Systematic review of current randomised control trials in chronic subdural haematoma and proposal for an international collaborative approach.

BACKGROUND: Chronic subdural haematoma (CSDH) is a pathology that is frequently encountered by neurosurgeons. Nevertheless, there is a lack of guidelines based on solid evidence. There has been a recent and considerable increase in the interest on management and outcomes for CSDH. Therefore, we systematically reviewed all currently running randomised controlled trials (RCTs) in chronic subdural haematoma to understand the areas under investigation and plan future collaborative trials. METHODS: Clinical trials databases (Cochrane Controlled Register of Trials, WHO ICTRP and clinical trials.gov) were searched for trials relevant to chronic subdural haematoma. It was then established which trials were currently running and fulfilled robust research methodology for a RCT. RESULTS: There are 26 currently running RCTs in CSDH, with the most common topics covering application of steroids (7), surgical techniques (5) and tranexamic acid (5). Further to this, there are trials running on other pharmacological agents (4), middle meningeal artery (MMA) embolisation (2) and peri-operative management (3). CONCLUSIONS: Pharmacological agents are a particular focus of CSDH management currently, and a wealth of studies on steroids will hopefully lead to more harmonised, evidence-based practice regarding this in the near future. Surgical techniques and new procedures such as MMA embolisation are also important focuses for improving patient outcomes. There is an on-going need for future RCTs and evidence-based guidelines in CSDH, particularly including low- and middle-income countries, and it is hoped that the establishment of the iCORIC (International COllaborative Research Initiative on Chronic Subdural Haematoma) will help address this.

Neuroprotective hypothermia - Why keep your head cool during ischemia and reperfusion.

BACKGROUND: Targeted temperature management (TTM) is the induced cooling of the entire body or specific organs to help prevent ischemia and reperfusion (I/R) injury, as may occur during major surgery, cardiac resuscitation, traumatic brain injury and stroke. Ischemia and reperfusion induce neuronal damage by mitochondrial dysfunction and oxidative injury, ER stress, neuronal excitotoxicity, and a neuroinflammatory response, which may lead to activation of apoptosis pathways. SCOPE OF REVIEW: The aim of the current review is to discuss TTM targets that convey neuroprotection and to identify potential novel pharmacological intervention strategies for the prevention of cerebral ischemia and reperfusion injury. MAJOR CONCLUSIONS: TTM precludes I/R injury by reducing glutamate release and oxidative stress and inhibiting release of pro-inflammatory factors and thereby counteracts mitochondrial induced apoptosis, neuronal excitotoxicity, and neuroinflammation. Moreover, TTM promotes regulation of the unfolded protein response and induces SUMOylation and the production of cold shock proteins. These advantageous effects of TTM seem to depend on the clinical setting, as well as type and extent of the injury. Therefore, future aims should be to refine hypothermia management in order to optimize TTM utilization and to search for pharmacological agents mimicking the cellular effects of TTM. GENERAL SIGNIFICANCE: Bundling knowledge about TTM in the experimental, translational and clinical setting may result in better approaches for diminishing I/R damage. While application of TTM in the clinical setting has some disadvantages, targeting its putative protective pathways may be useful to prevent I/R injury and reduce neurological complications.

Dlxin-1, a member of MAGE family, inhibits cell proliferation, invasion and tumorigenicity of glioma stem cells.

We have previously reported the presence of Dlxin-1, a member of the melanoma antigen gene (MAGE) family, in the brain and showed its function as a cell cycle arrest protein, suggesting that Dlxin-1 may have anti-proliferative functions in rapidly growing tumors. Using the cancer stem cell hypothesis, which attributes the initiation and progression of brain tumors to the cancer-initiating stem cells, we have investigated the role of Dlxin-1 in the glioma stem cells propagated by us as a cell culture system comprising of HNGC-2 cells. Our studies provide evidence about the role of Dlxin-1 as an anti-tumorigenic protein in the highly chemo-resistant glioma stem cells. Next, we show that these anti-proliferative effects are manifested by Dlxin-1 through down regulation of the activities of MMP-2 and MMP-9, and through interaction of Dlxin-1 with its target protein P311 that is involved in glioma cell invasion. In summary, we establish the roles for Dlxin-1, one as an anti-tumorigenic and anti-invasive protein in high-grade gliomas and the other as an inducer of differentiation of glioma stem cells. These two attributes, in conjunction, result in conversion of the drug-resistant brain tumor stem cells to the tumor-attenuated cells that may now be more amenable to effective therapeutic targeting.