The prevalence of hyperuricemia and chronic kidney disease (CKD) has been steadily increasing. The role of hyperuricemia and efficacy of uric acid-lowering agents against CKD progression remain ...controversial. This study aimed to evaluate the effect of hyperuricemia and uric acid-lowering agents on the progression of CKD. A total 2042 patients with CKD were analyzed in the KoreaN cohort Study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD), a prospective cohort study. Patients were classified into quartiles on the basis of their serum uric acid level and the prevalence of advanced CKD was higher in patients with a high uric acid level. A composite renal outcome was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate during the follow-up period. A Cox proportional hazard ratio model was applied to analyze the relationship between composite renal outcome and uric acid levels. The risk of progression to renal failure increased by 28% (hazard ratio HR, 1.277; 95% confidence interval CI, 1.212-1.345) for each 1 mg/dl increase in the baseline uric acid level. In multivariate models, an association was found between the highest quartile of uric acid and increased risk of composite renal outcome (HR, 3.590; 95% CI, 2.546-5.063). A propensity score matching analysis was performed to survey the effect of uric acid lowering agent. Both allopurinol and febuxostat did not affect the renal outcome. In conclusion, hyperuricemia appears to be an independent risk factor for composite renal outcome, but allopurinol and febuxostat did not show reno-protective effect.
Symbionts play an indispensable role in gut homeostasis, but underlying mechanisms remain elusive. To clarify the role of lactic-acid-producing bacteria (LAB) on intestinal stem-cell (ISC)-mediated ...epithelial development, we fed mice with LAB-type symbionts such as Bifidobacterium and Lactobacillus spp. Here we show that administration of LAB-type symbionts significantly increased expansion of ISCs, Paneth cells, and goblet cells. Lactate stimulated ISC proliferation through Wnt/β-catenin signals of Paneth cells and intestinal stromal cells. Moreover, Lactobacillus plantarum strains lacking lactate dehydrogenase activity, which are deficient in lactate production, elicited less ISC proliferation. Pre-treatment with LAB-type symbionts or lactate protected mice in response to gut injury provoked by combined treatments with radiation and a chemotherapy drug. Impaired ISC-mediated epithelial development was found in mice deficient of the lactate G-protein-coupled receptor, Gpr81. Our results demonstrate that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISC-mediated epithelial development in a Gpr81-dependent manner.
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•Symbiont-generated lactate is critical for Lgr5+ ISC-mediated epithelial development•Lactate signals through the G-protein-coupled receptor Gpr81 to elicit ISC proliferation•Lactobacillus plantarum lacking lactate dehydrogenase fails to induce ISC regeneration•Pre-feeding of lactate protects mice from chemotherapy- and radiation-induced gut damage
Lee et al. reveal how lactic-acid-producing bacteria, including Bifidobacterium and Lactobacillus spp., support intestinal epithelial cell regeneration. Symbiont-derived lactate is sensed by G-protein-coupled receptor 81 on Paneth and stromal cells to promote regeneration in a Wnt3/ β-catenin-dependent manner. Lactate pre-administration protects mice exposed to radiation- and chemotherapy-induced intestinal damage.
Background. Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and ...prognostic factors for patients with MDR TB. Methods. This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. Results. Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index ⩾18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. Conclusions. Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.
Miniaturization of electronics demands electromagnetic interference (EMI) shielding of nanoscale dimension. The authors report a systematic exploration of EMI shielding behavior of 2D Ti3C2Tx MXene ...assembled films over a broad range of film thicknesses, monolayer by monolayer. Theoretical models are used to explain the shielding mechanism below skin depth, where multiple reflection becomes significant, along with the surface reflection and bulk absorption of electromagnetic radiation. While a monolayer assembled film offers ≈20% shielding of electromagnetic waves, a 24‐layer film of ≈55 nm thickness demonstrates 99% shielding (20 dB), revealing an extraordinarily large absolute shielding effectiveness (3.89 × 106 dB cm2 g−1). This remarkable performance of nanometer‐thin solution processable MXene proposes a paradigm shift in shielding of lightweight, portable, and compact next‐generation electronic devices.
Self‐assembly of monolayer MXene and systematic exploration of the electromagnetic interference shielding behavior of 2D Ti3C2Tx MXene are presented. Theoretical models explain the shielding mechanism below skin depth. A monolayer assembled MXene film (2.3 nm) and 24‐layer film (≈55 nm) offer ≈20% and 99% shielding, respectively. The extraordinarily large absolute shielding effectiveness reaches 3.89 × 106 dB cm2 g−1.
Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-
(PPAR
) pathway through ...adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J
mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca
/calmodulin-dependent protein kinase kinase-
(CaMKK
) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in
mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKK
, phosphorylated Ser
LKB1, phosphorylated Thr
AMPK, and PPAR
expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca
levels that activated a CaMKK
/phosphorylated Ser
LKB1/phosphorylated Thr
AMPK/PPAR
pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca
/LKB1-AMPK/PPAR
pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.
