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Background Waste anesthetic gases (WAGs) contribute to greenhouse gas emissions. US anesthesiology resident education on how to reduce WAG-associated emissions is lacking, so we developed an electronic audit-and-feedback-based program to teach residents to reduce fresh gas flow (FGF) and WAG-associated emissions. Objective To assess the program's effectiveness, we measured individual and combined mean FGF of residents during their first, second, and last weeks of the 4-week rotation; then, we calculated the extrapolated annual emissions based on the combined resident mean FGFs. Resident attitudes toward the program were surveyed. Methods During 4-week rotations at a teaching hospital, anesthesia records were scanned to extract resident-assigned cases, FGF, and volatile anesthetic choice during the 2020-2021 academic year. Forty residents across 3 training years received weekly FGF data and extrapolated WAG-associated emissions data via email. Their own FGF data was compared to the low-flow standard FGF of ≤1 liter per minute (LPM) and to the FGF data of their peer residents on rotation with them. An online survey was sent to residents at the end of the project period. Results Between their first and last weeks on rotation, residents decreased their mean FGF by 22% (1.83 vs 1.42 LPM; STD 0.58 vs 0.44; 95% CI 1.67-2.02 vs 1.29-1.56; P<.0001). Ten of 18 (56%) residents who responded to the survey reported their individual case-based results were most motivating toward practice change. Conclusions An audit-and-feedback-based model for anesthesiology resident education, designed to promote climate-conscious practices with administration of volatile anesthetics, was effective.
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Anestesiologia , Anestésicos Inalatórios , Internato e Residência , Anestesiologia/educação , Humanos , Inquéritos e Questionários , Educação de Pós-Graduação em Medicina , Gases de Efeito EstufaRESUMO
BACKGROUND AND OBJECTIVE: Assessment of patients with hematuria (aH) remains a challenge in urological practice, balancing the benefits of diagnosing a potentially underlying bladder cancer (UCa) against the risks of possibly unnecessary diagnostic interventions. This study analyzes the potential of an mRNA-based urine assay, the Xpert® Bladder Cancer Detection- CE-IVD (Xpert BC-D), in patients with hematuria. MATERIALS AND METHODS: Overall, 368 patients with newly observed painless hematuria and no history of UCa were included in this observational study. Patients received urological workup, including urethrocystoscopy (WLC), upper tract imaging, urine cytology and Xpert BC-D. Patients with positive WLC were recommended to undergo tumor resection (TUR-B). RESULTS: After excluding non-assessable cases, 324 patients were considered for analysis (188 males, 136 females; median age: 61 years). Eight of twenty-eight patients with a positive TUR-B had Ta low grade (LG) tumors; the others were diagnosed with high grade (HG) lesions (Ta: 4, CIS: 2, T1:11, >âT1:3). The Xpert BC-D was more sensitive than urine cytology (96% vs. 61%) (pâ=â0.002). Increased risk ratios (RR) were observed for gross hematuria, gender, urine cytology, and positive Xpert BC-D (all pâ<â0.05). Age and positive Xpert BC-D remained independent predictors of UCa in multivariate analysis. Simulating a triage with WLC restricted to patients with positive Xpert BC-D could have saved 240 (74.1%) assessments at the cost of missing one pTa LG tumor. CONCLUSIONS: The results suggest a potential role for Xpert BC-D in preselecting patients with hematuria for either further invasive diagnosis or an alternate diagnostic procedure.
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An important property of the host innate immune response during microbial infection is its ability to control the expression of antimicrobial effector proteins, but how this occurs post-transcriptionally is not well defined. Here, we describe a critical antibacterial role for the classic antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1). Human OAS1 and its mouse ortholog, Oas1b, are induced by interferon-γ and protect against cytosolic bacterial pathogens such as Francisella novicida and Listeria monocytogenes in vitro and in vivo. Proteomic and transcriptomic analysis showed reduced IRF1 protein expression in OAS1-deficient cells. Mechanistically, OAS1 binds and localizes IRF1 mRNA to the rough endoplasmic reticulum (ER)-Golgi endomembranes, licensing effective translation of IRF1 mRNA without affecting its transcription or decay. OAS1-dependent translation of IRF1 leads to the enhanced expression of antibacterial effectors, such as GBPs, which restrict intracellular bacteria. These findings uncover a noncanonical function of OAS1 in antibacterial innate immunity.
