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The regulation of vascular tone by perivascular tissues is a complex interplay of various paracrine factors. Here, we investigate the anti-contractile effect of skeletal muscle surrounding the femoral and carotid arteries and its underlying mechanisms. Using male and female Wistar rats, we demonstrated that serotonin, phenylephrine, and U-46619 induced a concentration-dependent vasoconstrictor response in femoral artery rings. Interestingly, this response was diminished in the presence of surrounding femoral skeletal muscle, irrespective of sex. No anti-contractile effect was observed when the carotid artery was exposed to its surrounding skeletal muscle. The observed effect in the femoral artery persisted even in the absence of endothelium and when the muscle was detached from the artery. Furthermore, the skeletal muscle surrounding the femoral artery was able to promote an anti-contractile effect in three other vascular beds (basilar, mesenteric, and carotid arteries). Using inhibitors of lactate dehydrogenase and the 1/4 monocarboxylate transporter, we confirmed the involvement of lactate, as both inhibitors were able to abolish the anti-contractile effect. However, lactate did not directly promote vasodilation; rather, it exerted its effect by activating 5' AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (NOS1) in the skeletal muscle. Accordingly, Nω-propyl l-arginine, a specific inhibitor of NOS1, prevented the anti-contractile effect, as well as lactate-induced phosphorylation of NOS1 at the stimulatory serine site (1417) in primary skeletal muscle cells. Phosphorylation of NOS1 was reduced in the presence of Bay-3827, a selective AMPK inhibitor. In conclusion, femoral artery-associated skeletal muscle is a potent paracrine and endocrine organ that influences vascular tone in both sexes. Mechanistically, the anti-contractile effect involves muscle fiber type and/or its anatomical location but not the type of artery or its related vascular endothelium. Finally, the femoral artery anti-contractile effect is mediated by the lactate-AMPK-phospho-NOS1Ser1417-NO signaling axis., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

Non-B DNA G-quadruplex (G4) structures with guanine (G) runs of 2 to 4 repeats can trigger opposing experimental transcriptional impacts. Here, we used bioinformatic algorithms to comprehensively assess correlations of steady-state RNA transcript levels with all putative G4 sequence (pG4) locations genome-wide in three mammalian genomes and in normal and tumor human tissues. The human pG4-containing gene set displays higher expression levels than the set without pG4, supporting and extending some prior observations. pG4 enrichment at transcription start sites (TSSs) in human, but not chimpanzee and mouse genomes, suggests possible positive selection pressure for pG4 at human TSS, potentially driving genome rewiring and gene expression divergence between human and chimpanzee. Comprehensive bioinformatic analyses revealed lower pG4-containing gene set variability in humans and among different pG4 genes in tumors. As G4 stabilizers are under therapeutic consideration for cancer and pathogens, such distinctions between human normal and tumor G4s along with other species merit attention. Furthermore, in germline and cancer sequences, the most mutagenic pG4 mapped to regions promoting alternative DNA structures. Overall findings establish high pG4 at TSS as a human genome attribute statistically associated with robust well-coordinated transcription and reduced cancer transcriptome variation with implications for biology, model organisms, and medicine., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Multiple primary melanoma (MPM) is a diagnostic challenge even with ancillary imaging technologies available to dermatologists. In selected patients' phenotypes, the use of imaging approaches can help better understand lesion characteristics, and aid in early diagnosis and management., Methods: Under a 5-year prospective single-center follow-up, 58 s primary melanomas (SPMs) were diagnosed in two first-degree relatives, with fair skin color, red hair, green eyes, and personal history of one previous melanoma each. Patients' behavior and descriptive demographic data were collected from medical records. The information on the first two primary melanomas (PMs) were retrieved from pathology reports. The characteristics of 60 melanomas were collected from medical records, video dermoscopy software, and pathology reports. Reflectance confocal microscopy (RCM) was performed prior to excision of 22 randomly selected melanomas., Results: From February 2018 to May 2023, two patients underwent a pooled total of 214 excisional biopsies of suspect lesions, resulting in a combined benign versus malignant treatment ratio (NNT) of 2.0:1.0. The number of moles excised for each melanoma diagnosed (NNE) was 1.7:1.0 and 6.9:1.0 for the female and male patient respectively. The in-situ melanoma/invasive melanoma ratio (IIR) demonstrated a higher proportion of in-situ melanomas for both patients. From June 2018 to May 2023, a total of 58 SPMs were detected by the combination of total body skin exam (TBSE), total body skin photography (TBSP), digital dermoscopy (DD), and sequential digital dermoscopy imaging (SDDI) via comparative approach. The younger patient had her PM one month prior to the second and third cutaneous melanomas (CMs), characterizing a case of synchronous primary CM. The male older relative had a total of 7 nonsynchronous melanomas., Conclusions: This CM cohort is composed of 83.3% in-situ melanoma and 16.7% invasive melanoma. Both patients had a higher percentage of SPM with clinical nevus-like morphology (84.5%), global dermoscopic pattern of asymmetric multiple component (60.3%) and located on the lower limbs (46.6%). When RCM was performed prior to excision, 81% of SPM had features suggestive of malignancy. As well, invasive melanomas were more frequent in the lower limbs (40%). In the multivariate model, for the two high-risk patients studied, the chance of a not associated with nevus ("de novo") invasive SPM diagnosis is 25 times greater than the chance of a diagnosis of a nevus-associated invasive SPM.

