An increase in the probability of death has been a defining feature of aging, yet human perinatal mortality starts high and decreases with age. Previous evolutionary models suggested that organismal ...aging begins after the onset of reproduction. However, we find that mortality and incidence of diseases associated with aging follow a U-shaped curve with the minimum before puberty, whereas quantitative biomarkers of aging, including somatic mutations and DNA methylation, do not, revealing that aging starts early but is masked by early-life mortality. Moreover, our genetic analyses point to the contribution of damaging mutations to early mortality. We propose that mortality patterns are governed, in part, by negative selection against damaging mutations in early life, manifesting after the corresponding genes are first expressed. Deconvolution of mortality patterns suggests that deleterious changes rather than mortality are the defining characteristic of aging and that aging begins in very early life.
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•Mortality from age-related diseases is U-shaped with the nadir below reproductive age•Quantitative biomarkers of aging change continuously throughout life•Mutation burden causes early-life mortality and contributes to selection•Aging is best defined by damage rather than mortality and starts very early in life
Kinzina et al. highlight the importance of adequate definition of aging and address long-standing questions on the onset of aging and causes of early-life mortality. They show that aging is better represented by the accumulation of deleterious changes rather than mortality and thus starts early in life.
Relevance . Despite the large list of biological markers of cardiovascular diseases, not all have evidence-b ased effectiveness and independent prognostic value. Laboratory diagnostics of serum ...cardiospecific auto-antibodies for the diagnosis of myocyte cell damage has several potential advantages compared to the evaluation of traditional methods. These include the analysis of natural globulins to troponin I (cTnI), to alpha-a ctin 1 (ACTC1), to the heavy chain of beta-myosin 7B (MUN7B), which are based on a self-sustaining immune response to the myocardium’s own auto-antigens, which leads to damage to the cells expressing them. Purpose: To determine the diagnostic and practical value of quantitative indicators for the autoantibody complex to cardiomyocyte proteins to troponin I, to alpha-a ctin 1 and to the heavy chain of beta-myosin 7B in patients with cardiac pathology. Materials and Methods. The study of auto-antibodies to cTnI, ACTC1 and MUN7B in blood serum using laboratory enzyme immunoassay was carried out in patients with cardiac pathology undergoing inpatient treatment at the Regional Clinical Cardiology Dispensary in Stavropol. Additionally, an instrumental and laboratory examination was carried out in accordance with the clinical recommendations developed by the Association of Cardiovascular Surgeons, the Cardiological Society of Russia and approved by the Scientific and Practical Council of the Ministry of Health of the Russian Federation. The work was examined and approved by the Ethics Committee of the North Caucasus Federal University. Results and Discussion . Changes in the level of autoantibodies to cTnI, ACTC1 and MUN7B proteins in blood serum were statistically significant (p 0.01 v. s. p 0.01). A persistent increase in the level of auto-antibodies to cTnI by 2.36 ng/ml (694.11 %), to ACTC1 by 3.6 ng/ml (141.73 %) and to MUN7B by 1.74 ng/ml (119.17 %) was found in individuals with confirmed cardiac pathology, when other criteria for laboratory analysis were within acceptable values, which determine their diagnostic and evidentiary effectiveness. Conclusion . The results of the study showed the relationship of changes in the activity of cardiospecific auto-A T to cardiomyocyte proteins (Anti-cTnI, Anti ACTC1, Anti-M YH7B) in patients with cardiac pathologies, indicating not only systemic membrane disorders (membranopathies), but also serve as convincing evidence of direct chemical changes in cardiomyocytes. A correlation has also been established between cardiomarkers of necrosis and ischemia and autoimmune globulins Anti-cTnI, Anti ACTC1, Anti-MYH7B, that confirms diagnostic and practical value of this laboratory analysis.
Patients with systemic mastocytosis (SM) are at high risk of bone deterioration. However, the evaluation of bone microarchitecture in this disease remains unclear. We aimed to assess bone ...microarchitecture in patients with SM. This was a cross-sectional study of 21 adult patients with SM conducted in a quaternary referral hospital in Sao Paulo, Brazil. A healthy, age-, weight-, and sex-matched cohort of 63 participants was used to provide reference values for bone microarchitecture, assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). Total volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness at the radius were significantly lower in the control group compared with the SM group (all
P
< 0.001). Patients with aggressive SM had significantly lower trabecular number (Tb.N) (
P
= 0.035) and estimated failure load (F.load) (
P
= 0.032) at the tibia compared with those with indolent SM. Handgrip strength was significantly higher in patients who had more Tb.N at the radius (
ρ
, 0.46;
P
= 0.036) and tibia (
ρ
, 0.49;
P
= 0.002), and lower who had more trabecular separation at the radius (
ρ
, −0.46;
P
= 0.035) and tibia (
ρ
, −0.52;
P
= 0.016). Strong and positive associations between F.load (
ρ
, 0.75;
P
< 0.001) and stiffness (
ρ
, 0.70;
P
< 0.001) at the radius, and between F.load at the tibia (
ρ
, 0.45;
P
= 0.038) were observed with handgrip strength. In this cross-sectional study, aggressive SM was more susceptible to bone deterioration compared with indolent SM. In addition, the findings demonstrated that handgrip strength was associated with bone microarchitecture and bone strength.
