Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system

Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R squared for CSD-PROB (AUC=0.812; R squared=0.282) and JHU-TBSS (AUC=0.756; R squared=0.262), compared to CON-PROB (AUC=0.742; R squared=0.179) and JUEL-TBSS (AUC=0.719; R squared=0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC=0.796; R squared=0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question

Nietzsche’s meta-axiology: against the skeptical readings

In this paper, I treat the question of the meta-axiological standing of Nietzsche's own values, in the service of which he criticizes morality. Does Nietzsche, I ask, regard his perfectionistic valorization of human excellence and cultural flourishing over other ideals to have genuine evaluative standing, in the sense of being correct, or at least adequate to a matter-of-fact? My goal in this paper is modest, but important: it is not to attribute to Nietzsche some sophisticated meta-axiological view, because I am doubtful that he has one. It is, however, to show that Nietzsche's texts do not necessitate the sceptical meta-axiological positions that have been attributed to him in the recent secondary literature. And it is thereby to suggest that we need not give up on the idea that Nietzsche takes the values he champions to have genuine evaluative standing – not because he has some sophisticated realist theory to this effect, but in a more philosophically unreflective way

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates

Gender injustice in compensating injury to autonomy in English and Singaporean negligence law

The extent to which English law remedies injury to autonomy (ITA) as a stand-alone actionable damage in negligence is disputed. In this article I argue that the remedy available is not only partial and inconsistent (Keren-Paz in Med Law Rev, 2018) but also gendered and discriminatory against women. I first situate the argument within the broader feminist critique of tort law as failing to appropriately remedy gendered harms, and of law more broadly as undervaluing women’s interest in reproductive autonomy. I then show by reference to English remedies law’s first principles how imposed motherhood cases—Rees v Darlington and its predecessor McFarlane v Tayside Health Board—result in gender injustice when compared with other autonomy cases such as Chester v Afshar and Yearworth v North Bristol NHS Trust: A minor gender-neutral ITA is better remedied than the significant gendered harm of imposing motherhood on the claimant; men’s reproductive autonomy is protected to a greater extent than women’s; women’s reproductive autonomy is protected by an exceptional, derisory award. Worst of all, courts refuse to recognise imposed motherhood as detriment; and the deemed, mansplained, nonpecuniary joys of motherhood are used to offset pecuniary upkeep costs, forcing the claimant into a position she sought to avoid and thus further undermining her autonomy. The recent Singaporean case ACB v Thomson Medical Pte Ltd, awarding compensation for undermining the claimant’s genetic affinity in an IVF wrong-sperm-mix-up demonstrates some improvement in comparison to English law, and some shared gender injustices in the context of reproductive autonomy. ACB’s analysis is oblivious to the nature of reproductive autonomy harm as gendered; and prioritises the father’s interest in having genetic affinity with the baby over a woman’s interest in not having motherhood imposed upon her

Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage

Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family

Sex, age, and surgeon decision on nephron-sparing surgery are independent predictors of renal masses with benign histologic findings--a multicenter survey.

International audienceOBJECTIVES: To define the preoperative independent predictors indicating that renal mass has benign histologic features. METHODS: A total of 1664 patients with Stage T1-T2N0M0 with a unilateral renal mass underwent nephrectomy. The endpoint at multivariate analysis was benign versus malignant histologic features. RESULTS: The surgical approach (odds ratio [OR] 2.9, P = .0001), sex (OR 1.97, P = .0001), and age (OR 1.01, P = .007) were independent predictors for the malignant-benign distinction. Malignant tumors were more likely to occur in men (878 of 1009, 87%) versus women (515 of 651, 79%; P <.001). A weak relationship was found between an increasing tumor size and malignancy risk in men only. High-grade renal cell carcinoma was more prevalent in men (31% versus 21%, P = .001). The histologic tumor types were distributed differently between the 2 sexes: 8% papillary renal cell carcinoma in women versus 16% in men, 86% and 78% clear cell renal cell carcinoma, 33% and 57% oncocytoma, and 40% versus 12% angiomyolipoma, respectively. The physician's preoperative judgment regarding tumor amenability for nephron-sparing surgery resulted in patient selection: 10% benign tumors for radical nephrectomy versus 25% for partial nephrectomy (P = .001) and 31% versus 20% high-grade tumors, respectively (P = .0001). CONCLUSIONS: Renal tumors were consistently benign in 20% of women, regardless of size. In contrast, in men, the malignancy risk increased slightly with tumor size. The surgeons' preoperative decision regarding nephron-sparing surgery caused a selection bias in favor of benign lesions, regardless of sex. Our findings support the possibility of basing treatment decisions on the preoperative biopsy findings. Such changes could alter current practice and limit treatment of histologically proven benign lesions to surveillance or ablation only