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INTRODUCTION: The main objective of this study was to evaluate the impact of hemoadsorption on the elimination of inflammatory mediators. METHODS: A prospective, bicenter, observational cohort study was conducted between March 2020 and February 2022 to explore the immunomodulatory response, demographic and clinical characteristics of individuals with COVID-19 admitted to the ICU with severe acute respiratory failure and in need of CRRT with Oxiris® with or without AKI. RESULTS: Sixty-four patients were analyzed. Statistically significant differences were observed between exposed and unexposed groups, in relation to the reduction in D-dimer levels -15,614 (24,848.9) versus -4,136.5 (9,913.47) (p 0.031, d: 1.59, 95% CI: -21,830, -1,126). An increase in PCT was observed 0.47 (2.08) versus -0.75 (2.3) (p 0.044 95% CI: 0.03, 2.44). No differences were found in a decrease in CRP -4.21 (7.29) versus -1.6 (9.02) (p 0.22) nor in the rest of inflammatory parameters fibrinogen, IL-6, ferritin, lymphocytes, and neutrophils. Subgroup analysis in patients exposed to therapy also showed a significant decrease in D-dimer of 55% from baseline: 6,000 (1,984.5-27,750) pre-therapy versus 2,700 (2,119.5-6,145) (95% CI: -23,000, -2,489) post-therapy with a strong effect size (p 0.001, d: 0.65). CONCLUSION: The hemoadsorptive therapy in COVID-19 was associated with a significant decrease in D-dimer parameters without showing decreases in the rest of the clinical, inflammatory parameters and severity scales analyzed.
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OBJECTIVES: Dysregulated coagulation cascade has been implicated in development of fibrosis in systemic sclerosis (SSc). Thrombin, a key mediator of the coagulation pathway, has both proinflammatory and procoagulant properties. Here, we evaluated the efficacy of oral dabigatran, a direct thrombin inhibitor, on topoisomerase I dendritic cells (TOPOIA DCs)-induced lung and skin fibrosis, an experimental model of SSc. METHODS: Mice were repeatedly immunized with TOPOIA DCs. Dabigatran was administered in food either during the onset of fibrotic (late treatment) or inflammatory (early treatment) phase. RESULTS: Early administration of dabigatran caused an aggravation of pulmonary fibrosis associated with signs of severe perivascular inflammation while late treatment was not protective when compared to the untreated TOPOIA DCs group. Thrombin was increased in lungs of TOPOIA DCs immunized group and, paradoxically, further augmented by administration of dabigatran to immunized mice. As in lungs, early and not late drug administration exacerbated skin fibrosis. Moreover, early dabigatran treatment induced a profibrotic and inflammatory skin gene expression signature with upregulated expression of Col5a1, Timp1, Tweakr, Vwf, Il6, Il33, Il4 and Ifng. CONCLUSIONS: Dabigatran aggravated lung and skin fibrosis in a TOPOIA DCs-induced model of SSc-like disease. Therefore, our results argue against the use of dabigatran to treat patients with SSc.
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Antitrombinas/toxicidad , ADN-Topoisomerasas de Tipo I/inmunología , Dabigatrán/toxicidad , Células Dendríticas/inmunología , Fibrosis Pulmonar/etiología , Esclerodermia Sistémica/tratamiento farmacológico , Piel/patología , Animales , Femenino , Fibrosis , Masculino , RatonesRESUMEN
Osteoarthritis (OA) is an age-related progressive degenerative joint disease. Peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is suggested as an attractive therapeutic target to counteract degradative mechanisms associated with OA. Studies suggest that activation of PPARγ by its agonists can reduce the synthesis of OA catabolic and inflammatory factors and the development of cartilage lesions in OA animal models. Because these agonists impart several PPARγ-independent effects, the specific in vivo function of PPARγ in cartilage homeostasis and OA remains largely unknown. Herein, we describe the in vivo role of PPARγ in OA using cartilage-specific PPARγ knockout (KO) mice generated using the Cre-lox system. Adult PPARγ KO mice exhibited a spontaneous OA phenotype associated with enhanced cartilage degradation, hypocellularity, synovial and cartilage fibrosis, synovial inflammation, mononuclear cell influx in the synovium, and increased expression of catabolic factors, including matrix metalloproteinase-13, accompanied by an increase in staining for matrix metalloproteinase-generated aggrecan and type II collagen neoepitopes (VDIPEN and C1-2C). We demonstrate that PPARγ-deficient articular cartilage exhibits elevated expression of the additional catabolic factors hypoxia-inducible factor-2α, syndecan-4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 and of the inflammatory factors cyclooxygenase-2 and inducible nitric oxide synthase. In conclusion, PPARγ is a critical regulator of cartilage health, the lack of which leads to an accelerated spontaneous OA phenotype.
