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Coronavirus disease 2019 (COVID-19) can lead to acute organ dysfunction, and delirium is associated with long-term cognitive impairment and a prolonged hospital stay. This retrospective single-center study aimed to investigate the risk factors for delirium in patients with COVID-19 infection receiving treatment in an intensive care unit (ICU). A total of 111 patients aged >18 years with COVID-19 pneumonia who required oxygen therapy from February 2021 to April 2022 were included. Data on patient demographics, past medical history, disease severity, delirium, and treatment strategies during hospitalization were obtained from electronic health records. Patient characteristics and risk factors for delirium were analyzed. Old age (P < 0.001), hypertension (P < 0.001), disease severity (Sequential Organ Failure Assessment score) (P < 0.001), mechanical ventilator support (P < 0.001), neuromuscular blocker use (P < 0.001), and length of stay in the ICU (P < 0.001) showed statistically significant differences on the univariable analysis. Multivariable analysis with backward selection revealed that old age (odds ratio, 1.149; 95% confidence interval, 1.037-1.273; P = 0.008), hypertension (odds ratio, 8.651; 95% confidence interval, 1.322-56.163; P = 0.024), mechanical ventilator support (odds ratio, 226.215; 95% confidence interval, 15.780-3243.330; P < 0.001), and length of stay in the ICU (odds ratio, 30.295; 95% confidence interval, 2.539-361.406; P = 0.007) were significant risk factors for delirium. In conclusion, old age, ICU stay, hypertension, mechanical ventilator support, and neuromuscular blocker use were predictive factors for delirium in COVID-19 patients in the ICU. The study findings suggest the need for predicting the occurrence of delirium in advance and preventing and treating delirium.

Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVB/N-Trp53em2Hwl/Korl (FVB-Trp53+/-) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53+/- mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mg/kg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53+/- and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53+/- mice compared to the wild-type mice in the 50 and 75 mg/kg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mg/kg groups was 54.2 and 59.1% in FVB-Trp53+/- male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53+/- male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53+/- mice of the 25, 50, and 75 mg/kg groups, respectively. The main tumor types in FVB-Trp53+/- mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mg/kg.

Background Guidelines have recommended monitoring mean arterial pressure (MAP) and systolic arterial pressure (SAP) in cardiac arrest patients, but there has been relatively little regard for diastolic arterial pressure (DAP) and heart rate (HR). We aimed to determine the prognostic significance of hemodynamic parameters at all time points during targeted temperature management (TTM). Methods We reviewed the SAP, DAP, MAP, and HR data in out-of-hospital cardiac arrest (OHCA) survivors from the prospective multicenter registry of 22 teaching hospitals. This study included 1371 patients who underwent TTM among 10,258 cardiac arrest patients. The hemodynamic parameters were recorded every 6 hours from the return of spontaneous circulation (ROSC) to 4 days. The risks of those according to time points during TTM were compared. Results Of the included patients, 943 (68.8%) had poor neurological outcomes. The predictive ability of DAP surpassed that of SAP and MAP at all time points, and among the hemodynamic variables HR/DAP was the best predictor of the poor outcome. The risks in patients with DAP < 55 to 70 mmHg and HR > 70 to 100 beats/min were steeply increased for 2 days after ROSC and correlated with the poor outcome at all time points. Bradycardia showed lower risks only at 6 hours to 24 hours after ROSC. Conclusion Hemodynamic parameters should be intensively monitored especially for 2 days after ROSC because cardiac arrest patients may be vulnerable to hemodynamic instability during TTM. Monitoring HR/DAP can help access the risks in cardiac arrest patients.

