tbuckley/cabot-search huggingface dataset:
Sex-Specific Effects of Prenatal and Early Life Inorganic and Methylated Arsenic Exposure on Atherosclerotic Plaque Development and Composition in Adult ApoE−/− Mice
Authors: Luis Fernando Negro Silva, Kiran Makhani, Maryse Lemaire, Catherine A. Lemarié, Dany Plourde, Alicia M. Bolt, Christopher Chiavatti, D. Scott Bohle, Stéphanie Lehoux, Mark S. Goldberg, Koren K. Mann
Journal: Environmental Health Perspectives (2021)

Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed in vivo via the action of arsenic (+3 oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre- and perinatal effects are unclear. This is particularly important because methylated arsenicals are known to cross the placenta.We tested the effects of early life exposure to inorganic and methylated arsenicals on atherosclerotic plaque formation and its composition in apolipoprotein E knock-out (apoE-/-) mice and evaluated whether apoE-/- mice lacking As3MT expression were susceptible to this effect.We exposed apoE-/- or apoE-/-/As3MT-/- mice to 200 ppb inorganic or methylated arsenic in the drinking water from conception to weaning and assessed atherosclerotic plaques in the offspring at 18 wk of age. Mixed regression models were used to estimate the mean difference in each outcome relative to controls, adjusting for sex and including a random effects term to account for within-litter clustering.Early life exposure to inorganic arsenic, and more profoundly methylated arsenicals, resulted in significantly larger plaques in the aortic arch and sinus in both sexes. Lipid levels in these plaques were higher without a substantial difference in macrophage numbers. Smooth muscle cell content was not altered, but collagen content was lower. Importantly, there were sex-specific differences in these observations, where males had higher lipids and lower collagen in the plaque, but females did not. In mice lacking As3MT, arsenic did not alter the plaque size, although the size was highly variable. In addition, control apoE-/-/As3MT-/- mice had significantly larger plaque size compared with control apoE-/-.This study shows that early life exposure to inorganic and methylated arsenicals is pro-atherogenic with sex-specific differences in plaque composition and a potential role for As3MT in mice. https://doi.org/10.1289/EHP8171.
Abstract 14800: Presenilin 1 and Presenilin 2 Contribute to Mitophagy Including Alternative Pathway
Authors: Tsunenori Saito, Roberta A Gottlieb
Journal: Circulation (2020)

Introduction: Presenilin 1 (PS1) and presenilin 2 (PS2) are proteins that compose γ-secretase, which is a protease present in late endosome lysosomes. Recently, amyloid beta accumulation was found in the cardiomyocytes of Alzheimer's disease patients and cause cardiac dysfunction. Mutations in PSEN1 and PSEN2 , the causative genes of familial Alzheimer's disease, are involved in the development of dilated cardiomyopathy (DCM); however, their roles in cardiomyocytes have not been elucidated thoroughly. Hypothesis: We hypothesized that PS1 and PS2 might be playing a role in mitochondria-selective autophagy (mitophagy) of cardiomyocytes. Methods: Whole-exome sequencing of 32 DCM patients was focused on 29 autophagy-related genes and 16 genes encoding autophagy-related proteins. Based on the results, the expression of autophagy and mitophagy markers was examined using cultured rat cardiomyocytes silenced for PSEN1 or PSEN2 and exposed to starvation, 100 μM bafilomycin A1, inhibiting fusion between autophagosomes and lysosomes, or 10 μM carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler used to induce mitophagy. Results: A variant of PSEN2 (c.1262C&gt;T) may be the cause of DCM in a 50-year-old Japanese man. Electron microscopic observation of myocardium revealed a fibrillar substance in the expanded T-tube, suggesting failure to clear aggregates. FCCP treatment caused an increase in microtubule-associated protein 1 light chain 3 (LC3)-II and p62 which was further enhanced in cells with silenced PS1 or PS2. Rab9, which is associated with the alternative pathway of mitophagy, was also increased in cells silenced for PS1 or PS2. Parkin was decreased with FCCP treatment, suggesting its clearance via mitophagy, and this was further enhanced when PS1 was silenced. Voltage-dependent anion channel (VDAC) levels, a reflection of mitochondrial content, were slightly increased when PS1 and PS2 were silenced. LC3-II increased with starvation and further increased with bafilomycin A1 treatment: however, silencing PS2 did not result in further increase, suggesting that flux was impaired. Conclusions: PS2 and probably PS1 are required to support autophagic flux necessary for cardiomyocyte homeostasis.
Abstract 15218: Structural and Functional Alterations in a Premature Ventricular Contractions-induced Cardiomyopathy Model
Authors: Jaime Balderas Villalobos, Montserrat Samso, Christopher Lynch, Juan Torrado, Rafael J Ramirez, Alex Y Tan, Karoly Kaszala, Jose F Huizar, Jose M Eltit
Journal: Circulation (2020)

