ABSTRACT
In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.
Subject(s)
Genes, Immunoglobulin Heavy Chain , Genome-Wide Association Study , Mucocutaneous Lymph Node Syndrome/genetics , Adult , Alleles , B-Lymphocytes/metabolism , Computer Simulation , Datasets as Topic , Follow-Up Studies , Gene Expression Regulation , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Japan/epidemiology , Leukocytes/metabolism , Linkage Disequilibrium , Models, Genetic , Mucocutaneous Lymph Node Syndrome/epidemiology , Polymorphism, Single Nucleotide , Republic of Korea/epidemiology , Taiwan/epidemiology , Transcription, GeneticABSTRACT
BACKGROUND: The advancement of treatment with direct-acting antiviral (DAA) agents has improved the cure rate of hepatitis C virus (HCV) infection close to 100%. The aim of our study was to assess the real-world effectiveness and safety of DAA regimens for the treatment of patients with chronic HCV genotype 2. METHODS: We retrospectively analyzed the clinical data of patients treated with sofosbuvir plus ribavirin (SOF + RBV) or glecaprevir/pibrentasvir (G/P) for chronic HCV genotype 2 infection at seven university hospitals in the Korean southeast region. RESULTS: SOF + RBV therapy produced an 89% and 98.3% sustained virologic response 12 week (SVR12) after treatment completion in the full analysis set and per-protocol set, respectively, and the corresponding values for G/P therapy were 89.5% and 99.2%, respectively. The difference between the treatments was probably because 6.2% (59/953) of patients in the SOF + RBV group did not complete the treatment and 9.8% (14/143) in the G/P group did not test HCV RNA after treatment completion. Adverse events (A/Es) were reported in 59.7% (569/953) and 25.9% (37/143) of the SOF + RBV and G/P groups, respectively. In the SOF + RBV group, 12 (1.26%) patients discontinued treatment owing to A/Es, whereas no patients discontinued treatment because of A/Es in the G/P group. CONCLUSION: In both treatment groups, SVR was high when treatment was completed. However, there was a high dropout rate in the SOF + RBV group, and the dropout analysis showed that these were patients with liver cirrhosis (LC; 43/285, 15.1%), especially those with decompensated LC (12/32, 37.5%). Therefore, an early initiation of antiviral therapy is recommended for a successful outcome before liver function declines. Furthermore, patients with decompensated LC who are considered candidates for SOF + RBV treatment should be carefully monitored to ensure that their treatment is completed, especially those with low hemoglobin and high alanine transaminase.
Subject(s)
Liver Cirrhosis/drug therapy , Ribavirin/therapeutic use , Sofosbuvir/therapeutic use , Adult , Aged , Antiviral Agents/therapeutic use , Benzimidazoles , Drug Combinations , Female , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Humans , Liver Cirrhosis/virology , Male , Middle Aged , Pyrrolidines , Quinoxalines , Republic of Korea , Retrospective Studies , Ribavirin/adverse effects , Sofosbuvir/adverse effects , Sulfonamides , Sustained Virologic Response , Treatment OutcomeABSTRACT
We investigated the neurotoxic effects of capsaicin (CAP) on pain sensitivity and on the expression of capsaicin receptor, the vanilloid receptor (VR1), in rats. High-dose application of CAP has been known to degenerate a large fraction of the sensory neurons. Although the neurotoxic effects of CAP are well documented, the effects of CAP on the vanilloid receptor (VR1) are not yet known. In this paper, we investigated the effects of high-dose application of CAP on the expression of VR1 in rats. Thermal and mechanical pain sensitivity was reduced when neonatal rats were treated with a high dose of CAP. This reduction of pain sensitivity was significantly decreased after initiating carrageenan-induced inflammation. The expression of VR1 in dorsal root ganglia (DRG) isolated from the CAP-treated rats was reduced compared to that from the vehicle-treated rats. Therefore, we can conclude that the neurotoxic effect of CAP is related to the decrease of VR1 expression.
Subject(s)
Capsaicin/pharmacology , Pain Threshold/drug effects , Receptors, Drug/biosynthesis , Animals , Animals, Newborn , Behavior, Animal/drug effects , Blotting, Western , Capsaicin/administration & dosage , Female , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Injections, Subcutaneous , Male , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Human adenovirus type 36 (Ad36) as an obesity agent induces adiposity by increasing glucose uptake and promoting chronic inflammation in fat tissues; in contrast, exercise reduces total body fat and inflammation. Our objective was to determine the association between Ad36 and the effects of exercise on inflammation and glycemic control. In the human trials (n = 54), Korean children (aged 12-14 years) exercised for 60 min on three occasions each week for 2 months. We compared the body mass index (BMI) Z-scores before and after exercise. C57BL/6 mice were infected with Ad36 and Ad2 as a control, and these mice exercised for 12 weeks postinfection. After the exercise period, we determined the serum parameters and assessed the presence of inflammation and the mitochondrial function in the organs. Ad36-seropositive children who were subjected to a supervised exercise regimen had high BMI Z-scores whereas Ad36-seronegative children had lower scores. Similarly, Ad36-infected mice were resistant to weight loss and exhibited chronic inflammation of their adipose tissues despite frequent exercise. However, Ad36 combined with exercise reduced the levels of serum glucose, nonesterified fatty acids, total cholesterol, and insulin in virus-infected mice. Interestingly, virus infection increased the mitochondrial function in the liver, as demonstrated by the numbers of mitochondria, cytochrome c oxidase activity, and transcription of key mitochondrial genes. Therefore Ad36 counteracts the weight-loss effect of exercise and maintains the chronic inflammatory state, but glycemic control is improved by exercise synergistically because of increased mitochondrial activity in the liver.