Methotrexate-Induced Accelerated Nodulosis in a Patient with Systemic Lupus Erythematosus.

Methotrexate (MTX)-induced accelerated nodulosis (MIAN) reportedly occurs in patients with rheumatic arthritis receiving MTX therapy. However, it has also been reported in patients with other autoinflammatory conditions, such as systemic lupus erythematosus (SLE). A 38-year-old woman diagnosed with SLE presented with multiple movable, firm, flesh-colored nodules on both hands that had developed 3 years ago. She was taking oral medications, specifically hydroxychloroquine, azathioprine, and MTX. Histopathological examination revealed palisaded granulomatous inflammation, surrounded by histiocytes and lymphocytes, along the dermis to the subcutaneous fat layer. Fibrinoid degeneration was observed at the center of the granulomatous inflammation, and dermal mucin deposition was not observed. The patient was diagnosed with MIAN, and therefore discontinuation of MTX was recommended. Subsequently, the lesions almost completely disappeared with no signs of recurrence. MIAN exhibits clinicopathological features similar to those of rheumatoid nodules; therefore, it can be easily misdiagnosed. Herein, we report a case of MIAN in a patient with SLE to contribute to the accurate diagnosis and appropriate management.

Motor subtypes and clinical characteristics in sporadic and genetic Parkinson's disease groups: analysis of the PPMI cohort.

Introduction: The extensive clinical variations observed in Parkinson's disease (PD) pose challenges in early diagnosis and treatment initiation. However, genetic research in PD has significantly transformed the clinical approach to its treatment. Moreover, researchers have adopted a subtyping strategy based on homogeneous clinical symptoms to improve clinical diagnosis and treatment approaches. We conducted a study to explore clinical characteristics in genetic PD groups with motor symptom subtyping. Methods: Data was driven from the Parkinson's Progression Markers Initiative (PPMI) database. The sporadic PD (sPD) group and the genetic PD group including patients with leucine-rich kinase 2 (LRRK2) or glucosylceramidase ß (GBA) mutations were analyzed. Motor subtyping was performed using Movement Disorder Society-Unified Parkinson's disease rating scale (MDS-UPDRS) scores. I-123 FP-CIT SPECT scans were used to calculate specific binding ratios (SBRs) in the caudate and putamen. Clinical symptoms of each group were also compared. Results: MDS-UPDRS III scores were lower in the LRRK2 group, compared with the GBA and sPD group (P < 0.001), but no significant differences in striatal SBRs. The putaminal SBR value of the LRRK2 group was higher than the sPD group (P < 0.05). Within the GBA group, we observed lower SBR values in the postural instability/gait difficulty (PIGD) subtype GBA group compared to the tremor-dominant (TD) subtype GBA group (P < 0.05). The TD subtype GBA group exhibited superior putaminal SBRs compared to the TD subtype sPD group (P < 0.05). The TD subtype LRRK2 group had better putaminal SBR values (P < 0.001) and MDS-UPDRS Part III scores (P < 0.05) compared to the TD sPD group. Discussions: Our subtyping approach offers valuable insights into the clinical characteristics and progression of different genetic PD subtypes. To further validate and expand these findings, future research with larger groups and long-term follow-up data is needed. The subtyping strategy based on motor symptoms holds promise in enhancing the diagnosis and treatment of genetic PD.

Serial changes of I-123 FP-CIT SPECT binding asymmetry in Parkinson's disease: Analysis of the PPMI data.

