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BACKGROUND: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. METHODS: We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls. RESULTS: The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, Pâ <â 7.7â ×â 10-9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; Pâ <â .002; Pcâ =â 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells. CONCLUSIONS: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.
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COVID-19/genética , Predisposição Genética para Doença/genética , Receptores KIR/genética , Idoso , COVID-19/imunologia , COVID-19/patologia , Estudos Transversais , Feminino , Genótipo , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores KIR/metabolismo , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Dyslipidemia causes renal damage; however, the detailed molecular mechanism has not been clarified. It is known that carnitine palmitoyl transferase 1-a (CPT1a) gene encodes an enzyme involved in fatty acid oxidation and, therefore, lipid content. In the present study, we investigated whether the accumulation of lipids induced by 7-ketocholesterol (7-KC) in tubular epithelial cells produce a fibrotic and inflammatory response through CPT1a. METHODS: Using an epithelial cell line, NRK-52E, we determine if intracellular accumulation of 7-KC modulates profibrotic and inflammatory events through CPT1a gene expression. In addition, the direct effects of CPT1a genetic modification has been studied. RESULTS: Our results revealed that high levels of 7-KC induce increased expression of CPT1a, TGF-ß1, α- SMA and NLRP3 that was correlated with lipid content. GW3965 treatment, which have shown to facilitate the efflux of cholesterol, eliminated the intracellular lipid droplets of 7-KC laden cells and decreased the expression of CPT1a, TGF-ß1, α- SMA and NLRP3. Furthermore, CPT1a Knockdown and C75 pre-treatment increased lipid content but decreased TGF-ß1, α- SMA and NLRP3. CONCLUSIONS: Our findings reveal that the profibrotic effect of 7-KC on renal epithelial cells are mediated by CPT1a overexpression, which acts on TGF-ß1, α-SMA and NLRP3. Thus, CPT1a downregulation protects against 7-KC-induced fibrosis in tubular epithelial cells by downregulating TGF-ß1, α- SMA and NLRP3.
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Carnitina O-Palmitoiltransferase/metabolismo , Regulação para Baixo , Células Epiteliais/patologia , Inflamassomos/metabolismo , Túbulos Renais Proximais/patologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Benzoatos/farmacologia , Benzilaminas/farmacologia , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fibrose , Furanos/farmacologia , Cetocolesteróis , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RatosRESUMO
BACKGROUND: Macrophage are specialized cells that contributes to the removal of detrimental contents via phagocytosis. Lipid accumulation in macrophages, whether from phagocytosis of dying cells or from circulating oxidized low-density lipoproteins, alters macrophage biology and functionality. It is known that carnitine palmitoyl transferase 1-a (CPT1a) gene encodes an enzyme involved in fatty acid oxidation and, therefore, lipid content. However, the potential of CPT1a to activate macrophage phagocytic function have not been elucidated. METHODS: Using a murine macrophage cell line, RAW264.7, we determine if intracellular accumulation of 7-ketocholesterol (7-KC) modulates macrophage phagocytic function through CPT1a gene expression. In addition, the effects of CPT1a genetic modification on macrophage phenotype and phagocytosis has been studied. RESULTS: Our results revealed that CPT1a gene expression decreased by the accumulation of 7-KC at the higher dose of 7-KC. This was concomitant with an impair ability to phagocytize bioparticles and an inflammatory phenotype. GW3965 treatment, which have shown to facilitate the efflux of cholesterol, eliminated the intracellular lipid droplets of 7-KC-laden macrophages, increased the gene expression of CPT1a, diminished the gene expression of the inflammatory marker iNOS and restored macrophage phagocytosis. Furthermore, CPT1a Knockdown per se was detrimental for macrophage phagocytosis whereas transcriptional activation of CPT1a heightened the uptake of bioparticles. CONCLUSIONS: Altogether, our findings indicate that downregulation of CPT1a by lipid content modulates macrophage phagocytosis and inflammatory phenotype.