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles suggest dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of two genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced retinal degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible, albeit ineffective, compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurotoxicity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Hemodialysis patients have complications that increase fear of falling (FOF). This study evaluated the association between FOF and a retrospective history of falls in hemodialysis patients and investigated the ability of the Fall Efficacy Scale-International (FES-I) to discriminate fallers from nonfallers., Methods: A retrospective study was conducted with 183 patients to investigate the history of falls in the last 12 months and to evaluate FOF by the FES-I., Results: The univariate linear regression model showed that the FES-I score was significantly associated with a history of falls (p = 0.01). After adjustment for potential confounders, this association remained significant (R 2  = 0.19, p < 0.001). The FES-I score showed an area under the curve of 0.660 with a cutoff point of 25 (sensitivity-61.8%; specificity-62.2%)., Conclusion: FOF was associated with a history of falls in the 12-month period in hemodialysis patients, and FOF assessed by the FES-I was able to discriminate fallers from nonfallers., (© 2022 International Society for Apheresis and Japanese Society for Apheresis.)

Aspergillus welwitschiae causes bole rot disease in sisal (Agave sisalana and related species) which affects the production of natural fibers in Brazil, the main worldwide producer of sisal fibers. This fungus is a saprotroph with a broad host range. Previous research established A. welwitschiae as the only causative agent of bole rot in the field, but little is known about the evolution of this species and its strains. In this work, we performed a comparative genomics analysis of 40 Aspergillus strains. We show the conflicting molecular identity of this species, with one sisal-infecting strain sharing its last common ancestor with Aspergillus niger, having diverged only 833 thousand years ago. Furthermore, our analysis of positive selection reveals sites under selection in genes coding for siderophore transporters, Sodium‑calcium exchangers, and Phosphatidylethanolamine-binding proteins (PEBPs). Herein, we discuss the possible impacts of these gene functions on the pathogenicity in sisal., Competing Interests: Declaration of Competing Interest None of the authors have any competing interests., (Copyright © 2022. Published by Elsevier Inc.)

This study aimed to evaluate the potential for lowering blood pressure and beneficial effects on mesenteric resistance arteries (MRA) and conductance vessels (aorta) produced by dietary supplementation of an egg white hydrolysate (EWH) in rats with severe hypertension induced by deoxycorticosterone plus salt treatment (DOCA-salt), as well as the underlying mechanisms involved. The DOCA-salt model presented higher blood pressure, which was significantly reduced by EWH. The impaired acetylcholine-induced relaxation and eNOS expression observed in MRA and aorta from DOCA-salt rats was ameliorated by EWH. This effect on vessels (MRA and aorta) was related to the antioxidant effect of EWH, since hydrolysate intake prevented the NF-κB/TNFα inflammatory pathway and NADPH oxidase-induced reactive oxygen species (ROS) generation, as well as the mitochondrial source of ROS in MRA. At the plasma level, EWH blocked the higher ROS and MDA generation by DOCA-salt treatment, without altering the antioxidant marker. In conclusion, EWH demonstrated an antihypertensive effect in a model of severe hypertension. This effect could be related to its endothelium-dependent vasodilator properties mediated by an ameliorated vessel's redox imbalance and inflammatory state.

Fungi comprise a great diversity of species with distinct ecological functions and lifestyles. Similar to other eukaryotes, fungi rely on interactions with prokaryotes and one of the most important symbiotic events was the acquisition of mitochondria. Mitochondria are organelles found in eukaryotic cells whose main function is to generate energy through aerobic respiration. Mitogenomes (mtDNAs) are double-stranded circular or linear DNA from mitochondria that may contain core genes and accessory elements that can be replicated, transcribed, and independently translated from the nuclear genome. Despite their importance, investigative studies on the diversity of fungal mitogenomes are scarce. Herein, we have evaluated 788 curated fungal mitogenomes available at NCBI database to assess discrepancies and similarities among them and to better understand the mechanisms involved in fungal mtDNAs variability. From a total of 12 fungal phyla, four do not have any representative with available mitogenomes, which highlights the underrepresentation of some groups in the current available data. We selected representative and non-redundant mitogenomes based on the threshold of 90% similarity, eliminating 81 mtDNAs. Comparative analyses revealed considerable size variability of mtDNAs with a difference of up to 260 kb in length. Furthermore, variation in mitogenome length and genomic composition are generally related to the number and length of accessory elements (introns, HEGs, and uORFs). We identified an overall average of 8.0 (0-39) introns, 8.0 (0-100) HEGs, and 8.2 (0-102) uORFs per genome, with high variation among phyla. Even though the length of the core protein-coding genes is considerably conserved, approximately 36.3% of the mitogenomes evaluated have at least one of the 14 core coding genes absent. Also, our results revealed that there is not even a single gene shared among all mitogenomes. Other unusual genes in mitogenomes were also detected in many mitogenomes, such as dpo and rpo , and displayed diverse evolutionary histories. Altogether, the results presented in this study suggest that fungal mitogenomes are diverse, contain accessory elements and are absent of a conserved gene that can be used for the taxonomic classification of the Kingdom Fungi., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fonseca, De-Paula, Araújo, Tomé, Mendes-Pereira, Rodrigues, Del-Bem, Aguiar and Góes-Neto.)

