tbuckley/cabot-search huggingface dataset:
Clinical Hematology. A Practical Guide to the Examination of the Blood, with Reference to Diagnosis.
Journal: JAMA (1902)

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Burning Pain in the Legs
Authors: Aravind Reghukumar, Reshma Benson
Journal: New England Journal of Medicine (2020)

A 24-year-old woman who had been receiving antiretroviral therapy presented with severe, burning pain in the legs after taking ergotamine for a migraine headache. CT angiography revealed diffuse, symmetric narrowing of the arteries in both legs, a finding consistent with ergotism.
Membrane budding is a major mechanism of in vivo platelet biogenesis
Authors: Kathryn S. Potts, Alison Farley, Caleb A. Dawson, Joel Rimes, Christine Biben, Carolyn de Graaf, Margaret A. Potts, Olivia J. Stonehouse, Amandine Carmagnac, Pradnya Gangatirkar, Emma C. Josefsson, Casey Anttila, Daniela Amann-Zalcenstein, Shalin Naik, Warren S. Alexander, Douglas J. Hilton, Edwin D. Hawkins, Samir Taoudi
Journal: The Journal of Experimental Medicine (2020)

How platelets are produced by megakaryocytes in vivo remains controversial despite more than a century of investigation. Megakaryocytes readily produce proplatelet structures in vitro; however, visualization of platelet release from proplatelets in vivo has remained elusive. We show that within the native prenatal and adult environments, the frequency and rate of proplatelet formation is incompatible with the physiological demands of platelet replacement. We resolve this inconsistency by performing in-depth analysis of plasma membrane budding, a cellular process that has previously been dismissed as a source of platelet production. Our studies demonstrate that membrane budding results in the sustained release of platelets directly into the peripheral circulation during both fetal and adult life without induction of cell death or proplatelet formation. In support of this model, we demonstrate that in mice deficient for NF-E2 (the thrombopoietic master regulator), the absence of membrane budding correlates with failure of in vivo platelet production. Accordingly, we propose that membrane budding, rather than proplatelet formation, supplies the majority of the platelet biomass.
Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers
Authors: Massimiliano Lorenzini, Gabrielle Norrish, Ella Field, Juan Pablo Ochoa, Marcos Cicerchia, Mohammed M. Akhtar, Petros Syrris, Luis R. Lopes, Juan Pablo Kaski, Perry M. Elliott
Journal: Journal of the American College of Cardiology (2020)

Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.
Are we responsible for the racial inequalities of covid-19?
Authors: Varathagini Balakumar, Arangan Kirubakaran, Shabnam Tariq
Journal: BMJ (2020)

<h3>Abstract</h3> A notion of implied susceptible population size ISPS was introduced in the context of the SIR differential equations in Epidemiology, in a companion paper. It is the potential target population size for which the solution to the SIR equations would yield the current number of new affected cases. This notion is applied to the analysis and projection of Covid19 2020, illustrated on the data of Germany, Israel, Italy and USA.
Association of Interleukin 7 Immunotherapy With Lymphocyte Counts Among Patients With Severe Coronavirus Disease 2019 (COVID-19)
Authors: Pierre Francois Laterre, Bruno François, Christine Collienne, Philippe Hantson, Robin Jeannet, Kenneth E. Remy, Richard S. Hotchkiss
Journal: JAMA Network Open (2020)

lymphocytes returning to a reference level, appearing to reverse a pathologic hallmark of COVID-19.Importantly, previous studies have reported that IL-7-associated restoration of lymphocyte numbers enhanced the activity of antiviral agents. 6 A limitation of the current study is that no phenotypic or functional studies of immune cells were conducted.Administration of IL-7 alone or in combination with other therapies warrants serious consideration for patients with COVID-19 and evidence of immunosuppression.
Clinical impact of endoscopic ultrasound-guided through-the-needle microbiopsy in patients with pancreatic cysts
Authors: Bojan Kovacevic, Pia Klausen, Charlotte Vestrup Rift, Anders Toxværd, Hanne Grossjohann, John Gásdal Karstensen, Lene Brink, Hazem Hassan, Evangelos Kalaitzakis, Jan Storkholm, Carsten Palnæs Hansen, Jane Preuss Hasselby, Peter Vilmann
Journal: Endoscopy (2020)