Introduction: Previous studies of premature ventricular contractions (PVC)-induced cardiomyopathy (PVC-CM) in canines have showed reduction in L-type Ca 2+ current and Ca 2+ transient amplitude in isolated ventricular myocytes, concomitant with eccentric hypertrophy and a decline in left ventricular (LV) ejection fraction. Objectives: Assess potential alterations of PVC-CM related to: 1) the efficiency of the Ca 2+ recycling machinery in the sarcoplasmic reticulum (SR), and 2) the overall ultrastructural integrity of myocytes. Methods: Modified pacemakers were implanted in healthy canines to reproduce PVC-CM after 3 months of bigeminal PVC (50% burden at 200-220 ms coupling interval). Animals were randomized to either 50% PVC or no PVC (sham). Ventricular cardiomyocytes were isolated and paced to measure Ca 2+ transients using Fura2. Permeabilized cardiomyocytes loaded with Fluo-5N were used to assess SERCA2 activity in vitro . Additionally, expression of SERCA2, and phosphorylated versus total phospholamban (PLN) were measured with Western blot (WB). LV wall muscle was fixed, en-block stained with uranyl acetate, and thin-sectioned for electron microscopy (EM). Results: There was a non-statistically significant trend towards a reduction of SR-Ca 2+ reuptake efficiency in PVC-CM vs sham, evidenced by a 21% slower decay of the electrically-evoked cytosolic Ca 2+ transient and a 23% slower maximal rate of SR Ca 2+ uptake (PVC-CM n=42 cells, 4 animals vs sham n=50 cells, 3 animals). WB analysis showed a 23% reduction in SERCA2 expression (0.76 ± 0.18 vs 1 ± 0.25, P =0.002, n=6 animals each), a 40% increase in PLN expression (1.4 ± 0.18 vs 1 ± 0.1, P &lt;0.0001, n= 3 animals each), and a 64% reduction in phospho-PLN (0.35 ± 0.15 vs 1 ± 0.18, P &lt;0.0001, n=3 animals each) in PVC-CM vs sham. In addition, EM showed intact dyads, regularly shaped SR, but noticeable myofibril disorder in the PVC-CM derived samples. Conclusions: In PVC-CM, there is impaired electrically-evoked Ca 2+ cycling due to a combination of reduced L-type Ca 2+ channels and reduced SERCA-mediated SR Ca 2+ uptake. This combined with the apparent ultrastructural remodeling, underscore long-term cellular adaptations leading to LV systolic dysfunction associated to the chronic exposure to PVC.
Abstract 16438: Combined Prognostic Significance of Heart Failure and Chronic Kidney D in Patients With Acute Myocardial Infarction. The Fast-mi Programme
Authors: Nicolas Danchin, Guillaume Cayla, Yves Cottin, Pierre COSTE, Franck ALBERT, Etienne Puymirat, Jean Ferrieres, francois schiele, tabassome Simon
Journal: Circulation (2020)