Common fragile sites (CFSs) are difficult-to-replicate genomic regions that form gaps and breaks on metaphase chromosomes under replication stress. They are hotspots for chromosomal instability in cancer. Repetitive sequences located at CFS loci are inefficiently copied by replicative DNA polymerase (Pol) delta. However, translesion synthesis Pol eta has been shown to efficiently polymerize CFS-associated repetitive sequences in vitro and facilitate CFS stability by a mechanism that is not fully understood. Here, by locus-specific, single-molecule replication analysis, we identified a crucial role for Pol eta (encoded by the gene POLH ) in the in vivo replication of CFSs, even without exogenous stress. We find that Pol eta deficiency induces replication pausing, increases initiation events, and alters the direction of replication-fork progression at CFS-FRA16D in both lymphoblasts and fibroblasts. Furthermore, certain replication pause sites at CFS-FRA16D were associated with the presence of non-B DNA-forming motifs, implying that non-B DNA structures could increase replication hindrance in the absence of Pol eta. Further, in Pol eta-deficient fibroblasts, there was an increase in fork pausing at fibroblast-specific CFSs. Importantly, while not all pause sites were associated with non-B DNA structures, they were embedded within regions of increased genetic variation in the healthy human population, with mutational spectra consistent with Pol eta activity. From these findings, we propose that Pol eta replicating through CFSs may result in genetic variations found in the human population at these sites., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Purpose: Non-adherence (NA) to medication is a major contributor to treatment failure in hypertensive patients. Factors of the ecological model, at family/healthcare professional, service, and system levels, are rarely evaluated as correlates of NA in hypertensive patients., Methods: This crossectional study assessed the prevalence of and associated factors of NA to antihypertensive medication among 485 hypertensive patients upon receiving secondary healthcare. The Morisky Green Levine Scale (MGLS) measured the implementation phase of adherence, and the Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA) instrument, health literacy. Multivariate analysis to NA included variables according to the levels of the ecological model., Results: Most patients were female (56.3%), white (53.2%), mean age of 62.0 ± 12.6 years, illiterate (61.6%), with low health literacy (70.9%), and low income (65.4%). Uncontrolled BP was frequent (75.2%); 57.1% of patients were nonadherent. In multivariate analysis based on the ecological model, adjusted for micro, meso- and macro-level correlates, NA was associated only with variables of patient-level: low health literacy (OR 1.62, CI 1.07-2.44, p = 0.020), income ≥ two reference wages (OR 0.46, CI 0.22-0.93, p = 0.031), lack of homeownership (OR 1.99, CI 1.13-3.51, p = 0.017), sedentarism (OR 1.78, CI 1.12-2.83, p = 0.014), and complexity of treatment (number of medications taken ≥ two times/day) (OR 1.56, CI 1.01-2.41, p = 0.042)., Conclusion: In this group of severely hypertensive patients with high cardiovascular risk, only patient-related characteristics were associated with NA. Our findings highlight the need for effective actions to optimize clinical outcomes in similar healthcare programs., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.)

The mitochondrion is an organelle found in eukaryote organisms, and it is vital for different cellular pathways. The mitochondrion has its own DNA molecule and, because its genetic content is relatively conserved, despite the variation of size and structure, mitogenome sequences have been widely used as a promising molecular biomarker for taxonomy and evolution in fungi. In this study, the mitogenomes of two fungal species of Agaricomycetes class, Phellinotus piptadeniae and Trametes villosa, were assembled and annotated for the first time. We used these newly sequenced mitogenomes for comparative analyses with other 55 mitogenomes of Agaricomycetes available in public databases. Mitochondrial DNA (mtDNA) size and content are highly variable and non-coding and intronic regions, homing endonucleases (HEGs), and unidentified ORFs (uORFs) significantly contribute to the total size of the mitogenome. Furthermore, accessory genes (most of them as HEGs) are shared between distantly related species, most likely as a consequence of horizontal gene transfer events. Conversely, uORFs are only shared between taxonomically related species, most probably as a result of vertical evolutionary inheritance. Additionally, codon usage varies among mitogenomes and the GC content of mitochondrial features may be used to distinguish coding from non-coding sequences. Our results also indicated that transposition events of mitochondrial genes to the nuclear genome are not common. Despite the variation of size and content of the mitogenomes, mitochondrial genes seemed to be reliable molecular markers in our time-divergence analysis, even though the nucleotide substitution rates of mitochondrial and nuclear genomes of fungi are quite different. We also showed that many events of mitochondrial gene shuffling probably happened amongst the Agaricomycetes during evolution, which created differences in the gene order among species, even those of the same genus. Altogether, our study revealed new information regarding evolutionary dynamics in Agaricomycetes., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: We evaluated the effects of supervised intradialytic resistance training on physical activity in daily life (PADL), muscle strength, physical capacity and quality of life (QoL) in hemodialysis patients. Methods: Twenty-four hemodialysis patients were randomly assigned to either a 12-weeks moderate-intensity resistance training or a control period. An accelerometer evaluated PADL for seven consecutive days, measuring the time spent in different activities and positions of daily routine and the number of steps taken. Muscle strength, physical capacity and QoL were evaluated. Results: After 12 weeks of training, we did not find significant difference (post-pre values) in walking time (-1.2 ± 18.3 vs. -9.2 ± 13.1 min/day); standing time (-10.2 ± 28.6 vs. 3.2 ± 20.1 min/day); sitting time (20.8 ± 58.9 vs. -30.0 ± 53.0 min/day); lying down time (-9.3 ± 57.9 vs. 34.6 ± 54.0 min/day); number of steps taken [-147 (1834) vs. -454 (2066)] and muscle strength in training and control group, respectively. There was a significant increase in the six-minute walking test distance (48.8 ± 35.9 vs. 6.9 ± 45.9 m, p  < 0.05) and some domains of QoL in the training compared to the control group. Conclusions: PADL was not modified after 12 weeks of intradialytic resistance training in hemodialysis patients. However, the exercise program was able to increase the physical capacity and some domains of QoL.Implications for rehabilitationPhysical activity in daily life was not modified after 12 weeks of intradialytic resistance training in hemodialysis patients.The exercise program was able to increase the physical capacity, efficacy of dialysis and some domains of quality of life in hemodialysis patients.The protocol used in this study was safe since no complications were observed during and after resistance training.These results should be interpreted with caution because we applied a moderate resistance training in both lower limbs and in the contralateral arteriovenous fistula upper limb, using perceived exertion by Borg scale to exercise prescription. Moreover, the safety protocol evaluation was not conducted.

