The clinical utility of a type 2 diabetes mellitus (T2DM) polygenic risk score (PRS) in the East Asian population remains underexplored. We aimed to examine the potential prognostic value of a T2DM ...PRS and assess its viability as a clinical instrument. We first established a T2DM PRS for 5490 Korean individuals using East Asian Biobank data (269,487 samples). Subsequently, we assessed the predictive capability of this T2DM PRS in a prospective longitudinal study with baseline data and data from seven additional follow-ups. Our analysis showed that the T2DM PRS could predict the transition of glucose tolerance stages from normal glucose tolerance to prediabetes and from prediabetes to T2DM. Moreover, T2DM patients in the top-decile PRS group were more likely to be treated with insulin (hazard ratio = 1.69, p value = 2.31E-02) than were those in the remaining PRS groups. T2DM PRS values were significantly high in the severe diabetes subgroup, characterized by insulin resistance and
-cell dysfunction (p value = 0.0012). The prediction models with the T2DM PRS had significantly greater Harrel's C-indices than did corresponding models without it. By utilizing prospective longitudinal study data and extensive clinical risk factor information, our analysis provides valuable insights into the multifaceted clinical utility of the T2DM PRS.
Protective immunoglobulin A (IgA) responses to oral antigens are usually orchestrated by gut dendritic cells (DCs). Here, we show that lung CD103(+) and CD24(+)CD11b(+) DCs induced IgA class-switch ...recombination (CSR) by activating B cells through T cell-dependent or -independent pathways. Compared with lung DCs (LDC), lung CD64(+) macrophages had decreased expression of B cell activation genes and induced significantly less IgA production. Microbial stimuli, acting through Toll-like receptors, induced transforming growth factor-β (TGF-β) production by LDCs and exerted a profound influence on LDC-mediated IgA CSR. After intranasal immunization with inactive cholera toxin (CT), LDCs stimulated retinoic acid-dependent up-regulation of α4β7 and CCR9 gut-homing receptors on local IgA-expressing B cells. Migration of these B cells to the gut resulted in IgA-mediated protection against an oral challenge with active CT. However, in germ-free mice, the levels of LDC-induced, CT-specific IgA in the gut are significantly reduced. Herein, we demonstrate an unexpected role of the microbiota in modulating the protective efficacy of intranasal vaccination through their effect on the IgA class-switching function of LDCs.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular and renal outcomes in type 2 diabetes mellitus (T2DM) patients. However, the mechanisms by which SGLT2 inhibitors improve the ...clinical outcomes remain elusive. We evaluated whether empagliflozin, an SGLT2 inhibitor, ameliorates mitochondrial dysfunction and inflammatory milieu of the kidneys in T2DM patients. We prospectively measured copy numbers of urinary and serum mitochondrial DNA (mtDNA) nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND-1) and cytochrome-c oxidase 3 (mtCOX-3) and urinary interleukin-1β (IL-1β) in healthy volunteers (n = 22), in SGLT2 inhibitor-naïve T2DM patients (n = 21) at baseline, and in T2DM patients after 3 months of treatment with empagliflozin (10 mg, n = 17 or 25 mg, n = 4). Both urinary mtDNA copy numbers and IL-1β levels were higher in the T2DM group than in healthy volunteers. Baseline copy numbers of serum mtCOX-3 in the T2DM group were lower than those in healthy volunteers. Empagliflozin induced marked reduction in both urinary and serum mtND-1 and mtCOX-3 copy numbers, as well as in urinary IL-1β. Empagliflozin could attenuate mitochondrial damage and inhibit inflammatory response in T2DM patients. This would explain the beneficial effects of SGLT2 inhibitors on cardiovascular and renal outcomes.
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain ...lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.
Proton pump inhibitor use is associated with incident chronic kidney disease, chronic kidney disease progression and end-stage renal disease. However, the extent of proton pump inhibitor ...prescriptions to chronic kidney disease patients is still unclear.
