Background:
There are currently few studies regarding late-onset neuromyelitis optica spectrum disorder (LO-NMOSD).
Objective:
We aimed to describe the characteristic features of patients with ...LO-NMOSD in Korea.
Methods:
Anti-aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder (NMOSD) from nine tertiary hospitals were reviewed retrospectively. The patients were divided into two groups based on age of onset: LO-NMOSD (⩾50 years of age at onset) versus early-onset neuromyelitis optica spectrum disorder (EO-NMOSD) (<50 years of age at onset). Clinical, laboratory, and magnetic resonance imaging (MRI) parameters were investigated.
Results:
Among a total of 147 patients (125 female; age of onset, 39.4 ± 15.2 years), 45 patients (30.6%) had an age of onset of more than 50 years. Compared to patients with EO-NMOSD, patients with LO-NMOSD had more frequent isolated spinal cord involvement at onset (64.4% vs 37.2%, p = 0.002), less frequent involvement of the optic nerve (40.0% vs 67.7%, p = 0.002), and less frequent brain MRI lesions (31.1% vs 50.0%, p = 0.034). Furthermore, there was a significant positive correlation between age of onset and Expanded Disability Status Scale (EDSS) score at last follow-up (r = 0.246, p = 0.003).
Conclusion:
Age of onset could be an important predictor of lesion location and clinical course of patients with NMOSD.
Background:
Nearly three-quarters of anterior cruciate ligament (ACL) injuries occur as “noncontact” failures from routine athletic maneuvers. Recent in vitro studies revealed that repetitive ...strenuous submaximal knee loading known to especially strain the ACL can lead to its fatigue failure, often at the ACL femoral enthesis.
Hypothesis:
ACL failure can be caused by accumulated tissue fatigue damage: specifically, chemical and structural evidence of this fatigue process will be found at the femoral enthesis of ACLs from tested cadaveric knees, as well as in ACL explants removed from patients undergoing ACL reconstruction.
Study Design:
Controlled laboratory study.
Methods:
One knee from each of 7 pairs of adult cadaveric knees were repetitively loaded under 4 times–body weight simulated pivot landings known to strain the ACL submaximally while the contralateral, unloaded knee was used as a comparison. The chemical and structural changes associated with this repetitive loading were characterized at the ACL femoral enthesis at multiple hierarchical collagen levels by employing atomic force microscopy (AFM), AFM–infrared spectroscopy, molecular targeting with a fluorescently labeled collagen hybridizing peptide, and second harmonic imaging microscopy. Explants from ACL femoral entheses from the injured knee of 5 patients with noncontact ACL failure were also characterized via similar methods.
Results:
AFM–infrared spectroscopy and collagen hybridizing peptide binding indicate that the characteristic molecular damage was an unraveling of the collagen molecular triple helix. AFM detected disruption of collagen fibrils in the forms of reduced topographical surface thickness and the induction of ~30- to 100-nm voids in the collagen fibril matrix for mechanically tested samples. Second harmonic imaging microscopy detected the induction of ~10- to 100-µm regions where the noncentrosymmetric structure of collagen had been disrupted. These mechanically induced changes, ranging from molecular to microscale disruption of normal collagen structure, represent a previously unreported aspect of tissue fatigue damage in noncontact ACL failure. Confirmatory evidence came from the explants of 5 patients undergoing ACL reconstruction, which exhibited the same pattern of molecular, nanoscale, and microscale structural damage detected in the mechanically tested cadaveric samples.
Conclusion:
The authors found evidence of accumulated damage to collagen fibrils and fibers at the ACL femoral enthesis at the time of surgery for noncontact ACL failure. This tissue damage was similar to that found in donor knees subjected in vitro to repetitive 4 times–body weight impulsive 3-dimensional loading known to cause a fatigue failure of the ACL.
Clinical Relevance:
These findings suggest that some ACL injuries may be due to an exacerbation of preexisting hierarchical tissue damage from activities known to place larger-than-normal loads on the ACL. Too rapid an increase in these activities could cause ACL tissue damage to accumulate across length scales, thereby affecting ACL structural integrity before it has time to repair. Prevention necessitates an understanding of how ACL loading magnitude and frequency are anabolic, neutral, or catabolic to the ligament.
Background
Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial ...dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined.
Methods
Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group).
Results
Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P < 0.01), ATP production (−88.0%, P < 0.01), mtDNA (−53.1%, P < 0.01), and mitochondrial respiration (−52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi‐1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi‐1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR.
Conclusions
Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.