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Carnitina O-Palmitoiltransferase/genética , Expressão Gênica/fisiologia , Inflamação , Cetocolesteróis/fisiologia , Macrófagos/fisiologia , Fagocitose/fisiologia , Animais , Carnitina O-Palmitoiltransferase/fisiologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Cetocolesteróis/farmacologia , Ativação de Macrófagos/fisiologia , Camundongos , Células RAW 264.7 , TransfecçãoRESUMO
The Cu(+) pump ATP7B plays an irreplaceable role in the elimination of excess Cu(+) by the hepatocyte into the bile. The trafficking and site of action of ATP7B are subjects of controversy. One current proposal is that an increase in intracellular Cu(+) results in the translocation of ATP7B to the lysosomes and excretion of excess Cu(+) through lysosomal-mediated exocytosis at the bile canaliculus. Here, we show that ATP7B is transported from the trans-Golgi network (TGN) to the bile canaliculus by basolateral sorting and endocytosis, and microtubule-mediated transcytosis through the subapical compartment. Trafficking ATP7B is not incorporated into lysosomes, and addition of Cu(+) does not cause relocalization of lysosomes and the appearance of lysosome markers in the bile canaliculus. Our data reveal the pathway of the Cu(+)-mediated transport of ATP7B from the TGN to the bile canaliculus and indicates that the bile canaliculus is the primary site of ATP7B action in the elimination of excess Cu(.)
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Adenosina Trifosfatases/metabolismo , Canalículos Biliares/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Cobre/farmacologia , Transcitose/efeitos dos fármacos , Animais , Canalículos Biliares/efeitos dos fármacos , Brefeldina A/farmacologia , Compartimento Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , ATPases Transportadoras de Cobre , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células Hep G2 , Humanos , Hidrazonas/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrolídeos/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Transporte Proteico/efeitos dos fármacos , Ratos , Vesículas Secretórias/efeitos dos fármacos , Vesículas Secretórias/metabolismo , Rede trans-Golgi/efeitos dos fármacos , Rede trans-Golgi/metabolismoRESUMO
In this study, we investigated if the therapeutic potential of peripheral blood mononuclear cell (PBMC) therapy in a murine model of ischemic AKI is related with the survival pattern of monocyte/macrophages in tissue. CD-1 mice were subjected to bilateral renal ischemia followed by reperfusion to induce AKI. M2-polarized PBMCs isolated from CD-1 mice were administered intravenously at different time points post-injury. Our results demonstrate that early administration of PBMC therapy attenuates renal tissue damage, reduces tissue cell death and prevents fibrosis development. Reduction of tissue pyroptosis was observed by reduction on NLRP3 inflammasome activation and decreasing IL-1beta and Caspase-1 expression in the kidney. Furthermore, the therapy was shown to mitigate ferroptosis by inducing GPX4 overexpression. Early administration of PBMCs increased the survival pattern of renal tissue-macrophages, promoting a "pro-survival phenotype" resulting in decreased pyroptotic marker NLRP3, IL-1beta and Caspase 1 and increased anti-ferroptotic gene GPX4. Conversely, delayed administration of PBMC therapy exhibits diminished efficacy in preventing cell death and fibrosis in tissue and provoked a decrease in the pro-survival phenotype of both monocyte /macrophages in tissue. Our findings highlight the therapeutic potential of PBMC therapy in mitigating AKI and preventing CKD progression by modulating tissue-resident macrophage survival and reducing their cell death pathways. The fact that the effectiveness of the therapy depends on the time of administration after the injury underscores the importance of early intervention in AKI management.