Introduction: We assessed the interplay and potential cumulative effects of heart failure (HF) and chronic kidney disease (CKD) on one-year and 5-year outcomes in patients admitted for acute myocardial infarction (AMI). Methods: FAST-MI consists of 3 nationwide French surveys 5 years apart from 2005 to 2015, consecutively including STEMI and NSTEMI patients over 1-month periods. Using Cox regression, we analysed the association between CKD and non-fatal HF and death during the first year after discharge according to absence of HF, previous HF and acute stage HF. In those alive at 1 year, we also analysed the prognostic significance of admission for non-fatal HF after AMI and CKD on 5-year mortality. Results: Of 12,301 patients discharged alive, 7960 (64.7%) had normal renal function and no HF. Both CKD and type of HF were independent predictors of one-year death: one-year mortality was 3.6%, 14.3% and 24.5% in patients with no HF, acute stage HF, and prior history of HF, respectively. Within each group, mortality increased by increasing degree of CKD. In patients with no history of HF, CKD was a strong independent correlate of hospital admission for HF within one year of discharge: HR (95%CI) 1.33 (1.01-1.74), P=0.04 for CKD-EPI 30-60, and 1.76 (1.16-2.67), P=0.008 for CKD-EPI &lt;30, as was the case in patients with HF at the acute stage (Figure). Finally, in patients alive at 1year, both HF admission during the first year (adjusted HR 1.85, 1.42-2.39, P&lt;0.001) and CKD (HR 1,23, 1.04-1.47, P=0.02 and HR 1.86, 1.41-2.44, P&lt;0.001, respectively for moderate and severe renal dysfunction), were independent predictors of 5-year death. Conclusion: After AMI, CKD and HF are major independent prognostic factors for death and/or subsequent HF admission. Both are likely to be important therapeutic targets to improve long-term outcomes after AMI.
155P Profile of pathogenic mutations and evaluation of germline genetic testing criteria in consecutive breast cancer patients treated at a North Indian tertiary care center
Authors: A. Mittal, R. Pramanik, A. Gogia, A. Batra, A. Jha, L. Kumar, S. Deo, S. Bhoriwal, K.S. Deb, E. Dhamija, V. Ramprasad, O. Olopade
Journal: Annals of Oncology (2021)
Abstract 16143: A Novel Clinical Prediction Model for Familial Hypercholesterolemia: Implementation of a Statin-correction Calculator to Enhance Diagnostic Yield
Authors: Zahara A Kanji, Mohammad S Sheikh, Daniel Antwi-Amoabeng, Bryce H Beutler, Nageshwara Gullapalli, Christopher J Rowan
Journal: Circulation (2020)

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. Individuals with FH have a 22-fold greater risk of early-onset cardiovascular disease as compared to the general population. Early identification of patients with FH is essential to prevent cardiovascular events. Diagnosis may be challenging however for individuals with underlying FH who are already receiving statin therapy, as criteria for FH rely on pre-treatment low-density lipoprotein (LDL) levels. We calculated pre-treatment LDL levels utilizing prior published literature by adjusting for serum LDL levels in patients receiving statins. This increased the diagnostic yield for gene-positive FH. Hypothesis: Integration of statin-correction calculator with the Dutch Lipid Clinical Criteria (DLCC) and Simon Broome Criteria (SBC) for FH will increase sensitivity to identify gene-positive FH. Methods: 29,797 participants enrolled in the Healthy Nevada Project underwent whole-exome gene testing. 126 had a FH variant; 37 of these participants were on statin therapy. A statin-correction calculator was utilized to predict patients' pre-treatment LDL levels. The likelihood of FH was assessed based on two versions of the DLCC and SBC: the standard versions and enhanced versions with integration of the statin-correction calculator (eDLCC and eSBC). The McNemar test was used to compare the sensitivity of DLCC and SBC with eDLCC and eSBC, respectively, in identifying gene-positive FH. Results: By adjusting LDL levels for statin usage, 70.24% and 24.32% of participants with a negative diagnosis of FH were reclassified to positive using eDLCC and eSBC (p=0.001 and 0.008, respectively). Conclusions: Integration of statin-correction calculator to correct LDL increases diagnostic yield for clinical FH.
AB0447 Regulation of Serum Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases-1 following Rituximab Therapy in Patients with Rheumatoid Arthritis Refractory to Anti-Tumor Necrosis Factor Blockers
Authors: P.A. Klimiuk, I. Domyslawska, S. Sierakowski, J. Chwiecko
Journal: Annals of the Rheumatic Diseases (2014)

Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early rule-out protocols for AMI, when measured at presentation and again at 3–6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.
Isolated Pure Systolic Stress Upregulates Hypertrophy-related Genes, Whereas Isolated Diastolic Strain Upregulates Fibrosis-related Genes
Authors: Onitsuka Ken, Ide Tomomi, Arai Shinobu, Murayama Yoshinori, Kato Yuko, Takehara Takako, Hosokawa Kazuya, Sakamoto Takafumi, Sakamoto Kazuo, Tobushi Tomoyuki, Fujino Takeo, Saku Keita, Ikeda Masataka, Kakino Takamori, Sunagawa Kenji
Journal: Circulation (2012)
Health systems resilience in managing the COVID-19 pandemic: lessons from 28 countries
Authors: Victoria Haldane, Chuan De Foo, Salma M. Abdalla, Anne-Sophie Jung, Melisa Tan, Shishi Wu, Alvin Chua, Monica Verma, Pami Shrestha, Sudhvir Singh, Tristana Perez, See Mieng Tan, Michael Bartos, Shunsuke Mabuchi, Mathias Bonk, Christine McNab, George K. Werner, Raj Panjabi, Anders Nordström, Helena Legido-Quigley
Journal: Nature Medicine (2021)
AHA双晶参照部位(GARD研究実証プロジェクト)に対する高齢者(MACVIA ARIA)-EIPにおけるアレルギー性鼻炎と喘息多疾病罹患の革新の移動【Powered by NICT】
Authors: J Bousquet, I Agache, M R Aliberti, R Angles, I Annesi-Maesano, J M Anto, S Arnavielhe, E Asayag, E Bacci, A Bedbrook, C Bachert, I Baroni, B A Barreto, M Bedolla-Barajas, K C Bergmann, L Bertorello, M Bewick, T Bieber, S Birov, C Bindslev-Jensen, A Blua, M Bochenska Marciniak, I Bogus-Buczynska, S Bosnic-Anticevich, I Bosse, R Bourret, C Bucca, R Buonaiuto, M T Burguete Cabanas, D Caillaud, D P Caimmi, D Caiazza, P Camargos, G Canfora, V Cardona, A M Carriazo, C Cartier, G Castellano, N H Chavannes, L Cecci, M M Ciaravolo, C Cingi, A Ciceran, L Colas, E Colgan, J Coll, D Conforti, J Correia de Sousa, R M Cortes-Grimaldo, F Corti, E Costa, A L Courbis, E Cousein, A A Cruz, A Custovic, B Cvetkovski, C Dario, J da Silva, Y Dauvilliers, F De Blay, T Dedeu, G De Feo, B De Martino, P Demoly, G De Vries, S Di Capua Ercolano, N Di Carluccio, M Doulapsi, G Dray, R Dubakiene, E Eller, R Emuzyte, J G Espinoza-Contreras, A Estrada-Cardona, J Farrell, A Farsi, J Ferrero, W J Fokkens, J Fonseca, J F Fontaine, S Forti, J L Galvez-Romero, C I Garcia-Cobas, M H Garcia Cruz, B Gemicioglu, R Gerth van Wijk, M Guidacci, J Gomez-Vera, N A Guldemond, Z Gutter, T Haahtela, J Hajjam, P W Hellings, L Hernandez-Velazquez, M Illario, J C Ivancevich, E Jares, G Joos, J Just, O Kalayci, A F Kalyoncu, J Karjalainen, T Keil, N Khaltaev, L Klimek, V Kritikos, I Kull, P Kuna, V Kvedariene, V Kolek, E Krzych-Falta
Journal: Allergy (2018)
Continuation of Screening Endoscopy for Colorectal Cancer in Older Adults
Authors: Nirmala Bhoo-Pathy, Nur-Nadiatul-Asyikin Bujang, Chiu-Wan Ng
Journal: JAMA Oncology (2021)

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Successful biliary stone removal after resolution of post-endoscopic sphincterotomy papillary stenosis using temporary covered metal stent placement
Authors: Koichiro Mandai, Koji Uno, Kenjiro Yasuda
Journal: Endoscopy (2021)