The effect of heat treatment on the antioxidant activity of extracts from Citrus unshiu peels was evaluated. Citrus peels (CP) (5 g) were placed in Pyrex Petri dishes (8.0 cm diameter) and ...heat-treated at 50, 100, or 150 °C for 10, 20, 30, 40, 50, and 60 min in an electric muffle furnace. After heat treatment, 70% ethanol extract (EE) and water extract (WE) (0.1 g/10 mL) of CP were prepared, and total phenol contents (TPC), radical scavenging activity (RSA), and reducing power of the extracts were determined. The antioxidant activities of CP extracts increased as heating temperature increased. For example, heat treatment of CP at 150 °C for 60 min increased the TPC, RSA, and reducing power of EE from 71.8 to 171.0 μM, from 29.64 to 64.25%, and from 0.45 to 0.82, respectively, compared to non-heat-treated control. In the case of WE from CP heat-treated at the same conditions (150 °C for 60 min), the TPC, RSA, and reducing power also increased from 84.4 to 204.9 μM, from 15.81 to 58.26%, and from 0.27 to 0.96, respectively. Several low molecular weight phenolic compounds such as 2,3-diacetyl-1-phenylnaphthalene, ferulic acid, p-hydroxybenzaldoxime, 5-hydroxyvaleric acid, 2,3-diacetyl-1-phenylnaphthalene, and vanillic acid were newly formed in the CP heated at 150 °C for 30 min. These results indicated that the antioxidant activity of CP extracts was significantly affected by heating temperature and duration of treatment on CP and that the heating process can be used as a tool for increasing the antioxidant activity of CP. Keywords: Citrus peels; extracts; heat treatment; antioxidant activity
Abnormal expression of claudin-1 (CLDN1) has important roles in carcinogenesis and metastasis in various cancers. The role of CLDN1 in human oral squamous cell carcinoma (OSCC) remains unknown. Here, ...we report the functional role of CLDN1 in metastasis of human OSCC, as a potential target regulated by withaferin A. From gene expression profiling with microarray technology, we found that the majority of notable differentially expressed genes were classified into migration/invasion category. Withaferin A impaired the motility of human OSCC cells
in vitro
and suppressed metastatic nodule formation in an
in vivo
metastasis model, both associated with reduced CLDN1. CLDN1 overexpression enhanced metastatic nodule formation
in vivo
, resulting in severe metastatic lesions in lung tissue. Moreover, CLDN1 expression was positively correlated to lymphatic metastasis in OSCC patients. The impaired motility of human OSCC cells upon withaferin A treatment was restored by CLDN1 overexpression. Furthermore, upregulation of let-7a induced by withaferin A was inversely correlated to CLDN1 expression. Overall, these give us an insight into the function of CLDN1 for prognosis and treatment of human OSCC, substantiating further investigation into the use of withaferin A as good anti-metastatic drug candidate.
Graphical abstract
The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) ...decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.
Chemotherapy is a widely adopted method for the treatment of cancer. However, its use is often limited due to side effects produced by anti-cancer drugs. Therefore, various drug carriers, including ...polymeric micelles, have been investigated to find a method to overcome this limitation. In this study, alginate-based, self-assembled polymeric micelles were designed and prepared using alginate-g-poly(N-isopropylacrylamide) (PNIPAAm). Amino-PNIPAAm was chemically introduced to the alginate backbone via carbodiimide chemistry. The resulting polymer was dissolved in distilled water at room temperature and formed self-assembled micelles at 37 °C. Characteristics of alginate-g-PNIPAAm micelles were dependent on the molecular weight of PNIPAAm, the degree of substitution, and the polymer concentration. Doxorubicin (DOX), a model anti-cancer drug, was efficiently encapsulated in alginate-g-PNIPAAm micelles, and sustained release of DOX from the micelles was achieved at 37 °C in vitro. These micelles accumulated at the tumor site of a tumor-bearing mouse model as a result of the enhanced permeability and retention effect. Interestingly, DOX-loaded alginate-g-PNIPAAm micelles showed excellent anti-cancer therapeutic efficacy in a mouse model without any significant side effects. This approach to designing and tailoring natural polymer-based systems to fabricate nanoparticles at human body temperature may provide a useful means for cancer imaging and therapy.
Objectives:
To evaluate the validity of the revised 2017 McDonald criteria for multiple sclerosis (MS) compared with the 2010 McDonald criteria to predict conversion to clinically definite multiple ...sclerosis (CDMS) in patients with clinically isolated syndrome (CIS).
