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Autoantibodies to N-terminally Truncated GAD65(96-585): HLA Associations and Predictive Value for Type 1 Diabetes.
Pöllänen, PM, Härkönen, T, Ilonen, J, Toppari, J, Veijola, R, Siljander, H, Knip, M
The Journal of clinical endocrinology and metabolism. 2022;(3):e935-e946
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Abstract
OBJECTIVE To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD65(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential human leukocyte antigen (HLA) associations with such autoantibodies. DESIGN In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention study, the DIABIMMUNE study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants. RESULTS T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 (range 0.2-61.5) years. t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77% vs 53%; P < 0.001). CONCLUSIONS Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
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Effect of Cholesterol Molecules on Aβ1-42 Wild-Type and Mutants Trimers.
Nguyen, TH, Nguyen, PH, Ngo, ST, Derreumaux, P
Molecules (Basel, Switzerland). 2022;(4)
Abstract
Alzheimer's disease displays aggregates of the amyloid-beta (Aβ) peptide in the brain, and there is increasing evidence that cholesterol may contribute to the pathogenesis of the disease. Though many experimental and theoretical studies have focused on the interactions of Aβ oligomers with membrane models containing cholesterol, an understanding of the effect of free cholesterol on small Aβ42 oligomers is not fully established. To address this question, we report on replica exchange with a solute tempering simulation of an Aβ42 trimer with cholesterol and compare it with a previous replica exchange molecular dynamics simulation. We show that the binding hot spots of cholesterol are rather complex, involving hydrophobic residues L17-F20 and L30-M35 with a non-negligible contribution of loop residues D22-K28 and N-terminus residues. We also examine the effects of cholesterol on the trimers of the disease-causing A21G and disease-protective A2T mutations by molecular dynamics simulations. We show that these two mutations moderately impact cholesterol-binding modes. In our REST2 simulations, we find that cholesterol is rarely inserted into aggregates but rather attached as dimers and trimers at the surface of Aβ42 oligomers. We propose that cholesterol acts as a glue to speed up the formation of larger aggregates; this provides a mechanistic link between cholesterol and Alzheimer's disease.
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Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.
Sahu, S, Patil, CR, Kumar, S, Apparsundaram, S, Goyal, RK
Molecular and cellular biochemistry. 2022;(1):225-240
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Abstract
Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.
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Routine use of natriuretic peptides: Lessons from a big data analysis.
Goudot, FX, Msadek, S, Boukertouta, T, Schischmanoff, PO, Meune, C
Annals of clinical biochemistry. 2021;(5):481-486
Abstract
BACKGROUND Natriuretic peptides have broad indications during heart failure and the detection of left ventricular dysfunction in high-risk patients. They can also be used for the diagnosis/management of other cardiac diseases. However, very little is known regarding their use in routine practice. METHODS We examined all biological tests performed from February 2010 to August 2015 in two districts from the French Brittany, covering 13,653 km2 and including 22,265 physicians. We report the settings and conditions of N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements (the only locally natriuretic peptide available). RESULTS From a total of 3,606,432 tests requested in 557,650 adult (older than 20 years) patients, only 56,653 (1.6%) included at least one NT-proBNP measurement. NT-proBNP measurements gradually increased, from 9188 in 2011 to 12,938 in 2014 (P < 0.001). Most NT-proBNP tests were measured in urban laboratories (72.7%) and in private (62.9%) non-hospital/clinics laboratories; they were mostly ordered by general practitioners (66% compared with 11% by cardiologists). The number of NT-proBNP measurements increased with age up to 80-90 years, and 70.3% of tests were measured in ≥75 years patients. Creatinine and electrolytes were not associated with NT-proBNP in 15.8% and 19.7% of tests, respectively. CONCLUSION Among a very large cohort, we observed that natriuretic peptides remain largely undermeasured. NT-proBNP is mostly measured in elderly patients, and its interpretation may be hazardous in up to 16% of all individuals because no measurement of creatinine was associated to NT-proBNP.
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A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.
Hardy, MY, Goel, G, Russell, AK, Chen Yi Mei, SLG, Brown, GJE, Wang, S, Szymczak, E, Zhang, R, Goldstein, KE, Neff, KM, et al
Frontiers in immunology. 2021;:661622
Abstract
Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
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Predictive value of cardiac markers in the prognosis of COVID-19 in children.
Güllü, UU, Güngör, Ş, İpek, S, Yurttutan, S, Dilber, C
The American journal of emergency medicine. 2021;:307-311
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BACKGROUND AND AIM Occasionally, children with COVID-19 may develop arrhythmia, myocarditis, and cardiogenic shock involving multisystemic inflammatory syndrome in children (MIS-C). This study aimed to identify the laboratory parameters that may predict early cardiovascular involvement in these patients. MATERIALS AND METHODS Data of 320 pediatric patients, aged 0-18 years (average age, 10.46 ± 5.77 years; 156 female), with positive COVID-19 reverse transcription-polymerase chain reaction test and with cardiac biomarkers at the time of admission to the pediatric emergency department were retrospectively scanned. The age, sex, COVID-19-associated symptoms, pro-brain natriuretic peptide (proBNP), CK-MB, and troponin I levels of the patients were recorded. RESULTS Fever was noted in 58.1% of the patients, cough in 29.7%, diarrhea in 7.8%, headache in 14.7%, sore throat in 17.8%, weakness in 17.8%, abdominal pain in 5%, loss of taste in 4.1%, loss of smell in 5.3%, nausea in 3.4%, vomiting in 3.8%, nasal discharge in 4.4%, muscle pain in 5%, and loss of appetite in 3.1%. The proBNP value ≥282 ng/L predicted the development of MIS-C with 100% sensitivity and 93% specificity [AUC: 0.985 (0.959-1), P < 0.001]; CK-MB value ≥2.95 with 80% sensitivity and 77.6% specificity [AUC: 0.792 (0.581-1), P = 0.026]; and troponin I value ≥0.03 with 60% sensitivity and 99.2% specificity [AUC: 0.794 (0.524-1)]. CONCLUSIONS Cardiac markers (proBNP and troponin I), especially proBNP, could be used to detect early diagnosis of cardiac involvement and/or MIS-C in pediatric patients with COVID-19 and to predict related morbidity and mortality.