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2',5'-Oligoadenilato Sintetase , Imunidade Inata , Fator Regulador 1 de Interferon , 2',5'-Oligoadenilato Sintetase/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Animais , Humanos , Camundongos , Biossíntese de Proteínas/imunologia , Listeria monocytogenes/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Listeriose/imunologia , Interferon gama/metabolismo , Interferon gama/imunologiaRESUMO
BACKGROUND AND AIMS: Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction-associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy-1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. METHODS: The impact of Thy-1 on the development of SLD and progression to fibrosis was investigated in high-fat diet (HFD)-induced SLD wild-type and Thy-1-deficient mice. In addition, the serum soluble Thy-1 (sThy-1) concentration was analysed in patients with metabolic dysfunction-associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. RESULTS: We demonstrated that Thy-1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD-induced SLD mice. Mechanistically, Thy-1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy-1 prevents palmitic acid-mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy-1-deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy-1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. CONCLUSION: Our data strongly suggest that Thy-1 may function as a fibrosis-protective factor in mouse and human SLD.
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Dieta Hiperlipídica , Cirrose Hepática , Camundongos Endogâmicos C57BL , Antígenos Thy-1 , Animais , Cirrose Hepática/patologia , Camundongos , Humanos , Antígenos Thy-1/metabolismo , Masculino , Camundongos Knockout , Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/patologia , Fígado/metabolismo , Fígado Gorduroso/patologia , Pessoa de Meia-Idade , FemininoRESUMO
AIMS/HYPOTHESIS: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. METHODS: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. RESULTS: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised ß=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; ß=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (ß=0.090; p<0.001 for eGDR) and MZ (ß=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. CONCLUSIONS/INTERPRETATION: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes.
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Retinopatia Diabética , Intolerância à Glucose , Resistência à Insulina , Estado Pré-Diabético , Adulto , Humanos , Estudos Transversais , Retina , GlucoseRESUMO
In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.
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2',5'-Oligoadenilato Sintetase , Interferons , Oligorribonucleotídeos , Viroses , Febre do Nilo Ocidental , Animais , Humanos , Camundongos , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina , Antivirais/farmacologia , Febre do Nilo Ocidental/genética , Febre do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/patogenicidadeRESUMO
BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.
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Transplante de Rim , Insuficiência Renal Crônica , Humanos , Lactente , Pré-Escolar , Diálise Renal , Envelhecimento/genética , Metilação de DNA , Insuficiência Renal Crônica/terapia , Epigênese GenéticaRESUMO
RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Infarto do Miocárdio , Insuficiência Renal , Humanos , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/efeitos adversos , Estudos Retrospectivos , Insulina/uso terapêutico , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Diálise Renal , Hospitalização , Insuficiência Renal/complicaçõesRESUMO
OBJECTIVE: To explore whether insulin resistance, assessed by estimated glucose disposal rate (eGDR), is associated with cardiorenal risk and whether it modifies finerenone efficacy. RESEARCH DESIGN AND METHODS: In FIDELITY (N = 13,026), patients with type 2 diabetes, either 1) urine albumin-to-creatinine ratio (UACR) of ≥30 to <300 mg/g and estimated glomerular filtration rate (eGFR) of ≥25 to ≤90 mL/min/1.73 m2 or 2) UACR of ≥300 to ≤5,000 mg/g and eGFR of ≥25 mL/min/1.73 m2, who also received optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. Outcomes included cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained decrease of ≥57% in eGFR from baseline, or renal death) composites. eGDR was calculated using waist circumference, hypertension status, and glycated hemoglobin for 12,964 patients. RESULTS: Median eGDR was 4.1 mg/kg/min. eGDR Assuntos
Diabetes Mellitus Tipo 2
, Resistência à Insulina
, Insulinas
, Naftiridinas
, Insuficiência Renal Crônica
, Humanos
, Diabetes Mellitus Tipo 2/complicações
, Diabetes Mellitus Tipo 2/tratamento farmacológico
, Método Duplo-Cego
, Insuficiência Renal Crônica/complicações
, Glucose/uso terapêutico
, Insulinas/uso terapêutico
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The NLRP3 inflammasome is a central component of the innate immune system. Its activation leads to formation of the ASC speck, a supramolecular assembly of the inflammasome adaptor protein ASC. Different models, based on ASC overexpression, have been proposed for the structure of the ASC speck. Using dual-color 3D super-resolution imaging (dSTORM and DNA-PAINT), we visualized the ASC speck structure following NLRP3 inflammasome activation using endogenous ASC expression. A complete structure was only obtainable by labeling with both anti-ASC antibodies and nanobodies. The complex varies in diameter between â¼800 and 1000 nm, and is composed of a dense core with emerging filaments. Dual-color confocal fluorescence microscopy indicated that the ASC speck does not colocalize with the microtubule-organizing center at late time points after Nigericin stimulation. From super-resolution images of whole cells, the ASC specks were sorted into a pseudo-time sequence indicating that they become denser but not larger during formation.
