The protein corona formed on the surface of a nanoparticle in a biological medium determines its behavior in vivo. Herein, iron oxide nanoparticles containing the same core and shell, but bearing two ...different surface coatings, either glucose or poly(ethylene glycol), were evaluated. The nanoparticles’ protein adsorption, in vitro degradation, and in vivo biodistribution and biotransformation over four months were investigated. Although both types of nanoparticles bound similar amounts of proteins in vitro, the differences in the protein corona composition correlated to the nanoparticles biodistribution in vivo. Interestingly, in vitro degradation studies demonstrated faster degradation for nanoparticles functionalized with glucose, whereas the in vivo results were opposite with accelerated biodegradation and clearance of the nanoparticles functionalized with poly(ethylene glycol). Therefore, the variation in the degradation rate observed in vivo could be related not only to the molecules attached to the surface, but also with the associated protein corona, as the key role of the adsorbed proteins on the magnetic core degradation has been demonstrated in vitro.
Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant ...form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt. After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.
Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease characterised by extracellular deposition of amyloid fibrils composed by transthyretin. ATTR amyloidosis can be sub-classified as ...wild-type ATTR (ATTR-wt) or as hereditary amyloidosis (ATTR-m); the prevalence of both types are likely underestimated. There are tools that can help us to study ATTR-m, as gnomAD database. Our primary aim was to estimate prevalence of variants, especially amyloidogenic variants, in the TTR gene using gnomAD database. We analysed TTR missense variants found in gnomAD. The variables studied were classified according to their clinical significance and according to the different populations. We found 71 missense variants in the TTR gene. Eleven variants were described as affects function variants (prevalence 1:230). The most frequently detected variant were c.424G>A (p.(Val142Ile)) (prevalence 1:332, MAF 0.00151) and c.148G>A (p.(Val50Met)) (prevalence 1:4924, MAF 0.000102), which represented 88% and 5%, respectively, of all affects function variants detected. Seventeen variants were classified as probably affects function, 29 as unknown variants, 4 as probably does not affect function and 10 as does not affect function variants. In terms of different populations, c.424G>A (p.(Val142Ile)) was especially prevalent in African population (MAF 0.01602; prevalence of 1:31) and c.148G>A (p.(Val50Met)) in European population (MAF 0.000179; prevalence of 1:2792). Prevalence of amyloidogenic variants in the general population was higher than prevalence heretofore described. This difference could be explained by incomplete penetrance of the disease, but other factors contributing to this fact, fundamentally the underdiagnosis of the disease.
Background: A deficiency in alpha-1 antitrypsin (AAT1) is a rare disorder that represents a significant health threat and early diagnostic priority issue. We investigated the usefulness of the serum ...protein electrophoresis (SPE) as an opportunistic screening tool for AAT1 deficiency. Methods: For 6 months, all SPE carried out for any reasons were evaluated in our center. In those with less than 3% of alpha-1 globulins, AAT1 concentrations were studied. The SERPINA1 gene was subsequently sequenced in those patients displaying concentrations below 100 mg/dL. Results: Out of the total, 14 patients (0.3%) were identified with low AAT1 concentrations, with 11 of them agreeing to enter the study. Of those, mutations in the SERPINA1 gene were discovered in 10 patients (91%). Heterozygous mutations were detected in seven patients; three had the c.1096G>A mutation (p.Glu366Lys; Pi*Z), two had the c.863A>T mutation (p.Glu288Val; Pi*S), one had the c.221_223delTCT mutation (p.Phe76del; Pi*Malton), and the last one had the c.1066G>A (p.Ala356Thr) mutation, which was not previously described. Finally, one patient had the c.863A>T mutation in homozygosis, whereas two double heterozygous patients c.863A>T/c.1096G>A were detected. Conclusions: An altered result in the concentration of AAT1 anticipates a mutation in the SERPINA1 gene in a manner close to 91%. The relationship between a decrease in the alpha-1 globulin band of the SPE and an alteration in the AAT1 concentration is direct in basal states of health. The SPE is presented as a highly sensitive test for opportunistic screening of AAT1 deficiency.
