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Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB. [ABSTRACT FROM AUTHOR]

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo . Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties. [ABSTRACT FROM AUTHOR]

The reliability of a post-IR elevated temperature IRSL (290 °C; pIRIR 290 ) is tested on wind-blown, sand-sized (180–250 μm) K-rich feldspar grains. The pIRIR 290 ages were compared with quartz SAR-OSL data, other independent age controls and historical information. Three study areas along the coast of Sardinia (Italy) were selected: the south Alghero coast, the Bue Marino cave (E Sardinia) and the Alghero bay (NW Sardinia). Along the south Alghero coastline a thick dunefield system is widely recognised in the literature to represent the beginning of the last glacial phase ( post 80 ka). From a single block sand-sized grains for quartz SAR-OSL and K-feldspar pIRIR dating were collected. The natural quartz SAR-OSL sample lies below the saturation limit of the dose response curve (D e < 2xD 0 ) giving a reliable age of 76 ± 6 ka. The fading-uncorrected pIRIR 290 age of 73 ± 5 ka is in good agreement with the quartz result. A further test on older samples was carried out on the sedimentary succession at Bue Marino cave, which includes a sandy wind-blown unit, enclosed between two calcareous crusts. U-series dates of crusts constrain the aeolianite formation between ∼130 and ∼86 ka. The quartz SAR-OSL signals for aeolianite samples lies close to saturation and the resulting ages underestimate the independent age control. Instead, uncorrected pIRIR 290 ages on K-feldspar extracts point to a formation of the wind-blown unit between ∼100 and ∼80 ka, in good agreement with the U-series data. The bleachability of the pIRIR 290 signal was further investigated using samples from a modern coastal barrier system backing the Alghero bay. The dunefield was stabilized by plantation during the 1950s. The quartz SAR-OSL ages span from 2450 ± 170 years to 60 ± 13 years ago, consistent with the known coastal barrier stabilization. The pIRIR 290 ages indicate an offset up to ∼1000 years. We can conclude that the pIRIR 290 method on sand-sized K-feldspar grains shows great promise for samples at or beyond the quartz OSL age limit but should not be applied to Late Holocene or modern deposits. [ABSTRACT FROM AUTHOR]

Changes in the structure and function of inhibitory GABAA receptors may contribute to epileptogenesis. We have used the in situ hybridization technique to study GABAA receptor α2, α4, β3 and γ2 subunit mRNA expression in the hippocampus of spontaneously seizing rats with chronic temporal lobe epilepsy. In control rats, all four subunit mRNAs were expressed in the hippocampal subregions but the intensity of expression varied significantly between the subfields. In epileptic rats, α2 expression was decreased in CA3c, and α4 in CA1, but β3 was increased in all subregions, in particular in the granule cell layer. Our results suggest that GABAA receptor undergoes region selective subunit changes during epileptogenesis in the hippocampus of rats with chronic temporal lobe epilepsy. [Copyright &y& Elsevier]