Background: Dopaminergic denervation and motor symptoms are usually asymmetric at the onset of Parkinson's disease (PD). In this study, we estimated the asymmetry of specific binding ratio (SBR) of I-123 FP-CIT SPECT images during 4-years of follow up, to demonstrate the pattern of serial changes of asymmetry. Methods: Clinical and I-123 FP-CIT SPECT image data of 301 PD patients and 141 normal controls were reviewed from the Parkinson's Progression Markers Initiative cohort. I-123 FP-CIT SPECT images were taken at baseline, 1-, 2-, and 4-year follow up periods for PD patients, and at baseline for normal controls. Asymmetry index were calculated by two methods. Method 1, by using the ratio of absolute difference of right and left SBRs to the average SBR. Method 2, by using the ratio of absolute difference of right and left SBRs to the SBR values of age-matched normal controls. Results: Asymmetry index by method 2 revealed a more significant decrease during the 4-year follow up period, compared with method 1. The baseline asymmetry index of the putamen by method 2 showed significant correlation with the non-dominant putamen SBRs. However, there were no significant correlation with the baseline asymmetry index by method 2 and motor symptoms, cognition, nor autonomic symptoms. Conclusion: We suggest a novel asymmetry index in association to age-matched normal SBR values. This novel index could be adopted in predicting and evaluating the natural course of PD.

The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system.

Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

Correlation of Dopaminergic Denervation and the Progression of Autonomic Dysfunctions in Different Clinical Subtypes of Parkinson's Disease.

BACKGROUND: Autonomic dysfunctions occur in the early stage of Parkinson's disease (PD) and impact the quality of life during the progression of the disease. In this study, we evaluated the serial progression of autonomic dysfunctions between different subtypes of a prospective PD cohort. MATERIALS AND METHODS: From the Parkinson's Progression Markers Initiative (PPMI) database, 325 PD patients (age: 61.2 ± 9.7, M : F = 215 : 110) were enrolled. Patients were subgrouped into tremor-dominant (TD), indeterminate, and postural instability and gait disorder (PIGD) subtypes. The progression of autonomic dysfunctions and dopaminergic denervation from I-123 FP-CIT SPECT images of each group were analyzed and compared at baseline, 12 months, 24 months, and 48 months of follow-up periods. RESULTS: The SCOPA-AUT score of the indeterminate subtype was significantly higher than that of the TD subtype (P < 0.05) at baseline and was significantly higher than that of both TD and PIGD subtypes (P < 0.05) at 48 months. The indeterminate subtype had the most significant correlation between the aggravation of dopaminergic denervation in I-123 FP-CIT SPECT images and the increase of SCOPA-AUT scores during 48 months of follow-up (r = 0.56, P < 0.01). CONCLUSIONS: Autonomic dysfunctions were most severe in the indeterminate subtype throughout the 48 months of the follow-up period, with a significant correlation with dopaminergic denervation. We suggest a positive relationship between dopaminergic denervation and autonomic dysfunctions of the indeterminate subtype, beginning from the early stage of PD.

Mining of a novel esterase (est3S) gene from a cow rumen metagenomic library with organosphosphorus insecticides degrading capability: Catalytic insights by site directed mutations, docking, and molecular dynamic simulations.

A novel esterase (est3S) gene, 1026 bp in size, was cloned from a metagenomic library made of uncultured microorganisms from the contents of cow rumen. The esterolytic enzyme (Est3S) is composed of 342 amino acids and shows the highest identity with EstGK1 (71.7%) and EstZ3 (63.78%) esterases from the uncultured bacterium. The Est3S did not cluster in any up-to-date classes (I to XVIII) of esterase and lipase. Est3S protein molecular weight was determined to be 38 kDa by gel electrophoresis and showed optimum activity at pH 7.0 and 40 °C and is partially resistant to organic solvents. Est3S activity was enhanced by K+, Na+, Mg2+, and Ca2+ and its highest activity was observed toward the short-chain p-nitrophenyl esters. Additionally, Est3S can degrade chlorpyrifos (CP) and methyl parathion (70% to 80%) in an hour. A mutated Est3S (Ser132-Ala132) did not show any activity toward CP and ester substrates. Notably, the GHS132QG motif is superimposed with the homolog esterase and cutinase-like esterase. Therefore, Ser132 is the critical amino acid like other esterases. The Est3S is relatively stable with ester compounds, and the methyl parathion complex was confirmed by molecular dynamics simulation. NOVELTY STATEMENT: A novel esterase gene (est3S) expressing esters and organophosphorus insecticide degradation traits was isolated from the uncultured bacterium in the contents of cow rumen. The Est3S protein did not cluster in any up-to-date classes (I to XVIII) of esterase/lipase proteins. Est3S was stable with the ligands up to 100 ns during the molecular dynamic simulations.

