Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers ...released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.
Summary
Background
Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in ...plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors.
Objective
The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs.
Methods and Results
We show that NETs generated in vitro were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET‐degradation activity.
Conclusions
Our data indicate that DNase1‐mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro‐thrombotic NETs and thus promote microvascular thrombosis in TMA patients.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in elderly patients. Extracellular DNA is a pro-inflammatory and pro-thrombotic mediator in vitro and in animal models. Levels ...of circulating extracellular DNA (ceDNA) are increased in VTE patients, but the association of ceDNA with VTE extent and clinical outcome is poorly understood.
We analyzed the association of ceDNA with the extent of VTE, categorized as distal and proximal deep vein thrombosis and pulmonary embolism, and with the clinical outcomes VTE recurrence and mortality.
We quantified ceDNA by a fluorescent probe, as well as circulating nucleosomes and neutrophil extracellular traps (NETs) by ELISA in plasma from 611 patients aged ≥ 65 years with acute VTE of a prospective cohort study (SWITCO65+).
Levels of ceDNA and nucleosomes, but not NETs, correlated with VTE extent. Infectious comorbidities independently increased ceDNA levels in VTE. CeDNA strongly correlated with C-reactive protein and leukocytosis, suggesting an association of ceDNA with inflammation in VTE patients. CeDNA furthermore predicted PE-related and all-cause mortality, but not VTE recurrence, during a 3-year follow-up.
Our study suggests that ceDNA levels in VTE patients reflect the degree of inflammation and may serve as a biomarker to stratify VTE patients at risk for mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To examine the effects of DNase1 treatment on testicular damage after testicular torsion (TT). It has been demonstrated that TT induces thrombus formation and that anticoagulation significantly ...reduces testicular damage after TT. It was hypothesized that these thrombi are dependent on neutrophil extracellular traps (NETs) and thus NETs disintegration would reduce testicular cell damage.
A sham operation was performed in 10 rats. Thirty-four rats underwent induction of iatrogenic TT for 3 hours. After de-torsion and randomization, 24 rats received DNase1 or inactivated DNase1. The following parameters were assessed: testicular damage via Cosentino grading; spermatogenesis via Johnsen score; stem cell factor and c-Kit, apoptosis via Bax, Bcl2, Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling assay, and cleaved caspase3 staining; oxidative stress via superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde; neutrophil recruitment via myeloperoxidase and neutrophil elastase staining; and NET formation via cell-free DNA.
Forty-three rats were included in the study. Subjects treated with DNase1 showed significantly less cellular damage, oxidative stress, and apoptosis. Further, DNase1-treated rats demonstrated a significant improvement of spermatogenesis, compared with the controls.
The results of the study indicate that thrombus formation during TT is quite likely NET associated, and that dissolution of cell-free DNA (including NETs) significantly improves testicular damage in rats. As treatment with DNase1 reduced apoptosis, oxidative stress, and inflammation, without adversely affecting coagulation, it might be a suitable treatment for (neonatal) TT and ought to be evaluated in humans.
Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express ...specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life.
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•Chd4/NuRD complex regulates the lineage-specific gene expression of striated muscles•Loss of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes•Chd4 deficiency leads to cardiac and skeletal myopathies and sudden death•Chd4/NuRD regulates mitochondrial homeostasis in striated muscles
Despite similar organization, heart and skeletal muscles use lineage-specific sarcomeric proteins for contraction. Gómez-del Arco et al. show that the chromatin-remodeling complex Chd4/NuRD preserves the identity of each striated muscle by epigenetic repression of the alternate lineage gene expression program. Furthermore, this complex also maintains metabolic homeostasis in both striated tissues.
To evaluate the functional and subjective results of the Sauvé-Kapandji procedure as a treatment for distal radioulnar joint disorders.
A retrospective study was conducted on 27 patients treated ...using the Sauvé-Kapandji technique from January 2001 to March 2012. The aetiología, age, sex, laterality, articular movement, radiographical signs of joint degeneration, and cubitus varus, were analysed. The Mayo Clinic wrist assessment scale and the DASH questionnaire were used for the postoperative evaluation. The mean follow-up was 24 months (6-48 months). The mean age was 47.2 years, with 66.7% females, and 55% the dominant side.
At one year after surgery, 16 cases had mild or no pain (59.2%), 8 cases with moderate (29.6%) and 3 cases with severe pain (11.1%). The pronation-supination went from a pre-operative average of 96.8° to 136.4° postoperative, operatorios, which was a significant statistical difference (Wilcoxon test). The radioulnar ratio went from an pre-operative average of +2.6mm to -0.39 mm postoperative. Full functional recovery was observed in 48%. A grip strength of 50.6%, compared to the contralateral wrist was achieved.
The Sauvé-Kapandji technique could avoid the complications common in other procedures, such as cubital-carpal migration. Our study agrees with that in the literature with good results as regards the range of joint movement, with an acceptable improvement in pain compared to the previous stage, but it also demonstrates the frequent loss of grip strength and instability of the proximal radio-ulnar joint.
Resumen
Objetivo: El objetivo de este estudio es presentar los resultados a corto plazo de la artroplastia total de muñeca y estudiar los factores que determinan su evolución.
Material y método: Se ...han revisado retrospectivamente 15 pacientes intervenidos mediante prótesis total de muñeca Tipo Universal2
®
(KMI, Carlsbad, California). Se han estudiado los factores epidemiológicos, las radiografías, la movilidad y la fuerza prequirúrgica y postquirúrgica. Se han evaluado a los pacientes mediante el cuestionario DASH y la escala visual analógica, EVA. Se han utilizado diversos test estadísticos para el estudio de la predicción de la evolución. Se han descrito las complicaciones y las reintervenciones.
Resultados: Los pacientes han presentado una disminución del dolor estadísticamente significativa. No hemos obtenido diferencias estadísticamente significativas de ninguno de los valores para prever la evolución. Seis de los casos requirieron ser reintervenidos debido a complicaciones como pinzamiento, “impingement” cubital, neuropatía del nervio cubital y luxación del primer compartimento extensor.
Conclusiones: La artroplastia total de muñeca es una alternativa en el tratamiento de la artrosis radiocarpiana avanzada en pacientes que quieren preservar cierta movilidad en la muñeca. Las complicaciones han surgido debido a que se trata de una exigente técnica quirúrgica, y disminuyen con la curva de aprendizaje. No se han encontrado factores predictivos de su evolución.
Abstract
Objective: The purpose of this study was to present the short-term clinical results of total wrist arthroplasty and to explore possible factors determining the outcome.
Methods: We retrospectively reviewed 15 patients with a total wrist arthroplasty Universal2
®
type implanted (KMI, Carlsbad, California). We studied epidemiologic factors, radiographs, wrist motion and grip strength preoperatively and postoperatively. We administered the visual analog pain scale and Disabilities of the arm, shoulder and hand questionnaire. We used some statistical tests to study the prediction of the evolution. We described the complications and the reinterventions.
Results: The pain of the patients had a significant improvement. We didn’t find any differences in any of the factors to predict the evolution. Six cases required reinterventions because of some complications such dislocations, ulnar impingement, ulnar neuropathy and volar subluxation of the tendons of the first dorsal compartment.
Conclusions: Total wrist arthroplasty is a good alternative in the treatment of advanced radiocarpal osteoarthritis in patients who want to preserve some wrist mobility. We have not found any factors to predict the evolution of this surgery.
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