletion mutation in this region. We then assessed whether there is a genetic association between this mutation and essential hypertension (EH). The deletion allele lacks 8 nucleotides and alters binding sites for the activator protein-2 (AP-2) and Zeste transcriptional factors. We genotyped 200 EH and 200 normotensive (NT) individuals and found 9 subjects with the deletion (8 in the EH group and 1 in the NT group). All 9 individuals were heterozygous. The NT subject with the mutation had left ventricular hypertrophy without hypertension. Transcriptional activity of the deletion allele was <30% that of the wild-type allele. The plasma levels of brain NP in EH patients with the deleted allele were significantly higher than the levels in the EH patients with the wild-type allele, and plasma brain NP ...
Abstract 12723: 2D Speckle Tracking Myocardial Strain Gradients Have Positive Relationship With the Degree of Hypertrophy in LV Myocardium for Hypertrophic Cardiomyopathy and Severe Aortic Stenosis With Different Mechanism. A Novel Multi-Layer Technique TTE Study
Authors: Koya Ozawa, Nobusada Funabashi, Hiroyuki Takaoka, Yoshio Kobayashi
Journal: Circulation (2014)

Introduction:  A novel multi-layer technique on speckle tracking TTE can achieve quantitative strain measurements of all, subendocardial, and subepicardial layer of left ventricle (LV), respectively.   Aim:  To compare characteristics of hypertrophic LV myocardium between hypertrophic cardiomyopathy (HCM) and severe aortic stenosis (AS) both with preserved LV ejection fraction (EF) >50%, we measured myocardial strain gradient by 2D LV global longitudinal (GLS) and circumferential strain (GCS) using a multi-layer technique on TTE.   Methods:  60 subjects (40 HCM (30 male; 62 ± 15 yrs) and 20 severe AS (12 male, 74 ± 5 yrs, transaortic maximum velocity 4.9 ± 0.6 m/s, aortic valve area index 0.45 ± 0.13 cm2/m2)) underwent TTE (Vivid-E9). Apical 4, 2, and 3 chamber views for GLS and parasternal short axis views at level of mitral valve, papillary muscle, and apex for GCS were acquired. GLS was averaged from a total of 18 segments acquired from each view. We defined myocardial strain gradient as ratio of subendocardial to subepicardial strain.   Results:  Averaged GLS were significantly smaller in HCM than AS subjects in all, subendocardial and subepicardial layer, respectively. GCS were significantly smaller in HCM than AS subjects at level of mitral valve in subepicardial layer and at level of apex in all and subepicardial layer. There were no significant differences of subendocardial GCS at all levels and GLS gradient from each view between both groups. However GCS gradients at level of mitral valves and apex were significantly greater in HCM than in AS subjects. In HCM subjects, GCS gradient at mitral valve and papillary muscles significantly positively correlated with inter ventricular septum thickness in end diastole (IVStd) (R = 0.363, and 0.373, respectively). In AS subjects, GLS gradient from 4 chamber view and averaged GLS significantly positively correlated with IVStd (R = 0.467 and 0.487, respectively).   Conclusions:  In HCM subjects with preserved LV EF, GLS was significantly smaller than in AS subjects but there were no significant differences of GCS values and GLS gradient between both groups. GCS gradient at mitral valve and papillary muscles for HCM subjects and GLS gradient for severe AS subjects may have positive relationship with degree of LV hypertrophy.
Development of a thermostable spray dried outer membrane vesicle pertussis vaccine for pulmonary immunization
Authors: Gaurav Kanojia, René H.M. Raeven, Larissa van der Maas, Tim H.E. Bindels, Elly van Riet, Bernard Metz, Peter C. Soema, Rimko ten Have, Henderik W. Frijlink, Jean-Pierre Amorij, Gideon F.A. Kersten
Journal: Journal of Controlled Release (2018)

Worldwide resurgence of whooping cough calls for improved, next-generation pertussis vaccines that induce broad and long-lasting immunity. A mucosal pertussis vaccine based on outer membrane vesicles (omvPV) is a promising candidate. Further, a vaccine that is stable outside the cold chain would be of substantial advantage for worldwide distribution and application. A vaccine formulated as a powder could both stabilize the vaccine as well as make it suitable for pulmonary vaccination. To that end, we developed a spray dried omvPV with improved stability compared to the liquid omvPV formulation. Spray drying did not affect the structural integrity of the omvPV. The antigenicity of Vag8, a major antigen in omvPV was diminished slightly and an altered tryptophan fluorescence indicated some changes in protein structure. However, when administered via the pulmonary route in mice after reconstitution, spray dried omvPV showed comparable immune responses and protection against challenge with live B. pertussis as liquid omvPV. Mucosal IgA and Th17 responses were established in addition to broad systemic IgG and Th1/Th17 responses, indicating the induction of an effective immunity profile. Overall, a spray dried omvPV was developed that maintained effective immunogenic properties and has an improved storage stability.
An algorithm for learning shape and appearance models without annotations
Authors: John Ashburner, Mikael Brudfors, Kevin Bronik, Yaël Balbastre
Journal: Medical Image Analysis (2019)

This paper presents a framework for automatically learning shape and appearance models for medical (and certain other) images. The algorithm was developed with the aim of eventually enabling distributed privacy-preserving analysis of brain image data, such that shared information (shape and appearance basis functions) may be passed across sites, whereas latent variables that encode individual images remain secure within each site. These latent variables are proposed as features for privacy-preserving data mining applications. The approach is demonstrated qualitatively on the KDEF dataset of 2D face images, showing that it can align images that traditionally require shape and appearance models trained using manually annotated data (manually defined landmarks etc.). It is applied to the MNIST dataset of handwritten digits to show its potential for machine learning applications, particularly when training data is limited. The model is able to handle "missing data", which allows it to be cross-validated according to how well it can predict left-out voxels. The suitability of the derived features for classifying individuals into patient groups was assessed by applying it to a dataset of over 1900 segmented T1-weighted MR images, which included images from the COBRE and ABIDE datasets.