Abstract
Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with increased morbidity and mortality. Its early detection is challenging because of the low detection yield of ...conventional methods. We aimed to develop a deep learning-based algorithm to identify AF during normal sinus rhythm (NSR) using 12-lead electrocardiogram (ECG) findings. We developed a new deep neural network to detect subtle differences in paroxysmal AF (PAF) during NSR using digital data from standard 12-lead ECGs. Raw digital data of 2,412 12-lead ECGs were analyzed. The artificial intelligence (AI) model showed that the optimal interval to detect subtle changes in PAF was within 0.24 s before the QRS complex in the 12-lead ECG. We allocated the enrolled ECGs to the training, internal validation, and testing datasets in a 7:1:2 ratio. Regarding AF identification, the AI-based algorithm showed the following values in the internal and external validation datasets: area under the receiver operating characteristic curve, 0.79 and 0.75; recall, 82% and 77%; specificity, 78% and 72%; F1 score, 75% and 74%; and overall accuracy, 72.8% and 71.2%, respectively. The deep learning-based algorithm using 12-lead ECG demonstrated high accuracy for detecting AF during NSR.
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and a leading cause of cancer-related death worldwide. We propose a fully automated deep learning model to detect ...HCC using hepatobiliary phase magnetic resonance images from 549 patients who underwent surgical resection. Our model used a fine-tuned convolutional neural network and achieved 87% sensitivity and 93% specificity for the detection of HCCs with an external validation data set (54 patients). We also confirmed whether the lesion detected by our deep learning model is a true lesion using a class activation map.
Mucin-degrading bacteria are densely populated in the intestinal epithelium; however, their interaction with intestinal stem cells (ISCs) and their progeny have not been elucidated. To determine ...whether mucin-degrading bacteria play a role in gut homeostasis, mice were treated with Akkermansia muciniphila, a specialized species that degrades mucin. Administration of A. muciniphila for 4 weeks accelerated the proliferation of Lgr5
+
ISCs and promoted the differentiation of Paneth cells and goblet cells in the small intestine (SI). We found similar effects of A. muciniphila in the colon. The levels of acetic and propionic acids were higher in the cecal contents of A. muciniphila-treated mice than in PBS-treated mice. SI organoids treated with cecal contents obtained from A. muciniphila-treated mice were larger and could be diminished by treatment with G protein-coupled receptor (Gpr) 41/43 antagonists. Pre-treatment of mice with A. muciniphila reduced gut damage caused by radiation and methotrexate. Further, a novel isotype of the A. muciniphila strain was isolated from heathy human feces that showed enhanced function in intestinal epithelial regeneration. These findings suggest that mucin-degrading bacteria (e.g., A. muciniphila) may play a crucial role in promoting ISC-mediated epithelial development and contribute to intestinal homeostasis maintenance.
Mitochondria are essential organelles involved in the maintenance of cell growth and function, and have been investigated as therapeutic targets in various diseases. Recent studies have demonstrated ...that direct mitochondrial transfer can restore cellular functions of cells with inherited or acquired mitochondrial dysfunction. However, previous mitochondrial transfer methods are inefficient and time-consuming. Here, we developed a simple and easy mitochondrial transfer protocol using centrifugation, which can be applied to any cell type. By our simple centrifugation method, we found that the isolated mitochondria could be successfully transferred into target cells, including mitochondrial DNA-deleted Rho
cells and dexamethasone-treated atrophic muscle cells. We found that mitochondrial transfer normalised ATP production, mitochondrial membrane potential, mitochondrial reactive oxygen species level, and the oxygen consumption rate of the target cells. Furthermore, delivery of intact mitochondria blocked the AMPK/FoxO3/Atrogene pathway underlying muscle atrophy in atrophic muscle cells. Taken together, this simple and rapid mitochondrial transfer method can be used to treat mitochondrial dysfunction-related diseases.
Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates ...diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy.
AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to db/db mice (db + AdipoRon, n = 8) and age-matched male db/m mice (dm + AdipoRon, n = 8) from 17 weeks of age for 4 weeks. Control db/db (db cont, n = 8) and db/m mice (dm cont, n = 8) were fed a normal diet of mouse chow.
AdipoRon-fed db/db mice showed a decreased amount of albuminuria and lipid accumulation in the kidney with no significant changes in serum adiponectin, glucose, and body weight. Restoring expression of adiponectin receptor-1 and -2 in the renal cortex was observed in db/db mice with AdipoRon administration. Consistent up-regulation of phospho-Thr172 AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr473 Akt, phospho-Ser79Acetyl-CoA carboxylase (ACC), and phospho-Ser1177 endothelial NO synthase (eNOS), and down-regulation of protein phosphatase 2A (PP2A), sterol regulatory element-binding protein-1c (SREBP-1c), and inducible nitric oxide synthase (iNOS) were associated within the same group. AdipoRon lowered cellular ceramide levels by activation of acid ceramidase, which normalized ceramide to sphingosine-1 phosphate (S1P) ratio. In glomerular endothelial cells (GECs) and podocytes, AdipoRon treatment markedly decreased palmitate-induced lipotoxicity, which ultimately ameliorated oxidative stress and apoptosis.
AdipoRon may prevent lipotoxicity in the kidney particularly in both GECs and podocytes through an improvement in lipid metabolism, as shown by the ratio of ceramide to sphingosines, and further contribute to prevent deterioration of renal function, independent of the systemic effects of adiponectin. The reduction in oxidative stress and apoptosis by AdipoRon provides protection against renal damage, thereby ameliorating endothelial dysfunction in type 2 diabetic nephropathy.
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•Superfluous ceramide via decrease in acid ceramidase activity causes lipotoxicity.•Adiponectin and adiponectin receptors potentially increase ceramidase activity.•AdipoRon ameliorated renal lipotoxicity by AdipoR1-AMPK and AdipoR2-PPARα pathway.•AdipoRon is a promising tool for treatment of diabetic nephropathy in type 2 DM.
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