BackgroundThe early prediction of significant coronary artery lesion, including coronary vasospasm, have yet to be studied. It is essential to discern the disorders with significant coronary lesions (SCDs) requiring coronary angiography from mimicking disease. We aimed to determine which of all clinical variables were more important using conventional logistic regression (cLR) and machine learning (ML).MaterialsOf 3382 patients with chest pain/discomfort or dyspnea in whom CAG was performed, 1893 were included. All clinical data were divided as follows (i): Demographics, history, and physical examination; (ii): (i) plus electrocardiography; and (iii): (ii) plus echocardiography, and analyzed by cLR and ML.ResultsIn multivariable analysis via cLR, the AUC and accuracy of the model using the final 20 variables were 0.795 and 72.62%, respectively. In multivariable analysis via ML, the best AUCs in the internal validation were 0.8 with (i), 0.81 with (ii), 0.83 with (iii), and in external validation, the best AUCs were 0.71 with (i), 0.74 with (ii), and 0.79 with (iii). The best AUCs and accuracy of the fittest model including 21 importance variables by ML were 0.81 and 72.48% in internal validation; and 0.75 and 70.5% in external validation, respectively. The importance variables in ML and cLR were similar, but slightly different and the additional discriminators via ML were found.ConclusionThe assessment using the fittest importance variables can assist physicians in differentiating mimicking diseases in which coronary angiography may not be required in patients suspected of having acute coronary syndrome in emergency department.

Periodontal disease is one of the most common disorders in the oral cavity of dogs and humans. Periodontitis, the irreversible periodontal disease, arises progressively from gingivitis, the reversible inflammatory condition caused by dental plaque. Although the etiology of periodontitis has been widely studied in humans, it is still insufficient for the etiological studies on periodontitis in dogs. Many studies have reported that human periodontitis-related bacteria are putative pathogens responsible for periodontitis in dogs. However, most of these studies have focused on the appearance of a specific microbiome, and most of the cohort studies have insufficient sample sizes to generalize their results. In the present study, subgingival samples collected from 336 teeth were categorized into three groups at first, based on clinical outcomes (healthy, gingivitis, periodontitis). Subsequently, the periodontitis samples were further divided into three subgroups (early, moderate, and advanced periodontitis) according to the degree of periodontal attachment loss. Healthy and gingivitis were grouped as a reversible group, and the three subgroups were grouped as an irreversible group. To investigate trends of periodontopathic bacteria in the samples of dogs, a quantitative real-time polymerase chain reaction (PCR) was performed for quantification of 11 human periodontopathic bacteria as follows: Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythia, Treponema denticola (Td), Fusobacterium nucleatum, Prevotella nigrescens, Prevotella intermedia, Parvimonas micra, Eubacterium nodatum, Campylobacter rectus, and Eikenella corrodens. The PCR results showed that Aa and Pg, the representative periodontopathic bacteria, were not significantly correlated or associated with the periodontitis cases in dogs. However, interestingly, Td was strongly associated with the irreversible periodontal disease in dogs, in that it was the most prevalent bacterium detected from the dog samples. These findings indicate that the presence and numbers of Td could be used as a prognostic biomarker in predicting the irreversible periodontal disease and the disease severity in dogs.

This study aimed to evaluate image quality, the detection rate of enlarged lymph nodes, and radiation dose exposure of ultralow-dose and low-dose abdominopelvic computed tomography (CT) in patients with lymphoma. Patients with lymphoma who underwent abdominopelvic CT using dual-source scanner were retrospectively recruited from a single center. CT images were obtained at 90 kVp dual-source mode reformatted in three data sets using the advanced modelled iterative reconstruction algorithm: 100% (standard-dose CT), 66.7% (low-dose CT), and 33.3% (ultralow-dose CT). Two radiologists analyzed subjective image quality and detection of abdominal enlarged lymph nodes on ultralow-dose, low-dose, and standard-dose CT blindly and independently. The results were compared with reference standards. Three readers (two radiologists and one hematologist) reviewed overall image quality and spleen size. In total, 128 consecutive CT scans (77 complete response, 44 partial response, 6 progressive disease, and 1 initial evaluation) from 86 patients (64 B-cell lymphoma, 14 T/NK-cell lymphoma, and 8 Hodgkin's lymphoma cases) were assessed. The enlarged lymph node-based detection rates for two readers were 97.0% (96/99) and 94.0% (93/99) on standard-dose CT, 97.0% (96/99) and 94.0% (93/99) on low-dose CT, and 94.0% (93/99) and 89.9% (89/99) on ultralow-dose CT. Overall image quality was 3.8 ± 0.5, 3.9 ± 0.5, and 4.1 ± 0.5 on ultralow-dose CT; 4.7 ± 0.4, 4.6 ± 0.5, and 4.8 ± 0.3 on low-dose CT; and 4.8 ± 0.4, 4.7 ± 0.4, and 4.9 ± 0.2 on standard-dose CT, according to two radiologists and one hematologist, respectively. Intraclass correlation coefficients of spleen size were 0.90 (95% confidence interval [CI], 0.87-0.93), 0.91 (95% CI, 0.88-0.93), and 0.91 (95% CI, 0.88-0.93) on ultralow-dose, low-dose, and standard-dose CT, respectively. Mean effective radiation doses of standard-dose, low-dose, and ultralow-dose CT were 5.7 ±1.8 mSv, 3.8 ± 1.2 mSv, and 1.9 ± 0.6 mSv, respectively. Our findings suggest that ultralow-dose and low-dose CT, even with radiation doses reduced by 66.7% and 33.3%, respectively, maintained adequate image quality. These imaging modalities may be employed for follow-up lymphoma evaluation in consideration of the long surveillance periods.