Methods:
A total of 163 patients from seven referral hospitals in Korea, who experienced a first clinical event suggestive of MS between 2006 and 2017, were enrolled. Patients were stratified into two groups according to outcome at the last visit: CDMS converters who experienced a second clinical event and non-converters.
Results:
Of the 163 patients with a mean follow-up of 63 months, 60% converted to CDMS. The sensitivity, specificity, positive and negative predictive values and accuracy were, respectively, 88.8%, 43.1%, 70.2%, 71.8% and 70.6% for the 2017 McDonald criteria and 53.1%, 69.2%, 72.2%, 49.5% and 59.5% for the 2010 McDonald criteria. After exclusion of 82 patients who received disease-modifying agents before the second attack, the specificity of the 2017 and 2010 McDonald criteria increased to 85.0% and 95.0%, but sensitivity decreased to 83.6% and 47.5%, respectively.
Conclusion:
The 2017 McDonald criteria afforded higher sensitivity and accuracy but lower specificity compared with the 2010 McDonald criteria for prediction of conversion to CDMS in Korean CIS patients.
This study aimed to analyze pregnancy outcomes based on biologic agents use in women using the nationwide population-based database.
The study used the claims database to identify women of ...childbearing age with several rheumatic (rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis) and inflammatory bowel diseases (Crohn's disease and ulcerative colitis) who had pregnancy-related codes between January 2010 and December 2019. We analyzed live births and adverse pregnancy outcomes based on the previous use of biologics. We also stratified the patients according to duration of biologic agent exposure before pregnancy and the use of biologics during pregnancy to analyze the pregnancy outcomes by subgroups.
We identified 4,787 patients with pregnancy events. Among them, 1,034 (21.6%) used biologics before pregnancy. Live birth rate was not different between the biologics group and biologics naïve group (75.0% vs. 75.2%). Multivariate analyses showed that biologics use was associated with higher risk of intrauterine growth retardation (odds ratio OR, 1.780) and lower risk of gestational diabetes mellitus (OR, 0.776) compared with biologics naïve. Biologics use during pregnancy was associated with higher risk of preterm delivery (OR, 1.859), preeclampsia/eclampsia (OR, 1.762), intrauterine growth retardation (OR, 3.487), and cesarean section (OR, 1.831), but lower risk of fetal loss (OR, 0.274) compared with biologics naïve.
Although there was no difference in live birth rate between the biologics group and biologics naïve group, biologics use seems to be associated with several adverse pregnancy outcomes, especially in patients with biologics during pregnancy. Therefore, patients with biologics during pregnancy need to be carefully observed for adverse pregnancy outcomes.
Evidence for the associations between mental illness and the likelihood of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result and the clinical outcomes of COVID-19 is ...scarce. We aimed to investigate these associations with data from a national register in South Korea.
A nationwide cohort study with propensity score matching was done in South Korea using data collected from the Health Insurance Review and Assessment Service of Korea. We defined mental illness as present if one of the relevant ICD-10 codes was recorded at least twice within 1 year for an outpatient or inpatient. Severe mental illness was considered as non-affective or affective disorders with psychotic features. We included all patients aged older than 20 years who were tested for SARS-CoV-2 through services facilitated by the Korea Centers for Disease Control and Prevention, the Health Insurance Review and Assessment Service of Korea, and the Ministry of Health and Welfare, South Korea. We investigated the primary outcome (SARS-CoV-2 test positivity) in the entire cohort and the secondary outcomes (severe clinical outcomes of COVID-19: death, admission to the intensive care unit, or invasive ventilation) among those who tested positive.
Between Jan 1 and May 15, 2020, 216 418 people were tested for SARS-CoV-2, of whom 7160 (3·3%) tested positive. In the entire cohort with propensity score matching, 1391 (3·0%) of 47 058 patients without a mental illness tested positive for SARS-CoV-2, compared with 1383 (2·9%) of 48 058 with a mental illness (adjusted odds ratio OR 1·00, 95% CI 0·93-1·08). Among the patients who tested positive for SARS-CoV-2, after propensity score matching, 109 (8·3%) of 1320 patients without a mental illness had severe clinical outcomes of COVID-19 compared with 128 (9·7%) of 1320 with a mental illness (adjusted OR 1·27, 95% CI 1·01-1·66).
Diagnosis of a mental illness was not associated with increased likelihood of testing positive for SARS-CoV-2. Patients with a severe mental illness had a slightly higher risk for severe clinical outcomes of COVID-19 than patients without a history of mental illness. Clinicians treating patients with COVID-19 should be aware of the risk associated with pre-existing mental illness.
National Research Foundation of Korea.
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