Abstract Background The limited data on the utility of endoscopic ultrasound (EUS)-guided through-the-needle biopsies (TTNBs) in patients with pancreatic cystic lesions (PCLs) originate mainly from retrospective studies. Our aim was to determine the clinical impact of TTNBs, their added diagnostic value, and the adverse event rate in a prospective setting. Methods This was a prospective, single-center, open-label controlled study. Between February 2018 and August 2019, consecutive patients presenting with a PCL of 15 mm or more and referred for EUS were included. Primary outcome was a change in clinical management of PCLs following TTNB compared with cross-sectional imaging and cytology. Adverse events were defined according to the ASGE lexicon. Results 101 patients were included. TTNBs led to a change in clinical management in 11.9 % of cases (n = 12). Of these, 10 had serous cysts and surveillance was discontinued, while one of the remaining two cases underwent surgery following diagnosis of a mucinous cystic neoplasm. The diagnostic yield of TTNBs for a specific cyst diagnosis was higher compared with FNA cytology (69.3 % vs. 20.8 %, respectively; P &lt; 0.001). The adverse event rate was 9.9 % (n = 10; 95 % confidence interval 5.4 % – 17.3 %), with the most common event being acute pancreatitis (n = 9). Four of the observed adverse events were severe, including one fatal outcome. Conclusions TTNBs resulted in a change of clinical management in about one in every 10 patients; however, the associated adverse event risk was substantial. Further studies are warranted to elucidate in which subgroups of patients the clinical benefit outweighs the risks.
THU0091 Il-8 production induced by protein i/ii, a modulin from oral streptococci, in synoviocytes from rheumatoid arthritis (ra) patients involves the mapks and fak signalling pathways and nf-kb
Authors: L Neff, M Zeisel, FX Limbach, JP Klein, D Wachsmann, J Sibilia
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Protein I/II, an adhesin from viridans streptococci, commensal bacteria of the oral cavity, can stimulate different cells including endothelial cells. After binding to its receptor, integrin Α5Β1, protein I/II promotes release of IL-6 and IL-8 from endothelial cells, which contributes to the recruitment of circulating leukocytes from the blood into tissues. IL-8 has recently by associated with the pathogenesis of various chronic inflammatory disorders such as RA. IL-8 could be produced in response to commensal bacteria which could disseminate through bacteremia. <h3>Objectives</h3> To study the interactions of protein I/II with fibroblast-like synoviocytes from RA patients. <h3>Methods</h3> <h3>Results</h3> Protein I/II increased the IL-8 synthesis of fibroblast-like synoviocytes through transcriptional up-regulation of the IL-8 gene (ELISA and RT-PCR). IL-8 synthesis was inhibited by the tyrosine kinase inhibitor herbimycin A and by inhibitors of MAPKs such as apigenin and PD 98059, while focal adhesion kinase (FAK) and ERK1/2 phosphorylation was increased by Protein I/II. Protein I/II increased activated nuclear translocation of the transcription factor NF-ΚB (EMSA with an NF-ΚB specific probe). This was confirmed by inhibition with curcumin, an inhibitor of NF-ΚB, which blocked IL-8 release from protein I/II-activated synoviocytes. <h3>Conclusion</h3> After binding to synoviocytes, protein I/II induces IL-8 release by activaing the FAK and MAPKs signalling pathways. The transcription factor NF-ΚB plays a major role in the up-regulation of IL-8 synthesis and release mediated by NF-ΚB. Synoviocytes activation could be triggered by commensal bacteria, which could spread to the joints through bacteremia in RA and others forms of arthritis.
Evaluation of Online Risk Assessment To Identify Rabies Exposures Among Health Care Workers — Utah, 2019
Authors: Erin R. Whitehouse, Dallin Peterson, Keegan McCaffrey, Amit Eichenbaum, Randon Gruninger, Kristin K. Dascomb, Cherie Frame, Ryan Wallace, Jesse Bonwitt
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On November 7, 2018, the Utah Department of Health (UDOH) reported the first confirmed human rabies death in the state since 1944 (1). The case occurred in a person who had been treated over a period of 19 days at four health care facilities and an emergency medical transport service across three counties and two states. Human rabies is preventable through preexposure or postexposure vaccination but is invariably fatal upon symptom onset. Timely identification of persons who might have been exposed to rabies virus is therefore crucial to administer postexposure prophylaxis (PEP). Because of the large number of health care workers who had been involved in the patient's care, a standardized online risk assessment survey was developed by UDOH based on Advisory Committee on Immunization Practices recommendations (2). This online tool was evaluated for accuracy, acceptability, and administrative obligation by reviewing the results from the tool and conducting focus group discussions and a follow-up survey. Among 90 health care workers initially identified by the online risk assessment as being potentially exposed to infectious material, 74 were classified as exposed. All 74 health care workers received PEP following consultation with occupational health staff members, indicating a positive predictive value of the assessment tool of 82%. In a follow-up survey, 42 (76%) of the 55 respondents reported that they were satisfied with the assessment process. In focus group discussions, participants suggested that the survey could be improved by providing additional information about rabies exposures because many of them were unfamiliar with human-to-human rabies transmission. This evaluation highlighted the importance of adopting clear communication strategies, demonstrated the benefits of using an online risk assessment during a mass rabies exposure, and provided specific feedback for CDC to improve resources available for states and health care facilities after mass rabies exposures.
Population genetic screening efficiently identifies carriers of autosomal dominant diseases
Authors: J. J. Grzymski, G. Elhanan, J. A. Morales Rosado, E. Smith, K. A. Schlauch, R. Read, C. Rowan, N. Slotnick, S. Dabe, W. J. Metcalf, B. Lipp, H. Reed, L. Sharma, E. Levin, J. Kao, M. Rashkin, J. Bowes, K. Dunaway, A. Slonim, N. Washington, M. Ferber, A. Bolze, J. T. Lu
Journal: Nature Medicine (2020)
Feeding the Fire: The Comorbid and Inflammatory Backdrop of Clonal Hematopoiesis of Indeterminate Potential (CHIP) By Mutation Subtype
Authors: Elina K Cook, Terumi Izukawa, Sherylan Young, Gili Rosen, Mina Jamali, Brooke Snetsinger, Dylan Johnson, Eva Bain, Jamie Hilland, Jonah Buckstein, Janika Francis, Bushra Momtaz, Rena Buckstein, Michael J. Rauh
Journal: Blood (2017)
Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway
Authors: Lu Chen, Yanping Wang, Shulin Li, Bangjie Zuo, Xiangyu Zhang, Fengzhen Wang, Dong Sun
Journal: Theranostics (2020)

