Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson's disease and Multiple System Atrophy.

Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson′s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Identification, Functional Analysis and Preliminary Validation of Differentially Expressed Genes in Hyperacute Cerebral Infarction Patients

Background/AimsAt present, most studies on ischemic stroke and micro RNA are focused on 24h after stroke. Therefore, our experiment intends to analyze the differentially expressed genes in hyperacute cerebral infarction patients, and to analyze the relationship between the most significantly differentially expressed miRNA and clinical characteristics. MethodsDownload miRNA expression microarray and gene expression microarray from GEO database, screen differentially expressed genes and miRNA by bioinformatics method, and analyze their biological functions. The peripheral plasma of patients with hyperacute stroke was collected, the related miRNAs were extracted, and the relationship between them and clinical characteristics was analyzed. ResultsThe microarray included 39 hyperacute cerebral infarction patients patients and 33 healthy volunteers and 5 differentially expressed miRNAs and 1107 differentially expressed genes were obtained by analysis. MiR-3156-5p was selected to further analyze and verify the correlation with the clinical characteristics of patients. The results showed that the expression level of miR-3156-5p was significantly positively correlated with triglyceride level, and had a significant negative impact on stroke. The low level of miR-3156-5p in hyperacute cerebral infarction patients may be one of the initiating factors of neuroinflammation induced by ischemic stroke, and functional analysis and some existing experimental results also support this view. ConclusionsIn our study, a series of differentially expressed genes and differentially expressed miRNAs were screened by analyzing GEO data sets. In addition, the low expression of miR-3156-5p in hyperacute cerebral infarction patients may be one of the initiating factors of neuroinflammation induced by ischemic stroke.

Leptin Induced TLR4 Expression via the JAK2-STAT3 Pathway in Obesity-Related Osteoarthritis

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.

Medical device error and failure reporting: Learning from the car industry

Background Improving the design of technology relies in part, on the reporting of performance failures in existing devices. Healthcare has low levels of formal reporting of performance and failure of medical equipment. This paper examines methods of reporting in the car industry and healthcare and aims to understand differences and identify opportunities for improvement within healthcare. Methods A literature search was carried out in Pubmed, Medline, Embase, Engineering Village, Scopus. NHS England and MHRA publications and guidelines were also reviewed. Focus was placed on the current system of reporting in both industries, known degree of patient harm, initiating factors, barriers, quality and methods of incident investigation and their validity. The findings were used to compare error reporting system in the two industries. Results Derivation of healthcare incident data from different sources means the full extent of patient harm is not known. For example, in 2012 there were 13,549 and 38,395 incidents reported by MHRA and NRLS (National Reporting and Learning System) respectively leading to uncertainties on the extent of the problem. The car industry emphasises the role of reporting source in ensuring data quality. Utilising some aspects of this approach might benefit healthcare reporting. These include a specific reporting system that stresses the importance of organisational learning in improving safety and recognises the limitations of root cause analysis. Conclusions Learning from reporting systems within the car industry may help the healthcare sector improve its own reporting, aiding healthcare performance.

Cranial Mandibular Fibrosis Syndrome in Adult Farmed Rainbow Trout Oncorhynchus mykiss

An unusual condition affecting market size rainbow trout was investigated. This condition was prevalent for several years at low levels but affected a large proportion of stock during 2018 and 2019. Chronic fibrosis affecting cranial tissues and the jaw was observed in samples collected in 2018. A larger sampling was then conducted in 2019 to investigate the presence of an infectious agent(s). An extensive inflammatory response in the mandibular region was the main finding, however infectious agents in the lesions were not identified through classical virology and bacteriology analysis. Tetracapsuloides bryosalmonae infection, calcinosis, and a Gram-positive bacterial infection of a single fish cardiac tissue was observed, however, a correlation of these pathologies and the cranial mandibular fibrosis (CMF) syndrome was not established. The gene expression of a panel of 16 immune-related genes was studied. Among these, tgf-b, sIgM, il11, hspa, and the antimicrobial peptides lys and cath1 were up-regulated in jaw sections of CMF-affected fish, showing a strong positive correlation with the severity of the lesions. Idiopathic chronic fibrosis with the activation of the Tfg-B pathway and local hyper-immunoglobulaemia was therefore diagnosed. Initiating factors and causative agent(s) (biotic or abiotic) of CMF remain, at present, unclear.

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.

Acute Pancreatitis: Genetic Risk and Clinical Implications

Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%–30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Complex gene–environment interactions have been identified to play a role in the pathogenesis of pancreatitis, but so far no predictive genetic biomarkers could be implemented into the routine clinical care of AP patients. The current review explains common and rare etiologies of acute pancreatitis with emphasis on underlying genetic aberrations and ensuing clinical management.

INITIATING FACTORS OF COMPLICATIONS DEVELOPMENT DURING PROSTHETICS OF TEETH WITH FIXED PROSTHESES

The aim: Determination of the factors complications occurrence in prosthetics with metal-ceramic prostheses. Materials andmethods: Clinical, cytological, cytochemical methods and methods of statistical processing of the received data are applied. Results: A number of factors with different degrees of significance have been identified, which in the dynamics of clinical observations of the percentage of absorbed dispersion are decisive in the development of changes in the gums. At the stage of odontopreparation – the 1 factor, with the percentage of absorbed dispersion (12,3%) – preparation. The 2 factor – (11,9%) – traumatic. The 3 factor, periodontal, was slightly less significant (9,8%). In the dynamics of clinical observations for 45 days in the first place was the dissecting factor – (14%). The second most important factor was the vitality of the teeth – (11,5%). The 3 factor remained relatively stable – periodontal (8,5%). In the dynamics of clinical observations after 1 year, a redistribution of significance was noted. The largest percentage of absorbed dispersion covered periodontal factor – (15%). Vitality factor – (11%). Slightly lower, but clinically significant, of (8%) absorbed dispersion, was the preparation factor. Conclusions: Statistical analysis of the studied parameters made it possible to determine the key factors for predicting their development and diagnostics, it is important for organizing an increase in the effectiveness of orthopedic prophylactic therapeutic measures at the stages of restoration of dental hard tissues.