Although previous studies have shown the benefits of exercise training in hemodialysis patients, little is known about the effects of long-term of exercise program on these patients. We investigated the effects and the safety of long-term aerobic training and the effects of detraining on functional capacity and quality of life in hemodialysis patients. Ten patients were allocated to two groups: training and detraining. The training group completed at least 30 months of aerobic training, and the detraining group completed at least 20 months and then discontinued the training for at least 10 months. The outcomes were analyzed at baseline, after 3 months of aerobic training and at the 30-month follow-up. The training and detraining groups performed 37 (5.5) and 24 (3.0) months of aerobic training, respectively. The detraining group discontinued the training for 11.0 (2.0) months. After 3 months of aerobic training, six-minute walking test distance increased significantly in both groups (training group = 569 (287.8) vs 635.5 (277.0) m, p  = 0.04; detraining group = 454.5 (72.3) vs 515.0 (91.8) m, p  = 0.04). There was no significant difference in the six-minute walking test distance in the training group (576.5 (182.5), p   >   0.05 ) and a significant decrease (436.2 (89.6) m, p  = 0.04) in the detraining group at the follow-up compared to the third month of aerobic training. No significant difference was observed in quality of life during the study. No complications were found during the protocol of the exercise. These results suggest that long-term aerobic training is safe and can maintain functional capacity in hemodialysis patients. In contrast, detraining can result in loss of functional capacity in these patients.

The order Hypocreales (Ascomycota) is composed of ubiquitous and ecologically diverse fungi such as saprobes, biotrophs, and pathogens. Despite their phylogenetic relationship, these species exhibit high variability in biomolecules production, lifestyle, and fitness. The mitochondria play an important role in the fungal biology, providing energy to the cells and regulating diverse processes, such as immune response. In spite of its importance, the mechanisms that shape fungal mitogenomes are still poorly understood. Herein, we investigated the variability and evolution of mitogenomes and its relationship with the divergence time using the order Hypocreales as a study model. We sequenced and annotated for the first time Trichoderma harzianum mitochondrial genome (mtDNA), which was compared to other 34 mtDNAs species that were publicly available. Comparative analysis revealed a substantial structural and size variation on non-coding mtDNA regions, despite the conservation of copy number, length, and structure of protein-coding elements. Interestingly, we observed a highly significant correlation between mitogenome length, and the number and size of non-coding sequences in mitochondrial genome. Among the non-coding elements, group I and II introns and homing endonucleases genes (HEGs) were the main contributors to discrepancies in mitogenomes structure and length. Several intronic sequences displayed sequence similarity among species, and some of them are conserved even at gene position, and were present in the majority of mitogenomes, indicating its origin in a common ancestor. On the other hand, we also identified species-specific introns that advocate for the origin by different mechanisms. Investigation of mitochondrial gene transfer to the nuclear genome revealed that nuclear copies of the nad5 are the most frequent while atp8 , atp9 , and cox3 could not be identified in any of the nuclear genomes analyzed. Moreover, we also estimated the divergence time of each species and investigated its relationship with coding and non-coding elements as well as with the length of mitogenomes. Altogether, our results demonstrated that introns and HEGs are key elements on mitogenome shaping and its presence on fast-evolving mtDNAs could be mostly explained by its divergence time, although the intron sharing profile suggests the involvement of other mechanisms on the mitochondrial genome evolution, such as horizontal transference., (Copyright © 2020 Fonseca, Badotti, De-Paula, Araújo, Bortolini, Del-Bem, Azevedo, Brenig, Aguiar and Góes-Neto.)

Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.