The core composition of DNA block copolymer micelles dictates DNA hybridization properties, nuclease stabilities, and cellular uptake efficiencies.

Here, we report how the nature of the hydrophobic core affects the molecular interactions of DNA block copolymer assemblies. Three different amphiphilic DNA block copolymers, DNA-b-polystyrene (DNA-b-PS), DNA-b-poly(2-vinylpyridine) (DNA-b-P2VP), and DNA-b-poly(methyl acrylate) (DNA-b-PMA) were synthesized and assembled into spherical micelles composed of a hydrophobic polymer core and DNA corona. Interestingly, DNA block copolymer micelles having different hydrophobic cores exhibited markedly different molecular and biological interactions. DNA-b-PS exhibited higher melting temperature, sharper melting transition, higher stability to nuclease-catalyzed DNA degradation, and higher cellular uptake efficiency compared to DNA-b-P2VP and DNA-b-PMA. The investigation of the self-assembly behavior revealed a much higher aggregation number and DNA density for DNA-b-PS micelles, which explains the superior properties of DNA-b-PS. These results demonstrate that the type of the hydrophobic core polymer, which has been largely overlooked, has a profound impact on the molecular and biological interactions of the DNA shell.

Human Norovirus Replication in Temperature-Optimized MDCK Cells by Forkhead Box O1 Inhibition.

Human noroviruses (HuNoVs) are a leading cause of gastroenteritis outbreaks worldwide. However, the paucity of appropriate cell culture model for HuNoV replication has prevented developing effective anti-HuNoV therapy. In this study, first, the replication of the virus at various temperatures in different cells was compared, which showed that lowering the culture temperature from 37°C significantly increased virus replication in Madin-Darby canine kidney (MDCK) cells. Second, the expression levels of autophagy-, immune-, and apoptosis-related genes at 30°C and 37°C were compared to explore factors affecting HuNoV replication. HuNoV cultured at 37°C showed significantly increased autophagy- (ATG5 and ATG7) and immune- (IFNA, IFNB, ISG15, and NFKB) related genes compared to mock. However, the virus cultured at 30°C showed significantly decreased expression of autophagy- (ATG5 and ATG7) and not significantly different in major immune- (IFNA, ISG15, and NFKB) related genes compared to mock. Importantly, expression of the transcription factor FOXO1, which controls autophagy- and immune-related gene expression, was significantly lower at 30°C. Moreover, FOXO1 inhibition in temperature-optimized MDCK cells enhanced HuNoV replication, highlighting FOXO1 inhibition as an approach for successful virus replication. In the temperature-optimized cells, various HuNoV genotypes were successfully replicated, with GI.8 showing the highest replication levels followed by GII.1, GII.3, and GII.4. Furthermore, ultrastructural analysis of the infected cells revealed functional HuNoV replication at low temperature, with increased cellular apoptosis and decreased autophagic vacuoles. In conclusion, temperature-optimized MDCK cells can be used as a convenient culture model for HuNoV replication by inhibiting FOXO1, providing adaptability to different genotypes.

Toward a conceptual framework for the interdisciplinary function-focused care in nursing homes.

