ABSTRACT
Reactive oxygen species (ROS) and pro-inflammatory cytokines are crucial in ventricular remodelling, such as inflammation-associated myocarditis. We previously reported that tumour necrosis factor-α (TNF-α)-induced ROS in human aortic smooth muscle cells is mediated by NADPH oxidase subunit Nox4. In this study, we investigated whether TNF-α-induced ventricular remodelling was mediated by Nox2 and/or Nox4. An intravenous injection of murine TNF-α was administered to a group of mice and saline injection was administered to controls. Echocardiography was performed on days 1, 7 and 28 post-injection. Ventricular tissue was used to determine gene and protein expression of Nox2, Nox4, ANP, interleukin (IL)-1ß, IL-2, IL-6, TNF-α and to measure ROS. Nox2 and Nox4 siRNA were used to determine whether or not Nox2 and Nox4 mediated TNF-α-induced ROS and upregulation of IL-1ß and IL-6 in adult human cardiomyocytes. Echocardiography showed a significant increase in left ventricular end-diastolic and left ventricular end-systolic diameters, and a significant decrease in the ejection fraction and fractional shortening in mice 7 and 28 days after TNF-α injection. These two groups of mice showed a significant increase in ventricular ROS, ANP, IL-1ß, IL-2, IL-6 and TNF-α proteins. Nox2 and Nox4 mRNA and protein levels were also sequentially increased. ROS was significantly decreased by inhibitors of NADPH oxidase, but not by inhibitors of other ROS production systems. Nox2 and Nox4 siRNA significantly attenuated TNF-α-induced ROS and upregulation of IL-1ß and IL-6 in cardiomyocytes. Our study highlights a novel TNF-α-induced chronic ventricular remodelling mechanism mediated by sequential regulation of Nox2 and Nox4 subunits.
Subject(s)
Membrane Glycoproteins/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , NADPH Oxidases/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Ventricular Remodeling/drug effects , Animals , Antioxidants/pharmacology , Blotting, Western , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Humans , Immunoenzyme Techniques , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Mice , Myocytes, Cardiac/cytology , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/genetics , Oxidative Stress , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
We describe a patient with liver cirrhosis who presented with erosive oral and cutaneous lichen planus (LP) and incidentally was found simultaneously to have thymoma and hepatoma. We support the notion forwarded earlier that LP and chronic liver disease is more than a mere coincidence and that there is a non-coincidental association between LP and thymoma. We believe this is also the first reported case in the English Literature of coexistence of the three condition LP, thymoma and hepatoma complicating liver disease.
ABSTRACT
The aim of this investigation was to determine the prognostic value of coagulation abnormalities in a defined subset of patients with acute head injury. Prothrombin time, accelerated partial thromboplastin time (APTT), thrombin clotting time, fibrinogen assay, platelet count, fibrin degradation products (FDP) were assayed in 204 patients with acute closed head injury. Their values were graded on a score 0-3 and the sum score for each patient regarded as the disseminated intravascular coagulation (DIC) score. Moderate to severe DIC scores were evident in 38% of the cohort. At least one parameter was abnormal in 71% of patients. The DIC score correlated inversely with the Glasgow coma score (GCS) (p < 0.0001). In the GCS 13-15 subset, FDP scores were significant predictors of poor outcome (p < 0.001). In the GCS 6-12 subset, the APTT score (p < 0.001), and DIC score (p < 0.0001) predicted an adverse outcome. The DIC scores were significantly abnormal in most patients who had a poor outcome, without evidence of adverse predictors on CT. Logistic regression analysis confirmed the independent predictive capacity of APTT, FDP and DIC scores when values for GCS were fixed. Abnormal haemostatic parameters may enhance the predictive ability in subsets of patients with acute head injury defined by clinical or CT predictors.
Subject(s)
Blood Coagulation Disorders/blood , Craniocerebral Trauma/blood , Adolescent , Adult , Aged , Blood Coagulation Disorders/complications , Cerebral Hemorrhage/blood , Cerebral Hemorrhage/complications , Child , Child, Preschool , Craniocerebral Trauma/complications , Forecasting , Glasgow Coma Scale , Hemostasis , Humans , Infant , Middle Aged , Prognosis , Prospective Studies , Prothrombin Time , Time Factors , Tomography, X-Ray ComputedABSTRACT
The outcome of 151 children less than 15 years of age and admitted within 24 h of head injury was studied in relation to clinical and computed tomography (CT) scan features. Thirty one (20.5%) had a poor outcome (24 died, 6 were severely disabled at 6 months after injury and 1 was in a persistent vegetative state) while 120 (79.5%) had a good outcome (89 recovered well and 31 were moderately disabled). Factors associated with a poor outcome were Glasgow Coma Scale (GCS) score 24 h following injury, presence of hypoxia on admission and CT scan features of subarachnoid haemorrhage, diffuse axonal injury and brain swelling. GCS scores alone, in the absence of other factors, had limited predictive value. The prognostic value of GCS scores < 8 was enhanced two-to fourfold by the presence of hypoxia. The additional presence of the CT scan features mentioned above markedly increased the probability of a poor outcome to > 0.8, modified only by the presence of GCS scores > 12. Correct predictions were made in 90.1% of patients, indicating that it is possible to estimate the severity of a patient's injury based on a small subset of clinical and radiological criteria that are readily available.