Although few studies have reported the frequency of papillary stenosis after endoscopic sphincterotomy (EST), serious complications such as bleeding and duodenal perforation are reported with repeated EST [1]. For benign biliary stenosis, the usefulness of temporary placement of a fully covered self-expandable metal stent (FCSEMS) is reported [2]. Herein, we describe successful biliary stone removal after resolution of post-EST papillary stenosis using temporary placement of a dumbbell-shaped FCSEMS (BONASTENT M-Intraductal; Sci-Tech Inc., Seoul, South Korea), which has a central saddle portion with a diameter 2 mm less than that of the proximal and distal portions to prevent stent migration.
Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS‐52 is unaffected by eosinophilic status
Authors: Shigeharu Fujieda, Shoji Matsune, Sachio Takeno, Nobuo Ohta, Mikiya Asako, Claus Bachert, Tomoyuki Inoue, Yoshinori Takahashi, Hiroyuki Fujita, Yamo Deniz, Paul Rowe, Benjamin Ortiz, Yongtao Li, Leda P. Mannent
Journal: Allergy (2021)

Abstract Background The human monoclonal antibody dupilumab blocks interleukin (IL)‐4 andIL‐13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS‐52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS‐52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Methods Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund‐Mackay score assessed by CT (LMK‐CT) at week 24. Patients ( n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Results Dupilumab significantly improved NPS, NC, and LMK‐CT scores versus placebo at week 24 in all ECRS subgroups (p &lt; 0.001), with improvements maintained or increased at week 52 (p &lt; 0.001). There was no significant interaction between ECRS subgroup (non‐/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p &gt; 0.05), except LMK‐CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP.
Case 15-2021: A 76-Year-Old Woman with Nausea, Diarrhea, and Acute Kidney Failure
Authors: Oladapo O. Yeku, Arielle J. Medford, Andrew Z. Fenves, Sacha N. Uljon
Journal: New England Journal of Medicine (2021)

A 76-year-old woman with a history of type 2 diabetes, obstructive sleep apnea, coronary artery disease, and heart failure with reduced ejection fraction presented with nausea, abdominal cramps, and nonbloody diarrhea. The blood level of creatinine was 7.66 mg per deciliter, and the level of lactic acid was 7.4 mmol per liter. A diagnosis was made.
Abstract 14831: Racial Disparities and Modifiable Cardiovascular Risk Factors in Black Patients With Familial Hypercholesterolemia
Authors: Anandita P Agarwala, Elena Deych, Aliza Hussain, Laney Jones, Amy C Sturm, Karen E Aspry, Zahid Ahmad, Christie M Ballantyne, Anne C Goldberg
Journal: Circulation (2020)

Introduction: Black men and women are at higher risk for atherosclerotic cardiovascular disease (ASCVD) and when diagnosed, have greater morbidity and mortality as compared to individuals from European ancestry (EA). In patients with familial hypercholesterolemia (FH), it remains unknown whether Black patients have similarly increased risk for ASCVD. Hypothesis: To characterize the prevalence of ASCVD and to determine the strongest predictors of ASCVD in Black FH patients compared to EAs. Methods: The prevalence of ASCVD in 173 Black adult patients with FH followed in US-based lipid clinics was assessed retrospectively through a multicenter. A multivariate logistic regression model was used to determine the strongest predictors of ASCVD. Covariates included age, sex, diabetes mellitus, hypertension, and current smoking. ASCVD was defined as coronary, peripheral, and cerebrovascular events including angina, myocardial infarction, coronary angioplasty, peripheral arterial surgery, claudication, peripheral angioplasty, transient ischemic attack, stroke, and carotid endarterectomy. Results: Baseline characteristics of the 173 Black adult patients compared to EAs are shown in table 1. Black patients with FH were more likely to have higher BMI, hypertension, diabetes and to be current smokers. The prevalence of ASCVD in Black patients with FH was 38% compared to 30% in EAs, an absolute difference of 8% (p=0.047). The strongest predictors of ASCVD in Black patients with FH were hypertension and current smoking (table 2). Conclusions: Black patients with FH have a significantly higher prevalence of ASCVD when compared to EAs with FH. The strongest predictors of ASCVD in Black patients with FH were hypertension and current smoking. Aggressive primary prevention strategies specifically focused on the management of hypertension and smoking cessation should be tested for impact on the cardiovascular risk profile of Black patients with FH.