In a retrospective study, we enrolled patients (>18 years old) who received proton pump inhibitor in the out-patient setting from 2014 through 2015. All data was obtained from electronical medical records of Soonchunhyang Medical Center. The prescription patterns and characteristics of proton pump inhibitors were analyzed according to individual estimated glomerular filtration rate of the patients.
During the study period 178,228 patients visited the out-patient clinic. Proton pump inhibitors were prescribed to 9,109 (5.11%) patients. In our sample, 50% were females and 9.8% were chronic kidney disease (eGFR<60mL/min/1.73 m2) patients. Among the patients with chronic kidney disease, 730 (8.0%) were categorized as stage 3 or 4 and 166 (1.8%) were categorized as stage 5 or end-stage renal disease. The prevalence of proton pump inhibitors prescription among chronic kidney disease patients was higher than in the non-chronic kidney disease group (p<0.001). Median duration of usage was 120 interquartile range 63-273 days in the stage 3-4 group, 106 56-266 days in the stage 5-end-stage renal disease group and 90 56-176 days in the non-chronic kidney disease group. Patients in stage 3-4 group were prescribed longer duration of proton pump inhibitors than the non-chronic kidney disease group even after adjusting for age and sex (p<0.001). The main departments of medicine which prescribed proton pump inhibitors for the stage 3-4 group were gastroenterology (40.0%), cardiology (29.6%), nephrology (9.5%) and neurology (4.8%). Compared to the non-chronic kidney disease group, the stage 3-4 and stage 5-end-stage renal disease group were taking larger number of drugs simultaneously (6.90±4.17 vs4.54±2.43; p<0.001, 5.64±2.87 vs 4.54±2.34; p<0.001, respectively).
Chronic kidney disease patients are taking proton pump inhibitors for a much longer duration compared to non-chronic kidney disease patients. Physicians should pay careful attention when prescribing proton pump inhibitors to high risk groups.
Extracellular vesicle (EV)-microRNAs (miRNAs) are potential biomarkers for various renal diseases. This study attempted to identify the circulating EV-miRNA signature not only for discriminating ...idiopathic membranous nephropathy (IMN) from idiopathic nephrotic syndrome (INS), but also to predict the treatment response of patients with IMN.
We prospectively enrolled 60 participants, including those with IMN (n = 19) and INS (n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum EV-miRNA profiles of all participants. To identify the EV-miRNAs predictive of treatment response in IMN, we also analyzed EV-miRNAs among patients with IMN with and without clinical remission.
The expression levels of 3 miRNAs differed between IMN patients, INS patients and HVs. In addition, compared to HVs, RNA sequencing revealed differential expression of 77 and 44 EV-miRNAs in patients with IMN without and with remission, respectively. We also identified statistically significant (|fold change ≥ 2, p < 0.05) differences in the expression levels of 23 miRNAs in IMN without remission. Biological pathway analysis of miRNAs in IMN without remission indicated that they are likely involved in various pathways, including renal fibrosis.
Our study identified EV-miRNAs associated with IMN as well as those associations with therapeutic response. Therefore, these circulating EV-miRNAs may be used as potential markers for the diagnosis and prediction of treatment response in patients with IMN.
ITX 5061 is a scavenger receptor B1 antagonist that has entered phase 1 clinical trials in hepatitis C virus (HCV)-infected humans. We evaluated ITX 5061 in combination with interferon-α, ribavirin, ...and HCV protease and polymerase inhibitors in a genotype 2a infectious virus system. ITX 5061 is a potent inhibitor of HCV replication and is additive to synergistic with interferon-α, ribavirin, BILN2061, VX950, VX1, and 2′-C-methyladenosine. Resistance selection experiments were performed using a Jc1-FEO virus co-culture system and intermittent ITX 5061 exposure under neomycin selection. We identified a mutant virus with a substitution of aspartic acid for asparagine at the highly conserved position 415 in E2 (N415D). Introduction of this mutation into wild-type virus conferred high-level resistance to ITX 5061. There was no cross-resistance between ITX 5061 and HCV protease inhibitors or interferon-α. These results suggest that ITX 5061 is a promising compound for study in combination with other HCV inhibitors.