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Envejecimiento/metabolismo , Cartílago/metabolismo , Cartílago/patología , Osteoartritis/metabolismo , Osteoartritis/patología , PPAR gamma/deficiencia , Animales , Biomarcadores/metabolismo , Fibrosis , Eliminación de Gen , Inflamación/patología , Mediadores de Inflamación/metabolismo , Ratones , Ratones Noqueados , Especificidad de Órganos , PPAR gamma/metabolismo , Fenotipo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologíaRESUMEN
OBJECTIVE: Long bones develop through the strictly regulated process of endochondral ossification within the growth plate, resulting in the replacement of cartilage by bone. Defects in this process can result in skeletal abnormalities and a predisposition to degenerative joint diseases such as osteoarthritis (OA). Studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is an important therapeutic target in OA. To devise PPARγ-related therapies in OA, it is critical to identify the role of this transcription factor in cartilage biology. Therefore, this study sought to determine the in vivo role of PPARγ in endochondral ossification and cartilage development, using cartilage-specific PPARγ-knockout (KO) mice. METHODS: Cartilage-specific PPARγ-KO mice were generated using the Cre/loxP system. Histomorphometric and immunohistochemical analyses were performed to assess the patterns of ossification, proliferation, differentiation, and hypertrophy of chondrocytes, skeletal organization, bone density, and calcium deposition in the KO mice. RESULTS: PPARγ-KO mice exhibited reductions in body length, body weight, length of the long bones, skeletal growth, cellularity, bone density, calcium deposition, and trabecular bone thickness, abnormal organization of the growth plate, loss of columnar organization, shorter hypertrophic zones, and delayed primary and secondary ossification. Immunohistochemical analyses for Sox9, 5-bromo-2'-deoxyuridine, p57, type X collagen, and platelet endothelial cell adhesion molecule 1 revealed reductions in the differentiation, proliferation, and hypertrophy of chondrocytes and in vascularization of the growth plate in mutant mice. Isolated chondrocytes and cartilage explants from mutant mice showed aberrant expression of Sox9 and extracellular matrix markers, including aggrecan, type II collagen, and matrix metalloproteinase 13. In addition, chondrocytes from mutant mice exhibited enhanced phosphorylation of p38 and decreased expression of Indian hedgehog. CONCLUSION: The presence of PPARγ is required for normal endochondral ossification and cartilage development in vivo.
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Huesos/patología , Cartílago/patología , Condrocitos/metabolismo , Condrogénesis/fisiología , Osteogénesis/fisiología , PPAR gamma/biosíntesis , Animales , Biomarcadores/metabolismo , Densidad Ósea , Desarrollo Óseo , Huesos/metabolismo , Cartílago/crecimiento & desarrollo , Cartílago/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas Hedgehog/metabolismo , Hipertrofia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR gamma/deficiencia , PPAR gamma/genética , Fosforilación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVES: The survival of motor neuron (SMN) complex has an essential role in the assembly of small nuclear ribonucleoproteins (RNP). Recent reports have described autoantibodies (aAbs) to the SMN complex as novel biomarkers in anti-U1RNP+ myositis patients. The aim of this study was to compare phenotypic features of anti-U1RNP+ mixed connective tissue disease (MCTD) patients with and without anti-SMN aAbs. METHODS: A retrospective MCTD cohort was studied. Addressable laser bead immunoassay was used to detect specific anti-SMN aAbs with <300 mean fluorescence intensity (MFI) as normal reference range, 300-999 MFI as low-titre and ≥1000 MFI as high-titre positivity. Comparison of clinical features between anti-SMN+ and anti-SMN- subgroups used two-tailed Fisher's exact test, and logistic regression analyses. RESULTS: Sixty-six patients were included. Median age at MCTD diagnosis was 40.6 years, and duration of follow-up was 12 years. Based on the highest available titre, 39 (59%) were anti-SMN+: 10 (26%) had low titre and 29 (74%) had high titre. Anti-SMN+ patients had a higher frequency of fingertip pitting scars (anti-SMN+ 23% vs anti-SMN- 4%, p=0.04), lower gastrointestinal (GI) involvement (26% vs 4%, p=0.04), and myocarditis (16% vs 0%, p=0.04). The combined outcome of pitting scars and/or lower GI involvement and/or myositis and/or myocarditis was highest among high-titre anti-SMN+ patients: adjusted OR 7.79 (2.33 to 30.45, p=0.002). CONCLUSIONS: Anti-SMN aAbs were present in 59% of our MCTD cohort. Their presence, especially at high-titres, was associated with a severe systemic sclerosis (scleroderma) phenotype including myositis, myocarditis and lower GI involvement.