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Macrophages must remove apoptotic cells to shield tissues from the deleterious components of dying cells. The development of chronic inflammation and autoimmune symptoms in systemic lupus is influenced by a deficiency in phagocytosis of apoptotic cells but the underlying mechanism is still unknown. Modifications in monocyte/macrophage phenotype brought on by an increase in their inflammatory phenotype would cause them to decrease the expression of CPT1a, which would reduce their ability to phagocytose, aggravating kidney damage in lupus nephritis. We aim to demonstrate that the deficiency of CPT1A in the immunological system determines lupus. For this purpose, we will monitor CPT1a expression in blood monocytes and phagocytosis and CPT1a expression of macrophages isolated from kidneys and the inflammatory state in kidneys in two experimental models of lupus nephritis such as lupus induced pristane model and in the OVA-IC in vivo model. Additionally, we will test if reestablishing CPT1a expression in tissue macrophages restores the lost phagocytic function. We evidenced that blood monocytes and macrophages isolated from kidneys in the two in vivo models have a reduced expression of CPT1a and a reduced phagocytosis. Phagocytosis could be restored only if macrophage administration leads to an increase in CPT1a expression in kidney macrophages. A new cell therapy to reduce kidney nephritis in lupus could be developed based on these results.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Monócitos , Nefrite Lúpica/metabolismo , Fagocitose , Macrófagos , Inflamação/metabolismo , Lúpus Eritematoso Sistêmico/metabolismoRESUMO
BACKGROUND: HIV-1-associated neurocognitive disorders (HAND) in stable patients undergoing antiretroviral therapy (ART) may result from ongoing immune dysregulation and chronic inflammation. A contributing factor may result from the unstable HLA class I allele, HLA-C*07. OBJECTIVE: To assess the genetic profile of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigens (HLA), and immune activation or senescence markers and their association with HAND in stable HIV-1 patients receiving ART. METHODS: An observational cross-sectional study was carried out with 96 patients with asymptomatic or symptomatic HAND. HLA and KIR as well as immune activation/senescence biomarkers in peripheral blood cells were assessed by SSO-Luminex typing and flow cytometry, respectively. RESULTS: HLA-C*07 is associated with symptomatic HAND. The frequency of two copies of HLA-C*07 was higher in patients with symptomatic than with asymptomatic HAND (12.0 vs. 2.2%, ρ < 0.001). The percentage of senescent CD8+CD28- T-cells was higher in patients with two copies of HLA-C*07 (ρ < 0.05). In patients with symptomatic HAND, the percentages of non-senescent CD8+CD28+ T cells were inversely proportional to the number of copies of the HLA-C*07 (ρ < 0.05). CONCLUSION: Patients with symptomatic HAND showed a higher frequency of the homozygotic unstable HLA-C*07 allotype, which could be associated with neurocognitive complications. Two copies of HLA-C*07 were associated with immune senescent T lymphocyte profiles characterized by the loss of CD28 expression.
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INTRODUCTION: Remdesivir seems to reduce the risk of hospitalization and improve clinical outcome in hospitalized patients with COVID-19. OBJECTIVES: To compare the clinical outcome of COVID-19 hospitalized patients treated with remdesivir plus dexamethasone versus dexamethasone alone, according to their vaccination status. MATERIAL AND METHODS: A retrospective observational study was carried out in 165 patients hospitalized for COVID-19 from October 2021 to January 2022. Multivariate logistic regression, Kaplan-Meier and the log-rank tests were used to evaluate the event (need for ventilation or death). RESULTS: Patients treated with remdesivir plus dexamethasone (n=87) compared with dexamethasone alone (n=78) showed similar age (60±16, 47-70 vs. 62±37, 51-74 years) and number of comorbidities: 1 (0-2) versus 1.5 (1-3). Among 73 fully vaccinated patients, 42 (47.1%) were in remdesivir plus dexamethasone and 31 (41%) in dexamethasone alone. Patients treated with remdesivir plus dexamethasone needed intensive care less frequently (17.2% vs. 31%; p=0.002), high-flow oxygen (25.3% vs. 50.0%; p=0.002) and non-invasive mechanical ventilation (16.1% vs. 47.4%; p<0.001). Furthermore, they had less complications during hospitalization (31.0% vs. 52.6%; p=0.008), need of antibiotics (32.2% vs. 59%; p=0.001) and radiologic worsening (21.8% vs. 44.9%; p=0.005). Treatment with remdesivir plus dexamethasone (aHR, 0.26; 95% CI: 0.14-0.48; p<0.001) and vaccination (aHR 0.39; 95% CI: 0.21-0.74) were independent factors associated with lower progression to mechanical ventilation or death. CONCLUSIONS: Remdesivir in combination with dexamethasone and vaccination independently and synergistically protects hospitalized COVID-19 patients requiring oxygen therapy from progression to severe disease or dead.
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COVID-19 , Humanos , Tratamento Farmacológico da COVID-19 , Oxigênio , Vacinação , Dexametasona/uso terapêutico , Antivirais/uso terapêutico , Monofosfato de Adenosina/uso terapêuticoRESUMO
Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and anti-inflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality.