Cardiovascular diseases are the main cause of death in chronic kidney disease (CKD) patients. In dialysis patients, sudden cardiac death accounts for 40% of all deaths. In these patients, sudden cardiac death is usually secondary to an underlying cardiomyopathy, which is clinically identified by the high prevalence of left ventricular hypertrophy and the resultant mechanical and electrical dysfunction. CKD-related cardiomyopathy has a multifactorial pathophysiology. Recent evidence has highlighted the central pathophysiological role of chronic kidney disease-mineral and bone disorder (CKD-MBD) with hyperphosphatemia and high fibroblast growth factor 23 (FGF23) levels in these patients. Further, since CKD is known to be an αKlotho deficiency state, experimental studies have demonstrated that the deleterious effects of FGF23 can be minimized by reestablishing adequate soluble Klotho levels. Herein, we present a review that addresses not only the development of the understanding of CKD-related cardiomyopathy pathophysiology, but also explores the recent data that identify the triad of hyperphosphatemia, high FGF23 levels and αKlotho deficiency as playing a central role on it. Taken together, the data suggest that the uremic cardiomyopathy can be considered a new piece in the CKD-DMO puzzle.

Purpose: The aim of this study was to determine the gain and latency of arterial baroreflex control of heart rate in patients with resistant hypertension compared to patients with essential hypertension and normotensive subjects., Methods: Eighteen patients with resistant hypertension (56 ± 10 years, mean of four antihypertensive drugs), 17 patients with essential hypertension (56 ± 11 years, mean of two antihypertensive drugs), and 17 untreated normotensive controls (50 ± 15 years) were evaluated by spectral analysis of the spontaneous fluctuations of arterial pressure (beat-to-beat) and heart rate (ECG). This analysis estimated vasomotor and cardiac autonomic modulations, respectively. The transfer function analysis quantified the gain and latency of the response of output signal (RR interval) per unit of spontaneous change of input signal (systolic arterial pressure)., Results: The gain was similarly lower in patients with resistant hypertension and patients with essential hypertension in relation to normotensive subjects (4.67 ± 2.96 vs. 6.60 ± 3.30 vs. 12.56 ± 8.81 ms/mmHg; P < 0.01, respectively). However, the latency of arterial baroreflex control of heart rate was significantly higher only in patients with resistant hypertension when compared to patients with essential hypertension and normotensive subjects (-4.01 ± 3.19 vs. -2.91 ± 2.10 vs. -1.82 ± 1.09 s; P = 0.04, respectively). In addition, the index of vasomotor sympathetic modulation was significantly increased only in patients with resistant hypertension when compared to patients with essential hypertension and normotensive subjects (4.04 ± 2.86 vs. 2.65 ± 1.88 vs. 2.06 ± 1.70 mmHg 2 ; P < 0.01, respectively)., Conclusions: Patients with resistant hypertension have reduced gain and increased latency of arterial baroreflex control of heart rate. These patients also have increased vasomotor sympathetic modulation.

Background: Diabetes management involves multiple aspects that go beyond drug therapy as a way of providing high quality care. The objective of this study was to describe quality of care indicators for individuals with diabetes in southeast Brazil and to explore associations among these indicators., Methods: In this cross-sectional, observational study, health care providers filled out a questionnaire addressing health care structure and processes at 14 primary health care units (PHCUs). Clinical and laboratory data of diabetic patients attending the PHCUs and from patients referred to a secondary health care (SHC) center were collected., Results: There was a shortage of professionals in 53.8% of the PHCUs besides a high proportion of problems regarding referrals to SHC. At the PHCU, glycated hemoglobin results were available only in half of the medical records. A low rate of adequate glycemic control was also observed. An association between structure and process indicators and the outcomes analyzed was not found., Conclusion: Major deficiencies were found in the structure and processes of the PHCUs, in addition to unsatisfactory diabetes care outcomes. However, no association between structure, process, and outcomes was found.

Aims: To evaluate the effect of the processing method (conventional sintering, S, and heat-pressing, HP) and addition of potassium titanate fibers, PTF, on the microstructure, mechanical properties (flexural strength, σf, and Weibull parameters, m and σ5%), slow crack growth parameters n (stress corrosion susceptibility coefficient), and optical properties (translucency parameter, TP, and opalescence index, OI) of a feldsphatic dental porcelain., Methods: Disks (n = 240, Ø12 × 1 mm) of porcelain (Vintage-Halo, Shofu) were produced using S and HP methods with and without addition of 10 wt% (conventional sintering) or 5 wt% (heat-pressing) of PTF. For the S method, porcelain was sintered in a conventional furnace. In the HP technique, refractory molds were produced by lost wax technique. The porcelain slurry was dry-pressed (3t/30s) to form a cylinder with 12 mm (diameter) and 20mm (height), which was heat-pressed for 5 min/3.5 bar into the mold. Specimens were tested for biaxial flexural strength in artificial saliva at 37°C. Weibull analysis was used to determine m and σ5%. Slow crack growth (SCG) parameters were determined by the dynamic fatigue test, and specimens were tested in biaxial flexure at five stress rates: 10(-2), 10(-1), 10(0), 10(1) and 10(2)MPa/s (n=10), immersed in artificial saliva at 37°C. Parameter n was calculated and statistically analyzed according to ASTM F394-78. Optical properties were determined in a spectrophotometer in the diffuse reflectance mode., Results: The highest n value was obtained by the combination of heat-pressing with fiber addition (37.1) and this value was significantly higher than those obtained by both sintered groups (26.2 for control group and 27.7 for sintered with fiber). Although heat-pressing alone also resulted in higher n values compared to the sintered groups, there were no significant differences among them. Fiber addition had no effect on mechanical strength, but it resulted in decreased TP values and increased OI values for both processing methods. Heat-pressing alone was able to reduce the porosity level of the porcelain., Conclusions: Addition of PTF combined with heat-pressing can reduce strength degradation of a dental porcelain compared to sintered materials with or without fibers. Heat-pressing (HP) alone should be considered as a good alternative for clinical cases where high translucency is required., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Different factors can contribute to a sedentary lifestyle among hemodialysis (HD) patients, including the period they spend on dialysis. The aim of this study was to evaluate characteristics of physical activities in daily life in this population by using an accurate triaxial accelerometer and to correlate these characteristics with physiological variables. Nineteen HD patients were evaluated using the DynaPort accelerometer and compared to nineteen control individuals, regarding the time spent in different activities and positions of daily life and the number of steps taken. HD patients were more sedentary than control individuals, spending less time walking or standing and spending more time lying down. The sedentary behavior was more pronounced on dialysis days. According to the number of steps taken per day, 47.4% of hemodialysis patients were classified as sedentary against 10.5% in control group. Hemoglobin level, lower extremity muscle strength, and physical functioning of SF-36 questionnaire correlated significantly with the walking time and active time. Looking accurately at the patterns of activity in daily life, HDs patients are more sedentary, especially on dialysis days. These patients should be motivated to enhance the physical activity.