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Enfermedad Mixta del Tejido Conjuntivo , Miocarditis , Miositis , Esclerodermia Sistémica , Humanos , Autoanticuerpos , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Enfermedad Mixta del Tejido Conjuntivo/diagnóstico , Estudios Retrospectivos , Cicatriz/complicaciones , Miocarditis/complicaciones , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Miositis/complicaciones , FenotipoRESUMEN
Recent reports indicate the possible role of bladder CO(2) as a marker of low perfusion states. To test this hypothesis, shock was induced in six beagle dogs with 1 mg/kg of E. coli lipopolysaccharide, gastric CO(2) (CO(2)-G) was measured with a continuous monitor, and a pulmonary catheter was inserted in the bladder to measure CO(2) (CO(2)-B). Levels of CO(2)-B were found to be lower than those of CO(2)-G, with a mean difference of 36.8 mmHg (P < 0.001), and correlation between both measurements was poor (r(2) = 0.16). Even when the correlation between CO(2)-G and ΔCO(2)-G was narrow (r(2) = 0.86), this was not the case for the relationship between CO(2)-B and ΔCO(2)-B (r(2) = 0.29). Finally, the correlation between CO(2)-G and base deficit was good (r(2) = 0.45), which was not the case with the CO(2)-B correlation (r(2) = 0.03). In our experience, bladder CO(2) does not correlate to hemodynamic parameters and does not substitute gastric CO(2) for detection of low perfusion states.
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Dióxido de Carbono/metabolismo , Mucosa Gástrica/metabolismo , Choque Séptico/metabolismo , Vejiga Urinaria/metabolismo , Animales , Perros , Mucosa Gástrica/fisiopatología , Hemodinámica , Manometría/métodos , Membrana Mucosa/metabolismo , Membrana Mucosa/fisiopatología , Presión Parcial , Perfusión , Choque Séptico/diagnóstico , Choque Séptico/fisiopatología , Vejiga Urinaria/fisiopatologíaRESUMEN
OBJECTIVE: To evaluate whether first trimester fetal heart rate (FHR) and nuchal translucency (NT) associate with preterm birth (PTB). METHODS: This was a comparative case-control study of 518 normal pregnancies with no history of PTB, of which 272 delivered at term (TB) and 246 progressed to spontaneous PTB prior to 37, 34, 32, and 28 weeks. Fetal heart rate (FHR) and NT values at the first-trimester scan were compared by means of univariable (Mann-Whitney) and multivariable logistic regression analysis considering hourglass membranes (HM) as the most severe PTB subgroup. Finally, severity trends for both parameters were investigated using correlations with gestational age (GA) at delivery and Kruskal-Walls tests. RESULTS: Regardless of GA at delivery, pregnancies affected with PTB showed higher FHR and thicker NT at the first trimester scan. The association was confirmed by the multivariable analysis and the severity trends, which paired the highest FHR and NT values with the most severe cases of PTB (p < .001) (p < .0001). CONCLUSION: Fetuses with subsequent late, early and very early PTB show higher values of NT and FHR at the first-trimester scan.
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Medida de Translucencia Nucal , Nacimiento Prematuro , Embarazo , Femenino , Recién Nacido , Humanos , Primer Trimestre del Embarazo , Frecuencia Cardíaca Fetal , Estudios de Casos y Controles , Corazón Fetal/diagnóstico por imagenRESUMEN
OBJECTIVE: Because Nox2-containing NADPH oxidase is a major source of ROS in the vasculature, we investigated its potential role for the modulation of ischemia-induced neovascularization in conditions of increased oxidative stress. METHODS AND RESULTS: To mimic a clinical situation of increased oxidative stress, mice were exposed to cigarette smoke before and after the surgical induction of hindlimb ischemia. Nox2 expression and oxidative stress in ischemic tissues were significantly increased in wild-type mice, but not in mice deficient for the Nox2-containing NADPH oxidase (Nox2(-/-)). Nox2(-/-) mice demonstrated faster blood flow recovery, increased capillary density in ischemic muscles, and improved endothelial progenitor cell functional activities compared to Nox2(+/+) mice. In addition, Nox2 deficiency was associated with increased antioxidant and nitrite concentrations in plasma, together with a preserved expression of eNOS in ischemic tissues. In vitro, Nox2(-/-) endothelial cells exhibit resistance against superoxide induction and improved VEGF-dependent angiogenic activities compared to Nox2(+/+) endothelial cells. Importantly, the beneficial effects of Nox2 deficiency on neovascularization in vitro and in vivo were lost after treatment with the NO inhibitor L-NAME. CONCLUSIONS: Nox2-containing NADPH oxidase deficiency protects against ischemia in conditions of increased oxidative stress. The mechanism involves improved neovascularization through a reduction of ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells.
