tbuckley/cabot-search huggingface dataset:
18F-FDG PET/CT Imaging of Necrotizing Crescentic Glomerulonephritis With Anti–Glomerular Basement Membrane Disease
Authors: Emily Holt, Andrew Gough, Padmini Prasad, Fahmid U. Chowdhury
Journal: Clinical Nuclear Medicine (2017)

Abstract A 30-year-old woman presented with lethargy, night sweats, and fever with raised inflammatory markers. Anti–neutrophil cytoplasmic antibody was negative. Abdominopelvic CT was unremarkable. Subsequently, she underwent FDG PET/CT showing globally enlarged kidneys with diffuse hypermetabolic activity within the renal parenchyma bilaterally. Renal biopsies showed morphologic features of an active necrotizing crescentic glomerulonephritis, which was confirmed clinically and treated. This case demonstrates the role that FDG PET/CT can play in inflammatory conditions, such as glomerulonephritis, where it may be clinically useful when the presentation is atypical.
Abstract 141: Histone Methyltransferase Setdb2 is important for miRNA mediated cardiac reprogramming
Authors: Imke Kirste, Tilanthi M Jayawardena, J. A Payne, Victor J Dzau, Maria Mirotsou
Journal: Circulation Research (2013)

Rationale: Regeneration of damaged cardiac tissue after injury presents a daunting challenge in cardiovascular medicine. Recent developments in reprogramming of somatic cells directly to cells of other lineages have raised the possibility of using this approach for cardiac regenerative therapy. Our group recently demonstrated successful miRNA mediated cardiac reprogramming in vitro and in vivo using a combination of miRNAs 1, 133, 206 and 499. Although, the molecular mechanisms underlying miRNA mediated fibroblast reprogramming to cardiomyocytes are yet unknown, accumulating evidence suggest that reprogramming acts through distinct phases and that histone modifications play an important role in these processes. Objective: Identify key genes involved in initiating miRNA mediated reprogramming via histone modifications. Methods and Results: For this, we analyzed the expression levels of 81 different genes involved in chromatin modification 4 days after miRNA transfection using PCR arrays. This analysis revealed that 6 of the 81 tested genes showed differential gene expression (≤-1.5-fold and p &lt;0.02). JAK inhibitor-1 treatment, known for increasing reprogramming efficiency, further enhanced gene expression changes in 5 of these 6 genes. Setdb2, an H3K9 methyltransferase, was one of the most down-regulated targets 4 days after miRNA transfection (-1.4 fold, p&lt;0.001). This effect was enhanced further when miRNAs were combined with the JAK inhibitor-1 (-2.6 fold, p&lt;0.001). Silencing of Setdb2 using siRNAs further accentuated miRNA cardiac reprogramming as measured by cardiac transcription factor expression at 3 days and 6 days post treatment. Similar trends were observed by FACS analysis detecting increased percentage of αMHC-positive cells in siRNA treated fibroblasts compared to control treated only with the miRNA combination. Interestingly, our data showed that Setdb2 silencing alone was sufficient to initiate cardiac reprogramming, suggesting that Setdb2 might play a crucial role in defining cardiac cell fate. Conclusion: In conclusion our results indicate that Setdb2 down-regulation plays an important role in the direct reprogramming of fibroblasts to cardiomyocyte-like cells.
Insulin Dosing Error in a Patient With Severe Hyperkalemia
Authors: D. Brock Hewitt, Cynthia Barnard, Karl Y. Bilimoria
Journal: JAMA (2017)

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
Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy
Authors: Jesus G. Berdeja, Yi Lin, Noopur Raje, Nikhil Munshi, David Siegel, Michaela Liedtke, Sundar Jagannath, Marcela V. Maus, Ashley Turka, Lyh Ping Lam, Kristen Hege, Richard A. Morgan, Michael Travis Quigley, James N. Kochenderfer
Journal: Blood (2017)
Abstract 206: Stem Cell-derived Exosomes Induce Cardiac Repair via mRNA Modification
Authors: Prabhu Mathiyalagan, Yaxuan Liang, Adriano S Martins, Douglas W Losordo, Roger J Hajjar, Susmita Sahoo
Journal: Circulation Research (2016)

