land). B-type natriuretic peptide in the evaluation and management of dyspnoea in primary care. J Intern Med 2012; 272:504-513.Objectives. The rapid and accurate diagnosis of heart failure in primary care is a major unmet clinical need. We evaluated the additional use of B-type natriuretic peptide (BNP) levels. Design. A randomized controlled trial.Setting. Twenty-nine primary care physicians in Switzerland and Germany coordinated by the University Hospital Basel, Switzerland.Subjects. A total of 323 consecutive patients presenting with dyspnoea.Interventions. Assignment in a 1 : 1 ratio to a diagnostic strategy including point-of-care measurement of BNP (n = 163) or standard assessment without BNP (n = 160). The total medical cost at 3 months was the primary end-point. Secondary end-points were diagnostic certainty, time to appropriate therapy, functional capacity, hospitalization and mortality. The final diagnosis was adjudicated by a physician blinded to the BNP levels.Results. Heart failure was the final diagnosis in 34% of patients. The number of hospitalizations, functional status and total medical cost at 3 months [median $1655, interquartile range (IQR), 850-3331 vs. $1541, IQR 859-2827; P = 0.68] were similar in both groups. BNP increased diagnostic certainty as defined by the need for further diagnostic work-up (33% vs. 45%; P = 0.02) and accelerated the initiation of the appropriate treatment (13 days vs. 25 days; P = 0.01). The area under the receiver-operating characteristics curve for BNP to identify heart failure was 0.87 (95% confidence interval, 0.81-0.93).Conclusions. The use of BNP levels in primary care did not reduce total medical cost, but improved some of the secondary end-points including diagnostic certainty and time to initiation of appropriate treatment.
Misshaped red blood cells (RBCs), characterized by thorn-like protrusions known as acanthocytes, are a key diagnostic feature in Chorea-Acanthocytosis (ChAc), a rare neurodegenerative disorder. The altered RBC morphology likely influences their biomechanical properties which are crucial for the cells to pass the microvasculature. Here, we investigated blood cell deformability of five ChAc patients compared to healthy controls during up to 1-year individual off-label treatment with the tyrosine kinase inhibitor dasatinib or several weeks with lithium. Measurements with two microfluidic techniques allowed us to assess RBC deformability under different shear stresses. Furthermore, we characterized leukocyte stiffness at high shear stresses. The results showed that blood cell deformability–including both RBCs and leukocytes - in general was altered in ChAc patients compared to healthy donors. Therefore, this study shows for the first time an impairment of leukocyte properties in ChAc. During treatment with dasatinib or lithium, we observed alterations in RBC deformability and a stiffness increase for leukocytes. The hematological phenotype of ChAc patients hinted at a reorganization of the cytoskeleton in blood cells which partly explains the altered mechanical properties observed here. These findings highlight the need for a systematic assessment of the contribution of impaired blood cell mechanics to the clinical manifestation of ChAc.
Type 2 diabetes is characterized by a loss of normal pancreatic beta-cell function and mass. In beta-cells, tyrosine kinase Fibroblast Growth Factors Receptors (FGFRs) modulate insulin processing, fatty acid metabolism and cell survival. However, a deeper understanding of mechanisms that regulate function of these receptors will be necessary to use this pathway therapeutically. We have recently identified beta-cell expression of Fibroblast Growth Factor Receptor-like 1 (FGFRL1), a newly-identified member of the FGFR family. FGFRL1 shares the canonical extracellular domain of FGFRs but uniquely exhibits a short C-terminal histidine-rich zinc-binding domain rather than intracellular catalytic kinase domains. Zinc is a second messenger normally found at picomolar concentration in the cytosol that mediates phosphatase activity to regulate Mitogen-Activated Protein Kinase (MAPK) signaling. We determined that FGFRL1 co-localizes with insulin secretory granules where zinc accumulates at micromolar concentrations. We therefore postulate that FGFRL1 alters beta-cell MAPK signaling by chelating zinc and regulating its intracellular concentration. To measure intercellular zinc, we imaged living murine beta-cells expressing full-length and truncated fluorescent protein variants of FGFRL1 co-labeled with cell-permeable zinc indicators FluoZin-3 and RhodZin-3. Our data confirm that FGFRL1 reduces free intracellular zinc via the unique histidine-rich region. We further show that zinc induces FGFRL1 receptor dimerization at the cell membrane using homo-fluorescence resonance energy transfer (Homo-FRET) imaging. Dimerization of FGFRL1 and association with insulin secretory granules suggest receptor activity is tightly regulated by zinc and likely associated with glucose-stimulated insulin secretion. Elucidating novel signaling mechanisms that regulate FGFR-activity in betacells will improve our understanding of how this pathway can be used therapeutically to treat diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.