tbuckley/cabot-search huggingface dataset:
Abstract 14476: Glycosylation-Dependent Lipoprotein Binding of Low-Density Lipoprotein Receptor-Like Domain of Perlecan and Implications for Atherosclerosis
Authors: Yu-Xin Xu, David Ashline, Li Liu, Katya Ravid, Matthew Layne, Vernon Reinhold, Sekar Kathiresan
Journal: Circulation (2012)

Lipoprotein retention by proteoglycans in the arterial wall is a critical step for atherosclerosis. Perlecan is the major proteoglycan in the arterial wall, and various studies have linked it to atherosclerosis, but it has been poorly understood how perlecan contributes to the development of atherosclerosis. Perlecan is a gigantic molecule containing a core protein with five domains (I-V) and three heparan sulfate (HS) side chains. Domain I contains three attachment sites for HS. Domain II has five repeats and four of them are cysteine-rich, and highly homologous to the ligand-binding portion of LDL receptor, but the binding activity has never been investigated. In this study, we hypothesized that perlecan domain II is functional in LDL binding and its coordinated activity with the HS of domain I plays a significant role in the initial LDL retention. Using tagged expression system we expressed and purified the recombinant domain II. We found that the domain is heavily modified and the modification is only present in the secreted, not cellular, form. The modification is O-linked glycosylation containing N-acetyl-glucosamine, fucose, sialic acid, and galactose. In vitro binding assay shows that only the secreted form strongly interacts with LDL, indicating that the interaction is glycosylation-dependent. Two repeats of domain II, the second and fifth, are glycosylated, and most of the domain II glycosylation is from the second, which is serine/threonine rich, no cysteine residue. The mutation of all the glycosylated sites resulted in a mutant whose secreted form is glycosylation defective. We validate that the mutant is inactive in ApoB binding confirming the above glycosylation-dependent interaction. We prove that there is synergistic effect for domain II with the HS of domain I on the ApoB binding. The ligand-binding portion of LDL receptor has 7 cysteine-rich repeats, in which 5 were shown to be required for binding. Our results define the unique feature of perlecan domain II in LDL binding, namely the glycosylation enables the non-cysteine-rich domain to participate in LDL interaction. Thus our data clarify the molecular basis for perlecan in lipoprotein binding suggesting an important role for perlecan in the early LDL retention.
TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome
Authors: Ian A. Myles, Erik D. Anderson, Noah J. Earland, Kol A. Zarember, Inka Sastalla, Kelli W. Williams, Portia Gough, Ian N. Moore, Sundar Ganesan, Cedar J. Fowler, Arian Laurence, Mary Garofalo, Douglas B. Kuhns, Mark D. Kieh, Arhum Saleem, Pamela A. Welch, Dirk A. Darnell, John I. Gallin, Alexandra F. Freeman, Steven M. Holland, Sandip K. Datta
Journal: Journal of Clinical Investigation (2018)

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job’s syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.
Letter by Marín et al Regarding Article, “Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention: A Nationwide Cohort Study”
Authors: FranciscoMarín, LaurentFauchier, AndreaRubboli
Journal: Circulation (2013)
ADAPT: An Algorithm Incorporating PRO‐C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis
Authors: Samuel J. Daniels, Diana J. Leeming, Mohammed Eslam, Ahmed M. Hashem, Mette J. Nielsen, Aleksander Krag, Morten A. Karsdal, Jane I. Grove, Indra Neil Guha, Takumi Kawaguchi, Takuji Torimura, Duncan McLeod, Jun Akiba, Philip Kaye, Bastiaan de Boer, Guruprasad P. Aithal, Leon A. Adams, Jacob George
Journal: Hepatology (2018)

Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥ F3) is the most crucial, as these individuals have the greatest risk of adverse, long‐term, liver‐related outcomes. We aimed to investigate the role of PRO‐C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. We measured PRO‐C3 by enzyme‐linked immunosorbent assay in two large independent cohorts with extensive clinical phenotyping and liver biopsy: 150 in the derivation and 281 in the validation cohort. A PRO‐C3‐based fibrosis algorithm that included a ge, presence of d i a betes, P RO‐C3, and pla t elet count (ADAPT) was developed. PRO‐C3 increased with fibrosis stage (Rho 0.50; P &lt; 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval [CI] 1.02‐1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79‐0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83‐0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase to platelet ratio index (APRI), FIB‐4, and NAFLD fibrosis score (NFS) in most comparisons. Conclusion: PRO‐C3 is an independent predictor of fibrosis stage in NAFLD. A PRO‐C3‐based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB‐4, and NFS.
New health secretary pledges £0.5bn to transform technology in NHS
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The NHS in England is to receive almost half a billion pounds to invest in technology across the service, the new health and social care secretary has announced.

In his first speech since his appointment to replace Jeremy Hunt earlier this month,1 Matt Hancock announced a £487m (€545m; $635m) funding package to create what he described as “the most advanced health system in the world.”