AIM: To develop a conceptual framework to structure the shared roles and tasks of interdisciplinary teams for efficient function-focused care of nursing home (NH) residents. METHODS: A qualitative study using focus groups. Two focus group interviews were conducted on NH practitioners and professors. Focus group 1 consisted of six practitioners with more than 5 years of practical experience in NHs. Focus group 2 consisted of six professors with more than 5 years of educational experience in geriatrics or gerontology and who are capable of adopting theoretical approaches to older adults' functions. RESULTS: The post-acute care-rehabilitation quality framework furnished the underlying structure for the focus group interview questionnaire to develop the shared interdisciplinary function-focused care framework. The focus of the framework is how resident care processes should be based on individuality of the residents and include holistic continuous assessments, integration of care, and professional interventions by each discipline. An interdisciplinary process involves setting shared goals, communicating and coordinating roles and tasks of interdisciplinary teams, and providing complementary care. Shared final outcomes are defined as improving residents' independence and quality of life and reducing hospital transfer and admission rates. CONCLUSION: In this study, we have developed the first conceptual framework of interdisciplinary function-focused care in NHs, which will provide an evidence-based foundation for integrated and continuous function-focused care for NH residents. The results of this study will contribute to efficient communication among the interdisciplinary teams and improvement of the outcomes of function-focused care subjects.

The Shared Subjective Frames of Interdisciplinary Practitioners Involved in Function-Focused Care in a Nursing Home: Q-Methodology.

BACKGROUND: An interdisciplinary team-based approach in nursing homes has been suggested in the literature as a strategy for delaying functional decline in residents. Function-focused care is a philosophy-based approach in which interdisciplinary practitioners assess functional capacity and help older adults to optimize and maintain their remaining abilities. PURPOSE: This study explored and described the shared subjective frames of interdisciplinary practitioners as regards function-focused care for nursing home residents. METHODS: Q-methodology was used to analyze the subjectivity of each factor of function-focused care for nursing home residents. Data were collected from August to September 2016. Thirty-four Q-statements were selected and scored by the 30 interdisciplinary practitioners on a 9-point scale with a normal distribution. Data were analyzed using the PQ Method 2.33 program. RESULTS: The results revealed four factors of function-focused care, including (a) using a wait-and-see approach to encourage self-care, (b) maintaining interactive communications to identify and respond to changes, (c) reinforcing residents' inner and outer strengths for homeostasis, and (d) using a tailored approach based on comparisons between the past and the present. Shared subjectivity may provide an important collaborative framework to identify and solve complex problems related to the functional needs of nursing home residents. CONCLUSIONS: The results of this study elucidate the subjectivities of interdisciplinary practitioners and better enable their provision of effective care in support of the remaining functional abilities of older adults living in nursing homes. The findings may be used as a reference to establish communication methods and shared documentation for interdisciplinary practitioners in nursing homes and construct interdisciplinary function-focused care practice guidelines.

Sequential Two-Stage Network and Thematic Analysis for Exploring an Interdisciplinary Care Approach in Nursing Homes.

Since various groups of older adults with different conditions and levels of function coexist in nursing homes, it is necessary to develop integrated care strategies through collaboration among experts across related fields. The purposes of this study are to identify the regularity of information sharing in managing daily function for older adults, with a special focus on interdisciplinary cooperation, and to explore a practical care strategy for nursing home residents. The collaborative methods of network and thematic analysis were done by conducting in-depth interviews with 33 interdisciplinary experts working at seven nursing homes. This study proposed three relationships and three themes as interrelated key factors for providing interdisciplinary care to the elderly at various levels of function based on the experiences accumulated by the practitioners. First, independent sharing is required to make professional judgments about how daily function in older adults changes from reported baselines. Second, practitioners accurately judge clinical situations and supplement experts' judgments through partial sharing. Finally, all interdisciplinary consensus through complete sharing achieves the ultimate goal of maintaining remaining function in older adults. These findings can be the first step in developing practical care guidelines for interdisciplinary use, and the results can be used to develop integrated assessment and intervention strategies.

A dynamic DNA nanostructure with switchable and size-selective molecular recognition properties.

