66 research outputs found
Effectiveness of low level laser therapy (LLLT) in the treatment of lateral elbow tendinopathy (LET): an umbrella review
Purpose: The aim of this umbrella review is to determine the effectiveness of LLLT in the treatment of LET and to provide recommendations based on this evidence.
Methods: A comprehensive and systematic review was undertaken using Medline, EBSCO and EMBASE. Systematic reviews or meta-analysis were included if they compared Laser with at least one of the following: (i) placebo, (ii) no treatment, (iii) another treatment, conservative (physical therapy intervention or medical) or operative of LET. Principal outcomes included the assessment of short and long-term effect on functional status, pain, grip strength (pain-free or maximum) and a global measure (overall improvement).
Results: Seven papers met the inclusion criteria for the umbrella review, Five papers were of moderate and two of low methodological quality. All reviews reported benefits associated with laser therapy Vs other intervention or placebo, however the significance of the identified benefits differed between studies and reviews. No review reported negative effects of laser therapy or harm to patients. All reviews noted significant variance between included studies with 2 reviews citing statistically significant heterogeneity. It is essential to consider this in the interpretation of these data.
Conclusion: This umbrella review found poor results for the effectiveness of LLLT in the management of LET. Therefore, further research with well-designed RCTs is required to provide meaningful evidence on the effectiveness (absolute and relative) of LLLT for the management of LET
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Hippocampal and entorhinal cortex volume changes in Alzheimer's disease patients and mild cognitive impairment subjects.
Hippocampal and entorhinal cortex as scanned in Magnetic Resonance Imaging (MRI), are two of the most commonly used Regions of Interest (ROIs) for the assessment of Alzheimer’s disease (AD). Both structures are used for the classification between Normal Controls (NC), Mild Cognitive Impairment (MCI) and AD subjects and for the disease prognosis. The objective of this study was to evaluate how the volume of these two structures changes between the following groups: NC vs AD, NC vs MCI, MCI vs MCI converters (MCIc - subjects who had converted to AD within 48 months), and AD vs MCIc subjects. Both structures were significantly reduced in volume for MCIc and AD subjects compared to NC. For both MCI and MCIc groups, the atrophy rate was correlated for both structures. In AD subjects, entorhinal cortex was more affected by atrophy. In conclusion, structural MRI and volumetric measurements of the hippocampus and entorhinal cortex can be used as early signs for the assessment of AD, and this is in agreement with previous studies
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Corrigendum: Assessment of Alzheimer's Disease Based on Texture Analysis of the Entorhinal Cortex
[This corrects the article DOI: 10.3389/fnagi.2020.00176.]
Clinical practice recommendations on the management of perioperative cardiac arrest: A report from the PERIOPCA Consortium
Background: Perioperative cardiac arrest is a rare complication with an incidence of around 1 in 1400 cases, but it carries a high burden of mortality reaching up to 70% at 30 days. Despite its specificities, guidelines for treatment of perioperative cardiac arrest are lacking. Gathering the available literature may improve quality of care and outcome of patients. Methods: The PERIOPCA Task Force identified major clinical questions about the management of perioperative cardiac arrest and framed them into the therapy population [P], intervention [I], comparator [C], and outcome [O] (PICO) format. Systematic searches of PubMed, Embase, and the Cochrane Library for articles published until September 2020 were performed. Consensus-based treatment recommendations were created using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The strength of consensus among the Task Force members about the recommendations was assessed through a modified Delphi consensus process. Results: Twenty-two PICO questions were addressed, and the recommendations were validated in two Delphi rounds. A summary of evidence for each outcome is reported and accompanied by an overall assessment of the evidence to guide healthcare providers. Conclusions: The main limitations of our work lie in the scarcity of good quality evidence on this topic. Still, these recommendations provide a basis for decision making, as well as a guide for future research on perioperative cardiac arrest
Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia
Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice
Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation
Determination of permissible industrial pollution load at a municipal wastewater treatment plant
LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same
Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places
Fine-Mapping, Gene Expression and Splicing Analysis of the Disease Associated LRRK2 Locus
Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms
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