Exosomes are cell-derived nanovesicles that carry and shuttle microRNAs (miRNAs) to mediate cell-cell communication. Vast majority of cell types including cardiac myocytes and progenitors actively secrete exosomes, whose miRNA contents are altered after physiological or pathological changes such as myocardial ischemia (MI). In this new study, we have discovered that chemical modification to mRNAs is a novel regulator of ischemia-induced gene expression changes in the heart. We hypothesized that the benefits of human CD34 + stem cell-derived exosomes (CD34exo) are mediated by mRNA modifications in the target cells via miRNA delivery. MiRNA profiling and bioinformatic analysis identified that CD34exo is selectively enriched with a number of miRNAs that directly target genes implicated in regulation of mRNA modifications. Interestingly, under myocardial ischemia, there was a significant increase in mRNA modifications in the mouse heart, which was decreased by about 70% with CD34exo-treatment. In line with the in vivo MI data, in vitro hypoxic stimulation in neonatal / adult rodent myocytes and non-myocytes increased mRNA modifications and controls known regulators of those mRNA modifications. Loss-of-function studies for regulators of mRNA modifications attenuated hypoxia-induced changes to epitranscriptome indicating important roles for these molecules under stress conditions. Finally, using gain-of-function and loss-of-function studies, we demonstrate that miR-126, one of the most enriched miRNAs in CD34exo, plays a critical role in regulating the mRNA modifications. We conclude that miRNAs enriched in CD34exo mediate their cardioprotective effect at least in part, by regulating the mRNA epitranscriptome of the target cell. Our new data suggests hypoxia as a novel regulator of the mRNA epitranscriptome and provides novel insights to post-transcriptional gene regulation in the heart.
Abstract 28: Orthostatic Hypotension is Associated With 20-year Cognitive Decline and Incident Dementia: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Andreea Rawlings, Stephen Juraschek, Gerardo Heiss, Timothy Hughes, Michelle Meyer, Elizabeth Selvin, A. Richey Sharrett, B. Gwen Windham, Rebecca Gottesman
Journal: Circulation (2017)

Background: Orthostatic hypotension (OH) has been associated with incident cardiovascular disease and all-cause mortality, but few studies have examined long-term associations with cognitive decline and dementia Hypothesis: OH will be associated with greater cognitive decline and risk of incident dementia Methods: We prospectively analyzed 11503 participants who attended visit 1 (1987-1989) of the ARIC study and had no history of coronary heart disease or stroke. OH was defined as a drop in systolic blood pressure (BP) &gt;=20 mmHg or a drop in diastolic BP &gt;=10 mmHg upon standing from a supine position. Dementia was ascertained using cohort surveillance, telephone contact with the participant or their proxy, or a comprehensive cognitive and neurologic exam in 2011-2013. Cognition was measured via three neuropsychological tests administered in 1990-1992, 1996-1998, and 2011-2013 that were summarized using a Z score. We used adjusted Cox regression and linear mixed models. Results: At visit 1 (mean age 54 years, 57% female, 27% black) 6% of participants had OH. In adjusted models, persons with OH at baseline were 40% more likely to develop dementia than those without OH (HR: 1.40, 95%CI: 1.13, 1.73; Table). Associations were significantly larger in persons with hypertension (p-value for interaction=0.023). Persons with OH compared to those without had significantly more cognitive decline over 20 years (difference: -0.12, 95% CI: -0.23, -0.02; Table). Conclusions: OH assessed in midlife was independently associated with incident dementia and cognitive decline over 20 years. Although typically considered a transient mechanism, these data suggest that OH, or the underlying disease conditions manifesting as OH, persist over time. Whether OH is a marker of vulnerability beyond that of standard hypertension measures, or whether repeated transient exposure to hypotension reduces perfusion to the brain sufficiently to lead to long-term cerebral dysfunction is an important area for further research.
Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study
Authors: Zhang Wang, Richa Singh, Bruce E Miller, Ruth Tal-Singer, Stephanie Van Horn, Lynn Tomsho, Alexander Mackay, James P Allinson, Adam J Webb, Anthony J Brookes, Leena M George, Bethan Barker, Umme Kolsum, Louise E Donnelly, Kylie Belchamber, Peter J Barnes, Dave Singh, Christopher E Brightling, Gavin C Donaldson, Jadwiga A Wedzicha, James R Brown
Journal: Thorax (2017)

