Quadricuspid aortic valve (QAV) is a congenital heart anomaly in which the aortic valve has four cusps of various size possibilities, as opposed to the three symmetrical cusps generally observed. This cardiac valvular abnormality is rarely identified, with an estimated incidence rate of 0.013% to 0.043%, although recent technological advancements in diagnostics have contributed to an increase in detection. Historically, it had been typically encountered during open heart surgery or postmortem; however, it is presently diagnosed primarily via ultrasound echocardiography, and could go undetected unless specifically considered. It was first reported by Babington in 1847, and since then approximately 300 cases have been published. This condition is sporadically associated with additional congenital cardiovascular defects, with coronary artery irregularities being the most common. In more than half of published QAV incidences it has led to the progressive development of aortic regurgitation (AR) usually sans aortic stenosis, particularly amongst elderly patients, often requiring surgical intervention after 50 years of age. A fifth of total instances, but two-thirds of instances with AR, warrant surgery seldom amidst complications, with reconstructive tricuspidization preferred over valve replacement.
Protein sequences encode both structure and foldability. Whereas the interrelationship of sequence and structure has been extensively investigated, the origins of folding efficiency are enigmatic. We demonstrate that the folding of proinsulin requires a flexible N-terminal hydrophobic residue that is dispensable for the structure, activity, and stability of the mature hormone. This residue (Phe B1 in placental mammals) is variably positioned within crystal structures and exhibits 1 H NMR motional narrowing in solution. Despite such flexibility, its deletion impaired insulin chain combination and led in cell culture to formation of non-native disulfide isomers with impaired secretion of the variant proinsulin. Cellular folding and secretion were maintained by hydrophobic substitutions at B1 but markedly perturbed by polar or charged side chains. We propose that, during folding, a hydrophobic side chain at B1 anchors transient long-range interactions by a flexible N-terminal arm (residues B1-B8) to mediate kinetic or thermodynamic partitioning among disulfide intermediates. Evidence for the overall contribution of the arm to folding was obtained by alanine scanning mutagenesis. Together, our findings demonstrate that efficient folding of proinsulin requires N-terminal sequences that are dispensable in the native state. Such arm-dependent folding can be abrogated by mutations associated with -cell dysfunction and neonatal diabetes mellitus.The efficiency of protein folding poses a fundamental problem at the intersection of biophysics, cell biology, and medicine (1, 2). Because the existence of a unique and accessible ground state is unrepresentative of polypeptides as a class of heteropolymers, foldability is an evolved property of biological sequences (3). Current kinetic models envisage a funnel-shaped free-energy landscape, enabling multiple trajectories to the native state (4 -6). What distinguishes foldable from non-foldable sequences (7), and how are bottlenecks avoided (8 -10)? The salience of these questions has been reinforced by recognition of proteotoxicity as a general pathological mechanism underlying diverse diseases (11,12). Here, we describe a cryptic folding element in a protein that is dispensable once the native state has been reached.A model is provided by insulin, a globular protein central to the regulation of vertebrate metabolism (13). Its impaired biosynthesis causes -cell dysfunction and permanent neonatalonset diabetes mellitus (DM) 4 (14 -17). The insulin gene encodes a single-chain precursor, preproinsulin (Fig. 1A, top) (18). A signal peptide (gray bar) is cleaved on translocation into the endoplasmic reticulum (ER) to yield proinsulin. The precursor contains successive sequence motifs, defining B, C, and A domains (blue, black, and red , respectively, in Fig. 1A) (19). Whereas the translocated polypeptide is reduced and unfolded, oxidative folding in the ER yields a well organized A-B (insulinlike) core and disordered C-domain (dashed black segment in Fig. 1B) (20 -26). Folding is ...