Background: Cardiac involvement is common in amyloidosis, and the vast majority of cases of amyloid cardiomyopathy are attributed to primary amyloidosis or transthyretin amyloidosis (ATTR). Although ...the coexistence of scintigraphy suggestive of ATTR with monoclonal gammopathy of undetermined significance is well documented, the correct diagnosis is still challenging in non-referral centers. Methods: We performed a retrospective study reviewing all amyloid cardiomyopathy cases diagnosed at our center over the last 5 years, and described our experience and diagnostic approach. Results: During the last 5 years, 74 patients with positive scintigraphy were identified. Of these patients, 41 were included in this study as they had all necessary tests for a complete diagnosis. Two of these 41 patients had variant ATTR and 29 had wild-type ATTR. Ten patients had monoclonal gammopathy (24.4%), and it was consequently impossible to obtain a specific diagnosis. During follow-up, 14 patients (34.1%), five of them from the monoclonal gammopathy group, died, reflecting the severity of disease. Conclusions: In patients with ATTR-suggestive scintigraphy, monoclonal gammopathy frequently occurs concomitantly, thus not allowing to establish a specific diagnosis. A biopsy could only be replaced by genetic testing in selected cases.
Background: Cardiac involvement is common in amyloidosis, and the vast majority of cases of amyloid cardiomyopathy are attributed to primary amyloidosis or transthyretin amyloidosis (ATTR). Although ...the coexistence of scintigraphy suggestive of ATTR with monoclonal gammopathy of undetermined significance is well documented, the correct diagnosis is still challenging in non-referral centers. ＜br＞ Methods: We performed a retrospective study reviewing all amyloid cardiomyopathy cases diagnosed at our center over the last 5 years, and described our experience and diagnostic approach. ＜br＞ Results: During the last 5 years, 74 patients with positive scintigraphy were identified. Of these patients, 41 were included in this study as they had all necessary tests for a complete diagnosis. Two of these 41 patients had variant ATTR and 29 had wild-type ATTR. Ten patients had monoclonal gammopathy (24.4%), and it was consequently impossible to obtain a specific diagnosis. During follow-up, 14 patients (34.1%), five of them from the monoclonal gammopathy group, died, reflecting the severity of disease. ＜br＞ Conclusions: In patients with ATTR-suggestive scintigraphy, monoclonal gammopathy frequently occurs concomitantly, thus not allowing to establish a specific diagnosis. A biopsy could only be replaced by genetic testing in selected cases.
Study of Cellular Aging in a Cohort of Patients with Heart Failure Elena, Bularca; María Izarbe, Merino-Casallo; Susana, Olivera-González ...
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension
28, Številka:
1
Journal Article
Recenzirano
Cellular senescence and fibrosis are important phenomena in the development of heart failure (HF). These processes are closely related to telomeric length (TL).
To assess cellular senescence in HF ...through the study of TL in peripheral blood mononuclear cells (PBMCs).
Using real-time PCR, TL was measured in PBMCs from 20 patients diagnosed with HF, aged between 51 and 77 years (50% males). Ten patients had HF with reduced ejection fraction (HFrEF) and ten had preserved EF (HFpEF). TL was measured in 20 healthy controls matched by age and gender. Obtained values were compared with an internal control, the 36B4 gene, which never modifies its expression, and correlated with the clinical parameters.
TL mean was 1327 in patients with HF (95% CI 1309-1344) compared to 1286 (95% CI 1264-1308) in controls (p = 0.005). No differences were found when studying the correlation of telomere size with subgroups by gender, left ventricle ejection fraction (LVEF), presence of ischemic heart disease, smoking, Chronic Obstructive Pulmonary Disease (COPD), NYHA stage, degree of renal function or number of hospital admissions in the previous year. A significant and negative correlation was found between age and renal function (r = - 0.544, p < 0.05), as well as LVEF and NT-proBNP values (ρ = - 0.475, p < 0.05).
TL is shorter in patients with HF when compared with age and gender balanced controls. The shortening of TL is independent of age, gender and degree of kidney function, and does not correlate with LVEF decrease or functional status.
PDF