Background Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. Methods We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. Results The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. Conclusions Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. Trial registration number Results, NCT01620645 .
Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer
Authors: Jung-Suk Choi, Casey Seol Kim, Anthony Berdis
Journal: Cancer Research (2017)

Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2'-deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2'-deoxyriboside triphosphate, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. Cancer Res; 78(4); 1083-96. ©2017 AACR.
Validation of Risk Equations for Complications of Type 2 Diabetes (RECODe) Using Individual Participant Data From Diverse Longitudinal Cohorts in the U.S.
Authors: Sanjay Basu, Jeremy B. Sussman, Seth A. Berkowitz, Rodney A. Hayward, Alain G. Bertoni, Adolfo Correa, Stanford Mwasongwe, John S. Yudkin
Journal: Diabetes Care (2017)

OBJECTIVE We sought to validate Risk Equations for Complications of Type 2 Diabetes (RECODe) among diverse populations. RESEARCH DESIGN AND METHODS We compared risk predictions from RECODe equations and from two alternative risk models (UK Prospective Diabetes Study Outcomes Model 2 [UKPDS OM2] and American College of Cardiology/American Heart Association Pooled Cohort Equations) to observed outcomes in two studies: the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,555 adults with type 2 diabetes, median follow-up 9.1 years) and the Jackson Heart Study (JHS, n = 1,746 adults with type 2 diabetes, median follow-up 8.0 years). Outcomes included nephropathy by multiple measures (microalbuminuria, macroalbuminuria, renal failure, end-stage renal disease, and reduction in glomerular filtration rate), moderate to severe diabetic retinopathy by Airlie House classification, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, congestive heart failure, and all-cause mortality. RESULTS RECODe equations for microvascular and cardiovascular outcomes had C-statistics for discrimination ranging from 0.71 to 0.85 in MESA and 0.64 to 0.91 in JHS for alternative outcomes. Calibration slopes in MESA ranged from 0.62 for a composite nephropathy outcome, 0.83–1.04 for individual nephropathy outcomes, 1.07 for retinopathy, 1.00–1.05 for cardiovascular outcomes, and 1.03 for all-cause mortality. Slopes in JHS ranged from 0.47 for retinopathy, 0.97–1.16 for nephropathy, 0.72–1.05 for cardiovascular outcomes, and 1.01 for all-cause mortality. The alternative models had C-statistics 0.50–0.72 and calibration slopes 0.07–0.60. CONCLUSIONS RECODe equations improved risk estimation for diverse patients with type 2 diabetes, as compared with two commonly used alternatives.
Liraglutide reduced a composite renal outcome at a median 4 y in patients with type 2 diabetes and high CV risk
Authors: Lorraine L. Lipscombe
Journal: Annals of Internal Medicine (2017)

ACP Journal Club19 December 2017Liraglutide reduced a composite renal outcome at a median 4 y in patients with type 2 diabetes and high CV riskLorraine L. Lipscombe, MD, MScLorraine L. Lipscombe, MD, MScWomen's College Hospital, Toronto, Ontario, Canada (L.L.L.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-167-12-066 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMann JFE, Ørsted DD, Brown-Frandsen K, et al; LEADER Steering Committee and Investigators. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839-48. https://pubmed.ncbi.nlm.nih.gov/28854085Clinical Impact RatingsGIM/FP/GP: Cardiology: Endocrinology: Nephrology: References1 American Diabetes Association. 9. Cardiovascular disease and risk management. Diabetes Care. 2017;40:S75-87. [PMID: 27979896] Google Scholar2 Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-22. [PMID: 27295427] Google Scholar3 Zoungas S, Arima H, Gerstein HC, et al; Collaborators on Trials of Lowering Glucose (CONTROL) group. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5:431-7. [PMID: 28365411] Google Scholar4 Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435-43. [PMID: 26559744] Google Scholar5 Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-28. [PMID: 26378978] Google Scholar Author, Article, and Disclosure InformationAffiliations: Women's College Hospital, Toronto, Ontario, Canada (L.L.L.)This article was published at Annals.org on 5 December 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 December 2017Volume 167, Issue 12Page: JC66KeywordsEstimated glomerular filtration rateHbA1cRenal analysisRenal diseasesSubcutaneous injectionsThyroidThyroid carcinomaType 1 diabetesType 2 diabetesWeight loss ePublished: 19 December 2017 Issue Published: 19 December 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial
Authors: Laszlo Hegedüs, Steven I. Sherman, R. Michael Tuttle, Bernt J. von Scholten, Søren Rasmussen, Julie D. Karsbøl, Gilbert H. Daniels
Journal: Diabetes Care (2017)

