Reversal of pathological pain through specific spinal GABAA receptor subtypes

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.     

Synthesis of titanium oxycarbonitride by carbothermal reduction and nitridation of ilmenite with recycling of polyethylene terephthalate (PET)

An innovative and sustainable carbothermal reduction and nitridation (CTRN) process of ilmenite (FeTiO₃) using a mixture of polyethylene terephthalate (PET) and coal as the primary reductant under an H₂-N₂ atmosphere was proposed.The use of PET as an alternative source of carbon not only enhances the porosity of the pellets but also results in the separation of Fe from titanium oxycarbonitride (TiO_xC_yN_z) particles because of the differences in surface tension.The experiments were carried out at 1250℃ for 3 h using four different PET contents ranging from 25wt% to 100wt% in the reductant.X-ray diffraction (XRD),scanning electron microscopy (SEM) in conjunction with energy-dispersive X-ray spectroscopy (EDX),and LECO elemental analysis were used to study the phases and microstructures of the reduced samples.In the case of 75wt% PET,iron distinctly separated from the synthesized TiO_xC_yN_z phase.With increasing PET content in the sample,the reduction and nitridation rates substantially increased.The synthesis of an oxycarbonitride with stoichiometry of TiO_0.02C_0.13N_0.85 with minimal intermediate titanium sub-oxides was achieved.The results also showed that the iron particles formed from CTRN of FeTiO₃ exhibited a spherical morphology,which is conducive for Fe removal via the Becher process.     

A single-nucleotide polymorphism tagging set for human drug metabolism and transport

Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.