Chronic impact of traumatic brain injury on outcome and quality of life : a narrative review

Traditionally seen as a sudden, brutal event with short-term impairment, traumatic brain injury (TBI) may cause persistent, sometimes life-long, consequences. While mortality after TBI has been reduced, a high proportion of severe TBI survivors require prolonged rehabilitation and may suffer long-term physical, cognitive, and psychological disorders. Additionally, chronic consequences have been identified not only after severe TBI but also in a proportion of cases previously classified as moderate or mild. This burden affects the daily life of survivors and their families; it also has relevant social and economic costs. Outcome evaluation is difficult for several reasons: co-existing extra-cranial injuries (spinal cord damage, for instance) may affect independence and quality of life outside the pure TBI effects; scales may not capture subtle, but important, changes; co-operation from patients may be impossible in the most severe cases. Several instruments have been developed for capturing specific aspects, from generic health status to specific cognitive functions. Even simple instruments, however, have demonstrated variable inter-rater agreement. The possible links between structural traumatic brain damage and functional impairment have been explored both experimentally and in the clinical setting with advanced neuro-imaging techniques. We briefly report on some fundamental findings, which may also offer potential targets for future therapies. Better understanding of damage mechanisms and new approaches to neuroprotection-restoration may offer better outcomes for the millions of survivors of TBI

Accuracy of intracranial pressure monitoring : systematic review and meta-analysis

Introduction: Intracranial pressure (ICP) measurement is used to tailor interventions and to assist in formulating the prognosis for traumatic brain injury patients. Accurate data are therefore essential. The aim of this study was to verify the accuracy of ICP monitoring systems on the basis of a literature review. Methods: A PubMed search was conducted from 1982 to 2014, plus additional references from the selected papers. Accuracy was defined as the degree of correspondence between the pressure read by the catheter and a reference "real" ICP measurement. Studies comparing simultaneous readings from at least two catheters were included. Drift was defined as the loss of accuracy over the monitoring period. Meta-analyses of data from the studies were used to estimate the overall mean difference between simultaneous ICP measurements and their variability. Individual studies were weighted using both a fixed and a random effects model. Results: Of 163 articles screened, 83 compared two intracranial catheters: 64 reported accuracy and 37 drift(some reported both). Of these, 10 and 17, respectively, fulfilled the inclusion criteria for accuracy and zero drift analysis. The combined mean differences between probes were 1.5mmHg (95% confidence interval (CI) 0.7-2.3) with the random effects model and 1.6mmHg (95% CI 1.3-1.9) with the fixed effects model. The reported mean drift over a long observation period was 0.75mmHg. No relation was found with the duration of monitoring or differences between various probes. Conclusions: This study confirms that the average error between ICP measures is clinically negligible. The random effects model, however, indicates that a high percentage of readings may vary over a wide range, with clinical implications both for future comparison studies and for daily care

Perfil comparativo do déficit de vegetação natural em APPs - matas ciliares e nascentes - em bacias hidrográficas no bioma Mata Atlântica - RJ.

A proteção de Áreas de Preservação Permanente (APP) tem sido foco de muita discussão na concepção da nova Lei 12.651/2012 que substitui a Lei 4.771/1965 que instituía o Código Florestal Brasileiro, com divergências entre ruralistas e ambientalistas no que tange à conservação ambiental. Quantificar e identificar o estado de degradação destas áreas é de fundamental importância para a orientação de políticas públicas e ações voltadas à conservação dos recursos florestais, com implicações na qualidade do solo e da água, e fauna. Desta forma, o presente estudo se propôs a traçar um perfil comparativo do déficit de vegetação natural em APPs - matas ciliares e nascentes - em duas bacias hidrográficas sob o bioma Mata Atlântica - RJ, Guapi-Macacu e Caceribu. Para tal, foram utilizadas ferramentas implementadas em SIG para processamento e organização de dados cartográficos e delimitação das APPs, bem como para identificação de áreas de vegetação natural presentes em APPs de matas ciliares e nascentes e cálculo de áreas. Dados secundários como o mapa de uso e cobertura da terra (obtido pelo processamento de imagens de 2007 do satélite Landsat) foram utilizados para a obtenção das áreas de vegetação. Foi obtido um mapa final com as áreas de vegetação natural em APPs de matas ciliares diferenciadas de áreas de vegetação natural em APPs de nascentes, apresentando também a vegetação natural presente em ambas as bacias que não em áreas de APPs de matas ciliares e nascentes. Os resultados apontaram que a bacia do Caceribu possui um déficit de vegetação natural em APP de matas ciliares e nascentes da ordem de 91%, e no caso da bacia Guapi-Macacu esse déficit é de aproximadamente 38%. Estes dados, apesar de terem sido obtidos na escala 1:50.000, a partir de imagens de média resolução espacial - 30 metros, chamam a atenção para o fato de que ações de revegetação destas áreas são prioritárias perante sua importância para a prestação de diversos serviços ambientais, essenciais para o bem estar das populações que vivem nestas bacias ou em bacias próximas.bitstream/item/124482/1/BPD-204-Perfil-comparativo.pd