The reversible modification of cysteine residues by thioester formation with palmitate (S-palmitoylation) is an abundant lipid post-translational modification (PTM) in mammalian systems. ...S-palmitoylation has been observed on mitochondrial proteins, providing an intriguing potential connection between metabolic lipids and mitochondrial regulation. However, it is unknown whether and/or how mitochondrial S-palmitoylation is regulated. Here we report the development of mitoDPPs, targeted fluorescent probes that measure the activity levels of "erasers" of S-palmitoylation, acyl-protein thioesterases (APTs), within mitochondria of live cells. Using mitoDPPs, we discover active S-depalmitoylation in mitochondria, in part mediated by APT1, an S-depalmitoylase previously thought to reside in the cytosol and on the Golgi apparatus. We also find that perturbation of long-chain acyl-CoA cytoplasm and mitochondrial regulatory proteins, respectively, results in selective responses from cytosolic and mitochondrial S-depalmitoylases. Altogether, this work reveals that mitochondrial S-palmitoylation is actively regulated by "eraser" enzymes that respond to alterations in mitochondrial lipid homeostasis.
Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of ...studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes.
We have performed a combined analysis of three healthy volunteers before and after capsule FMT by evaluating their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene and shotgun sequencing. The data analysis demonstrated profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria and persistence of this effect for almost ∼1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events, however, one volunteer developed a systemic inflammatory response syndrome.
The FMT leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition and represents a relatively safe procedure to the recipients without long-term adverse events.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Knowledge on chronic myelomonocytic leukemia (CMML) patients from Argentina and Brazil is limited. Our series of 280 patients depicted an older age at diagnosis (median 72 years old), 26% of aberrant ...karyotypes, and a prevalence of myelodysplastic (60%) and CMML-0 subtypes (56%). The median overall survival (OS) was 48.2 months for patients in CMML-0 (Ref.), 24.7 months for those in CMML-1 (HR = 2.0,
p
= 0.001), and 8.8 months for patients in CMML-2 (HR = 4.6,
p
< 0.001). In the CMML-0 category, median OS were different between myelodysplastic and myeloproliferative subtypes (63.7 vs 21.2 months,
p
< 0.001); however, no differences were observed within CMML-1 and CMML-2 subtypes (24.7 vs 23.7 months,
p
= 0.540, and 9.1 vs 8.2 months,
p
= 0.160). The prognostic impact of 24 variables and 7 prognostic systems was adjusted to the WHO 2016 after validating their usefulness. Multivariate analysis were performed, and the final model revealed Hb ≥ 8 -< 10g/dL (HR 1.7), Hb < 8g/dL (HR 2.8), poor karyotypes (HR 2.1), WHO 2016-CMML-1 (HR 2.1), and CMML-2 (HR 3.5) as independent adverse clinical parameters in our cohort with a borderline influence of platelets count < 50 × 10
9
/L (HR 1.4). We could validate several scoring systems, the WHO 2016 proposal and its prognostic capability, along with accessible covariates, on predicting the outcome in our series of CMML patients from Latin America.
•Here, diverse regimens combined with imatinib were employed, with an OS of 25 %.•Relapse incidence and non-relapse mortality were 29 % and 42 %, respectively.•Age was associated with OS and higher ...TKI doses related to non-relapse mortality.•Accessibility to drugs and transplantation is essential in middle-income countries.
Outside of clinical trials, few studies have addressed the outcomes of Ph+ acute lymphoblastic leukemia (ALL) in adults, especially from developing world. In this study, we conducted a multicenter analysis on the outcomes of patients aged > 15 years with Ph+ ALL, aiming to get to know an overview of the Brazilian experience as well as to explore baseline factors associated with relapse and mortality in our setting. Over these 10 years, patients were treated with diverse protocols, all of them always combined with a frontline tyrosine-kinase inhibitor. A total of 123 Ph+ ALL patients was included. Imatinib was the first line TKI in 97 %. The complete response rate was 79 %. The early death rate was 15 %, being associated with increasing age at diagnosis (p = 0.06). The use of intensive versus attenuated induction regimen was not associated with higher induction mortality (p = 0.99). Overall, 29 % of patients aged ≤ 60 years underwent allogeneic transplantation, 87 % in first CR. 4-year overall survival (OS) and relapse-free survival were 25 % and 24 %, respectively. The incidence of relapse (death as a competitor) was 29 %, while the non-relapse mortality was 42 %. Only age was independently associated with OS, and lactate dehydrogenase level and central nervous disease at diagnosis were related to relapse in our cohort. This is the first historical cohort multicenter study on Ph+ ALL from Brazil. Reporting these outcomes is essential to encourage public policies to expand access to new drugs and transplantation in middle-income countries.
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