Single-cell transcriptomics reveals variations in monocytes and Tregs between gout flare and remission.

Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.

Investigation of Structural Energy Absorption Performance in 3D-Printed Polymer (Tough 1500 Resin) Materials with Novel Multilayer Thin-Walled Sandwich Structures Inspired by Peano Space-Filling Curves.

Inspired by Peano space-filling curves (PSCs), this study introduced the space-filling structure design concept to novel thin-walled sandwich structures and fabricated polymer samples by 3D printing technology. The crushing behaviors and energy absorption performance of the PSC multilayer thin-walled sandwich structures and the traditional serpentine space-filling curve (SSC) multilayer thin-walled sandwich structures were investigated using quasi-static compression experiments and numerical analysis. Taking the initial peak crushing force (IPF), specific energy absorption (SEA), and crushing force efficiency (CFE) as evaluation criteria, the effects of geometric parameters, including the curve order, layer height, septa thickness, and wall thickness, on energy absorption performance were comprehensively examined. The results indicated that the energy absorption capacity of the PSC structure was significantly enhanced due to its complex hierarchy. Specifically, the second-order PSC structure demonstrated a 53.2% increase in energy absorption compared to the second-order SSC structure, while the third-order PSC structure showed more than a six-fold increase in energy absorption compared to the third-order SSC structure. Furthermore, a multi-objective optimization method based on the response surface method and the NSGA-II algorithm were employed to optimize the wall thickness and layer height of the proposed novel PSC structures. The optimal solutions suggested that a reasonable wall thickness and layer height were two important factors for designing PSC structures with better energy absorption performance. The findings of this study provide an effective guide for using the space-filling concept with Peano curves for the design of a novel polymer thin-walled energy absorber with high energy absorption efficiency.

ORM1 promotes tumor progression of kidney renal clear cell carcinoma (KIRC) through CALR-mediated apoptosis.

Kidney renal clear cell carcinoma (KIRC) is the most prevalent type of kidney cancer and causes thousands of deaths each year. The prognosis for KIRC is poor. One critical factor is that the mechanism beneath KIRC is unclear. ORM1 is a reactant to acute inflammation. In this study, we demonstrated that methylation of ORM1 promoter was low and ORM1 was expressed significantly higher in KIRC. KIRC with higher ORM1 expression exhibited worse survival probability. Meanwhile, ORM1 was expressed higher in KIRC cell lines. When ORM1 was knocked down, cell proliferation ability was inhibited potently compared to the NC control. Cell migration as well as invasion ability were also suppressed dramatically. At molecular level, the expression of active caspase-3 and Bax was upregulated in ORM1-KD group while Bcl-2 downregulated. Moreover, CALR decreased following ORM1-KD and rescued expression of CALR increased Bcl-2 level but reduced the level of cleaved caspase-3 and Bax. Consistently, the apoptotic rate of 786-O and Caki-2 cells was upregulated in ORM1-KD but downregulated after CALR overexpression. The activity of caspase-3 was also regulated by ORM1-KD. In addition, the inhibition rate of sorafenib was enhanced in ORM1 KD group but reduced after overexpression of ORM1. Conclusively, ORM1 is clinically associated with progression of KIRC and regulates cell proliferation, migration, invasion, and apoptosis in KIRC. Moreover, ORM1 affects the efficiency of sorafenib in KIRC and regulates caspase-3 mediated cascades response through CALR molecule. This study provides us a new way to recognize the development and progression in KIRC.

Effect of hip CPM on gross motor function and development of the hip joint: a single-center randomized controlled study on spastic cerebral palsy children with hip dysplasia.

Objective: To investigate the effectiveness of hip continuous passive motion (hCPM) on hip development at skeletal maturity and gross motor function for spastic cerebral palsy children with hip dysplasia. Methods: Prospective case-control research of hCPM with goal-directed training versus merely goal-directed training. On the basis of goal-directed training, the hCPM group used the hip joint CPM instrument (the external fixator was connected to the power device to make the hip joint carry out continuous passive movement) for 40-60 min, twice a day, and five times a week, and received continuous training for 8 weeks simultaneously. The control group received only goal-directed training for 8 weeks. Functional outcomes pertaining to the affected hip joints were assessed via gross motor function measure (GMFM), migration percentage (MP), acetabular index (AI), and Harris hip functional score (HHS) at the time of enrollment and the end of the intervention. Results: The case-control research included 65 participants (mean age = 46.20 months, SD = 17.09 months; Gross Motor Function Grading System level: III = 41, IV = 24) who were randomly selected to either the hCPM (n = 45) or the control group (n = 20). No differences were found in baseline (acquisition phase) GMFM, MP, AI, or HHS (t = -1.720, P = 0.090; t* = 1.836, P* = 0.071; t# = -1.517, P# = 0.139; t* = -1.310, P* = 0.195; t# = -1.084, P# = 0.097; t = -1.041, P = 0.301). At the 8-week follow-up, GMFM, MP, AI, and HHS significantly improved over baseline in the hCPM group (hCPM group: t = 18.59, 20.172*, 40.291#, 16.820*, 32.900#, 28.081; P < 0.001). Between-group differences at 8-week follow-up times points favored the hCPM group for GMFM (t = -2.637, P = 0.011), MP (t* = 2.615, P* = 0.014; t# = 3.000, P# = 0.006), AI (t* = 2.055, P* = 0.044; t# = 2.223, P# = 0.030), HHS (t = -4.685, P < 0.001) (*: left side; #: right side). Conclusion: Spastic cerebral palsy children with hip dysplasia achieved meaningful functional improvement after 8 weeks of goal-directed training with hCPM therapy.

