BAY 61-3606, CDKi, and Sodium Butyrate Treatments Modulate p53 Protein Level and Its Site-Specific Phosphorylation in Human Vestibular Schwannomas In Vitro

This study is done to evaluate the effect of spleen tyrosine kinase inhibitor (BAY 61-3606), cyclin-dependent kinase inhibitor (CDKi), and sodium butyrate (Na-Bu) on the level and phosphorylation of p53 protein and its binding to murine double minute 2 (MDM2) homologue in human vestibular schwannomas (VS). Primary cultures of the tumor tissues were treated individually with optimum concentrations of these small molecules in vitro. The results indicate modulation of p53 protein status and its binding ability to MDM2 in treated samples as compared to the untreated control. The three individual treatments reduced the level of total p53 protein. These treatments also decreased Ser392 and Ser15 phosphorylated p53 in tumor samples of young patients and Ser315 phosphorylated p53 in old patients. Basal level of Thr55 phosphorylated p53 protein was present in all VS samples and it remained unchanged after treatments. The p53 protein from untreated VS samples showed reduced affinity to MDM2 binding in vitro and it increased significantly after treatments. The MDM2/p53 ratio increased approximately 3-fold in the treated VS tumor samples as compared to the control. The differential p53 protein phosphorylation status perhaps could play an important role in VS tumor cell death due to these treatments that we reported previously

Casemix, management, and mortality of patients rreseceiving emergency neurosurgery for traumatic brain injury in the Global Neurotrauma Outcomes Study: a prospective observational cohort study.

BackgroundTraumatic brain injury (TBI) is increasingly recognised as being responsible for a substantial proportion of the global burden of disease. Neurosurgical interventions are an important aspect of care for patients with TBI, but there is little epidemiological data available on this patient population. We aimed to characterise differences in casemix, management, and mortality of patients receiving emergency neurosurgery for TBI across different levels of human development.MethodsWe did a prospective observational cohort study of consecutive patients with TBI undergoing emergency neurosurgery, in a convenience sample of hospitals identified by open invitation, through international and regional scientific societies and meetings, individual contacts, and social media. Patients receiving emergency neurosurgery for TBI in each hospital's 30-day study period were all eligible for inclusion, with the exception of patients undergoing insertion of an intracranial pressure monitor only, ventriculostomy placement only, or a procedure for drainage of a chronic subdural haematoma. The primary outcome was mortality at 14 days postoperatively (or last point of observation if the patient was discharged before this time point). Countries were stratified according to their Human Development Index (HDI)-a composite of life expectancy, education, and income measures-into very high HDI, high HDI, medium HDI, and low HDI tiers. Mixed effects logistic regression was used to examine the effect of HDI on mortality while accounting for and quantifying between-hospital and between-country variation.FindingsOur study included 1635 records from 159 hospitals in 57 countries, collected between Nov 1, 2018, and Jan 31, 2020. 328 (20%) records were from countries in the very high HDI tier, 539 (33%) from countries in the high HDI tier, 614 (38%) from countries in the medium HDI tier, and 154 (9%) from countries in the low HDI tier. The median age was 35 years (IQR 24-51), with the oldest patients in the very high HDI tier (median 54 years, IQR 34-69) and the youngest in the low HDI tier (median 28 years, IQR 20-38). The most common procedures were elevation of a depressed skull fracture in the low HDI tier (69 [45%]), evacuation of a supratentorial extradural haematoma in the medium HDI tier (189 [31%]) and high HDI tier (173 [32%]), and evacuation of a supratentorial acute subdural haematoma in the very high HDI tier (155 [47%]). Median time from injury to surgery was 13 h (IQR 6-32). Overall mortality was 18% (299 of 1635). After adjustment for casemix, the odds of mortality were greater in the medium HDI tier (odds ratio [OR] 2·84, 95% CI 1·55-5·2) and high HDI tier (2·26, 1·23-4·15), but not the low HDI tier (1·66, 0·61-4·46), relative to the very high HDI tier. There was significant between-hospital variation in mortality (median OR 2·04, 95% CI 1·17-2·49).InterpretationPatients receiving emergency neurosurgery for TBI differed considerably in their admission characteristics and management across human development settings. Level of human development was associated with mortality. Substantial opportunities to improve care globally were identified, including reducing delays to surgery. Between-hospital variation in mortality suggests changes at an institutional level could influence outcome and comparative effectiveness research could identify best practices.FundingNational Institute for Health Research Global Health Research Group

An international, prospective observational study on traumatic brain injury epidemiology study protocol: GEO-TBI: Incidence [version 2; peer review: 2 approved]

