Microstructural abnormalities in deep and superficial white matter in youths with mild traumatic brain injury

BACKGROUND: Diffusion Tensor Imaging (DTI) studies of traumatic brain injury (TBI) have focused on alterations in microstructural features of deep white matter fibers (DWM), though post-mortem studies have demonstrated that injured axons are often observed at the gray-white matter interface where superficial white matter fibers (SWM) mediate local connectivity. OBJECTIVES: To examine microstructural alterations in SWM and DWM in youths with a history of mild TBI and examine the relationship between white matter alterations and attention. METHODS: Using DTIDWM fractional anisotropy (FA) and SWM FA in youths with mild TBI (TBI, n=63) were compared to typically developing and psychopathology matched control groups (n=63 each). Following tract-based spatial statistics, SWM FA was assessed by applying a probabilistic tractography derived SWM mask, and DWM FA was captured with a white matter fiber tract mask. Voxel-wise z-score calculations were used to derive a count of voxels with abnormally high and low FA for each participant. Analyses examined DWM and SWM FA differences between TBI and control groups, the relationship between attention and DWM and SWM FA and the relative susceptibility of SWM compared to DWM FA to alterations associated with mild TBI. RESULTS: Case-based comparisons revealed more voxels with low FA and fewer voxels with high FA in SWM in youths with mild TBI compared to both control groups. Equivalent comparisons in DWM revealed a similar pattern of results, however, no group differences for low FA in DWM were found between mild TBI and the control group with matched psychopathology. Slower processing speed on the attention task was correlated with the number of voxels with low FA in SWM in youths with mild TBI. CONCLUSIONS: Within a sample of youths with a history of mild TBI, this study identified abnormalities in SWM microstructure associated with processing speed. The majority of DTI studies of TBI have focused on long-range DWM fiber tracts, often overlooking the SWM fiber type

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

CD4陽性T細胞に発現するA20(tnfaip3) はTh2型アレルギー性気道炎症を抑制する

研究科: 千葉大学大学院医学薬学府（先端医学薬学専攻）学位記番号: 千大院医薬博甲第医1412号博士（医学）千葉大学 = Chiba Universit

Premature white matter microstructure in female children with a history of concussion

Childhood concussion may interfere with neurodevelopment and influence cognition. Females are more likely to experience persistent symptoms after concussion, yet the sex-specific impact of concussion on brain microstructure in children is understudied. This study examined white matter and cortical microstructure, based on neurite density (ND) from diffusion-weighted MRI, in 9-to-10-year-old children in the Adolescent Brain Cognitive Development Study with (n = 336) and without (n = 7368) a history of concussion, and its relationship with cognitive performance. Multivariate regression was used to investigate relationships between ND and group, sex, and age in deep and superficial white matter, subcortical structures, and cortex. Partial least square correlation was performed to identify associations between ND and performance on NIH Toolbox tasks in children with concussion. All tissue types demonstrated higher ND with age, reflecting brain maturation. Group comparisons revealed higher ND in deep and superficial white matter in females with concussion. In female but not male children with concussion, there were significant associations between ND and performance on cognitive tests. These results demonstrate a greater long-term impact of childhood concussion on white matter microstructure in females compared to males that is associated with cognitive function. The increase in ND in females may reflect premature white matter maturation