A 43-year-old man with an unremarkable medical history presented to our hospital with 2 weeks of headaches, ataxia and confusion. CT of the head revealed a large haemorrhagic cystic lesion. A subsequent chest CT revealed a large left atrial mass. The mass was subsequently biopsied with positive immunohistochemistry staining for MDM2, FLI1 and vimentin. Real-time PCR revealed MDM2 amplification, confirming the diagnosis of intimal sarcoma. The patient underwent surgical resection and reconstruction of the atrium with subsequent discharge to short-term rehabilitation, but his symptoms continued to progress. A repeat CT of the head revealed a new cerebellar mass. He underwent a second resection, but continued to experience worsening symptoms. He was diagnosed with stage IV intimal sarcoma and referred to hospice. The patient died 5 months after initial presentation. Autopsy was performed and revealed the cause of death as pneumonia. There was no involvement of the pulmonic or aortic vessels.
Electronic cigarettes may increase the risk of long-term cardiovascular morbidity. To protect the heart, awareness should be raised of the risks and limits of E-cigarette aerosol exposure. Thus, this systematic review and meta-analysis assessed the cardiovascular risk of e-smoking. This systematic review was conducted by using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. We searched PubMed, Embase, Scopus, Web of Science, and Science Direct databases in December 2022 to identify studies investigating e-cigarettes' impact on the heart. The study was supported by meta-analysis and qualitative review. Out of the initial 493 papers, only 15 met the inclusion criteria and were included in the study. The cumulative number of participants in the myocardial infarction (MI) group was 85,420, and in the sympathetic groups in whom the systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR) were measured, were 332 cigarette smokers. The control group included the “never use,” “non-smokers,” and “never smoke.” The pooled analysis showed a significant difference between the e-cigarette smokers and the control group regarding the risk of developing MI in former smokers (OR= 0.12; 95% CI: 0.01-1.72, P = 0.12) and never smoked (OR= 0.02; 95% CI: 0.00-0.44, P = 0.01) favoring the control group. The pooled analysis of the included studies showed a significant difference between the e-cigarette smokers with nicotine and the control group regarding the mean difference (MD) of the SBP (MD = 2.89; 95% CI: 1.94-3.84; P < 0.001), the DBP (MD = 3.10; 95% CI: 0.42-5.78; P = 0.02), the MBP (MD = 7.05; 95% CI: 2.70-1.40; P = 0.001), and HF (MD = 3.13; 95% CI: 0.96-5.29; P = 0.005) favoring the control group. We conclude that using e-cigarettes has a detrimental effect on cardiac health. The risk of severe cardiac conditions increases with e-cigarettes. Thus, vaping can do more harm than good. Consequently, the misleading notion that e-cigarettes are less harmful should be challenged.
Background: The H2FPEF score is a validated scoring system to determine whether dyspnea may be due to heart failure with preserved ejection fraction (HFpEF). Recent evidence has suggested that H2FPEF scoring system may correlate with outcomes in established HFpEF. Its utilization for estimating mortality in patients who die within one year of discharge is not known. Methods: We collected clinical demographics and echocardiographic parameters from reports to calculate H2FPEF scores for 301 patients admitted with decompensated HFpEF between August 2016 and 2017. Patients were included if an echocardiographic report was available within 3 months, confirming an ejection fraction > 50%. E/E’ and filling pressures were scored as 0 if not recorded in the echocardiographic report. Results: Median age was 81 years (IQR: 71-89), with 62.9% female. One-year follow-up was confirmed for 268 patients, with 56 deaths (20.9%). Receiver operating curve analysis suggest borderline significance of H2FPEF in predicting one-year mortality (area under curve, 0.576, 95% CI: 0.493-0.658, p=0.073). Optimal H2FPEF cutpoint score was 4.5 (73% sensitivity, 50% specificity). On univariate analysis, body mass index (BMI) > 30, hypertension, atrial fibrillation (p<0.001) and pulmonary artery systemic pressure > 35 mmHg (p=0.038) were associated with one-year mortality. On stepwise logistic regression, only BMI > 30 and atrial fibrillation remained associated with mortality in multivariate analysis. Conclusion: The utilization of H2FPEF in established HFpEF might confer some ability to predict one-year mortality, driven by obesity (2 points) and atrial fibrillation (3 points). Validation in larger cohorts with longer follow-up is necessary to establish its potential role in discharge planning and transitions of care of decompensated HFpEF.
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.