Defining the role of dexmedetomidine in the prevention of delirium in the intensive care unit (ICU)

Dexmedetomidine is a highly selective α2 agonist used as a sedative agent. It also provides anxiolysis and sympatholysis without significant respiratory compromise or delirium. We conducted a systematic review to examine whether sedation of patients in the intensive care unit (ICU) with dexmedetomidine was associated with a lower incidence of delirium as compared to other nondexmedetomidine sedation strategies. A search of PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews yielded only three trials from 1966 through April 2015 that met our predefined inclusion criteria and assessed dexmedetomidine and outcomes of delirium as their primary endpoint. The studies varied in regard to population, comparator sedation regimen, delirium outcome measure, and dexmedetomidine dosing. All trials are limited by design issues that limit our ability definitively to conclude that dexmedetomidine prevents delirium. Evidence does suggest that dexmedetomidine may allow for avoidance of deep sedation and use of benzodiazepines, factors both observed to increase the risk for developing delirium. Our assessment of currently published literature highlights the need for ongoing research to better delineate the role of dexmedetomidine for delirium prevention

Clinical effectiveness of baclofen for the treatment of alcohol dependence: A review

Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen’s role for the treatment of alcohol dependence

Vemurafenib and dabrafenib downregulates RIPK4 level

Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1) - a suppressor of the BRAF/MEK/ERK pathway - via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors

Thermal Evolution of the Proton Irradiated Structure in Tungsten–5 wt% Tantalum

We have monitored the thermal evolution of the proton irradiated structure of W–5 wt% Ta alloy by in-situ annealing in a transmission electron microscope at fusion reactor temperatures of 500–1300 °C. The interstitial-type a/2 dislocation loops emit self-interstitial atoms and glide to the free sample surface during the early stages of annealing. The resultant vacancy excess in the matrix originates vacancy-type a/2 dislocation loops that grow by loop and vacancy absorption in the temperature range of 600–900 °C. Voids form at 1000 °C, by either vacancy absorption or loop collapse, and grow progressively up to 1300 °C. Tantalum delays void formation by a vacancy-solute trapping mechanism

Ultrafine grained plates of Al-Mg-Si alloy obtained by Incremental Equal Channel Angular Pressing : microstructure and mechanical properties

In this study, an Al-Mg-Si alloy was processed using via Incremental Equal Channel Angular Pressing (I-ECAP) in order to obtain homogenous, ultrafine grained plates with low anisotropy of the mechanical properties. This was the first attempt to process an Al-Mg-Si alloy using this technique. Samples in the form of 3 mm-thick square plates were subjected to I-ECAP with the 90˚ rotation around the axis normal to the surface of the plate between passes. Samples were investigated first in their initial state, then after a single pass of I-ECAP and finally after four such passes. Analyses of the microstructure and mechanical properties demonstrated that the I-ECAP method can be successfully applied in Al-Mg-Si alloys. The average grain size decreased from 15 - 19 µm in the initial state to below 1 µm after four I-ECAP passes. The fraction of high angle grain boundaries in the sample subjected to four I-ECAP passes lay within 53-57 % depending on the examined plane. The mechanism of grain refinement in Al-Mg-Si alloy was found to be distinctly different from that in pure aluminium with the grain rotation being more prominent than the grain subdivision, which was attributed to lower stacking fault energy and the reduced mobility of dislocations in the alloy. The ultimate tensile strength increased more than twice, whereas the yield strength - more than threefold. Additionally, the plates processed by I-ECAP exhibited low anisotropy of mechanical properties (in plane and across the thickness) in comparison to other SPD processing methods, which makes them attractive for further processing and applications