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We propose the use of a peripheral blood mononuclear cell therapy based on cell NGAL release to be used in the clinical setting for acute kidney injury (AKI) and the derived fibrosis. First, we designed a procedure whereby PBMC overexpress NGAL and anti-inflammatory agents when subjected to repetitive anoxia/reoxygenation (PBMC (A/R)). Using an in vivo AKI model, we observed that PBMC(A/R) reduces BUN and creatinine levels in blood and inflammation, enhances anti-inflammation, induces proliferation of tubular epithelial cells and reduces AKI-induced fibrosis. Flow cytometry analysis evidenced that monocytes are the only cells accumulated in the injured kidney and phenotype analysis of freshly isolated kidney macrophages, revealed that the healing phenotype is maintained the time needed for recovery. NGAL release from PBMC(A/R) determines the beneficial effect of the therapy since administration of a NGAL antibody previous to the therapy or injection of PBMC(A/R) obtained from NGAL KO animals abolished the beneficial effects. CD11b-NGAL positive cells were enhanced in tissue after PBMC (A/R) therapy and were produced by the injected monocytes. In an in vitro model with tubular epithelial cells (NRK52e) we proved that NGAL release by PBMC(A/R) induced epithelial proliferation and activation of PI3K/Akt pathway.
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Injúria Renal Aguda , Leucócitos Mononucleares , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Animais , Biomarcadores , Fibrose , Leucócitos Mononucleares/metabolismo , Lipocalina-2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
BACKGROUND: Physical activity has anti-inflammatory effects and reduces morbidity and mortality in the general population, but its role in the clinical, CD4/CD8 ratio, and immune activation status of HIV-infected patients has been poorly studied. METHODS: A cross-sectional study was carried out in a cohort of 155 HIV-infected patients on stable antiretroviral therapy (ART) to compare clinical, biochemical, CD4/CD8 ratio, and immune activation status according to their physical activity in the last 2 years (sedentary/low vs moderate/intense) assessed by the iPAQ. A binary logistic regression and mixed analysis of variance were performed to evaluate the impact of levels of physical activity on CD4/CD8 ratio. RESULTS: In our series, 77 (49.7%) out of 155 patients were sedentary, and 78 (50.3%) practiced moderate/intense physical activity. Moderate/intense physical activity was associated with better metabolic control (lower body mass index, Pâ =â .024; glucose, Pâ =â .024; and triglyceride, Pâ =â .002) and CDC HIV stage (Pâ =â .046), lower CD8+ (Pâ =â â .018), CD4+CD8+ (Pâ =â .026), CD4+CD86+ (Pâ =â .045), CD4+HLA-DR+ (Pâ =â .011), CD8+HLA-DR+ (Pâ =â .048) T lymphocytes and CD16+HLA-DR+ natural killer cells (Pâ =â .026), and higher CD3+CD4+ T lymphocytes (Pâ =â .016) and CD4/CD8 ratio (Pâ =â .001). Sedentary lifestyle (odds ratio [OR],â 2.12; Pâ =â .042), CD4 nadir (OR,â 1.005; Pâ <â .001), and CD8+CD38+ T cells (OR,â 1.27; Pâ =â .006) were independently associated with low CD4/CD8 ratio (<0.8). Earlier and more intense CD4/CD8 ratio recovery was observed in patients with higher physical activity in the 2-year follow-up with a significant interaction between these variables: F(2, 124)â =â 3.31; Pâ =â .049; partial η2â =â 0.042. CONCLUSIONS: Moderate to high physical activity is associated with beneficial health effects, improvement in metabolic profile, and reduction of chronic inflammation in patients with HIV. Although more studies and clinical trials are needed to confirm these findings, a healthy lifestyle including at least moderate physical activity should be recommended to HIV patients on stable ART.
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Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.