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Miembro Posterior/irrigación sanguínea , Isquemia/prevención & control , Glicoproteínas de Membrana/fisiología , NADPH Oxidasas/fisiología , Estrés Oxidativo , Animales , Células Endoteliales/fisiología , Isquemia/metabolismo , Glicoproteínas de Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 2 , NADPH Oxidasas/deficiencia , Neovascularización Fisiológica , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Humo/efectos adversos , Células Madre/fisiología , Nicotiana/efectos adversosRESUMEN
OBJECTIVE: To estimate the usefulness of 2-h creatinine clearance (CrCl) in the ICU and define variables that may reduce agreement. DESIGN: Prospective study. SETTING: Polyvalent ICU of a university hospital. PATIENTS: 359 patients. INTERVENTIONS: We compared 24-h CrCl (CrCl-24h), as the standard measure, with 2-h CrCl (CrCl-2h) (at the start of the period) and the Cockroft-Gault equation (Ck-G). MEASUREMENTS AND RESULTS: The 2-h sample was lost in two patients (0.6%) and the 24-h sample was lost in 50 patients (13.9%). The mean Ck-G was 87.4+/-3.05, with CrCl-2h 109.2+/-4.46 and CrCl-24h 100.9+/-4.21 ml/min/1.73 m2 (r2 of 0.88 for CrCl-2h and 0.84 for Ck-G). The differences from ClCr-24h were 21.8+/-3.3 (p<0.001) for the Ck-G and 8.3+/-2.6 (p<0.05) for CrCl-2h (p<0.05). In the subgroup of patients with CrCl-24h<100 ml/min/1.73 m2, the CrCl-24h value was 52.9+/-2.71 vs. 51.6+/-2.14 for CrCl-2h (p=ns) and 57.6+/-2.56 (p<0.001) for the Ck-G. Patients with CrCl<100 ml/min only showed variability in hyperglycemia during the 24-h period. CONCLUSIONS: In intensive care patients, 24-h CrCl results in a large proportion of non-valid determinations, even under conditions of close monitoring. Two-hour CrCl is an adequate substitute, even in patients who are unstable or who have irregular diuresis where a 24-h collection is impossible. The Cockroft-Gault equation seems less useful in this setting.
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Creatina/metabolismo , Unidades de Cuidados Intensivos , Pautas de la Práctica en Medicina , Algoritmos , Creatina/sangre , Cuidados Críticos , Enfermedad Crítica , Femenino , Hospitales Universitarios , Humanos , Riñón/lesiones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , EspañaRESUMEN
Patients with systemic sclerosis (SSc) display altered intestinal microbiota. However, the influence of intestinal dysbiosis on the development of experimental SSc remains unknown. Topoisomerase I peptide-loaded dendritic cell immunization induces SSc-like disease, with progressive skin and lung fibrosis. Breeders were given streptomycin and pups continued to receive antibiotic (ATB) until endpoint (lifelongATB). Alternately, ATB was withdrawn (earlyATB) or initiated (adultATB) during adulthood. Topoisomerase I peptide-loaded dendritic cell (no ATB) immunization induced pronounced skin fibrosis, with increased matrix (Col1a1), profibrotic (Il13, Tweakr), and vascular function (Serpine1) gene expression. Remarkably, earlyATB exposure was sufficient to augment skin Col5a1 and Il13 expression, and inflammatory cell infiltration, which included IL-13+ cells, mononuclear phagocytes, and mast cells. Moreover, skin pathology exacerbation was also observed in lifelongATB and adultATB groups. Oral streptomycin administration induced intestinal dysbiosis, with exposure limited to early life (earlyATB) being sufficient to cause long-term modification of the microbiota and a shift toward increased Bacteroidetes/Firmicutes ratio. Finally, aggravated lung fibrosis and dysregulated pulmonary T-cell responses were observed in earlyATB and lifelongATB but not adultATB-exposed mice. Collectively, intestinal microbiota manipulation with streptomycin exacerbated pathology in two distinct sites, skin and lungs, with early life being a critical window to affect the course of SSc-like disease.