In a speech to staff at West Suffolk Hospital in Bury St Edmunds, the former secretary for digital, culture, media, and sport said that technology, workforce, and prevention would be his early priorities in his new role. “They are intertwined, and they cut across everything my department does,” he …
Association Between the New York Sepsis Care Mandate and In-Hospital Mortality for Pediatric Sepsis
Authors: Idris V. R. Evans, Gary S. Phillips, Elizabeth R. Alpern, Derek C. Angus, Marcus E. Friedrich, Niranjan Kissoon, Stanley Lemeshow, Mitchell M. Levy, Margaret M. Parker, Kathleen M. Terry, R. Scott Watson, Scott L. Weiss, Jerry Zimmerman, Christopher W. Seymour
Journal: JAMA (2018)

<h3>Importance</h3> The death of a pediatric patient with sepsis motivated New York to mandate statewide sepsis treatment in 2013. The mandate included a 1-hour bundle of blood cultures, broad-spectrum antibiotics, and a 20-mL/kg intravenous fluid bolus. Whether completing the bundle elements within 1 hour improves outcomes is unclear. <h3>Objective</h3> To determine the risk-adjusted association between completing the 1-hour pediatric sepsis bundle and individual bundle elements with in-hospital mortality. <h3>Design, Settings, and Participants</h3> Statewide cohort study conducted from April 1, 2014, to December 31, 2016, in emergency departments, inpatient units, and intensive care units across New York State. A total of 1179 patients aged 18 years and younger with sepsis and septic shock reported to the New York State Department of Health who had a sepsis protocol initiated were included. <h3>Exposures</h3> Completion of a 1-hour sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour. <h3>Main Outcomes and Measures</h3> Risk-adjusted in-hospital mortality. <h3>Results</h3> Of 1179 patients with sepsis reported at 54 hospitals (mean [SD] age, 7.2 [6.2] years; male, 54.2%; previously healthy, 44.5%; diagnosed as having shock, 68.8%), 139 (11.8%) died. The entire sepsis bundle was completed in 1 hour in 294 patients (24.9%). Antibiotics were administered to 798 patients (67.7%), blood cultures were obtained in 740 patients (62.8%), and the fluid bolus was completed in 548 patients (46.5%) within 1 hour. Completion of the entire bundle within 1 hour was associated with lower risk-adjusted odds of in-hospital mortality (odds ratio [OR], 0.59 [95% CI, 0.38 to 0.93],<i>P</i> = .02; predicted risk difference [RD], 4.0% [95% CI, 0.9% to 7.0%]). However, completion of each individual bundle element within 1 hour was not significantly associated with lower risk-adjusted mortality (blood culture: OR, 0.73 [95% CI, 0.51 to 1.06],<i>P</i> = .10; RD, 2.6% [95% CI, −0.5% to 5.7%]; antibiotics: OR, 0.78 [95% CI, 0.55 to 1.12],<i>P</i> = .18; RD, 2.1% [95% CI, −1.1% to 5.2%], and fluid bolus: OR, 0.88 [95% CI, 0.56 to 1.37],<i>P</i> = .56; RD, 1.1% [95% CI, −2.6% to 4.8%]). <h3>Conclusions and Relevance</h3> In New York State following a mandate for sepsis care, completion of a sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour was associated with lower risk-adjusted in-hospital mortality among patients with pediatric sepsis and septic shock.
Is the Over-the-Counter Availability of Human Insulin in the United States Good or Bad?
Authors: Jennifer N. Goldstein, Madeline McCrary, Kasia J. Lipska
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
18F-FDG PET/CT With Diffusely High FDG Uptake Throughout Subcutaneous Adipose Tissues
Authors: Melissa Cindy Kong, Helen Ruth Nadel
Journal: Clinical Nuclear Medicine (2018)

A 9-year-old girl presented with facial rash, angioedema, fevers, and night sweats. She was diagnosed with chronic active Epstein-Barr virus infection and placed on chronic steroid treatment. F-FDG PET/CT performed 3 weeks following presentation revealed diffuse subcutaneous soft tissue FDG activation throughout the entire body, with likely localization to white subcutaneous adipose tissue. This highly unusual appearance may have been due to the patient being treated with corticosteroids at the time of the scan.
A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella
Authors: Hannah E. Ledvina, Katherine A. Kelly, Aria Eshraghi, Rachael L. Plemel, S. Brook Peterson, Brian Lee, Shaun Steele, Marlen Adler, Thomas H. Kawula, Alexey J. Merz, Shawn J. Skerrett, Jean Celli, Joseph D. Mougous
Journal: Cell Host & Microbe (2018)
GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain
Authors: Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, Zhen-Zhong Xu, Ru-Rong Ji
Journal: Journal of Clinical Investigation (2018)