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Carnitina O-Palmitoiltransferase/metabolismo , Rim/patologia , Macrófagos/transplante , Fagocitose , Obstrução Ureteral/complicações , Animais , Antígeno CD11b/metabolismo , Carnitina O-Palmitoiltransferase/genética , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Perfilação da Expressão Gênica , Masculino , Camundongos , Células RAW 264.7RESUMO
BACKGROUND: To date, available data on premature aging in young HIV-infected adults are scarce and no reports offer comprehensive assessment of telomere shortening (TS) in relation to subclinical atherosclerosis (SCA). In this study, we investigate if telomere shortening and immune activation markers are associated with SCA, which is one of the main degenerative diseases in young HIV-infected adults. METHODS: A descriptive cross-sectional study was carried out in 149 HIV-infected patients on stable antiretroviral regimen (ART). Carotid intima-media thickness (cIMT) was estimated by carotid ultrasound. Quantitative singleplex PCR was performed to evaluate TS. The expression of activation/senescence markers was evaluated by multiparametric flow cytometry. RESULTS: TS was observed in 73 patients (49%). Higher cIMT was observed in patients with TS than those without it (0.86 vs. 0.80 mm; p=0.041). Patients under the age of 50 (defined as young adults) with TS showed higher absolute numbers of activated lymphocyte T cells CD8+CD38+ (3.94 vs. 2.34 cell/µl; p=0.07) and lymphocyte B cells CD19+CD38+ (3.07 vs. 2.10 cell/µl; p=0.004) compared to those without TS. In the multivariate analysis, the only factor independently associated with TS was the absolute number of lymphocyte T cells CD8+CD38+ T cells (OR = 1.18; 95%-CI = 1.00-1.39; p = 0.05). CONCLUSION: Young HIV-infected adults show premature biological aging with accentuated immune activation. Chronic inflammation with excessive T-cells activation could be associated to TS, premature aging, and SCA in young HIV-infected adults.
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Senilidade Prematura , Aterosclerose/imunologia , Espessura Intima-Media Carotídea , Infecções por HIV/imunologia , Encurtamento do Telômero , Adulto , Antirretrovirais/uso terapêutico , Aterosclerose/diagnóstico por imagem , Aterosclerose/virologia , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Artérias Carótidas/diagnóstico por imagem , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Modelos Logísticos , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Erectile dysfunction (ED) is frequent in HIV-infected patients, and it can be associated with atherosclerosis and cardiovascular events. So, the objective was to evaluate whether the presence of moderate-severe ED was a marker of subclinical atherosclerosis (SCA) in HIV-infected patients. METHODS: A cross-sectional study was conducted in a cohort of HIV-infected patients. The presence of ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. The presence of SCA was determined by calculating the mean carotid intima-media thickness with Doppler ultrasound. A logistic regression analysis was performed to check the variables associated with SCA. RESULTS: One hundred thirty-nine men of 45 (10) years of age were included, of which 130 (94.9%) received antiretroviral therapy. In 30 (22%) patients, the Framingham score was higher than 10%. In 36 (25.9%) patients, ED was detected in a moderate-severe degree and in 53 (38.1%), SCA was detected. In the multivariate analysis, variables independently associated with the presence of SCA were as follows: older age [odds ratio (OR) = 1.22, confidence interval (CI) 95%: 1.1 to 1.35, P < 0.001] and moderate-severe ED (OR = 4.68, CI 95%: 1.18 to 18.5; P = 0.028). Variables associated with moderate-severe ED were as follows: age (OR = 1.107, CI 95%: 1.041 to 1.17, P < 0.001) and having antibodies for hepatitis C virus (OR = 5.12, CI 95%: 1.54 to 17.03, P < 0.001). CONCLUSIONS: HIV-Infected patients often have moderate-severe ED, especially the elderly and coinfected patients with hepatitis C virus. ED can be an early clinical manifestation of incipient atherosclerosis, so its presence should involve a deep control of cardiovascular risk factors and using a regimen with a better atherogenic profile.
