Attenuation of Brain Nitrostative and Oxidative Damage by Brain Cooling during Experimental Traumatic Brain Injury

The aim of the present study was to ascertain whether brain cooling causes attenuation of traumatic brain injury by reducing brain nitrostative and oxidative damage. Brain cooling was accomplished by infusion of 5 mL of 4°C saline over 5 minutes via the external jugular vein. Immediately after the onset of traumatic brain injury, rats were randomized into two groups and given 37°C or 4°C normal saline. Another group of rats were used as sham operated controls. Behavioral and biochemical assessments were conducted on 72 hours after brain injury or sham operation. As compared to those of the sham-operated controls, the 37°C saline-treated brain injured animals displayed motor deficits, higher cerebral contusion volume and incidence, higher oxidative damage (e.g., lower values of cerebral superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, but higher values of cerebral malondialdehyde), and higher nitrostative damage (e.g., higher values of neuronal nitric oxide synthase and 3-nitrotyrosine). All the motor deficits and brain nitrostative and oxidative damage were significantly reduced by retrograde perfusion of 4°C saline via the jugular vein. Our data suggest that brain cooling may improve the outcomes of traumatic brain injury in rats by reducing brain nitrostative and oxidative damage

Differential expression of centrosomal proteins at different stages of human glioma

BACKGROUND: High-grade gliomas have poor prognosis, requiring aggressive treatment. The aim of this study is to explore mitotic and centrosomal dysregulation in gliomas, which may provide novel targets for treatment. METHODS: A case-control study was performed using 34 resected gliomas, which were separated into low- and high-grade groups. Normal human brain tissue was used as a control. Using immunohistochemical analysis, immunofluorescent microscopy, and RT-PCR, detection of centrins 1 and 2, γ-tubulin, hNinein, Aurora A, and Aurora B, expression was performed. Analysis of the GBM8401 glioma cell line was also undertaken to complement the in vivo studies. RESULTS: In high-grade gliomas, the cells had greater than two very brightly staining centrioles within large, atypical nuclei, and moderate-to-strong Aurora A staining. Comparing with normal human brain tissue, most of the mRNAs expression in gliomas for centrosomal structural proteins, including centrin 3, γ-tubulin, and hNinein isoforms 1, 2, 5 and 6, Aurora A and Aurora B were elevated. The significant different expression was observed between high- and low-grade glioma in both γ-tubulin and Aurora A mRNA s. In the high-grade glioma group, 78.6% of the samples had higher than normal expression of γ-tubulin mRNA, which was significantly higher than in the low-grade glioma group (18.2%, p < 0.05). CONCLUSIONS: Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas. Therefore, these results are clinically useful for glioma staging as well as the development of novel treatments strategies

Pka-Dependent Activation of Pkc, P38 Mapk and Ikk in Macrophage: Implication in the Induction of Inducible Nitric Oxide Synthase and Interleukin-6 by Dibutyryl Camp

In this study, we examined the signal transduction of dibutyryl cyclic adenosine monophosphate (dBcAMP) to stimulate the release of nitric oxide (NO) and interleukin-6 (IL-6) from J774 macrophages. These actions of dBcAMP were diminished by the presence of the inhibitors of protein kinase A (PKA), protein kinase C (PKC), p38 MAPK and nuclear factor-kappa B (NF- kappaB). In contrast, Go 6976 and PD 98059 had no significant effects. Consistently, dBcAMP caused membrane translocation of PKCbetaII, delta, mu , lambda and zeta isoforms, and increased atypical protein kinase C (aPKC) and p38 MAPK activities. The nuclear translocation and DNA-binding study revealed that dBcAMP stimulated NF-kappaB, activator protein-1 (AP-1), and CAAT/ enhancer-binding protein (c/EBPbeta). Via PKA, PKC and p38 MAPK- dependent signals, dBcAMP also induced inhibitory subunit of NF-kappaB ( IkappaB) degradation, IkappaB kinase ( IKK) activation, nuclear translocation of NF-kappaB subunit p65 and its association with the CREB- binding protein (CBP) . These results illustrate that PKA activation in macrophages is able to stimulate PKC and p38 MAPK, which lead to IKK- dependent NF-kappaB activation and contribute to the induction of inducible nitric oxide synthase (iNOS) and IL-6 genes

Etanercept Attenuates Traumatic Brain Injury in Rats by Reducing Brain TNF-α Contents and by Stimulating Newly Formed Neurogenesis

It remains unclear whether etanercept penetrates directly into the contused brain and improves the outcomes of TBI by attenuating brain contents of TNF-α and/or stimulating newly formed neurogenesis. Rats that sustained TBI are immediately treated with etanercept. Acute neurological and motor injury is assessed in all rats the day prior to and 7 days after surgery. The numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain injury that occurred during TBI were counted by immunofluorescence staining. Enzyme immunoassay for quantitative determination of TNF-α or etanercept in brain tissues is also performed. Seven days after systemic administration of etanercept, levels of etanercept can be detected in the contused brain tissues. In addition, neurological and motor deficits, cerebral contusion, and increased brain TNF-α contents caused by TBI can be attenuated by etanercept therapy. Furthermore, the increased numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain tissues caused by TBI can be potentiated by etanercept therapy. These findings indicate that systemically administered etanercept may penetrate directly into the contused brain tissues and may improve outcomes of TBI by reducing brain contents of TNF-α and by stimulating newly formed neurogenesis

Impact of grouping complications on mortality in traumatic brain injury: A nationwide population-based study.

Traumatic brain injury (TBI) is an important health issue with high mortality. Various complications of physiological and cognitive impairment may result in disability or death after TBI. Grouping of these complications could be treated as integrated post-TBI syndromes. To improve risk estimation, grouping TBI complications should be investigated, to better predict TBI mortality. This study aimed to estimate mortality risk based on grouping of complications among TBI patients. Taiwan's National Health Insurance Research Database was used in this study. TBI was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes: 801-804 and 850-854. The association rule data mining method was used to analyze coexisting complications after TBI. The mortality risk of post-TBI complication sets with the potential risk factors was estimated using Cox regression. A total 139,254 TBI patients were enrolled in this study. Intracerebral hemorrhage was the most common complication among TBI patients. After frequent item set mining, the most common post-TBI grouping of complications comprised pneumonia caused by acute respiratory failure (ARF) and urinary tract infection, with mortality risk 1.55 (95% C.I.: 1.51-1.60), compared with those without the selected combinations. TBI patients with the combined combinations have high mortality risk, especially those aged <20 years with septicemia, pneumonia, and ARF (HR: 4.95, 95% C.I.: 3.55-6.88). We used post-TBI complication sets to estimate mortality risk among TBI patients. According to the combinations determined by mining, especially the combination of septicemia with pneumonia and ARF, TBI patients have a 1.73-fold increased mortality risk, after controlling for potential demographic and clinical confounders. TBI patients aged<20 years with each combination of complications also have increased mortality risk. These results could provide physicians and caregivers with important information to increase their awareness about sequences of clinical syndromes among TBI patients, to prevent possible deaths among these patients