The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MΦs. Activation of GPR37 by NPD1 and TX14 triggers MΦ phagocytosis of zymosan particles via calcium signaling. Hind paw injection of pH-sensitive zymosan particles not only induces inflammatory pain and infiltration of neutrophils and MΦs, but also causes GPR37 upregulation in MΦs, phagocytosis of zymosan particles and neutrophils by MΦs in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in MΦ phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient MΦs also show dysregulations of proinflammatory and antiinflammatory cytokines. MΦ depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient MΦs promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating MΦ phagocytosis and inflammatory pain resolution.
Prophylactic Haloperidol for Critically Ill Adults
Authors: Heather Torbic, Abhijit Duggal
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cognitive characteristics in Chinese non-demented PD patients based on gender difference
Authors: Ke Yang, Bo Shen, Da-ke Li, Ying Wang, Jue Zhao, Jian Zhao, Wen-Bo Yu, Zhen-yang Liu, Yi-lin Tang, Feng-tao Liu, Huan Yu, Jian Wang, Qi-hao Guo, Jian-jun Wu
Journal: Translational Neurodegeneration (2018)

Cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD). In the present study, we aim to examine the cognitive function of non-demented Parkinson's disease patients and compare the results between male and female patients as well as control groups in search of any gender effect. Sixty PD Patients (30 males and 30 females) from the Movement Disorders Clinic at Huashan Hospital Affiliated to Fudan University were recruited to participate in the study. One hundred age and gender matched control subjects without neurological or psychiatric disorders were voluntarily recruited. The participants were administered measures of cognition in five domains including memory, language, spatial processing abilities, attention and executive function. PD patients attained significantly lower scores in the visual spatial function, language and attention/executive function compared with the control group. Anti-parkinsonian treated patients performed worse in Rey-copy score, Clock Drawing Test (CDT) and Verbal Fluency-City than untreated ones. In regard to gender differences, though no general cognitive differences were found in Mini-mental State Examination (MMSE), men surpassed women on Boston naming test (BNT) while women were superior on Auditory Verbal Learning Test-long (AVLT) delayed cued recall test. Cognitive impairments were common in PD patients even in the absence of dementia. PD patients with anti-parkinsonian medication had worse cognitive impairment than untreated patients. Genders may have different manifestations of cognitive impairment in PD patients.
Proton pump inhibitors increase the risk of cholecystitis: a population-based case–control study
Authors: Shih-Chieh Chuang, Che-Chen Lin, Cheng-Yuan Peng, Wen-Hsin Huang, Wen-Pang Su, Shih-Wei Lai, Hsueh-Chou Lai
Journal: Gut (2018)

We read with great interest the article by Cheung et al 1 reporting long-term exposure to proton pump inhibitors (PPIs) following Helicobacter pylori (HP) eradication associated with increased risk of gastric cancer. PPIs are widely used worldwide to treat gastro-oesophageal reflux disorder, peptic ulcer and HP, but multiple reports have found they got some negative effects, such as increasing risk of the intra-abdominal infection, like spontaneous bacterial peritonitis,2 pseudomembranous colitis,3 liver abscess4 and affecting the gut microbiome.5 6 PPIs may theoretically increase risk of gaining acute cholecystitis due to the increasing the number of enteric organisms and risk of secondary infection; however, few reports have supported this hypothesis. Thus, we conducted a nationwide population-based case–control study to analyse the relationship between PPI exposure and …
Expression of corticosteroid-regulated genes by PBMCs in children with asthma
Authors: Elena Goleva, Denise C. Babineau, Michelle A. Gill, Leisa P. Jackson, Baomei Shao, Zheng Hu, Andrew H. Liu, Cynthia M. Visness, Christine A. Sorkness, Donald Y.M. Leung, Alkis Togias, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2018)
Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias
Authors: Michael W. Schmitt, Justin R. Pritchard, Scott M. Leighow, Bella I. Aminov, Lan Beppu, Daniel S. Kim, J. Graeme Hodgson, Victor M. Rivera, Lawrence A. Loeb, Jerald P. Radich
Journal: Clinical Cancer Research (2018)

Purpose: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely.Experimental Design: To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations.Results: A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations.Conclusions: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. Clin Cancer Res; 24(21); 5321-34. ©2018 AACR.
Sixty seconds on . . .Love Island
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Move over tennis fans, there’s a new sport in town. The summer’s big hit across the age spectrum is the conscious coupling and uncoupling show. Its stars are 20+ singletons who take pride in their appearance and are looking to form a lasting connection with someone with whom they share interests and looks—I mean outlook.

The ITV2 show that’s gripped the nation at 9 pm every evening since 4 June has attracted 3.7m viewers some nights and spawned its own vocabulary. …
Cardioprotection by ε-Protein Kinase C Activation From Ischemia
Authors: KoichiInagaki, RebeccaBegley, FumiakiIkeno, DariaMochly-Rosen
Journal: Circulation (2005)

Background— We previously showed that a selective activator peptide of e-protein kinase C (PKC), ψeRACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of ψeRACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether ψeRACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo. Methods and Results— After ψeRACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas ψeRACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with ψeRACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of ePKC, and no adverse effects after sustained ψeRACK delivery. Porcine hearts were subjecte...