Performance of 3D-Printed Bionic Conch-Like Composite Plate under Low-Velocity Impact.

Biological armors can provide an effective protection against predators. In this study, inspired by conch shell, beetle exoskeleton, and nacre, three different types of bionic composites plates were fabricated: Bio-S, Bio-B, and Bio-N, as well as an equivalent monolithic plate formed from the same stiff material designed and manufactured by additive manufacturing, respectively. Low velocity impact tests using drop tower were conducted to study their impact resistance. Experimental findings indicated that the Bio-S composite had superior impact resistance compared with the other bionic composites and the monolithic plate. Furthermore, the influence of the ply angle on the impact resistance of the Bio-S composite plate was investigated. The (0°/30°/0°/30°) arrangement was able to provide the highest impact resistance. Finally, the crack propagation mode in Bio-S composites plates was analyzed, enhancing our understanding of the underlying mechanisms during impact. Such findings may lead to the development of superior lightweight protective structures with improved anti-impact performance.

A 3D-Printed Sole Design Bioinspired by Cat Paw Pad and Triply Periodic Minimal Surface for Improving Paratrooper Landing Protection.

Paratroopers are highly susceptible to lower extremity impact injuries during landing. To reduce the ground reaction force (GRF), inspired by the cat paw pad and triply periodic minimal surface (TPMS), a novel type of bionic cushion sole for paratrooper boots was designed and fabricated by additive manufacturing. A shear thickening fluid (STF) was used to mimic the unique adipose tissue with viscoelastic behavior found in cat paw pads, which is formed by a dermal layer encompassing a subcutaneous layer and acts as the primary energy dissipation mechanism for attenuating ground impact. Based on uniaxial compression tests using four typical types of cubic TPMS specimens, TPMSs with Gyroid and Diamond topologies were chosen to fill the midsole. The quasi-static and dynamic mechanical behaviors of the bionic sole were investigated by quasi-static compression tests and drop hammer tests, respectively. Then, drop landing tests at heights of 40 cm and 80 cm were performed on five kinds of soles to assess the cushioning capacity and compare them with standard paratrooper boots and sports shoes. The results showed that sports shoes had the highest cushioning capacity at a height of 40 cm, whereas at a height of 80 cm, the sole with a 1.5 mm thick Gyroid configuration and STF filling could reduce the maximum peak GRF by 15.5% when compared to standard paratrooper boots. The present work has implications for the design of novel bioinspired soles for reducing impact force.

Metabolomics analysis of human plasma reveals decreased production of trimethylamine N-oxide retards the progression of chronic kidney disease.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all-cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood. EXPERIMENTAL APPROACH: Plasma from patients with uraemia and from healthy controls (n = 30 per group) was analysed with LC-MS/MS-based non-targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort (n = 195) by quantitative analysis of the markers, using LC-MS/MS. The most promising marker was identified by correlation analysis and further validated using HK-2 cells and mouse models. KEY RESULTS: Trimethylamine N-oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK-2 cells with TMAO decreased cell viability and up-regulated expression of α-smooth muscle actin. In mice, a TMAO-containing diet decreased kidney mass and increased protein expression of α-smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3-dimethyl-1-butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD. CONCLUSION AND IMPLICATIONS: Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.

Uremic toxin indoxyl sulfate induces dysfunction of vascular smooth muscle cells via integrin-ß1/ERK signaling pathway.