Mesenchymal stem cells (MSCs) have emerged as ideal cell-based therapeutic candidates for the structural and functional restoration of the diseased kidney. Glial cell line-derived neurotrophic factor (GDNF) has been demonstrated to promote the therapeutic effect of MSCs on ameliorating renal injury. The mechanism may involve the transfer of endogenous molecules via paracrine factors to salvage injured cells, but these factors remain unknown. Methods: GDNF was transfected into human adipose mesenchymal stem cells via a lentiviral transfection system, and exosomes were isolated (GDNF-AMSC-exos). Using the unilateral ureteral obstruction (UUO) mouse model and human umbilical vein endothelial cells (HUVECs) against hypoxia/serum deprivation (H/SD) injury models, we investigated whether GDNF-AMSC-exos ameliorate peritubular capillary (PTC) loss in tubulointerstitial fibrosis and whether this effect is mediated by the Sirtuin 1 (SIRT1) signaling pathway. Additionally, by using SIRT1 activators or siRNAs, the roles of the candidate mRNA and its downstream gene in GDNF-AMSC-exo-induced regulation of endothelial cell function were assessed. PTC characteristics were detected by fluorescent microangiography (FMA) and analyzed by the MATLAB software. Results: The green fluorescent PKH67-labeled exosomes were visualized in the UUO kidneys and colocalized with CD81. GDNF-AMSC-exos significantly decreased PTC rarefaction and renal fibrosis scores in mice with UUO. In vitro studies revealed that GDNF-AMSC-exos exerted cytoprotective effects on HUVECs against H/SD injury by stimulating migration and angiogenesis as well as conferring apoptosis resistance. Mechanistically, GDNF-AMSC-exos enhanced SIRT1 signaling, which was accompanied by increased levels of phosphorylated endothelial nitric oxide synthase (p-eNOS). We also confirmed the SIRT1-eNOS interaction in HUVECs by immunoprecipitation. Furthermore, we observed a correlation of the PTC number with the SIRT1 expression level in the kidney in vivo. Conclusion: Our study unveiled a mechanism by which exosomes ameliorate renal fibrosis: GDNF-AMSC-exos may activate an angiogenesis program in surviving PTCs after injury by activating the SIRT1/eNOS signaling pathway.
Дифференцированный подход к органосохраняющим операциям в лечении желчнокаменной болезни
Authors: B.F. Shevchenko, A.M. Babiy
Journal: GASTROENTEROLOGY (2013)

