Mechanisms and treatment of ischaemic stroke: insights from genetic associations

The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

Interesting trends in direct current electrical conductivity of chemical vapor deposited diamond sheets

Self-supported diamond sheets of the thickness ranging from 15 to 30 mum were prepared using hot filament chemical vapor deposition technique. The controlled variation of the deposition parameters resulted in the sheets with varying amount of nondiamond impurities. Routine characterization of the sheets was carried out using scanning electron microscopy, x-ray diffractometry, Raman spectroscopy, Fourier transform infrared spectroscopy, and Positron annihilation spectroscopy techniques. Detailed measurements of room temperature electrical conductivity (sigma (300)), current-voltage (I-V) characteristics, and annealing studies on the sheets deposited with various structural disorder have yielded useful information about the electrical conduction in this interesting material. sigma (300) and I-V characteristic measurements were done in sandwiched configuration taking care off the surface effects. The diamond sheets deposited at low deposition pressure (P-d1, in high voltage range. In contrast the sheets deposited at higher pressure (60 Torr and higher), containing high concentration of nondiamond impurities, show a sharp reduction in the values of sigma (300). Interestingly, the conduction in these sheets is ohmic with n values nearly equal to unity. Similarly the sheets deposited with nitrogen also show a sharp reduction in sigma (300). Annealing of all types of diamond sheets results in a decrease in sigma (300) values by several orders of magnitude. In the sheets deposited at low P-d, the n values increase sharply with annealing. On the other hand the values of n in the sheets deposited at higher pressure remain constant with annealing. The above results are explained in terms of hydrogen abstraction from the traps and compensation of donor-acceptor pairs. (C) 200

Effect of heavy ion irradiation on self-supported diamond sheets

The self-supported diamond sheets were deposited at various deposition pressure (Pd) using HFCVD technique. The sheets were characterized using X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM). XRD shows the growth of cubic diamond. This is confirmed by Raman spectroscopy showing a sharp line at 1332 cm−1 in all the sheets. The sheets deposited at low pressures show clean sharp facets. The sheets were irradiated with high energy Au and Ag ions of varying energy and dose. The energy range was 100–120 MeV and the dose varied between 1×1012 and 3×1013 ions. Raman spectra showed the reduction in the intensity of diamond line (1332 cm−1) as well as non-diamond band at 1550 cm−1 after irradiation. SEM images of irradiated sheets show a phase transformation on the surface of the crystal. A photoluminescence (PL) signal is observed after the irradiation of the sheets at 2.634 eV.© Elsevie