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- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Johnson, Kara A., et al.
(författare)
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Basal Ganglia Pathways Associated With Therapeutic Pallidal Deep Brain Stimulation for Tourette Syndrome
- 2021
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Ingår i: Biological Psychiatry. - : Elsevier. - 2451-9022. ; 6:10, s. 961-972
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Tidskriftsartikel (refereegranskat)abstract
- Background: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients’ symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes.Methods: Retrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement.Results: The best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation.Conclusions: Differences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes.
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- Martinez-Ramirez, Daniel, et al.
(författare)
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Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome : The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry
- 2018
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 75:3, s. 353-359
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome.OBJECTIVE To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome.DESIGN, SETTING, AND PARTICIPANTS The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide.EXPOSURES Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]).MAIN OUTCOMES AND MEASURES Scores on the Yale Global Tic Severity Scale and adverse events.RESULTS The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P<.001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P <.001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P <.001). The overall adverse event rate was 35.4%(56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]).CONCLUSIONS AND RELEVANCE Deep brain stimulationwas associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.
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