IGF2BP3 stabilizes SESN1 mRNA to mitigate oxidized low-density lipoprotein-induced oxidative stress and endothelial dysfunction in human umbilical vein endothelial cells by activating Nrf2 signaling.

Atherosclerosis (AS) represents a prevalent initiating factor for cardiovascular events. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein that participates in cardiovascular diseases. This work aimed to elaborate the effects of IGF2BP3 on AS and the probable mechanism by using an oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) model. Results indicated that IGF2BP3 expression was declined in the blood of AS patients and ox-LDL-induced HUVECs. IGF2BP3 elevation alleviated ox-LDL-provoked viability loss, apoptosis, oxidative DNA damage and endothelial dysfunction in HUVECs. Moreover, IGF2BP3 bound SESN1 and stabilized SESN1 mRNA. Furthermore, SESN1 interference reversed the impacts of IGF2BP3 overexpression on the apoptosis, oxidative DNA damage and endothelial dysfunction of ox-LDL-challenged HUVECs. Additionally, the activation of Nrf2 signaling mediated by IGF2BP3 up-regulation in ox-LDL-treated HUVECs was blocked by SESN1 absence. Collectively, SESN1 stabilized by IGF2BP3 might protect against AS by activating Nrf2 signaling.

Synthesis and initial evaluation of radioiodine-labelled deuterated tropane derivatives targeting dopamine transporter.

The dopamine transporter (DAT) is closely related to a variety of neurological disorders including Parkinson's disease (PD) and other neurodegenerative diseases. In vivo imaging of DAT with radio-labelled tracers has become a powerful technique in related disorders. The radioiodine-labelled tropane derivative [123I]FP-CIT ([123I]1a) is widely used in clinical single photon emission computed tomography (SPECT) imaging as a DAT imaging agent. To develop more metabolically stable DAT radioligands for accurate imaging, this work compared two novel deuterated tropane derivatives ([131I]1c-d) with non-deuterated tropane derivatives ([131I]1a-b). [131I]1a-d were obtained in high radiochemical purity (RCP) above 99 % with molar activities of 7.0-10.0 GBq/µmol. The [131I]1a and [131I]1c exhibited relatively higher affinity to DAT (Ki: 2.0-3.12 nM) than [131I]1b and [131I]1d. Biodistribution results showed that [131I]1c consistently exhibited a higher ratio of the target to non-target (striatum/cerebellum) than [131I]1a. Furthermore, metabolism studies indicated that the in vivo metabolic stability of [131I]1c was superior to that of [131I]1a. Ex vivo autoradiography showed that [131I]1c selectively localized on DAT-rich striatal regions and the specific signal could be blocked by DAT inhibitor. These results indicated that [131I]1c might be a potential probe for DAT SPECT imaging in the brain.

Rational design, synthesis, and antimicrobial evaluation of novel 1,2,4-trizaole-substituted 1,3,4-oxadiazole derivatives with a dual thioether moiety.

In this paper, a series of novel 1,2,4-trizaole-substituted 1,3,4-oxadiazole derivatives with a dual thioether moiety were constructed. The synthetic compounds were characterized by 1H NMR, 13C NMR, HRMS, and single crystal diffraction. The antimicrobial activities of title compounds against fungi (Pyricutaria oryzae Cav., Phomopsis sp., Botryosphaeria dothidea, cucumber Botrytis cinerea, tobacco Botrytis cinerea, blueberry Botrytis cinerea) and bacteria (Xanthomonas oryzae pv. oryzicola, Xoc; Xanthomonas axonopodis pv. citri, Xac) revealed these compounds possessed excellent antibacterial activity through mycelial growth rate method and turbidity method, respectively. Among them, compounds 7a, 7d, 7g, 7k, 7l, and 7n had the antibacterial inhibition rate of 90.68, 97.86, 93.61, 97.70, 97.26, and 92.34%, respectively. The EC50 values of 7a, 7d, 7g, 7k, 7l, and 7n were 58.31, 48.76, 58.50, 40.11, 38.15, and 46.99 µg/mL, separately, superior to that of positive control pesticide thiodiazole copper (104.26 µg/mL). The molecular docking simulation of compound 7l and glutathione s-transferase also confirmed its good activity. The in vivo bioassay toward Xac infected citrus leaves was also performed to evaluate the potential of compounds as efficient antibacterial reagent. Further study of antibacterial mechanism was also carried out, including extracellular polysaccharide production, permeability of bacterial membrane, and scanning electron microscope observations. The excellent antibacterial activities of these compounds provided a strong support for its application for preventing and control plant diseases.

Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity.

Manganese (Mn) is an essential metal that induces incurable parkinsonism at elevated levels. However, unlike other essential metals, mechanisms that regulate mammalian Mn homeostasis are poorly understood, which has limited therapeutic development. Here, we discovered that the exposure of mice to a translationally relevant oral Mn regimen up-regulated expression of SLC30A10, a critical Mn efflux transporter, in the liver and intestines. Mechanistic studies in cell culture, including primary human hepatocytes, revealed that 1) elevated Mn transcriptionally up-regulated SLC30A10, 2) a hypoxia response element in the SLC30A10 promoter was necessary, 3) the transcriptional activities of hypoxia-inducible factor (HIF) 1 or HIF2 were required and sufficient for the SLC30A10 response, 4) elevated Mn activated HIF1/HIF2 by blocking the prolyl hydroxylation of HIF proteins necessary for their degradation, and 5) blocking the Mn-induced up-regulation of SLC30A10 increased intracellular Mn levels and enhanced Mn toxicity. Finally, prolyl hydroxylase inhibitors that stabilize HIF proteins and are in advanced clinical trials for other diseases reduced intracellular Mn levels and afforded cellular protection against Mn toxicity and also ameliorated the in vivo Mn-induced neuromotor deficits in mice. These findings define a fundamental homeostatic protective response to Mn toxicity-elevated Mn levels activate HIF1 and HIF2 to up-regulate SLC30A10, which in turn reduces cellular and organismal Mn levels, and further indicate that it may be possible to repurpose prolyl hydroxylase inhibitors for the management of Mn neurotoxicity.

Vitamin D nutritional status in early pregnancy and its relationship with periconceptional multiple micronutrients supplementation.

BACKGROUND AND OBJECTIVES: To assess the vitamin D nutritional status (VDN) of pregnant women in early pregnancy and investigate the effects of periconceptional supplementation with multiple micronutrients (MMs) on this status. METHODS AND STUDY DESIGN: Data were taken from the Pregnancy Health Care System and Hospital Information System in 2018 in Beijing. Vitamin D nutritional status in early pregnancy was evaluated among 4,978 pregnant women, and 4,540 women who took folic acid only (FA) or multiple mi-cronutrients supplements (MM) during the periconceptional period, were include to estimate the associations between periconceptional supplementation with MM and prevalence of vitamin D deficiency or insufficiency with logistic regression model. RESULTS: The mean early-pregnancy vitamin D concentration was 18.6 (±7.5) ng/mL, and the rates of deficiency and insufficiency were 31.6% and 60.5%, respectively. Compared to the FA group, the adjusted odds ratio (aOR, 95%confidence interval, CI) for insufficiency or deficiency of the MM group were 0.25(0.18-0.34), and the aOR (95%CI) for deficiency of the MM group were 0.17 (0.12-0.23). Women who took MMs for a longer period of time, at higher frequencies, and with higher compliance scores had lower rates of deficiency and insufficiency. In winter, spring, and autumn, taking MMs could reduce deficiency by about 70%; in summer, there was little effect. CONCLUSIONS: Among women in Beijing, serum concentrations of vitamin D in early pregnancy are relatively low, and the rates of deficiency and insufficiency are high. Taking MMs during the periconceptional period could improve this situation.

Visible-Light Photocatalytic Synthesis of Difluoromethylated Selenides from Selenosulfonates through a Radical Process.

A photocatalytic synthesis of difluoromethylated selenides from selenosulfonates is described here. Bench-stable difluoromethyl phosphonium salt [Ph3PCF2H]Br reacts smoothly with selenosulfonates to give a series of functionalized difluoromethylated selenides in moderate to good yields via a radical process. This protocol is free of a stoichiometric base and reductant, has tolerance of functional groups, and has successful late-stage modification of bioactive molecules, which provides facile access to molecules of pharmaceutical relevance.

Healing Diabetic Ulcers with MoO3-X Nanodots Possessing Intrinsic ROS-Scavenging and Bacteria-Killing Capacities.