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Doenças das Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Disfunção Erétil/patologia , Infecções por HIV/patologia , Adulto , Doenças das Artérias Carótidas/complicações , Estudos Transversais , Disfunção Erétil/complicações , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The main objective of this study is to evaluate the predictive capacity of T cell activation/senescence in subclinical atherosclerosis (SCA) in a group of HIV-infected patients. So, a cross-sectional analysis was performed on 91 long-term triple-ART therapy HIV-infected patients from an observational and prospective cohort. Carotid Intima Media Thickness (cIMT) was measured. Binary logistic regression was used to evaluate independent variables associated with SCA. Compared to patients without SCA, patients with SCA (60.4%) were older (41.33⯱â¯9.04 vs. 51.73⯱â¯8.44 years old, pâ¯<â¯0.001) and showed Framingham risk score (2.63⯱â¯3.127 vs. 7.66⯱â¯5.84, pâ¯=â¯0.008), as well as higher numbers of CD4+CD8+ double positive T cells (0.50⯱â¯0.42% vs. 0.81⯱â¯0.79%, pâ¯=â¯0.037), CD8+CD28- T cells (41.70⯱â¯16.96% vs. 50.22⯱â¯16.15%, pâ¯=â¯0.018), higher expression of CD28 on CD8+CD28+ T cells (1865⯱â¯789 vs. 2243⯱â¯917 MFI, Pâ¯=â¯0.046). In contrast, they showed lower expression of CD38 on CD19+ B cells (65.38⯱â¯27.47% vs. 42.67⯱â¯30.26%, Pâ¯<â¯0.001). Logistic multivariable analysis showed that Framingham risk score >10% (ORâ¯=â¯14.84, CI95% 1.63-125; pâ¯=â¯0.016) and numbers of CD8+CD28- T cells (ORâ¯=â¯1.032, CI 95% 1-1.065; pâ¯=â¯0.045) were independent factors associated with SCA. Patients with CD8+CD28- T cells ≥59% compared to those <59% had higher risk of SCA (ORâ¯=â¯4, CI95% 1.19-13.3, pâ¯=â¯0.024). Interestingly, 27.4% of patients with low Framingham risk score had elevated levels of CD8+CD28- T cells. In conclusion, immune senescence represented by accumulation of CD8+CD28- T cells may contribute to improve the predictive capacity of the Framingham risk score, especially when the scores are low and can explain, at least in part, the higher prevalence of SCA observed in long-term ART-treated stable HIV infected patients.
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Aterosclerose/imunologia , Senescência Celular/imunologia , Infecções por HIV/complicações , Ativação Linfocitária , Linfócitos T/patologia , Adulto , Aterosclerose/virologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Linfócitos T/imunologiaRESUMO
BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP) and sepsis. In this paper, we examined the ability of MR-proADM to predict organ damage and long-term mortality in sepsis patients, compared to that of procalcitonin, C-reactive protein and lactate. METHODS: This was a prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to internal service department. The association between biomarkers and 90-day mortality was assessed by Cox regression analysis and Kaplan-Meier curves. The accuracy of biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: A total of 148 patients with severe sepsis, according to the criteria of the campaign to survive sepsis, were enrolled. Eighty-five (57.4%) had sepsis according to the new criteria of Sepsis-3. MR-proADM showed the best AUROC to predict sepsis as defined by the Sepsis-3 criteria (AUROC of 0.771, 95% CI 0.692-0.850, p <0.001) and was the only marker independently associated with Sepsis-3 criteria (OR = 4.78, 95% CI 2.25-10.14; p < 0.001) in multivariate analysis. MR-proADM was the biomarker with the best AUROC to predict mortality in 90 days (AUROC of 0.731, CI 95% 0.612-0.850, p <0.001) and was the only marker that kept its independence [hazard ratio (HR) of 1.4, 95% CI 1.2-1.64, p <0.001] in multivariate analysis. The cut-off point of MR-proADM of 1.8 nmol/L (HR of 4.65, 95% CI 6.79-10.1, p < 0.001) was the one that had greater discriminative capacity to predict 90 days mortality. All patients with MR-proADM concentrations ≤0.60 nmol/L survived up to 90 days. In patients with SOFA ≤ 6, the addition of MR-proADM to SOFA score increased the ability of SOFA to identify non-survivors, AUROC of 0.65 (CI 95% 0.537-0.764) and AUROC of 0.700 (CI 95% 0.594-0.800), respectively (p < 0.05 for both). CONCLUSIONS: MR-proADM is a good biomarker in the early identification of high risk septic patients and may contribute to improve the predictive capacity of SOFA scale, especially when scores are low.