To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER) trial over a 3.5-5-year period.Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms.At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients.There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group.
Effect of adjuvant trastuzumab (T) among patients treated with neoadjuvant T-based chemotherapy.
Authors: Mariana Chavez-Mac Gregor, Napa Parinyanitikul, Elizabeth Ann Mittendorf, Xiudong Lei, Hong Zhang, Aman Buzdar, Kelly Hunt, Gabriel N. Hortobagyi, Vicente Valero, Ana M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2014)

644 Background: Neoadjuvant T-based chemotherapy is commonly used in the treatment of invasive HER2-positive breast cancer. Pathological complete response (pCR) is a surrogate of improved long-term outcomes; the impact of adjuvant T among patients achieving a pCR is unknown. Among patients treated with neoadjuvant T-based chemotherapy we evaluated the impact of completion of adjuvant T. Methods: Patients with primary HER2-positive breast cancer treated with T-based neoadjuvant chemotherapy at our institution between 2001-2012 were included and categorized according to adjuvant T administration and pCR (no invasive residual tumor in the breast and ipsilateral axillary lymph nodes). Descriptive statistics and Cox proportional hazard models were used. Results: 589 patients were included. 203 (34.5%) achieved a pCR. 109 (18.5%) did not receive adjuvant including 53 (26.1%) that achieved a pCR and 56 (14.5%) that did not achieve a pCR. Median follow up was 45 months. The 5 year-OS for patients who did and did not receive adjuvant T was 91% vs 93% (p=0.97) and the 5-year RFS was 92% vs 85% (p=0.33). Among patients that achieved a pCR, the 5-year OS was 96% vs 100% (p=0.23) and the RFS was 93% vs 100% (p=0.06) for patient that did and did not receive adjuvant T. Among those without a pCR, the 5-year OS was 92% vs 83% (p=0.28) and the RFS was 81% vs 84% (p=0.67) for patients that did and did not receive adjuvant T. In the multivariable analysis after adjusting for pCR, adjuvant T had no impact on outcome (HR=0.85 p=0.68 for OS and HR 1.05 p=0.9 for RFS). Among patients with pCR, adjuvant T did not improve OS or RFS (HR=2.7 p=0.35 and HR=8.02 p=0.93), the benefit of adjuvant T in OS and RFS did not achieve statistical significance among patients without a pCR (HR=0.64 p=0.3 and 0.76 p=0.44). Conclusions: Our data demonstrates that patients treated with neoadjuvant T-based chemotherapy that achieve a pCR, have excellent outcome regardless of whether they received or not adjuvant T. Among patients not achieving a pCR, the use of newer agents should be studied in order to further improve outcomes. Our results are relevant as our field evaluates the appropriate duration, therapeutic index, and cost of additional targeted therapies.
Online access to GPs can offer benefits to GPs and patients
Authors: Stephen Black
Journal: BMJ (2017)

The BMJ reports a study that found online consultations increase workload for general practitioners (GPs).1 But we shouldn’t write off the benefits of electronic consultation tools for either GPs or patients on the basis of a study of a single system that achieved very low rates of use.

Some alternatives to eConsult have very different philosophies. eConsult and some competitors use complex algorithms to supplement …