Coronary heart disease leading to myocardial ischemia is a major cause of heart failure. A hallmark of heart failure is myocardial fibrosis. Using a murine model of myocardial ischemia/reperfusion ...injury (IRI), we showed that, following IRI, in mice genetically deficient in the central factor of complement system, C3, myocardial necrosis was reduced compared with WT mice. Four weeks after the ischemic period, the C3−/− mice had significantly less cardiac fibrosis and better cardiac function than the WT controls. Overall, our results suggest that innate immune response through complement C3 plays an important role in necrotic cell death, which contributes to the cardiac fibrosis that underlies post-infarction heart failure.
•Following IRI, in mice genetically deficient in the central factor of complement system, C3, myocardial necrosis was reduced compared with WT mice.•Four weeks after the ischemic period, the C3−/− mice had significantly less cardiac fibrosis and better cardiac function than the WT controls.•Innate immune response via C3 is critical in necrotic cell death.
The radiodensity and volume of epicardial adipose tissue (EAT) on computed tomography angiography (CTA) may provide information regarding cardiovascular risk and long-term outcomes. EAT volume is ...associated with mortality in patients undergoing incident hemodialysis. However, the relationship between EAT radiodensity/volume and all-cause mortality in patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis remains elusive. In this retrospective study, EAT radiodensity (in Hounsfield units) and volume (in cm
) on coronary CTA were quantified for patients with ESRD using automatic, quantitative measurement software between January 2012 and December 2018. All-cause mortality data (up to December 2019) were obtained from the Korean National Statistical Office. The prognostic values of EAT radiodensity and volume for predicting long-term mortality were assessed using multivariable Cox regression models, which were adjusted for potential confounders. A total of 221 patients (mean age: 64.88 ± 11.09 years; 114 women and 107 men) with ESRD were included. The median follow-up duration (interquartile range) after coronary CTA was 29.63 (range 16.67-44.7) months. During follow-up, 82 (37.1%) deaths occurred. In the multivariable analysis, EAT radiodensity (hazard ratio HR 1.055; 95% confidence interval CI 1.015-1.095; p = 0.006) was an independent predictor of all-cause mortality in patients with ESRD. However, EAT volume was not associated with mortality. Higher EAT radiodensity on CTA is associated with higher long-term all-cause mortality in patients undergoing prevalent hemodialysis, highlighting its potential as a prognostic imaging biomarker in patients undergoing hemodialysis.
To investigate the feasibility of a public health center-based aerobic and resistance training program for primary prevention of cardiovascular disease in people with visual, auditory, or ...physical/brain impairments.
The study included 25 adults aged >40 years who lived in Cheorwon-gun in South Korea, had a disability registered for visual, auditory, or physical/brain impairments under the Disability Welfare Act, and had either known cardiovascular disease or two or more risk factors for cardiovascular disease. The program comprised four education sessions and 12 weeks of customized aerobic and strengthening exercises performed twice a week at moderate intensity, with each exercise session lasting for 1 hour. The body mass index (BMI), percent body fat, 6-minute walk distance (6MWD), and 30-second sit-to-stand test results were measured at baseline and on program completion.
Seventeen subjects (68%) completed the program. There were significant decreases in BMI and percent body fat (both p<0.05), with a significant increase in 30-second sit-to-stand strength (p<0.05) but no changes in the 6MWD. In subjects with visual or auditory impairments, BMI and percent body fat were significantly decreased after the program; however, there was no significant change in the results of the 30-second sit-to-stand strength test or the 6MWD.
In people with disabilities, a 3-month community-based exercise program can decrease body mass index and percent body fat and increase sit-to-stand strength. The 30-second sit-to-stand test may be a useful measure of the strength and endurance of the lower extremities in people with disabilities.
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