Обследовано 163 пациента с неосложненным одиночным холецистолитиазом. На основании данных клинико-лабораторных, инструментальных исследований и лапароскопии были уточнены известные и дополнены новые критерии отбора пациентов для осуществления органосохраняющей операции — холецистолитотомии, которая выполнена в 67 (41,1 %) случаях, остальным 96 пациентам произведена холецистэктомия. В отдаленном периоде (в сроки до 6,2 года) рецидив камнеобразования после холецистолитотомии отмечен в 5 (10,6 %) случаях, функциональные нарушения органов пищеварения после холецистэктомии — в 22,2 % случаев.
THU0109 The destructive process of rheumatoid arthritis synovial fibroblasts (ra-sf) is independent of p53
Authors: CA Seemayer, S Kuchen, M Neihart, P Kuenzler, E Neumann, M Pruschy, T Pap, WK Aicher, U Muller-Ladner, BA Michel, RE Gay, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of this study was to investigate, whether the destructive process of synovial fibroblasts in rheumatoid arthritis is dependent on the expression of p53. Moreover, we searched for the expression of p53 in RA-SF <i>in vitro</i> and <i>in vivo</i>. In addition, we examined the inducibility of p53 in RA-SF by X-rays <i>in vitro</i>. <h3>Methods</h3> Paraffin embedded synovial tissues from 14 RA, 3 osteoarthritis (OA), 3 normal synovia and a neurological p53 positive tumour were investigated with DO7 anti-p53 antibodies by immunohistochemistry. RA-SF from passages 2 to 12 (n = 10), OA-SF (n = 2), normal synoviocytes (N-SF, n = 1) and foreskin fibroblasts (FSFB, n = 1)) from passages 4–8 were grown on chamber slides and analysed with the same primary antibodies utilising immunofluorescence. SV40 transformed RA-SF (HSE) and SV40 transformed N-SF (K4IM) as well as the SV40 transformed bronchial epithelial cell line BEAS 2B served as positive controls. The percentage of positive cells was evaluated by a scoring system. RA-SF and HSE cultured <i>in vitro</i> were co-implanted with human cartilage under the renal capsule or the under the skin of SCID mice and kept there for 60 days. Paraffin sections from these SCID mice experiments were stained for p53. In addition, sections from former SCID mouse experiments including retroviral and adenoviral gene transfer studies revealing a strong invasion of synovial cells into the cartilage were investigated for the expression of p53. Moreover, RA-SF (n = 2) and controls (FSFB, n = 1) were irradiated with 10 Gy (X-rays) and analysed time dependently for the expression of p53 by immunofluorescence. <h3>Results</h3> In vivo, p53 was not abundantly expressed in RA synovial tissue and in particular not at sites of invasion. In general, less than 5% of the cells in RA and OA synovial tissues stained positively for p53, while no staining in the normal synovia occurred. In contrast, the positive control revealed a strong nuclear p53 signal in almost 100% of the tumour cells. <i>In vitro</i>, the expression rate of p53 in RA-SF was comparable low, while the SV40 transformed cells demonstrated a strong and specific nuclear staining. Furthermore, RA-SF invading the human cartilage in the SCID mouse co-implantation model did not show any expression of p53 at sites of invasion, whereas the implanted SV40 transformed HSE revealed a strong p53 staining indicating that those cells survived at least for 60 days in SCID mice. RA-SF and FSFB cultured <i>in vitro</i> responded equally to the irradiation with X-rays by producing transiently p53, demonstrating an adequate and functional response of p53. <h3>Conclusion</h3> We suggest that the expression of p53 plays only a limited role in the pathogenesis of RA and particularly not in the invasive process of RA-SF.
Paradoxical gastrointestinal effects of interleukin-17 blockers
Authors: Marine Fauny, David Moulin, Ferdinando D'Amico, Patrick Netter, Nadine Petitpain, Djesia Arnone, Jean-Yves Jouzeau, Damien Loeuille, Laurent Peyrin-Biroulet
Journal: Annals of the Rheumatic Diseases (2020)

Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn's disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.
MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma
Authors: Abigail R Molloy, Chloé Najac, Pavithra Viswanath, Aliya Lakhani, Elavarasan Subramani, Georgios Batsios, Marina Radoul, Anne Marie Gillespie, Russell O Pieper, Sabrina M Ronen
Journal: Theranostics (2020)

Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response.
Mechanical stimulation of Schwann cells promote peripheral nerve regeneration via extracellular vesicle-mediated transfer of microRNA 23b-3p
Authors: Bing Xia, Jianbo Gao, Shengyou Li, Liangliang Huang, Lei Zhu, Teng Ma, Laihe Zhao, Yujie Yang, Kai Luo, Xiaowei Shi, Liangwei Mei, Hao Zhang, Yi Zheng, Lei Lu, Zhuojing Luo, Jinghui Huang
Journal: Theranostics (2020)

Peripheral nerves are unique in their remarkable elasticity. Schwann cells (SCs), important components of the peripheral nervous system (PNS), are constantly subjected to physiological and mechanical stresses from dynamic stretching and compression forces during movement. So far, it is not clear if SCs sense and respond to mechanical signals. It is also unknown whether mechanical stimuli can interfere with the intercellular communications between neurons and SCs, and what role extracellular vesicles (EVs) play in this process. The present study aimed to examine the effect of mechanical stimuli on the EV-mediated intercellular communication between neurons and SCs, explore their effect on axonal regeneration, and investigate the underlying mechanism.