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Disbiosis/genética , Microbioma Gastrointestinal/efectos de los fármacos , Fibrosis Pulmonar/patología , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/inmunología , Estreptomicina/farmacología , Factores de Edad , Animales , Células Cultivadas , ADN Bacteriano/análisis , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Disbiosis/microbiología , Femenino , Microbioma Gastrointestinal/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Fibrosis Pulmonar/genética , Distribución Aleatoria , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Factores de Riesgo , Esclerodermia Sistémica/patología , Estadísticas no ParamétricasRESUMEN
DNA Topoisomerase I (TopoI) is a candidate autoantigen for diffuse cutaneous systemic sclerosis (dcSSc) associated with fatal lung disease. Dendritic cells (DCs) contribute to bleomycin-induced lung fibrosis. However, the possibility that TopoI-loaded DCs are involved in the initiation and/or perpetuation of dcSSc has not been explored. Here, we show that immunization with TopoI peptide-loaded DCs induces anti-TopoI autoantibody response and long-term fibrosis. Mice were repeatedly immunized with unpulsed DCs or DCs loaded with either TOPOIA or TOPOIB peptides, selected from different regions of TopoI. At week 12 after initial DC immunization, TOPOIA DCs but not TOPOIB DCs immunization induced mixed inflammation and fibrosis in lungs and skin. At a late time point (week 18), both TOPOIA DCs and TOPOIB DCs groups displayed increased alpha-smooth muscle actin expression in lungs and dermis along with skin fibrosis distal from the site of injection when compared with unpulsed DCs. Both TopoI peptide-DC-immunized groups developed IgG2a anti-TopoI autoantibody response. At week 10, signs of perivascular, peribronchial, and parenchymal pulmonary inflammation were already observed in the TOPOIA DCs group, together with transient elevation in bronchoalveolar lavage cell counts, IL-17A expression, and CXCL4 production, a biomarker of early human dcSSc. Collectively, TopoI peptide DCs induce progressive autoantibody response as well as development of protracted skin and lung dcSSc-like disease. Pronounced lung inflammation, transient IL-17A, and CXCL4 expression precede fibrosis development. Our immunization strategy, that uses self immune system and autoantigen, will help to further investigate the pathogenesis of this complex autoimmune disorder with unmet medical needs.
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Autoanticuerpos/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Células Dendríticas/inmunología , Pulmón/inmunología , Pulmón/patología , Péptidos/inmunología , Piel/inmunología , Piel/patología , Actinas/metabolismo , Animales , Autoinmunidad , Biomarcadores , Biopsia , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , ADN-Topoisomerasas de Tipo I/química , Células Dendríticas/metabolismo , Fibrosis , Inmunización , Pulmón/metabolismo , Ratones , Piel/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: C-reactive protein (CRP) has been considered a marker for infection and an aid for diagnosing sepsis. We analyze the relation of CRP to infection and outcome in intensive care units (ICU) patients. PATIENTS AND METHOD: Prospective study on 77 ventilated patients. Expected short ICU stay or (suspected or confirmed) infection at admission were excluding criteria. 55 admissions after elective surgery were the controls. CRP measurement the first (CRP-1), third (CRP-3) and sixth (CRP-6) day of stay. APACHE II (Acute Physiology Score and Chronic Health Evaluation), SOFA (Sepsis-related Organ Failure Assessment), shock, respiratory or renal failure, leucocytes, platelets and albumin were registered. Follow-up until day 9 for infection and ICU discharge for outcome. RESULTS: CRP-1 in controls was 5.3 (3.9) mg/l and cases 67.8 (77.4) (p < 0.001). Shock on admission was related to CRP-1: patients in shock had higher CRP-1 levels (118.6 [82.8] vs 62.8 [75.6]; p = 0.06). 40.25% of cases developed infection, and CRP-1 levels were higher in this patients (88.8 [93.9] vs 53.8 [60.9]; p < 0.05). ROC area under curve was 0.6 with a sensibility of 23% and a specificity of 89% for a level of CRP-1 > 100. Mortality was 23.4% in cases and 1.8% in controls. Age, shock, APACHE II and SOFA were related to mortality, but CRP-1 did not. ROC area under curve for CRP-1 as mortality predictor in all patients was 0.62 (0.76 for APACHE II and 0.77 for SOFA) but only in cases was of 0.49 (0.69 for APACHE II and 0.67 for SOFA). CONCLUSIONS: CRP level on admission is an useful marker for early infection but not for outcome in critically ill patients admited to the ICU.