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Adrenomedulina/sangue , Precursores de Proteínas/sangue , Sepse/sangue , Sepse/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos , Valor Preditivo dos Testes , Pró-Calcitonina/sangue , Estudos Prospectivos , Curva ROC , Sepse/patologiaRESUMO
BACKGROUND: The objective of this study was to investigate the long-term impact of low-level viremia (LLV) on all-cause mortality, AIDS and non-AIDS events (NAEs), and virological failure in patients receiving antiretroviral therapy (ART). METHODS: We analyzed ART-naive adults from the cohort of the Spanish AIDS Research Network (CoRIS) who initiated ART from 2004 to 2015 and achieved plasma viral load (VL) below 50 copies per milliliter. LLV50-199 was defined as 2 consecutive VL between 50 and 199 copies per milliliter, and LLV200-499 as 2 consecutive VL between 50 and 499 copies per milliliter with at least one between 200 and 499 copies per milliliter. Multivariable Cox models were used to estimate the association of LLV with AIDS events/death, non-AIDS events, and virological failure. RESULTS: Of 5986 patients included, 237 (4.0%) experienced LLV50-199 and 168 (2.8%) developed LLV200-499. One hundred seventy-one patients died or developed an AIDS event, 245 had any serious NAE and 280 had virological failure. LLV200-499 was strongly associated with a higher risk of both AIDS events/death [adjusted hazard ratio (aHR), 2.89; 95% confidence interval (CI), 1.41 to 5.92] and virological failure (aHR, 3.25; 95% CI: 1.77 to 5.99), whereas no differences were observed between LLV50-199 and no LLV neither for AIDS events/death (aHR, 1.84; 95% CI: 0.89 to 3.82) nor virological failure (aHR, 1.42; 95% CI: 0.78 to 2.58). LLV was not associated with the occurrence of any serious NAE. CONCLUSIONS: In this cohort, LLV200-499 was strongly associated with AIDS events/death and virological failure, but not with any serious NAE. Therefore, vigorous treatment should be implemented in patients with more than 200 copies per milliliter.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Viremia , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Infecções por HIV/virologia , Humanos , MasculinoRESUMO
Hepatic steatosis is a widespread condition of high prevalence in Western populations, and its asymptomatic nature represents a hefty problem in liver surgery and transplantation. Current diagnostic methods rely mainly on biopsy and blood tests, and are thus time consuming and expensive. Here we report the use of direct impedance measurements on liver tissue as a promising alternative to conventional diagnostic methods in surgery and transplantation. Working on a dual Zucker Fat (ZF), Zucker Lean (ZL) rat experimental model, we show that certain parameters extracted from multi-frequency impedance measurements correlate well with the presence of steatosis and that these results can be adequately approximated with bi-frequency measurements extracting the impedance modulus at 1 kHz and the impedance phase angle at 5.7 kHz. We further support our findings on a theoretical model of tissue impedance, and the simulations carried out suggest a possible mechanism to expound the negative effect of steatosis in post-transplant graft function.
Assuntos
Fígado Gorduroso/diagnóstico , Animais , Tamanho Celular , Simulação por Computador , Impedância Elétrica , Eletrodos , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Fígado/patologia , Masculino , Ratos , Ratos ZuckerRESUMO
OBJECTIVES: To develop a nomograph to predict a poor outcome (death during hospitalization or a hospital stay longer than 15 days) in emergency patients with sepsis and at low risk of organ damage according to Sepsis-related Organ Failure Assessment (SOFA). MATERIAL AND METHODS: Prospective, observational study carried out in a single universitary hospital. All patients admitted from the emergency department with sepsis and SOFA scores of 6 or lower were enrolled. We used bivariate logistic regression analysis to develop a predictive nomogram. RESULTS: A total of 174 patients were included. Seventeen patients (9.8%) died during hospitalization and the average hospital stay was greater than 15 days in 29 (16.7%) patient. The outcome was poor in a total of 42 patients (24.1%);. Independent variables that were significantly associated with a poor outcome were SOFA score (odds ratio [OR], 1.3; 95% CI, 1.06-1.71; P<.05), C-reactive protein (CRP) concentration (OR, 1.04; 95% CI, 1.0-1.09; P<.05), N-terminal fragment of brain natriuretic peptide (NT-proBNP) concentration over 1330 ng/mL (OR, 2.64; 95% CI, 1.17-6.22; P<.05), and septic shock (OR, 8.3; 95% CI, 1.16-166.5; P<.05). For a SOFA score of 2 or more the crude OR was 4.44 (95%, CI, 1.91-10.34) and the OR adjusted for other variables was 3.08 (95% CI, 1.24-7.69). CONCLUSION: A high percentage of patients predicted to be at low risk of organ failure had poor outcomes, associated with SOFA score, the presence of septic shock, CRP concentration, and elevated NT-proBNP concentration. The SOFA score by itself is an inadequate prognostic tool in patients at low risk of organ damage. Other clinical and analytical variables are required to complement the SOFA score.