Introduction: Hypertension is highly prevalent in patients with chronic kidney disease and hypervolemia is one of the principal causes., Objective: To evaluate the influence of the reduction of volemia on blood pressure as well as on echocardiographic parameters in patients on continuous ambulatory peritoneal dialysis., Methods: Twelve patients with no clinical evidence of hypervolemia were submitted to an increase in the rate of the dialysis with the purpose of reducing body weight by 5%. The volemia was evaluated by electrical bioimpedance and by ultrasound of the inferior cava vena (ICV). Blood pressure was measured by ambulatory blood pressure monitoring and cardiac function was evaluated by echocardiography both at baseline and 5 weeks after the intervention period., Results: After the increase in the ultrafiltration, body weight, extracellular water and the inspiratory diameter of the ICV decreased significantly in parallel with a non-significant increase in the collapsing ICV index. Despite the reduction of anti-hypertensive drugs, systolic blood pressure during the sleep period decreased from 138.4 ± 18.6 to 126.7 ± 18.0 mmHg, the nocturnal blood pressure drop increased and the final systolic left ventricular diameter decreased significantly., Conclusion: Reduction of the volemia of patients on peritoneal dialysis, with no signs of hypervolemia, was associated with a better blood pressure control and with a decrease of the final systolic left ventricular diameter.

Introduction: A dysfunctional autonomic nervous system (ANS) has also been recognized as an important mechanism contributing to the poor outcome in CKD patients, with several studies reporting a reduction in heart rate variability (HRV)., Objective: Evaluate the sympathovagal balance in patients with chronic kidney disease on conservative treatment., Methods: In a cross-sectional study, patients with CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy subjects (CON group) underwent continuous heart rate recording during two twenty-minute periods in the supine position (pre-inclined), followed by passive postural inclination at 70° (inclined period). Power spectral analysis of the heart rate variability was used to assess the normalized low frequency (LFnu), indicative of sympathetic activity, and the normalized high frequency (HFnu), indicative of parasympathetic activity. The LFnu/HFnu ratio represented sympathovagal balance., Results: After tilting, CKD patients had lower sympathetic activity, higher parasympathetic activity, and lower sympathovagal balance than patients in the CON group. Compared to patients in stage 3, patients in stage 5 had a lower LFnu/HFnu ratio, suggesting a more pronounced impairment of sympathovagal balance as the disease progresses., Conclusion: CKD patients not yet on dialysis have reduced HRV, indicating cardiac autonomic dysfunction early in the course of CKD.

Introduction: Drug interactions (DIs) are common in clinical practice and are directly related to factors such as polypharmacy, aging, hepatic metabolism and decreased renal function. Individuals with chronic kidney disease (CKD) often require multiple classes of drugs being at important risk for the development of DIs., Objective: Identify potential interactions among drugs prescribed to patients with CKD on conservative treatment, and factors associated with their occurrence., Methods: Observational cross-sectional study, with analysis of 558 prescriptions. Potential DIs were identified by the database MICROMEDEX®, software that provides an internationally known pharmacopoeia., Results: There was a predominance of males (54.7%), seniors (69.4%), stage 3 CKD (47.5%), overweight and obese patients (66.7%). The most prevalent comorbidities were hypertension (68.5%) and diabetes mellitus (31.9%). Potential DIs were detected in 74.9% of prescriptions. Among the 1364 DIs diagnosed, 5 (0.4%) were contraindicated and 229 (16.8%) of greater severity, which need immediate intervention. Interactions of moderate and low severity were identified in 1049 (76.9%) and 81 (5.9%) prescriptions, respectively. The probability of one DI increased by 2.5 times for each additional drug (CI = 2.18 to 3.03). Obesity, hypertension, diabetes as well as advanced stage of CKD were risk factors strongly associated with DI occurrence., Conclusion: Drug associations in individuals with CKD were related to high prevalence of serious DIs, especially in the later stages of the disease.