PurposeWe evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival.Patients and methodsBetween 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed.ResultsThe median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS.ConclusionsFor older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.

PurposeStereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.Patients and methodsWe retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.ResultsA total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.ConclusionsLAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.

We investigated the relationship between 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT) standardized uptake value (SUV) and 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer.One hundred sixty-seven patients were identified among those who underwent preoperative 18F-FDG-PET-CT and had RS. Maximum SUV was obtained from 18F-FDG-PET-CT; the cut-off point was 4.The continuous RS and SUV correlated positively (Pearson's R = 0.555; P < 0.001). An inverse correlation was found between progesterone receptor (PR) expression by reverse transcriptase-polymerase chain reaction, and SUV (Pearson's R = -0.408; P < 0.001). Good agreement between dichotomized RS (

The aim of this study was to appraise the value of laparoscopic distal pancreatectomy (LDP) for left-sided pancreatic cancer based on a large volume cohort study.We reviewed data for all consecutive patients undergoing LDP for left-sided pancreatic cancer at Asan Medical Center (Seoul, Korea) between December 2006 and December 2014.A total of 91 male and 61 female patients, with a median age of 62.7 years were included in this study. The median operative duration was 234 minutes. Pathological reports revealed the following: a median tumor size of 3.0 cm (range, 0.4-10.0), T stages (T1 in 7.9%, T2 in 5.3%, T3 in 86.8%, and no T4), the tumor differentiation (well differentiated in 16.4%, moderately differentiated in 75.4%, and poorly differentiated in 8.2%), and R0 resection in 126 patients (82.9%). After pancreatectomy, 96 patients (63.2%) received adjuvant chemotherapy, and the median time to chemotherapy was 30 days. The median length of hospital stay was 8 days (range, 5-31), and the median time to diet resumption was 1 day. Grade B or C postoperative pancreatic fistula occurred in 14 patients (9.2%) and grade II or III complications occurred in 27 (17.7%). The median overall survival was 43.0 months. A Cox proportional hazards model showed that tumor size, N1 stage, combined resection, and incompleteness of planned adjuvant chemotherapy affect patient survival.LDP for left-sided pancreatic cancer is reasonable within selected indications. An international consensus on laparoscopic surgery for pancreatic cancer would be desirable and timely.

Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06-2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06-2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment.

Currently ketamine is not used often as an analgesic in the emergency department (ED). Nonetheless, it can increase the efficiency of opioids and decrease their side effects. The purpose of this systematic review and meta-analysis was to evaluate whether low-dose ketamine in the ED provides better analgesia with fewer adverse effects.The PubMed, EMBASE, and Cochrane Library databases were searched by two reviewers independently (last search performed on January 2016). Data were also extracted independently.A total of 6 trials involving 438 patients were included in the current analysis. Our subgroup analysis of pain reduction indicates that the favorable effects of ketamine were similar or superior to those of placebo or opioids, although these effects were heterogeneous. However, low-dose ketamine was associated with a higher risk of neurological (relative risk [RR] = 2.17, 95% confidence interval [CI] = 1.37-3.42, P < 0.001) and psychological events (RR = 13.86, 95% CI = 4.85-39.58, P < 0.001). In contrast, the opioid group had a higher risk of major cardiopulmonary events (RR = 0.22, 95% CI = 0.05-1.01, P = 0.05).The efficiency of ketamine varies depending on the pain site, but low-dose ketamine may be a key agent for pain control in the ED, as it has no side effects. It may also help to reduce the side effects of opioids.