OBJETIVO: Elaborar un nomograma que permita predecir el mal pronóstico (mortalidad durante el ingreso o estancia media > 15 días) en pacientes procedentes de urgencias con sepsis y baja probabilidad de daño orgánico evaluado por SOFA (Sepsis-related Organ Failure Assessment). METODO: Estudio observacional prospectivo realizado en un único hospital. Se incluyeron de forma consecutiva pacientes del servicio de urgencias con sepsis y SOFA igual o inferior a 6 puntos. Se realizó un análisis de regresión logística binaria y se elaboró un nomograma predictivo. RESULTADOS: Se incluyeron 174 pacientes. Diecisiete (9,8%) pacientes fallecieron durante la hospitalización y 29 (16,7%) tuvieron una estancia media prolongada. En total, 42 (24,1%) pacientes tuvieron mal pronóstico. Las variables independientes de mal pronóstico fueron: la puntuación SOFA (OR 1,3; IC 95% 1,06-1,71; p < 0,05), las concentraciones de proteína C reactiva (PCR) (OR 1,04; IC 95% 1-1,09; p < 0,05), NT-proBNP > 1.330 ng/ml (OR 2,64; IC 95% 1,17-6,22; p < 0,05) y la presencia de shock séptico (OR 8,3; IC 95% 1,16-166,5; p < 0,05). Si tenemos en cuenta el índice SOFA >= 2, la OR cruda fue 4,44 (IC 95% 1,91-10,34) y ajustada por el resto de variables fue de 3,08 (IC 95%, 1,24-7,69). CONCLUSIONES: Una elevada proporción de pacientes con baja probabilidad de tener daño orgánico tuvieron mal pronóstico en relación con la puntuación en la escala SOFA, la presencia de shock séptico, concentraciones de PCR y NTproBNP. La utilización de la escala pronóstica SOFA en pacientes con bajo riesgo es insuficiente para predecir el pronóstico en estos pacientes y se hace necesario complementarla con otras variables clínicas y analíticas.
Assuntos
Escores de Disfunção Orgânica , Sepse/terapia , Idoso , Idoso de 80 Anos ou mais , Emergências , Feminino , Mortalidade Hospitalar , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Prognóstico , Estudos Prospectivos , Sepse/complicações , Sepse/mortalidade , Choque Séptico/etiologia , Resultado do TratamentoRESUMO
INTRODUCTION: The purpose of this study was to investigate the value of N-terminal pro brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and procalcitonin (PCT) in predicting mortality in septic patients during hospitalization with mortality risk<10% evaluated by Sepsis-related Organ Failure Assessment (SOFA). MATERIAL AND METHODS: Prospective, observational study performed in sepsis patients with SOFA risk<10%. We obtained levels of biomarkers in the first 72h after admission in hospital. All patients were monitored during hospitalization or until death. We used ROC curves to determine area under curve (AUC) and identify the best cutoff concentrations to predict mortality. RESULTS: A total of 174 patients were analyzed. Seventeen (9.8%) patients died during hospitalization. The AUC of NT-proBNP was 0.793 (95% CI 0.686-0.9; P<.0005) compared to AUC of CRP (0.728; 95% CI 0.617-0.839; P=.004) and AUC of PCT (0.684; 95% CI 0.557-0.811; P=.019). Factors independently associated with in-hospital mortality were NT-proBNP>1,330pg/ml (OR=23.23; 95% CI 2.92-182.25; P=.003) and to have predisposing factors (OR=3.05; 95% CI 1.3-9.3; P=.044) CONCLUSIONS: In patients with low mortality risk according to SOFA score, NT-proBNP obtained in the first 72h after admission prove to be a powerful predictor of mortality. Their implementations in clinical practice would improve the predictive ability of clinical severity scores.