Objective: to assess cardiovascular risk by means of the traditional Framingham score and the version modified through the incorporation of emerging risk factors, such as family history of acute myocardial infarction, metabolic syndrome and chronic kidney disease., Method: participants were 50 hypertensive patients under outpatient treatment. The clinical data were collected through a semi-structured interview and the laboratory data from patients' histories., Results: it was verified that the traditional Framingham score was predominantly low (74%), with 14% showing medium risk and 12% high risk. After the inclusion of emerging risk factors, the chance of a coronary event was low in 22% of the cases, medium in 56% and high in 22%., Conclusions: the comparison between the traditional Framingham risk score and the modified version demonstrated a significant difference in the cardiovascular risk classification, whose correlation shows discreet agreement between the two scales. Lifestyle elements seem to play a determinant role in the increase in cardiovascular risk levels.

Introduction: The treatment of arterial hypertension (AH) in patients with metabolic syndrome (MS) is a challenge, since non drug therapies are difficult to implement and optimal pharmacological treatment is not fully established., Objective: To assess the blockade of the rennin angiotensin aldosterone system (RAAS) in blood pressure (BP) in renal function and morphology in an experimental model of MS induced by high fat diet., Methods: Wistar rats were fed on high fat diet from the fourth week of life, for 20 weeks. The groups received Losartan or Spironolactone from the eighth week of life. We weekly evaluated the body weight and BP by tail plethysmography. At the end of the experiment oral glucose tolerance, lipid profile, creatinine clearance tests, and the direct measurement of BP were performed. A morphometric kidney analysis was performed., Results: The administration of high-fat diet was associated with the development of MS, characterized by central fat accumulation, hypertension, hyperglycemia and hypertriglyceridemia. In this model there were no changes in renal histomorphometry. The blockade of angiotensin II (Ang II) receptor AT1 prevented the development of hypertension. The mineralocorticoid blockage did not have antihypertensive efficacy but was associated with reduction of abdominal fat., Conclusion: The dissociation of the antihypertensive response to the blockades of Ang II receptors and mineralocorticoid indicates the involvement of Ang II in the pathogenesis of hypertension associated with obesity. Reduction of central obesity with Spironolactone suggests the presence of mineralocorticoid adipogenic effect.

Objective: We investigated the impact of weight loss on urinary albumin excretion (UAE) and creatinine clearance in obese patients with metabolic syndrome., Methods: Thirty-five obese patients undertook a 12-week calorie-restricted diet. The patients underwent a metabolic (oral glucose tolerance test, plasma lipids, and uric acid) and renal hemodynamic evaluations (creatinine clearance and urinary albumin excretion) before (phase 1), and after the 12-week diet (phase 2)., Results: After the dietary intervention, the subjects were divided into two groups: patients who achieved the target weight reduction (R: responders, n = 14), and patients who did not (NR: non-responders, n = 21). The patients in Group R showed an improvement in lipid profile, a decrease in UAE (median = 162.5 mg/24 hours, range: 0.8 to 292 mg/24 hours, at phase 1 versus 10.4 mg/24 hours, range: 1.6 to 22.4 mg/24 hours, at phase 2), and a significant reduction in creatinine clearance (121.4 ± 66.5 mL/min. in phase 1 to 92.9 ± 35.6 mL/min. at the end of phase 2, p = 0.001). In Group NR, no statistically significant differences were observed between phases 1 and 2., Conclusion: Body weight reduction has a positive impact on renal hemodynamics, decreasing urinary albumin excretion as well as glomerular hyperfiltration in obese patients with metabolic syndrome.

Introduction: Decreased heart rate variability (HRV) in patients with end stage renal disease (ESRD) undergoing hemodialysis is predictive of cardiac death, especially due to sudden death., Objective: To evaluate the effects of aerobic training during hemodialysis on HRV and left ventricular function in ESRD patients., Methods: Twenty two patients were randomized into two groups: exercise (n = 11; 49.6 ± 10.6 years; 4 men) and control (n = 11; 43.5 ± 12.8; 4 men). Patients assigned to the exercise group were submitted to aerobic training, performed during the first two hours of hemodialysis, three times weekly, for 12 weeks. HRV and left ventricular function were assessed by 24 hours Holter monitoring and echocardiography, respectively., Results: After 12 weeks of protocol, no significant differences were observed in time and frequency domains measures of HRV in both groups. The ejection fraction improved non-significantly in exercise group (67.5 ± 12.6% vs. 70.4 ± 12%) and decreased non-significantly in control group (73.6 ± 8.4% vs. 71.4 ± 7.6%)., Conclusion: A 12-week aerobic training program performed during hemodialysis did not modify HRV and did not significantly improve the left ventricular function.

Hypertension and cardiovascular diseases are highly prevalent in hemodialysis patients and are associated with the reduction of physical functioning and quality of life. We evaluated the effects of supervised aerobic exercise training on physical functioning, blood pressure, quality of life, and laboratory data in hemodialysis patients. Fourteen patients were evaluated at the beginning and after 12 weeks of stretching exercises (control phase) and at the end of 12 weeks of aerobic exercise training performed during hemodialysis sessions (intervention phase). Patients underwent a 6-min walking test (6MWT), 24-h ambulatory blood pressure monitoring, a Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) quality of life questionnaire, and blood sample collections. After the intervention phase, the 6MWT distance increased from 508.7 +/- 91.9 m to 554.9 +/- 105.8 m (P = 0.001), systolic and diastolic blood pressure decreased respectively from 150.6 +/- 18.4 mm Hg to 143.5 +/- 14.7 mm Hg and from 94.6 +/- 10.5 mm Hg to 91.4 +/- 9.7 mm Hg (P < 0.05), while hemoglobin levels increased from 10.8 +/- 1.2 g/dL to 11.6 +/- 0.8 g/dL (P < 0.05). Moreover, there was a significant increase in the physical functioning, social functioning, and mental health dimensions of the SF-36. Aerobic exercise training during hemodialysis increased physical functioning, reduced blood pressure levels, and improved the control of anemia and quality of life in patients with end-stage renal disease.