Diabetic ulcers (DUs) appearing as chronic wounds are difficult to heal due to the oxidative stress in the wound microenvironment and their high susceptibility to bacterial infection. A routine treatment combining surgical debridement with anti-infection therapy is widely used for treating DUs in the clinic, but hardly offers a satisfying wound healing outcome. It is known that a long-term antibiotic treatment may also lead to the drug resistance of pathogens. To address these challenges, new strategies combining both reactive oxygen species (ROS) scavenging and bacterial sterilization have been proposed for fighting against DUs. Following this idea, oxygen deficient molybdenum-based nanodots (MoO3-X ) for healing the DUs are reported. The ROS scavenging ability of MoO3-X nanodots is investigated and the antibacterial property of the nanodots is also demonstrated. The systematic cell and animal experimental results indicate that the MoO3-X nanodots can effectively reduce inflammation, promote epithelial cell regeneration, accelerate angiogenesis, and facilitate DUs recovery. Most importantly, they present excellent capacity to diminish infection of methicillin-resistant Staphylococcus aureus, manifesting the potent application prospect of MoO3-X nanodots for diabetic wound therapy.

Synthesis and biological evaluation of 18F-labelled dopamine D3 receptor selective ligands.

The dopamine D3 receptor (D3R) is highly expressed in the limbic regions of the brain and closely related to a variety of neurological disorders including Parkinson's disease, schizophrenia and drug-seeking behavior. In vivo imaging of D3R with radio-labelled tracers and positron emission tomography (PET) has become a powerful technique in related disorders. In this study, we synthesized three novel aromatically 18F-labelled phenylpiperazine-like D3R selective radioactive ligands ([18F]5b, [18F]8b and [18F]11b) and developed a simple, rapid and efficient 18F-labelling method by condition optimization. Radiosynthesis of [18F]5b, [18F]8b and [18F]11b was achieved by 18F-fluorination from nitroarene precursors. Final radiochemical purities of [18F]5b, [18F]8b and [18F]11b solution were > 99% and remained good stability (> 98% for up to 6 h) in PBS and FBS. PET imaging and cellular binding studies revealed that [18F]8b had a higher D3R affinity than [18F]5b and [18F]11b. Autoradiography and biodistribution studies of the brain showed that [18F]8b had medium intensity specific accumulation in the striatum and cortex. Meanwhile, the low skeletal uptake of [18F]8b revealed a good in vivo stability with negligible defluorination. These results indicated that [18F]8b might be a potential 18F-labelled D3R PET imaging agent.

Reduced expression of lipoxygenase genes improves flour processing quality in soft wheat.

Lipoxygenases (Loxs) are dioxygenases that play an important role in plant growth and defense. Loxs affect flour processing quality in common wheat (Triticum aestivum). We conducted a genome-wide association study (GWAS) that identified 306 significant single-nucleotide polymorphisms (SNPs) related to Lox activity in Chinese wheat accessions. Among them, a novel lipoxygenase-encoding (Lpx) gene, TaLpx-B4, was detected on chromosome 3B in a biparental population. Analysis of mutant wheat lines induced using ethyl methanesulfonate confirmed the role of TaLpx-B4 in modulating Lox activity. A phylogenetic tree of various plant Lpx genes indicated the predominance of the 9-Lpx type in common wheat. Further analysis revealed conserved intron number, exon length, and motif number in the TaLpx gene family. GWAS, linkage mapping, and gene annotation collectively showed that 14 out of 29 annotated TaLpx genes played a critical role in regulating Lox activity in the Chinese wheat accessions. Transgenic wheat grains with knockdown of Lpx family genes by RNAi showed significantly lower Lox activity than the wild type. One TaLpx-RNAi line had significantly reduced starch content and dough stability, and thus possessed relatively superior biscuit quality in soft wheat. Further analysis of the transcriptome, lipid components, and other metabolites revealed that knockdown of TaLpx genes significantly increased biscuit quality via changes in unsaturated fatty acid content as well as in starch, sucrose, and galactose metabolism. Our results provide new insights into the role of the TaLpx gene family that will be beneficial in improving soft wheat flour quality.

Nucleophilic Substitution of Selenosulfonates with Me3SiCF2Br: Facile and Efficient Access to Bromodifluoromethylated Selenides under Metal-Free Conditions.