Background The epidemiology of traumatic brain injury (TBI) is unclear – it is estimated to affect 27–69 million individuals yearly with the bulk of the TBI burden in low-to-middle income countries (LMICs). Research has highlighted significant between-hospital variability in TBI outcomes following emergency surgery, but the overall incidence and epidemiology of TBI remains unclear. To address this need, we established the Global Epidemiology and Outcomes following Traumatic Brain Injury (GEO-TBI) registry, enabling recording of all TBI cases requiring admission irrespective of surgical treatment. Objective The GEO-TBI: Incidence study aims to describe TBI epidemiology and outcomes according to development indices, and to highlight best practices to facilitate further comparative research. Design Multi-centre, international, registry-based, prospective cohort study. Subjects Any unit managing TBI and participating in the GEO-TBI registry will be eligible to join the study. Each unit will select a 90-day study period. All TBI patients meeting the registry inclusion criteria (neurosurgical/ICU admission or neurosurgical operation) during the selected study period will be included in the GEO-TBI: Incidence. Methods All units will form a study team, that will gain local approval, identify eligible patients and input data. Data will be collected via the secure registry platform and validated after collection. Identifiers may be collected if required for local utility in accordance with the GEO-TBI protocol. Data Data related to initial presentation, interventions and short-term outcomes will be collected in line with the GEO-TBI core dataset, developed following consensus from an iterative survey and feedback process. Patient demographics, injury details, timing and nature of interventions and post-injury care will be collected alongside associated complications. The primary outcome measures for the study will be the Glasgow Outcome at Discharge Scale (GODS) and 14-day mortality. Secondary outcome measures will be mortality and extended Glasgow Outcome Scale (GOSE) at the most recent follow-up timepoint

Case for transoral decompression of craniovertebral junction and C1 and odontoid for fixed atlanto axial dislocation and basilar invagination

Transoral decompression of the craniovertebral junction is an established and safe method. Lateral atlanto-axial joints may be distracted and then fused posteriorly in some cases. The decision should be individualized based on the imaging and clinical picture

A preliminary study of natural history of mild traumatic brain injury by using multidimensional approach

Background & objectives: Spectrum of post-traumatic symptoms is frequent among mild traumatic brain injury (mTBI) patients. They account for symptoms in 30-80 per cent of patients during 3-4 months and 20-30 per cent of patients six months post-injury. There are no studies from India in this area. The present longitudinal study was conducted to evaluate the natural recovery of post-traumatic symptoms in mTBI patients. Methods: Twenty five mTBI patients presenting with initial Glasgow coma scale score of 15 were recruited initially 2-3 wk post-injury. All patients were followed up twice, after 3-4 and 6-7 months. The patients were evaluated with neuropsychological test, post-traumatic symptoms and quality of life after injury. Results: Sustained attention and sensory registration were first to improve. Memory and executive domains improved partially until three months and then after complete recovery. However, a few facets of learning/memory did not improve even at six months. The post-traumatic symptoms decreased since baseline from 76 to 52 per cent at 3-4 months and further to 28 per cent at 6-7 months. The quality of life improved partially from baseline till 3-4 months and much more by 6-7 months. Interpretation & conclusions: The study findings showed the course of changes in cognition, traumatic symptoms and quality of life since the time of injury till 6-7 months post-injury. Though majority of post-traumatic symptoms recovered after mTBI without any intervention, but residuals were not uncommon

Sodium butyrate induces p53 dependent and independent cell death in human brain tumor cells in primary culture <em>in vitro</em>

747-755The anticancer effect of sodium butyrate (Na-Bu) has been demonstrated in many model systems. In this study, effect of Na-Bu on the survival of human brain tumor cells in primary culture was analyzed. A total of 20 glioblastoma multiforme (GBM), 15 astrocytomas, 15 meningiomas and 32 neurofibromatosis type 2 (NF2) tumor tissues were minced and cultured in primary cultures and the status of Fas, Bax, Bcl-2, p21 and p53 proteins were analyzed by western blotting after 48 h of Na-Bu exposure. Na-Bu treatment caused 75-80% cell death and it also increased the level of Fas protein in GBMs, astrocytomas, and meningiomas with mutant p53 but not with wild type p53. All the NF2 tumors had wild type p53, they had a trace level of Fas protein and Na-Bu exposure caused little change in Fas level. These data suggest that Na-Bu caused p53-dependent and p53-independent cell death in the brain tumors with wild type and mutant p53, respectively. All the Na-Bu treated samples had increased levels of pro-apoptotic Bax and anti-oncogenic p21 proteins, and decreased level of oncogenic, antiapoptotic Bcl-2 protein. These data indicate that the Na-Bu exposure caused cell death in these brain tumors due to apoptosis. Na-Bu could be developed as a therapeutic agent in the management of human brain tumors regardless of the p53 mutation status

The Role of Neurosurgery in Global Health Head Trauma

Twenty-seven million people are estimated to sustain a traumatic brain injury (TBI) every year. In this chapter, we first begin by considering the history of the diagnosis and treatment of TBI from trepanation in the Mesolithic period to seminal advances in the twentieth century such as CT scanning, ICP monitoring and the creation of the Glasgow Coma Score. Thereafter, we consider contemporary efforts to reduce morbidity and mortality due to TBI. Firstly, we review efforts to prevent TBI including helmet usage. We then consider the issues globally in the provision of adequate pre-hospital care, critical care, surgery and rehabilitation for this patient cohort. Throughout the chapter, we highlight specific issues faced in low-resource settings such as a lack of functional CT scanners and trained neurosurgeons. Moreover, we discuss innovative ways to provide high-quality care despite these challenges such as task sharing and the novel utilisation of existing technologies. Finally, we consider exciting new methodologies to improve care for these patients including precision medicine and systems science

Malignant nodular hidradenoma of scalp

Malignant nodular hidradenoma (MNH) is a rare tumor of sweat gland known by many names in the literature. Scalp is a known and yet uncommon site of occurrence. We describe two patients with scalp MNH with brain parenchymal invasion. Both tumors recurred in spite of total excision and radiotherapy