Intracranial pressure after subarachnoid hemorrhage

Objectives: To describe mean intracranial pressure after aneurysmal subarachnoid hemorrhage, to identify clinical factors associated with increased mean intracranial pressure, and to explore the relationship between mean intracranial pressure and outcome. Design: Analysis of a prospectively collected observational database. Setting: Neuroscience ICU of an academic hospital. Patients: One hundred sixteen patients with subarachnoid hemorrhage and intracranial pressure monitoring. Interventions: None. Measurements and Main Results: Episodes of intracranial pressure greater than 20 mm Hg lasting at least 5 minutes and the mean intracranial pressure for every 12-hour interval were analyzed. The highest mean intracranial pressure was analyzed in relation to demographic characteristics, acute neurologic status, initial radiological findings, aneurysm treatment, clinical vasospasm, and ischemic lesion. Mortality and 6-month outcome (evaluated using a dichotomized Glasgow Outcome Scale) were also introduced in multivariable logistic models. Eighty-one percent of patients had at least one episode of high intracranial pressure and 36% had a highest mean intracranial pressure more than 20 mm Hg. The number of patients with high intracranial pressure peaked 3 days after subarachnoid hemorrhage and declined after day 7. Highest mean intracranial pressure greater than 20 mm Hg was significantly associated with initial neurologic status, aneurysmal rebleeding, amount of blood on CT scan, and ischemic lesion within 72 hours from subarachnoid hemorrhage. Patients with highest mean intracranial pressure greater than 20 mm Hg had significantly higher mortality. When death, vegetative state, and severe disability at 6 months were pooled, however, intracranial pressure was not an independent predictor of unfavorable outcome. Conclusions: High intracranial pressure is a common complication in the first week after subarachnoid hemorrhage in severe cases admitted to ICU. Mean intracranial pressure is associated with the severity of early brain injury and with mortality

Brain oxygen tension, oxygen supply, and oxygen consumption during arterial hyperoxia in a model of progressive cerebral ischemia

We investigated the changes in brain oxygen tension (ptiO(2)) after ventilation with pure O-2 in order to (1) clarify the pathophysiology of O-2 exchange in the cerebral microcirculation; and (2) investigate the relationship between brain O-2 tension, O-2 delivery, and consumption in steady-state conditions during stepwise cerebral blood flow (CBF) reductions. A swine model was developed to reduce CBF in three stable steps: (1) baseline (CBF 100%), (2) CBF of 50-60% of baseline, and (3) CBF of (30% of baseline. CBF was reduced by infusing saline into the left lateral ventricle through a catheter connected with an infusion pump. At each step, hyperoxia was tested by increasing the inspired oxygen fraction up to 100%, PtiO(2) reflected the CBF reductions, since it was respectively 27.95 ( +/-10.15), 14.77 (+/-3.58), and 3.45 (+/-2.89) mm Hg during the three CBF steps. Hyperoxia was followed by an increase in ptiO(2), although the increase was significantly lower when hyperoxia was applied during progressive ischemia. O-2 supply to the brain did not change during hyperoxia. Arteriovenous oxygen difference (AVDO(2)) decreased during the phases of intact CBF and moderate impairment, but not during the phase of severe CBF reduction. In conclusion, ptiO(2) reductions closely reflect the imbalance between oxygen delivery and demand; this implies a link between low ptiO(2) and defective O-2 supply due to impaired CBF. However, this relation is not necessarily reciprocal, since manipulating brain oxygen tension does not always influence brain oxygen delivery, as in the case of ventilation with pure oxygen

Efficacy of acute administration of inhaled argon on traumatic brain injury in mice

BACKGROUND: Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI. METHODS: Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry. RESULTS: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. CONCLUSIONS: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue

