Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative condition. There are no effective treatments. The only globally licensed medication, that prolongs life by 2-3 months, was approved by the FDA in 1995. One reason for the absence of effective treatments is disease heterogeneity noting that ALS is clinically heterogeneous and can be considered to exist on a neuropathological spectrum with frontotemporal dementia. Despite this significant clinical heterogeneity, protein misfolding has been identified as a unifying pathological feature in these cases. Based on this shared pathophysiology, we carried out a systematic review and meta-analysis to assess the therapeutic efficacy of compounds that specifically target protein misfolding in preclinical studies of both ALS and FTD. Methods: Three databases: (i) PubMed, (ii) MEDLINE, and (iii) EMBASE were searched. All studies comparing the effect of treatments targeting protein misfolding in pre-clinical ALS or FTD models to a control group were retrieved. Results: Systematic review identified 70 pre-clinical studies investigating the effects of therapies targeting protein misfolding on survival. Meta-analysis revealed that targeting protein misfolding did significantly improve survival compared to untreated controls (p < 0.001, df = 68, α = 0.05, CI 1.05-1.16), with no evidence of heterogeneity between studies (I 2 = 0%). Further subgroup analyses, evaluating the effect of timing of these interventions, showed that, only treating prior to symptom onset (n = 33), significantly improved survival (p < 0.001, df = 31, α = 0.05, CI 1.08-1.29), although this likely reflects the inadequate sample size of later time points. Furthermore, arimoclomol was found to Elliott et al. Systematic-Review of Therapies Targeting Proteostasis significantly reduce secondary outcome measures including: (i) histological outcomes, (ii) behavioral outcomes, and (iii) biochemical outcomes (p < 0.005). Conclusions: This analysis supports the hypothesis that protein misfolding plays an important role in the pathogenesis of ALS and FTD and that targeting protein misfolding, at least in pre-clinical models, can significantly improve survival, especially if such an intervention is administered prior to symptom onset.
Critics contend that Aristotelianism demands too much of the virtuous person in the way of knowledge to be credible. This general charge is usually directed against either of two of Aristotelianism’s apparent claims about the necessary conditions for the possession of a single virtue, namely that 1) one must know what all the other virtues require, and 2) one must also be the master of a preternatural range of technical/empirical knowledge. I argue that Aristotelianism does indeed have a very high standard when it comes to the knowledge necessary for the full possession of a virtue, in both of these respects. However, focus on the necessary conditions for full virtue tends to obscure an important fact: some kinds of knowledge are much more important to various virtues than others are. A proper appreciation of the significance of this fact will go a long way toward answering critics’ worries about Aristotelianism’s knowledge requirements.
Empathy is a form of emotionally charged imaginative perspective‐taking. It is also the unique source of a particular form of understanding, which I will call humane understanding. Humane understanding consists in the direct apprehension of the intelligibility of others’ emotions. This apprehension is an epistemic good whose ethical significance is multifarious. In this paper, I focus on elaborating the sense in which humane understanding of others is non‐instrumentally valuable to its recipients. People have a complex but profound need to be humanely understood. Because we respond to others’ very real need when we pursue this sort of understanding of their emotions, empathy is best understood as itself a way of caring, rather than just a means to promote other caring behavior.
Our collective enthusiasm for empathy reflects a sense that it is deeply valuable. I show that empathy bears a complex and surprisingly problematic relation to another social epistemic phenomenon that we have reason to value, namely testimonial trust. My discussion focuses on empathy with and trust in people who are members of one or more oppressed groups. Empathy for oppressed people can be a powerful tool for engendering a certain form of testimonial trust, because there is a tight connection between empathy and a (limited) approval of another's outlook. I then argue that the qualities of empathy that make it such a powerful tool for bridging differences and building trust also have a problematic upshot: they make it the case that reliance on empathy will sometimes have a distorting effect upon the ways we extend testimonial trust.
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