This study examined the importance of aldosterone (ALDO) in mediating changes in renal function and increased mean arterial pressure (MAP) during the development of dietary-induced obesity in chronically instrumented dogs. Mean arterial pressure, heart rate (HR), and cardiac output (CO) were recorded 24 hours per day in lean dogs (n=7) before and after administration of an ALDO antagonist, eplerenone (EP) (10 mg/kg twice daily), for 10 days. After 10 days of EP treatment, the dogs (n=7) were given a supplement of cooked beef fat for 5 weeks while EP was continued. An untreated group (n=6) was fed a high fat diet for 5 weeks and used as control (C). In lean dogs, EP decreased MAP from 89+/-4 to 84+/-4 mm Hg and glomerular filtration rate from 67.4+/-6.8 to 53.2+/-4.9 mL/min while inducing a small negative Na+ balance (-42+/-12 mEq). Plasma renin activity increased from 0.4+/-0.1 to 2.7+/-0.7 ng AI/mL per hour and plasma K+ increased from 4.8+/-0.1 to 6.1+/-0.3 mEq/L. After 5 weeks of a high fat diet, body weight increased 45% to 53% in EP and C obese dogs. In C dogs, MAP increased by 16+/-3 mm Hg, compared with only 7+/-1 mm Hg in EPLE dogs. Compared with untreated dogs, the EP dogs had smaller increases in CO (18+/-4.6% versus 43+/-1.5%), HR (33+/-5% versus 60+/-3%), glomerular filtration rate (19+/-5% versus 38+/-6%), and cumulative Na+ balance (138+/-35 mEq versus 472+/-110 mEq) after 5 weeks of a high fat diet. Thus, EP markedly attenuated glomerular hyperfiltration, sodium retention, and hypertension associated with chronic dietary-induced obesity. These observations indicate that ALDO plays an important role in the pathogenesis of obesity hypertension.

Purpose of Review: The worldwide prevalence of obesity and its associated metabolic and cardiovascular disorders has risen dramatically during the past two decades. Our objective is to review the mechanisms that link obesity with hypertension and altered kidney function., Recent Findings: Current evidence suggests that excess weight gain may be responsible for 65-75% of the risk for essential hypertension. Abnormal renal pressure natriuresis, due initially to increased renal tubular sodium reabsorption, is a key factor linking obesity with hypertension. Obesity increases renal sodium reabsorption by activating the renin-angiotensin and sympathetic nervous systems, and by altering intrarenal physical forces. Adipose tissue functions as an endocrine organ, secreting hormones/cytokines (e.g. leptin) that may activate the sympathetic nervous system and alter kidney function. Excess visceral adipose tissue may physically compress the kidneys, increasing intrarenal pressures and tubular reabsorption. Sustained obesity eventually causes structural changes in the kidneys and loss of nephron function, further increasing arterial pressure and leading to severe renal disease in some cases., Summary: Despite considerable progress in understanding the pathophysiology of obesity, there are still no specific guidelines for the treatment of obesity hypertension other than weight reduction. Special considerations for obese hypertensive patients, in addition to controlling blood pressure, are correcting the metabolic abnormalities and protecting the kidneys from injury. This remains an important area for further research, especially in view of the current 'epidemic' of obesity in most industrialized countries.

Arginine vasopressin (AVP) has been found to participate in blood pressure maintenance especially when other pressor systems are endogenously or pharmacologically impaired. The purpose of this study was to assess the pressor contribution of AVP to orthostatic blood pressure maintenance in otherwise healthy patients with essential hypertension. Twenty-seven patients were grouped according to age (young n = 13, elderly n = 14) and race (white n = 13, black n = 14). Integrity of autonomic nervous system (ANS) was assessed by Valsalva's maneuver, cold pressor test and head-up tilt. AVP contribution to blood pressure was estimated by the fall in mean arterial pressure in response to IV injection of 0.5 mg of a V1 AVP inhibitor (AVPi). Elderly subjects were found to have a mild (subclinical) ANS impairment as indicated by absence of bradycardia in phase 4 of Valsalva's maneuver and hypotension without concurrent tachycardia during head up tilt. Depressor responses to AVPi while subjects were in the upright position, were greater in elderly and blacks (-15 +/- 11 mm Hg and -15 +/- 12 mm Hg, respectively, P < .05) than young and whites (-8 +/- 6 and -7 +/- 6 mm Hg, respectively, ns). The greater importance of the AVP component in the elderly may be at least partially explained by a mild ANS impairement, whereas hormonal characteristics of hypertension in blacks may explain greater AVPi induced fall in mean arterial pressure. Our data show that both age and race influence the response to AVPi.