Complications associated with the use of bisphosphonate (BP) have risen over the years due to an increase in the prescription of BP. BP-related osteonecrosis of jaw (BRONJ), one of the complications linked to the consumption of BP, greatly affects patients with minor dental trauma, incurring a long healing period. While BRONJ afflicts only a minority of patients prescribed with BP, BRONJ is a multigenic disease affected both by environmental and genetic factors having a distinctive phenotype. This study aims to discover genetic biomarkers associated with BRONJ via whole exome sequencing (WES) followed by statistical analysis. Sixteen individuals who had been prescribed with bisphosphonate medication and diagnosed as BRONJ were chosen and each individual's saliva sample was collected for WES. 126 randomized subsamples from the GSK project representing 109 male and 17 female Koreans were used as a control data set. Fisher's exact test was carried out to assess the significance of genetic variants in BRONJ patients. Gene set enrichment analysis (GSEA) (DAVID Bioinformatics Resource 6.7) was used to perform a cluster analysis of variants found from Fisher's exact test. The results from this study suggest that BRONJ-inducing factors are genetically associated and BRONJ occurs due to the malfunctioning of post-translational modification in osteoclast leading to the impairment of cell morphology and adhesion.

The noninvasive imaging of dendritic cells (DCs) migrated into lymph nodes (LNs) can provide helpful information on designing DCs-based immunotherapeutic strategies. This study is to investigate the influence of transduction of human ferritin heavy chain (FTH) and green fluorescence protein (GFP) genes on inherent properties of DCs, and the feasibility of FTH as a magnetic resonance imaging (MRI) reporter gene to track DCs migration into LNs. FTH-DCs were established by the introduction of FTH and GFP genes into the DC cell line (DC2.4) using lentivirus. The changes in the rate of MRI signal decay (R2*) resulting from FTH transduction were analyzed in cell phantoms as well as popliteal LN of mice after subcutaneous injection of those cells into hind limb foot pad by using a multiple gradient echo sequence on a 9.4 T MR scanner. The transduction of FTH and GFP did not influence the proliferation and migration abilities of DCs. The expression of co-stimulatory molecules (CD40, CD80 and CD86) in FTH-DCs was similar to that of DCs. FTH-DCs exhibited increased iron storage capacity, and displayed a significantly higher transverse relaxation rate (R2*) as compared to DCs in phantom. LNs with FTH-DCs exhibited negative contrast, leading to a high R2* in both in vivo and ex vivo T2*-weighted images compared to DCs. On histological analysis FTH-DCs migrated to the subcapsular sinus and the T cell zone of LN, where they highly expressed CD25 to bind and stimulate T cells. Our study addresses the feasibility of FTH as an MRI reporter gene to track DCs migration into LNs without alteration of their inherent properties. This study suggests that FTH-based MRI could be a useful technique to longitudinally monitor DCs and evaluate the therapeutic efficacy of DC-based vaccines.

Peri-implantitis is a frequently occurring gum disease linked to multi-factorial traits with various environmental and genetic causalities and no known concrete pathogenesis. The varying severity of peri-implantitis among patients with relatively similar environments suggests a genetic aspect which needs to be investigated to understand and regulate the pathogenesis of the disease. Six unrelated individuals with multiple clusterization implant failure due to severe peri-implantitis were chosen for this study. These six individuals had relatively healthy lifestyles, with minimal environmental causalities affecting peri-implantitis. Research was undertaken to investigate pathogenic genes in peri-implantitis albeit with a small number of subjects and incomplete elimination of environmental causalities. Whole-exome sequencing was performed on collected saliva samples via self DNA collection kit. Common variants with minor allele frequencies (MAF) > = 0.05 from all control datasets were eliminated and variants having high and moderate impact and loss of function were used for comparison. Gene set enrichment analysis was performed to reveal functional groups associated with the genetic variants. 2,022 genes were left after filtering against dbSNP, the 1000 Genomes East Asian population, and healthy Korean randomized subsample data (GSK project). 175 (p-value

Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases.Postmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls.In Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation.Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.

SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau. [ABSTRACT FROM AUTHOR]