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Dyslipidemia in chronic kidney disease (CKD) contributes to the increasing cardiovascular risk during progression of the disease. Statins reduces the risk of ischemic cardiovascular events in CKD patients not treated with dialysis and treatment is generally recommended in patients above 50 years old. In CKD patients on maintenance dialysis treatment, it is not recommended to initiate statins based on evidence from randomized clinical trials. In an article by Marx et al. in this issue of CKJ, a post hoc analysis of cardiovascular events in the 4D study of dialysis patients with diabetes mellitus shows different time trends for events in statin-treated patients compared with those in the placebo group. Although the numbers of cardiovascular events were not different, the risk increased over time in the placebo group whereas it stabilized after 1.5 years and remained constant in the atorvastatin group. In this Editorial we discuss this analysis in the context of current guidelines and clinical practice in dialysis patients.
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The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP-1. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.
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Nucleotídeos , Transdução de Sinais , Humanos , Citocinas , Imunidade , Macrófagos/metabolismo , Nucleotídeos/metabolismo , Replicação ViralRESUMO
BACKGROUND: Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has recently been characterized as an endocrine factor affecting energy balance and lipid metabolism. However, regulation of ACBP in women with gestational diabetes mellitus (GDM) during pregnancy, as well as postpartum, has not been investigated, so far. METHODS: ACBP was quantified in 74 women with GDM and 74 healthy, gestational age-matched, pregnant controls using an enzyme-linked immunosorbent assay. Furthermore, ACBP was quantified post-partum in 82 women (i.e. 41 women with previous GDM vs. 41 previous control women). ACBP was related to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation during pregnancy and postpartum. RESULTS: During pregnancy, median [interquartile range] ACBP levels were not significantly different in women with GDM (40.9 [40.0] µg/l) compared to healthy, pregnant controls (29.1 [32.3] µg/l) (p = 0.215). ACBP serum concentrations increased from 30.3 [40.5] µg/l during pregnancy to 59.7 [33.2] µg/l after pregnancy in the entire cohort (p < 0.001). This observed elevation was consistent across both subgroups of women, those with prior GDM and those without. Multivariate analysis revealed that homeostasis model assessment of beta cell function (HOMA2-B) and creatinine positively and independently correlated with serum ACBP after pregnancy, while multivariate analysis during pregnancy showed no significant correlations. CONCLUSIONS: Circulating ACBP is not a marker of GDM status, but ACBP is decreased during pregnancy, irrespective of GDM status. Furthermore, ACBP is related to beta cell function and renal markers in women after pregnancy.
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Diabetes Gestacional , Gravidez , Feminino , Humanos , Inibidor da Ligação a Diazepam , Período Pós-Parto , Análise Multivariada , DiazepamRESUMO
Given the pathophysiological continuum of chronic kidney disease (CKD), different molecular determinants affecting progression may be associated with distinct disease phases; thus, identification of these players are crucial for guiding therapeutic decisions, ideally in a non-invasive, repeatable setting. Analyzing the urinary peptidome has been proven an efficient method for biomarker determination in CKD, among other diseases. In this work, after applying several selection criteria, urine samples from 317 early (stage 2) and advanced (stage 3b-5) CKD patients were analyzed using capillary electrophoresis coupled to mass spectrometry (CE-MS). The entire two groups were initially compared to highlight the respective pathophysiology between initial and late disease phases. Subsequently, slow and fast progressors were compared within each group in an attempt to distinguish phase-specific disease progression molecules. The early vs. late-stage CKD comparison revealed 929 significantly different peptides, most of which were downregulated and 268 with collagen origins. When comparing slow vs. fast progressors in early stage CKD, 42 peptides were significantly altered, 30 of which were collagen peptide fragments. This association suggests the development of structural changes may be reversible at an early stage. The study confirms previous findings, based on its multivariable-matched progression groups derived from a large initial cohort. However, only four peptide fragments differed between slow vs. fast progressors in late-stage CKD, indicating different pathogenic processes occur in fast and slow progressors in different stages of CKD. The defined peptides associated with CKD progression at early stage might potentially constitute a non-invasive approach to improve patient management by guiding (personalized) intervention.
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Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott-Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated.
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Transforming growth factor beta-1 (TGFß1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFß1 in pregnancy and child growth and the source of cord TGFß1 are yet unknown. In this study, we sought to clarify the correlation of TGFß1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother-child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann-Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFß1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFß1 levels at birth and child weight at U6. Furthermore, cord TGFß1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFß1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex.