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Factors associated with baseline and serial changes in circulating NT-proBNP and high-sensitivity cardiac troponin T in a population-based cohort (Dallas Heart Study).
Puleo, CW, Ayers, CR, Garg, S, Neeland, IJ, Lewis, AA, Pandey, A, Drazner, MH, de Lemos, JA
Biomarkers in medicine. 2021;(16):1487-1498
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Abstract
Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) associate with structural heart disease and heart failure risk in individuals without known cardiovascular disease (CVD). However, few data are available regarding whether factors influencing levels of these two biomarkers are similar or distinct. We performed serial measurement of NT-proBNP and hs-cTnT in a contemporary multiethnic cohort with extensive phenotyping, with the goal of identifying their respective biological determinants in a population without known or suspected CVD. Methods: We evaluated 1877 participants of the Dallas Heart Study who had NT-proBNP and hs-cTnT measured and were free from clinical CVD at the each of its two examinations (2000-2002 and 2007-2009). Variables collected included demographic and risk factors, high-sensitivity C-reactive protein, body composition via dual-energy x-ray absorptiometry, coronary artery calcium by computed tomography, and cardiac dimensions and function by cardiac MRI. Linear regression was used to identify associations of these factors with each biomarker at baseline and with changes in biomarkers over follow-up. Results: NT-proBNP and hs-cTnT were poorly correlated at baseline (Spearman rho 0.083, p = 0.015), with only moderate correlation between change values (rho 0.18, p < 0.001). hs-cTnT positively associated and NT-proBNP inversely associated with male gender and black race. At baseline, both NT-proBNP and hs-cTnT associated with left ventricular end-diastolic volume and wall thickness, but only NT-proBNP associated with left atrial size. Changes in cardiac dimensions between phases were more strongly associated with changes in NT-proBNP than hs-cTnT. NT-proBNP was more strongly associated with high-sensitivity C-reactive protein and measures of body composition than hs-cTnT. Conclusion: Among individuals without CVD in the general population, NT-proBNP and hs-cTnT are nonredundant biomarkers that are differentially associated with demographic and cardiac factors. These findings indicate that hs-cTnT and NT-proBNP may reflect different pathophysiological pathways.
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Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women.
Staunstrup, LM, Bager, CL, Frederiksen, P, Helge, JW, Brunak, S, Christiansen, C, Karsdal, M
EBioMedicine. 2021;:103391
Abstract
BACKGROUND The signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women. METHODS 5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic age-related diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models. FINDINGS Formation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00). INTERPRETATION Endotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases. FUNDING The funder of the PERF study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Urinary Titin N-Fragment Evaluation in a Randomized Controlled Trial of Beta-Hydroxy-Beta-Methylbutyrate for Acute Mild Trauma in Older Adults.
Nakano, H, Hashimoto, H, Mochizuki, M, Naraba, H, Takahashi, Y, Sonoo, T, Matsuishi, Y, Ogawa, Y, Shimojo, N, Inoue, Y, et al
Nutrients. 2021;(3)
Abstract
The effects of beta-hydroxy-beta-methylbutyrate (HMB) complex administration and the significance of titin, a biomarker of muscle injury, in elderly minor trauma patients in acute phase has not been established. In this single-center, randomized controlled study, trauma patients aged ≥ 70 years with an injury severity score < 16 were included. Titin values on days 1 and 3 were measured and the intervention group received HMB complex (2.4 g of HMB + 14 g of glutamine + 14 g of arginine) and the control group received glutamine complex (7.2 g of protein including 6 g of glutamine). The cross-sectional area of the rectus femoris (RFCSA) on ultrasound, grip strength, and the Barthel Index were assessed on the first day of rehabilitation and after 2 weeks. We analyzed 24 HMB and 25 control participants. Titin values on day 3 correlated with grip strength (r = -0.34, p = 0.03) and the Barthel Index (r = -0.39, p = 0.01) at follow-up. HMB complex supplementation had no effect on the RFCSA (2.41 vs. 2.45 cm2, p = 0.887), grip strength (13.3 vs. 13.1 kg, p = 0.946), or the Barthel Index (20.0 vs. 50.0, p = 0.404) at follow-up. Titin values might associate with subsequent physical function. Short-term HMB complex supplementation from acute phase did not ameliorate muscle injury.
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Poor Masticatory Capacity and Blood Biomarkers of Elevated Cardiovascular Disease Risk in the Community: The Paris Prospective Study III.
Chatzopoulou, E, Rangé, H, Deraz, O, Boutouyrie, P, Perier, MC, Guibout, C, Thomas, F, Andrieu, M, Bailly, K, Vedie, B, et al
Arteriosclerosis, thrombosis, and vascular biology. 2021;(7):2225-2232
Abstract
[Figure: see text].