Herein, we report a dynamic DNA nanostructure exhibiting switchable and size-selective molecular recognition properties. A DNA block copolymer, polystyrene-b-DNA (PS-b-DNA), and a thermo-responsive block copolymer, PS-b-poly(N-isopropylacrylamide) (PS-b-PNIPAM), were simultaneously assembled to form hybrid micelles composed of a PS core and a DNA/PNIPAM corona. PNIPAM strands did not significantly hinder the binding of molecular DNA for a broad range of PNIPAM lengths. On the other hand, they exerted significant steric hindrance for interactions with nanoscale species, which can be reversibly turned off by increasing the temperature above the lower critical solution temperature (LCST) of PNIPAM. Owing to the switchable and size-selective steric hindrance, the hybrid DNA micelles showed thermally controllable enzymatic degradation and cellular uptake. These results demonstrate that the binary self-assembly of two different responsive block copolymers is a promising approach to prepare dynamic nanostructures with controllable biological recognition properties.

Enzymatic Synthesis of Self-assembled Dicer Substrate RNA Nanostructures for Programmable Gene Silencing.

Enzymatic synthesis of RNA nanostructures is achieved by isothermal rolling circle transcription (RCT). Each arm of RNA nanostructures provides a functional role of Dicer substrate RNA inducing sequence specific RNA interference (RNAi). Three different RNAi sequences (GFP, RFP, and BFP) are incorporated within the three-arm junction RNA nanostructures (Y-RNA). The template and helper DNA strands are designed for the large-scale in vitro synthesis of RNA strands to prepare self-assembled Y-RNA. Interestingly, Dicer processing of Y-RNA is highly influenced by its physical structure and different gene silencing activity is achieved depending on its arm length and overhang. In addition, enzymatic synthesis allows the preparation of various Y-RNA structures using a single DNA template offering on demand regulation of multiple target genes.

Catalytic degradation of phenols by recyclable CVD graphene films.

Ferrous ion-based catalysts have been widely employed to oxidatively destruct the major industrial pollutants such as phenolic compounds through advanced oxidation processes (AOPs). These agents, however, inevitably show several drawbacks including the need for pH adjustment and further purification steps to remove residual salts. Here we report the use of a chemical vapour deposition (CVD) graphene film as a novel metal-free catalyst for the AOP-based degradation of phenols in aqueous solution, which does not require additional steps for salt removal nor external energy to activate the process. We have also verified that the catalytic activity is strongly dependent on the surface area of the graphene film and the degradation efficiency can be markedly improved by exploiting an array of multiple graphene films. Finally, the recyclability of the graphene film has been validated by performing repetitive degradation tests to ensure its practical use.

Validation of MoCA-MMSE Conversion Scales in Korean Patients with Cognitive Impairments.

BACKGROUND AND PURPOSE: Two conversion scales between the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) have been validated for Korean patients with Parkinson's disease. The aim of the present study was to validate these conversion scales for all patients with cognitive impairments regardless of dementia subtype. METHODS: Medical records of 323 subjects who completed both MMSE and MoCA on the same day were retrospectively reviewed. Mean, median, and root mean squared error (RMSE) of the difference between true and equivalent MMSE scores were calculated. Intraclass correlation coefficients (ICCs) between true and equivalent MMSE scores were also calculated. The validity of MoCA-MMSE conversion scales was evaluated according to educational level (low educated: ≤6 years; high educated: ≥7 years) and subtypes of cognitive impairment. RESULTS: The difference between true and equivalent MMSE scores had a median value of 0, a mean value of 0.19 according to the van Steenoven scale, a mean value of 0.57 according to the Lawton scale, RMSE value of 2.2 according to the van Steenoven scale, and RMSE value of 0.42 according to the Lawton scale. Additionally, ICCs between true and equivalent MMSE scores were 0.92 and 0.90 on van Steenovan and Lawton conversion scales, respectively. These results were maintained in subgroup analyses. CONCLUSIONS: Findings of the present study suggest that both van Steenovan and Lawton MoCA-MMSE conversion scales are applicable to transforming MoCA scores into MMSE scores in patients with cognitive impairments regardless of dementia subtype or educational level.