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Proteína C-Reactiva/metabolismo , Enfermedad Crítica/mortalidad , Sepsis/sangre , APACHE , Adulto , Anciano , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Respiración Artificial , Sepsis/fisiopatologíaRESUMEN
BACKGROUND: Psychological stress (PS) has been associated with the development of cardiovascular diseases and adverse long-term outcomes after ischemic events. However, the precise mechanisms involved are not completely understood. Here we investigated the effect of PS on ischemia-induced neovascularization, and the potential therapeutic effect of fluoxetine in this condition. METHODS AND RESULTS: Balb/c mice were subjected or not to chronic restraint stress. After 3 weeks, hindlimb ischemia was surgically induced by femoral artery removal. We found that blood flow recovery was significantly impaired in mice exposed to PS compared to controls (Doppler flow ratio (DFR) 0.61 ± 0.07 vs. 0.80 ± 0.07, p < 0.05). At the microvascular level, capillary density was significantly reduced in ischemic muscles of mice exposed to PS (38 ± 1 vs. 74 ± 3 capillaries per field, p < 0.001). This correlated with increased oxidative stress levels and reduced expression of VEGF and VEGF signalling molecules (p44/p42 MAPK, Akt) in ischemic muscles. We found that the number of pro-angiogenic cells (PACs) was significantly reduced in mice exposed to PS. In addition, oxidative stress levels (DCF-DA, DHE) were increased in PACs isolated from mice exposed to PS, and this was associated with impaired PAC functional activities (migration, adhesion, and integration into tubules). Importantly, treatment of mice exposed to PS with the selective serotonin reuptake inhibitor (SSRI) fluoxetine improved all the angiogenic parameters, and completely rescued PS-induced impairment of neovascularization. CONCLUSION: PS impairs ischemia-induced neovascularization. Potential mechanisms involved include reduced activation of the VEGF pathway in ischemic tissues, increased oxidative stress levels and reduced number and functional activities of PACs. Our results suggest that fluoxetine may represent a novel therapeutic strategy to improve neovascularization and reduce ischemia in patients suffering from cardiovascular diseases and exposed to PS.
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Fluoxetina/uso terapéutico , Isquemia/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Estrés Psicológico , Animales , Antidepresivos de Segunda Generación/uso terapéutico , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Peso Corporal , Movimiento Celular , Colágeno/química , Combinación de Medicamentos , Células Endoteliales/metabolismo , Miembro Posterior/irrigación sanguínea , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isquemia/psicología , Laminina/química , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo , Proteoglicanos/química , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: This work sought to inquire on the father's role on the decision making regarding home birth from the perspective of both partners. METHODOLOGY: The design was ethnographic of qualitative nature, conducted in the province of Alicante, Spain. A total of 11 couples participated voluntarily in the study. To gather the data, the following techniques were used: two life stories, five narrations, and in-depth interviews of all the study participants. The data obtained were analyzed with the ATLAS-ti v6.2 software. RESULTS: Four fundamental categories were obtained: father's attitude, role performed, influencing factors, and perception of the woman. Theproposal to carry out the delivery at home tends to be made by the woman, but its decision is made jointly. This decision is influenced by different factors, like: good evolution of the pregnancy, accompaniment by a professional, and the couple's beliefs on the delivery. The fathers consider they must be respectful of the woman's decision and accompany them during the whole process; the women are comforted by their unconditional support and accompaniment, considering it essential. CONCLUSION: The father's role is fundamental in the planned decision of having a home birth; a decision discussed and mediated by the couple in which their fears and beliefs are determinant in their decision. The woman has her partner's support to implement her decision.