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BACKGROUND: Chronic kidney disease (CKD) patients exhibit a heightened cardiovascular (CV) risk which may be partially explained by increased medial vascular calcification. Although gut-derived uremic toxin trimethylamine N-oxide (TMAO) is associated with calcium-phosphate deposition, studies investigating phenylacetylglutamine's (PAG) pro-calcifying potential are missing. METHODS: The effect of TMAO and PAG in vascular calcification was investigated using 120 kidney failure patients undergoing living-donor kidney transplantation (LD-KTx), in an observational, cross-sectional manner. Uremic toxin concentrations were related to coronary artery calcification (CAC) score, epigastric artery calcification score, and markers of established non-traditional risk factors that constitute to the 'perfect storm' that drives early vascular aging in this patient population. Vascular smooth muscle cells were incubated with TMAO or PAG to determine their calcifying effects in vitro and analyse associated pathways by which these toxins may promote vascular calcification. RESULTS: TMAO, but not PAG, was independently associated with CAC score after adjustment for CKD-related risk factors in kidney failure patients. Neither toxin was associated with epigastric artery calcification score; however, PAG was independently, positively associated with 8-hydroxydeoxyguanosine. Similarly, TMAO, but not PAG, promoted calcium-phosphate deposition in vitro, while both uremic solutes induced oxidative stress. CONCLUSIONS: In conclusion, our translational data confirm TMAO's pro-calcifying effects, but both toxins induced free radical production detrimental to vascular maintenance. Our findings suggest these gut-derived uremic toxins have different actions on the vessel wall and therapeutically targeting TMAO may help reduce CV-related mortality in CKD.
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Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Cálcio , Estudos Transversais , Fosfatos , Insuficiência Renal Crônica/complicações , Calcificação Vascular/metabolismoRESUMO
Ageing is an inevitable aspect of life and thus successful ageing is an important focus of recent scientific efforts. The biological process of ageing is mediated through the interaction of genes with environmental factors, increasing the body's susceptibility to insults. Elucidating this process will increase our ability to prevent and treat age-related disease and consequently extend life expectancy. Notably, centenarians offer a unique perspective on the phenomenon of ageing. Current research highlights several age-associated alterations on the genetic, epigenetic and proteomic level. Consequently, nutrient sensing and mitochondrial function are altered, resulting in inflammation and exhaustion of regenerative ability.Oral health, an important contributor to overall health, remains underexplored in the context of extreme longevity. Good masticatory function ensures sufficient nutrient uptake, reducing morbidity and mortality in old age. The relationship between periodontal disease and systemic inflammatory pathologies is well established. Diabetes, rheumatoid arthritis and cardiovascular disease are among the most significant disease burdens influenced by inflammatory oral health conditions. Evidence suggests that the interaction is bi-directional, impacting progression, severity and mortality. Current models of ageing and longevity neglect an important factor in overall health and well-being, a gap that this review intends to illustrate and inspire avenues for future research.
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Saúde Bucal , Proteômica , Idoso de 80 Anos ou mais , Humanos , Envelhecimento/genética , Longevidade/genética , Expectativa de VidaRESUMO
Periodontitis and chronic kidney failure (CKF) are potentially related to each other. This bioinformatics analysis aimed at the identification of potential cross-talk genes and related pathways between periodontitis and CKF. Based on NCBI Gene Expression Omnibus (GEO), datasets GSE10334, GSE16134, and GSE23586 were extracted for periodontitis. A differential expression analysis (p < 0.05, |log2(FC)| > 0.5) was performed to assess deregulated genes (DEGs). CKF-related genes were extracted from DisGeNET and examined regarding their overlap with periodontitis-related DEGs. Cytoscape was used to construct and analyze a protein-protein interaction (PPI) network. Based on Cytoscape plugin MCODE and a LASSO regression analysis, the potential hub cross-talk genes were identified. Finally, a complex PPI of the hub genes was constructed. A total of 489 DEGs for periodontitis were revealed. With the 805 CKF-related genes, an overlap of 47 cross-talk genes was found. The PPI network of the potential cross-talk genes was composed of 1081 nodes and 1191 edges. The analysis with MCODE resulted in 10 potential hub genes, while the LASSO regression resulted in 22. Finally, five hub cross-talk genes, CCL5, FCGR3B, MMP-9, SAA1, and SELL, were identified. Those genes were significantly upregulated in diseased samples compared to controls (p ≤ 0.01). Furthermore, ROC analysis showed a high predictive value of those genes (AUC ≥ 73.44%). Potentially relevant processes and pathways were primarily related to inflammation, metabolism, and cardiovascular issues. In conclusion, five hub cross-talk genes, i.e., CCL5, FCGR3B, MMP-9, SAA1, and SELL, could be involved in the interplay between periodontitis and CKF, whereby primarily inflammation, metabolic, and vascular issues appear to be of relevance.