A facile synthesis of bromodifluoromethylated selenides under metal-free conditions is described here. Commercially available Me3SiCF2Br and bench-stable selenosulfonates react smoothly to give a broad scope of alkyl- and aryl-substituted bromodifluoromethylated selenides in moderate to good yields via a difluorocarbene intermediate. This protocol features a short reaction time, the absence of toxic waste, good scalability, and successful late-stage modification of bioactive molecules. In addition, the title products can be easily converted to different fluorinated and 18F-labeled selenides.

SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity.

The essential metal manganese becomes neurotoxic at elevated levels. Yet, the mechanisms by which brain manganese homeostasis is regulated are unclear. Loss-of-function mutations in SLC30A10, a cell surface-localized manganese efflux transporter in the brain and liver, induce familial manganese neurotoxicity. To elucidate the role of SLC30A10 in regulating brain manganese, we compared the phenotypes of whole-body and tissue-specific Slc30a10 knockout mice. Surprisingly, unlike whole-body knockouts, brain manganese levels were unaltered in pan-neuronal/glial Slc30a10 knockouts under basal physiological conditions. Further, although transport into bile is a major route of manganese excretion, manganese levels in the brain, blood, and liver of liver-specific Slc30a10 knockouts were only minimally elevated, suggesting that another organ compensated for loss-of-function in the liver. Additional assays revealed that SLC30A10 was also expressed in the gastrointestinal tract. In differentiated enterocytes, SLC30A10 localized to the apical/luminal domain and transported intracellular manganese to the lumen. Importantly, endoderm-specific knockouts, lacking SLC30A10 in the liver and gastrointestinal tract, had markedly elevated manganese levels in the brain, blood, and liver. Thus, under basal physiological conditions, brain manganese is regulated by activity of SLC30A10 in the liver and gastrointestinal tract, and not the brain or just the liver. Notably, however, brain manganese levels of endoderm-specific knockouts were lower than whole-body knockouts, and only whole-body knockouts exhibited manganese-induced neurobehavioral defects. Moreover, after elevated exposure, pan-neuronal/glial knockouts had higher manganese levels in the basal ganglia and thalamus than controls. Therefore, when manganese levels increase, activity of SLC30A10 in the brain protects against neurotoxicity.

Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice.

The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

A hybrid model combining wavelet transform and recursive feature elimination for running state evaluation of heat-resistant steel using laser-induced breakdown spectroscopy.

Heat-resistant steel is widely used in various industries, and the running state is of great importance for equipment function and safety. In this work, laser-induced breakdown spectroscopy (LIBS) is applied to evaluate the running state of steel using indicators of micro and macro properties. The hybrid model based on wavelet threshold denoising (WTD) and K-fold-support vector machine-recursive feature elimination (K-SVM-RFE) is proposed to estimate the different indictors of various service conditions of steel. Fourteen T91 specimens, including 4 industrial specimens obtained from different service conditions in the power plant boiler, were used as the analytes. Firstly, the noise signal of the LIBS spectra of each specimen was analyzed and removed with WTD. Secondly, an improved approach K-SVM-RFE was applied to select the optimal feature subset and build the classification models of aging grade and hardness grade. The influence of denoising pretreatment on model performance was compared and discussed. Finally, the assessment matrix, established using the indicators from the aging grade and hardness grade, was used to evaluate the running state of steel. The results show that the test assessment matrix obtained with the hybrid model based on WTD and K-SVM-RFE is consistent with the reference matrix on the running state of steel.

Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production.

SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction.

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice.

Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology.

Association of Single-Nucleotide Polymorphisms of C-Reactive Protein Gene with Susceptibility to Infantile Sepsis in Southern China.

BACKGROUND C-reactive protein (CRP) is an important biomarker of sepsis. Several single-nucleotide polymorphisms (SNPs) in the CRP gene can determine plasma CRP levels and are risk factors in many diseases, such as cancer, arteritis, and diabetes. However, it is unknown whether polymorphisms in CRP are associated with susceptibility to and outcome of infantile sepsis. We explored the effect of these SNPs on CRP response in infantile sepsis, and compared genetic data on patients with sepsis. MATERIAL AND METHODS A total of 49 infants with sepsis and 20 healthy infants were enrolled during hospitalization, and 3 SNPs in the CRP gene region (rs1205, rs2808530, and rs3091244) were genotyped and then analyzed for associations with CRP levels and sepsis. RESULTS The CRP means concentration results showed that mean CRP concentration was different in the 4 groups (healthy, sepsis, severe sepsis, and septic shock) and was positively correlated with the severity of infantile sepsis. There was also a difference in CRP SNP rs1205 between infants with septic shock and healthy infants, and between infants with septic shock and infants with sepsis. No differences were observed in SNP rs2808630 and SNP rs3091244. CONCLUSIONS Our study suggests that rs1205 genetic variability in the CRP gene determines the CRP levels in sepsis of different severities, while SNP rs3091244 and SNP rs2808630 are not associated with sepsis. However, the results of the present study on SNP rs1205, rs3091244, and rs2808630 in the CRP gene should be interpreted with caution due to limited sample size and sample heterogeneity. Large-scale, well-designed studies are needed to validate our findings.