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BACKGROUND: Specific cutaneous involvement in patients with multiple myeloma (MM) is very uncommon. It usually occurs in late stages of MM as a reflection of increased tumor cell burden. We studied 8 patients with cutaneous involvement of MM without underlying bony lesions and reviewed the literature on this rare dermatologic manifestation. DESIGN: We were particularly interested in the clinical course of patients with MM and cutaneous metastases, including survival once metastases were detected and the possible influence of various forms of therapy. Our goal was also to identify the immunoglobulin and the light-chain type in these cases, with emphasis on any possible association between a particular immunoglobulin class and cutaneous involvement, as well as the histopathologic, immunohistochemical, and cytogenetic features of the neoplastic plasma cells involving the skin. SETTING: University department of dermatology, university hospital, and private practice. PATIENTS: Medical records and biopsy specimens from 8 patients with MM and specific cutaneous lesions were reviewed. RESULTS: Cutaneous lesions consisted of multiple erythematous or violaceous nodules or plaques with a wide anatomical distribution. Histopathologically, 2 different patterns were identified: nodular and diffuse interstitial. Neoplastic plasma cells showed atypical features, and in 1 case they displayed a spindle shape, giving a sarcomatoid appearance to the lesion. Immunohistochemical studies demonstrated that neoplastic plasma cells were strongly positive for CD79a, CD138, and epithelial membrane antigen, and variably positive for VS38c and CD43. In each case the immunoglobulin profile and the light-chain type expression of the neoplastic cells were the same as those identified in the serum of the patients: 5 cases were IgA lambda; 2 cases were IgG kappa; and 1 case was IgA kappa. In cases 2, 3, and 4, polymerase chain reaction investigations revealed monoclonal rearrangement for IgH genes, whereas the investigations for human herpesvirus 8 and Epstein-Barr virus yielded negative results. Fluorescent in situ hybridization investigations in these 3 cases demonstrated that the cutaneous neoplastic plasma cells showed the deletion of the rb-1 (retinoblastoma) gene. Despite aggressive chemotherapy, all 8 patients died a few months after the development of cutaneous involvement. CONCLUSIONS: In our series, there was a perfect correlation of immunoglobulin and light-chain type between the serum electrophoresis and the cutaneous plasma cells. Patients with MM showed a short survival once cutaneous metastases appeared independently of the therapy. The deletion the rb-1 gene may provide prognostically relevant information to identify a high-risk subset of patients with MM.
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Mieloma Múltiple/patología , Neoplasias Cutáneas/secundario , Anciano , Antígenos CD/análisis , Femenino , Eliminación de Gen , Genes de Retinoblastoma/genética , Humanos , Inmunoglobulinas/análisis , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mieloma Múltiple/química , Mieloma Múltiple/genética , Células Plasmáticas/patología , Piel/inmunología , Piel/patología , Neoplasias Cutáneas/química , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: Liver transplant is an effective procedure for fulminant hepatitis or chronic liver disease and offers an adequate quality of life. However, even though it is a consolidated treatment, patients can develop serious complications in the immediate postoperative course. PATIENTS AND METHOD: Prospective observational study of 131 patients admitted in our intensive care unit after liver transplant surgery. We studied variables related with the development of complications and their relation to outcome. RESULTS: Intensive care unit mortality was 11.5%. Median stay was 4 days. 90% of patients presented 2 or more complications. Hyperglycemia, thrombocytopenia and hypothermia were the most frequent complications but they were not related with mortality. Less frequent but related to outcome complications were acute renal failure (23.6% mortality vs. 1.3%; p < 0.01), ADRS (63.6% vs 6.7%; p < 0,01), low cardiac output (71.4% vs 4.3%; p < 0.01), > or = 2 vasoactive drugs (61.9% vs 1.8%; p < 0.01), encephalopathy (37.5% vs 9.8%; p < 0.05), pneumonia (80% vs 8%; p < 0.01) and hemorrhage (29.4% vs 8.8%; p < 0.05). Graph ischemia, coagulopathy, reperfusion syndrome and use of blood derivatives during surgery were factors related with the development of complications and mortality. Multivariate analysis showed a relationship with mortality and low cardiac output, number of vasoactive drugs and total time of graft ischemia. CONCLUSIONS: Complications during the postoperative course of liver transplant are frequent but most of them have no effect on prognosis. The negative effect of severe complications should be limited by optimizing the hemodynamic support in these patients and minimizing ischemia of transplanted organs.
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Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Complicaciones Posoperatorias , Estudios de Cohortes , Humanos , Unidades de Cuidados Intensivos , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Fish oil consumption has been associated with a reduced incidence of cardiovascular diseases. However, the precise mechanisms involved are not completely understood. Here we tested the hypothesis that a fish oil-enriched diet improves neovascularization in response to ischemia. METHODS AND RESULTS: C57Bl/6 mice were fed a diet containing either 20% fish oil, rich in long-chain n-3 polyunsaturated fatty acids (PUFAs), or 20% corn oil, rich in n-6 PUFAs. After 4 weeks, hindlimb ischemia was surgically induced by femoral artery removal. We found that blood flow recovery was significantly improved in mice fed a fish oil diet compared to those fed a corn oil diet (Doppler flow ratio (DFR) at day 21 after surgery 78 ± 5 vs. 56 ± 4; p < 0.01). Clinically, this was associated with a significant reduction of ambulatory impairment and ischemic damage in the fish oil group. At the microvascular level, capillary density was significantly improved in ischemic muscles of mice fed a fish oil diet. This correlated with increased expression of VEGF and eNOS in ischemic muscles, and higher NO concentration in the plasma. Endothelial progenitor cells (EPCs) have been shown to have an important role for postnatal neovascularization. We found that the number of EPCs was significantly increased in mice fed a fish oil diet. In addition, oxidative stress levels (DCF-DA, DHE) were reduced in EPCs isolated from mice exposed to fish oil, and this was associated with improved EPC functional activities (migration and integration into tubules). In vitro, treatment of EPCs with fish oil resulted in a significant increase of cellular migration. In addition, the secretion of angiogenic growth factors including IL6 and leptin was significantly increased in EPCs exposed to fish oil. CONCLUSION: Fish oil-enriched diet is associated with improved neovascularization in response to ischemia. Potential mechanisms involved include activation of VEGF/NO pathway in ischemic tissues together with an increase in the number and the functional activities of EPCs.