Serial I-123-FP-CIT SPECT Image Findings of Parkinson's Disease Patients With Levodopa-Induced Dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a major complication of dopamine replacement drug usage in Parkinson's disease (PD) patients. Since the mechanism of LID is yet unclear, we analyzed serial [I-123] N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (I-123 FP-CIT) single photon emission computed tomography (SPECT) images. We investigated the changes of dopaminergic innervation during the progression of PD in relation to the development of LID. Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Two hundred and ninety PD dopamine replacement drug-naïve patients (age 61.0 ± 9.7, M: F = 195: 95) were enrolled. I-123 FP-CIT SPECT images from baseline, 12, 24, and 48 months were analyzed among with clinical factors. specific binding ratios (SBRs) of the striatal regions from I-123 FP-CIT SPECT images were analyzed. We used independent tests and logistic regression for analysis of LID risk association. Results: Among 290 patients, 36 patients developed LID after 48 months follow-up. Baseline MDS-UPDRS Part II and III scores were significantly higher in the PD patients with LID, compared with the PD patients without LID. Striatal SBRs were significantly lower in the PD patients with LID at baseline, 24 and 48 months (p < 0.001). Multivariate analysis revealed MDS-UPDRS Part II and putaminal SBRs at baseline and 24 months to be significantly associated with the development of LID (p < 0.001). Also, patients who developed LID at 48 months had a higher decrease rate of putaminal SBR at the 24 months (p < 0.05), and 48 months (p < 0.01) period. Conclusion: In this study, we demonstrated the serial changes of the nigrostriatal dopaminergic innervation in relationship to LID development for the first time. The deterioration rate of dopaminergic innervation was significantly higher in the PD patients who developed LID, compared with the PD patients who did not develop LID. Serial follow up I-123 FP-CIT SPECT acquisition during the course of PD could be helpful in predicting the development of LID.

Effectiveness of Periodic Treatment of Quercetin against Influenza A Virus H1N1 through Modulation of Protein Expression.

Kimchi, a traditional fermented food regularly consumed in Korea, contains various types of antimicrobial compounds. Among the tested compounds present in common spices used in Kimchi, quercetin showed the highest selectivity index against influenza A virus (IAV) H1N1. In this study, the effect of pretreatment and periodic treatment with quercetin against IAV in Madin-Darby canine kidney cells was observed. Compared to pretreatment, periodic treatment resulted in significantly higher cell viability but lower relative expression of the IAV PA gene and total apoptosis and cell death. To explain the mechanisms underlying the antiviral effects of quercetin treatment, a comparative proteomic analysis was performed in four samples (mock, quercetin-treated, IAV-infected, and quercetin-treated IAV-infected). Among the 220 proteins, 56 proteins were classified nonhierarchically into three clusters and were differentially modulated by quercetin treatment in IAV-infected cells. Post-translational modifications were identified in 68 proteins. In conclusion, periodic treatment with quercetin is effective in reducing IAV infection, and differentially regulates the expression of key proteins, including heat shock proteins, fibronectin 1, and prohibitin to reduce IAV replication.

Asterixis in the leg induced by anterior cerebral artery infarction.

Asterixis commonly occurs in a patient with metabolic encephalopathy, whereas focal brain lesions such as thalamus, cerebellum, or frontal area also cause focal or unilateral asterixis in the arms. We report a novel case of asterixis in the leg after unilateral anterior cerebral artery territory infarction. A 76-year-old man was admitted with sudden-onset mild right leg weakness and postural instability due to knee buckling. He was diagnosed with ischemic stroke in the left prefrontal area and cingulated gyrus by brain magnetic imaging. Needle electromyography of the right vastus lateralis muscle while standing showed intermittent periods of EMG silence, consistent with asterixis. There were no abnormal involuntary movements in the upper extremities. This case suggests that gait disturbance or postural instability after structural lesions in the prefrontal area may be directly related to asterixis in the leg, not in the arm associated with postural failure.