Engineering Fast Ion Conduction and Selective Cation Channels for a High-Rate and High-Voltage Hybrid Aqueous Battery.

The rechargeable aqueous metal-ion battery (RAMB) has attracted considerable attention due to its safety, low costs, and environmental friendliness. Yet the poor-performance electrode materials lead to a low feasibility of practical application. A hybrid aqueous battery (HAB) built from electrode materials with selective cation channels could increase the electrode applicability and thus enlarge the application of RAMB. Herein, we construct a high-voltage K-Na HAB based on K2 FeFe(CN)6 cathode and carbon-coated NaTi2 (PO4 )3 (NTP/C) anode. Due to the unique cation selectivity of both materials and ultrafast ion conduction of NTP/C, the hybrid battery delivers a high capacity of 160 mAh g-1 at a 0.5 C rate. Considerable capacity retention of 94.3 % is also obtained after 1000 cycles at even 60 C rate. Meanwhile, high energy density of 69.6 Wh kg-1 based on the total mass of active electrode materials is obtained, which is comparable and even superior to that of the lead acid, Ni/Cd, and Ni/MH batteries.

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription.

B cells are the center of humoral immunity and produce Abs to protect against foreign Ags. B cell defects lead to diseases such as leukemia and lymphomas. Histone arginine methylation is important for regulating gene activation and silencing in cells. Although the process commonly exists in mammalian cells, its roles in B cells are unknown. To explore the effects of aberrant histone arginine methylation on B cells, we generated mice with a B cell-specific knockout of PRMT7, a member of the methyltransferases that mediate arginine methylation of histones. In this article, we showed that the loss of PRMT7 led to decreased mature marginal zone B cells and increased follicular B cells and promoted germinal center formation after immunization. Furthermore, mice lacking PRMT7 expression in B cells secreted low levels of IgG1 and IgA. Abnormal expression of germinal center genes (i.e., Bcl6, Prdm1, and Irf4) was detected in conditional knockout mice. By overexpressing PRMT7 in the Raji and A20 cell lines derived from B cell lymphomas, we validated the fact that PRMT7 negatively regulated Bcl6 expression. Using chromatin immunoprecipitation-PCR, we found that PRMT7 could recruit H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter. These results provide evidence for the important roles played by PRMT7 in germinal center formation.

Hepatitis C virus infection increases the risk of developing peripheral arterial disease: a 9-year population-based cohort study.

BACKGROUND & AIMS: The relationship between hepatitis C virus (HCV) infection and peripheral arterial disease (PAD) development remains unclear. METHODS: Health insurance claims data were used to construct a cohort of HCV-infected patients diagnosed during the period 1998-2011. Patients younger than 20 years and those with history of hepatitis B or PAD were excluded. We selected 7641 HCV-infected patients and 30564 matched controls. The adjusted risk of developing PAD was analyzed using a multivariate Cox hazard model. RESULTS: The results show that the excess risk of PAD development in HCV-infected patients is 1.43-fold higher (95% CI=1.23-1.67) compared with non-HCV patients. The adjusted risk of PAD development increases with age; compared with the 20-34 year-old patients, the risk is 3.96-fold higher in HCV-infected patients aged 35-49 years, and 11.7-fold higher in those aged 65 years and above. CKD/ESRD has the highest risk for PAD (HR=1.80, 95% CI=1.29-2.53). HCV-infected patients with four comorbidities exhibit a substantially higher risk of developing PAD (HR=9.25, 95% CI=6.35-13.5). Excess risk of developing PAD is observed from the first year of follow-up till the third year. CONCLUSION: HCV-infected patients have an independently higher risk of developing PAD. HCV-infected patients with comorbidity have increased risk of developing PAD.