Neurofilament light chain levels in ventricular cerebrospinal fluid after acute aneurysmal subarachnoid haemorrhage

PURPOSE: The contribution of axonal injury to brain damage after aneurysmal subarachnoid haemorrhage (aSAH) is unknown. Neurofilament light chain (NF-L), a component of the axonal cytoskeleton, has been shown to be elevated in the cerebrospinal fluid of patients with many types of axonal injury. We hypothesised that patients with aSAH would have elevated cerebrospinal fluid (CSF) NF-L levels and sought to explore the clinical correlates of CSF NF-L dynamics. METHODS: Serial ventricular CSF (vCSF) samples were collected from 35 patients with aSAH for up to 15 days. vCSF NF-L measurements were determined by enzyme-linked immunosorbent assay. NF-L levels were analysed in relation to acute clinical status, radiological findings and 6-month outcomes. RESULTS: vCSF NF-L concentrations were elevated in all patients with aSAH. Patients with early cerebral ischaemia (ECI), defined as a CT hypodense lesion visible within the first 3 days, had higher acute vCSF NF-L levels than patients without ECI. These elevated NF-L levels were similar in patients with ECI associated with intracranial haemorrhage and ECI associated with surgical/endovascular complications. vCSF NF-L levels did not differ as a function of acute clinical status, clinical vasospasm, delayed cerebral ischaemia or 6-month Glasgow Outcome Scale. CONCLUSIONS: Elevated vCSF NF-L levels may in part reflect increased injury to axons associated with ECI. However, our results suggest that axonal injury after aSAH as reflected by release of NF-L into the CSF may not play a major role in either secondary adverse events or long-term clinical outcome

Diagnóstico e alternativas para a recuperação ambiental da Bacia Hidrográfica do Rio Guandu (BHRG) - RJ.

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Protein Expr Purif

E6 is a small oncoprotein involved in tumorigenesis induced by papillomaviruses (PVs). E6 often recognizes its cellular targets by binding to short motifs presenting the consensus LXXLL. E6 proteins have long resisted structural analysis. We found that bovine papillomavirus type 1 (BPV1) E6 binds the N-terminal LXXLL motif of the cellular protein paxillin with significantly higher affinity as compared to other E6/peptide interactions. Although recombinant BPV1 E6 was poorly soluble in the free state, provision of the paxillin LXXLL peptide during BPV1 E6 biosynthesis greatly enhanced the protein's solubility. Expression of BPV1 E6/LXXLL peptide complexes was carried out in bacteria in the form of triple fusion constructs comprising, from N- to C-terminus, the soluble carrier protein maltose binding protein (MBP), the LXXLL motif and the E6 protein. A TEV protease cleavage site was placed either between MBP and LXXLL motif or between LXXLL motif and E6. These constructs allowed us to produce highly concentrated samples of BPV1 E6, either covalently fused to the C-terminus of the LXXLL motif (intra-molecular complex) or non-covalently bound to it (inter-molecular complex). Heteronuclear NMR measurements were performed and showed that the E6 protein was folded with similar conformations in both covalent and non-covalent complexes. These data open the way to novel structural and functional studies of the BPV1 E6 in complex with its preferential target motif

A quantitative LumiFluo assay to test inhibitory compounds blocking p53 degradation induced by human papillomavirus oncoprotein E6 in living cells

High-risk human papillomaviruses (HR-HPVs) are the causative agents for the onset of several epithelial cancers in humans. The deregulated expression of the viral oncoproteins E6 and E7 is the driving force sustaining the progression of malignant transformation in pre-neoplastic lesions. Targeting the viral E6 oncoprotein through inhibitory compounds can counteract the survival of cancer cells due to the reactivation of p53-mediated pathways and represents an intriguing strategy to treat HPV-associated neoplasias. Here, we describe the development of a quantitative and easy-to-perform assay to monitor the E6-mediated degradation of p53 in living cells to be used for small-molecule testing. This assay allows to unbiasedly determine whether a compound can protect p53 from the E6-mediated degradation in cells, through a simple 3-step protocol. We validated the assay by testing two small molecules, SAHA and RITA, reported to impair the E6-mediated p53 degradation. Interestingly, we observed that only SAHA efficiently rescued p53, while RITA could not provide the same degree of protection. The possibility to specifically and quantitatively monitor the ability of a selected compound to rescue p53 in a cellular context through our LumiFluo assay could represent an important step towards the successful development of anti-HPV drugs