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Inductores de la Angiogénesis/farmacología , Endotelio Vascular/efectos de los fármacos , Aceites de Pescado/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Isquemia/prevención & control , Neovascularización Fisiológica/efectos de los fármacos , Animales , Peso Corporal , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Aceite de Maíz/farmacología , Modelos Animales de Enfermedad , Endotelio Vascular/fisiología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Miembro Posterior/irrigación sanguínea , Isquemia/dietoterapia , Isquemia/fisiopatología , Lípidos/sangre , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE: This study aimed to measure the point prevalence of kidney dysfunction (KD) in the intensive care setting. MATERIALS AND METHODS: A point-prevalence, single-day, prospective study was conducted. Of 919 patients present in 42 Intensive care units (ICUs) for 2 specific days (September 2009 and March 2010), 832 cases were included. Mild KD was defined as a measured creatinine clearance of 90 to 60 mL min(-1) 1.73 m(-2), and severe KD was defined as a creatinine clearance less than 60 mL min(-1) 1.73 m(-2). RESULTS: Prevalence of mild KD was 15.9/100 patients/d (13.5-18.5), and severe KD was 42.4/100 patients/d (39.1-45.8). We considered as having a low probability of experiencing KD those patients without chronic kidney disease, acute kidney injury network stage 0, and a serum creatinine less than 1.2 mg/dL, but among them (557 patients), 18.1% (15.2%-21.6%) had mild KD and 24.2% (20.9%-28%) had severe KD. ICU mortality was 10.6% (7.81%-14.4%) for patients without dysfunction, 16.6% (11.2%-24%) for patients with mild KD, and 29.7% (25.2%-34.7%; P<.001) for patients with severe KD, with a relative risk for severe KD vs no KD of 2.54 (1.90-3.40). In 54.3% patients, at least 1 renal insult was reported. One nephrotoxic drug was administered to 34.4% and 2 or more to 14.9% patients, with a lower frequency among those with chronic kidney disease (30.6% vs 50.8%; P<.05). CONCLUSIONS: Each day of study, more that half of the patients admitted to the ICU showed some derangement in kidney function. More than 25% of patients not fulfilling the KD criteria by serum creatinine or acute kidney injury network showed, in fact, a severe KD, and this finding was associated with higher mortality. More than 50% of the patients admitted to the ICU were subjected to at least 1 renal insult.
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Lesión Renal Aguda/epidemiología , Unidades de Cuidados Intensivos , Lesión Renal Aguda/mortalidad , Anciano , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Índice de Severidad de la Enfermedad , España/epidemiologíaRESUMEN
Glomerular filtration rate (GFR) is an accepted measure for assessment of kidney function. For the critically ill patient, creatinine clearance is the method of reference for the estimation of the GFR, although this is often not measured but estimated by equations (i.e., Cockroft-Gault or MDRD) not well suited for the critically ill patient. Functional evaluation of the kidney rests in serum creatinine (Crs) that is subjected to multiple external factors, especially relevant overhydration and loss of muscle mass. The laboratory method used introduces variations in Crs, an important fact considering that small increases in Crs have serious repercussion on the prognosis of patients. Efforts directed to stratify the risk of acute kidney injury (AKI) have crystallized in the RIFLE or AKIN systems, based in sequential changes in Crs or urine flow. These systems have provided a common definition of AKI and, due to their sensitivity, have meant a considerable advantage for the clinical practice but, on the other side, have introduced an uncertainty in clinical research because of potentially overestimating AKI incidence. Another significant drawback is the unavoidable period of time needed before a patient is classified, and this is perhaps the problem to be overcome in the near future.