BACKGROUND: Protein-bound uremic toxins (PBUTs) are reported to be one of the major culprits in chronic kidney disease-cardiovascular disease (CKD-CVD) development, yet its mechanism is not fully clear. Our previous study confirmed elevated expression of integrin-ß1 (ITGß1) in vascular smooth muscle cells of uremic patients. Thus, this study aimed to explore the relationship between PBUTs and ITGß1 in uremic vasculature injury. METHODS: Human umbilical vein smooth muscle cells (HUVSMCs) and endothelial cells (HUVECs) were treated with two representative PUBTs, indoxyl sulfate (IS) and p-cresyl sulfate (PC). Both cells were measured for the expression of ITGß1 and downstream signaling pathways and assayed for proliferation, migration, adhesion and apoptosis. RESULTS: The IS treatments were observed with significantly up-regulated ITGß1 in HUVSMCs but not in HUVECs, while PC did not induce ITGß1 alteration in either HUVSMCs or HUVECs. Furthermore, overexpression of ITGß1 revealed activated downstream signal-regulated kinase (ERK) signaling pathway with promoted focal adhesion, migration, proliferation but no apoptosis in HUVSMCs by IS. These functional and pathway alterations could be significantly suppressed by RNA interference of ITGß1. More importantly, the application of ERK1/2 inhibitor significantly suppressed the focal adhesion, migration and proliferation of HUVSMCs. CONCLUSION: We first demonstrated that ITGß1/ERK signaling pathway mediated abnormal focal adhesion, migration and proliferation of vascular smooth muscle cells stimulated by IS. ITGß1/ERK signaling may serve as a novel therapeutic target for CKD-CVD.

Exploration of Hierarchical Metal-Organic Framework as Ultralight, High-Strength Mechanical Metamaterials.

Due to the extraordinarily high surface to volume ratio and enormous structural and chemical diversities, metal-organic frameworks (MOFs) have drawn much attention in applications such as heterogeneous catalysis, gas storage separation, and drug delivery, and so on. However, the potential of MOF materials as mechanical metamaterials has not been investigated. In this work, we demonstrated that through the concerted effort of molecular construct and mesoscopic structural design, hierarchical MOFs can exhibit superb mechanical properties. With the cutting-edge in situ transmission and scanning electron microscope (TEM and SEM) techniques, the mechanical properties of hollow UiO-66 octahedron particles were quantitatively studied by compression on individual specimens. Results showed that the yield strength and Young's modulus of the hierarchical porous framework material presented a distinct "smaller is stronger and stiffer" size dependency, and the maximum yield strength and Young's modulus reached 580 ± 55 MPa and 4.3 ± 0.5 GPa, respectively. The specific strengths were measured as 0.15 ± 0.03 to 0.68 ± 0.11 GPa g-1 cm3, which is comparable to the previously reported state-of-the-art mechanical metamaterials like glassy carbon nanolattices and pyrolytic carbon nanolattices. This work revealed that MOF materials can be made into a new class of low-density, high-strength mechanical metamaterials and provided insight into the mechanical stability of nanoscale MOFs for practical applications.

Histopathological and proteomic analyses identify integrin-ß1 as a potential mediator of phlebosclerosis in uremic patients.

BACKGROUND: Patients with uremia have an excessive mortality from cardiovascular disease (CVD). Arterial remodeling is mainly responsible for uremia-induced CVD and has been well studied, yet venous remodeling is poorly understood. Here we investigate the histopathology and proteomic profiles of venous remodeling in uremic patients. METHODS: Forearm cephalic veins were isolated from nine uremic patients during surgeries for arteriovenous fistula, and from nine healthy controls when applying surgical debridement. Hematoxylin-eosin, Masson's trichrome, von Kossa, and immunohistochemistry (IHC) against proliferating cell nuclear antigen were stained for histopathology. Isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis was executed to explore the proteome of the veins. The core regulatory protein was validated by western blot, IHC, and immunofluorescence. RESULTS: Phlebosclerosis, characterized by intimal rarefaction and medial thickening with disordered proliferation of vascular smooth muscle cells (VSMCs), was the prominent pathological manifestation of peripheral veins in uremic patients, while inflammatory cell infiltration, atherosclerosis or calcification were not obviously detected. iTRAQ analysis showed that 350 proteins were significantly changed in phlebosclerosis of uremic patients compared with healthy controls, of which integrin-ß1 (ITGß1) exhibited the strongest regulatory ability by intermolecular interaction network analysis. The enhanced ITGß1 expression was mainly co-expressed with the disordered proliferation of VSMCs while a little with vascular endothelial cells in the forearm cephalic veins of uremic patients. CONCLUSIONS: Phlebosclerosis is the prominent pathological manifestation in peripheral veins of uremic patients. This pathological alteration mainly attributes to the disordered proliferation of VSMCs, which is potentially mediated by ITGß1.

Metabolitic profiling of amino acids in paraquat-induced acute kidney injury.

BACKGROUND: The herbicide paraquat (1, 1'-dimethyl-4, 4'-bipyridylium dichloride; PQ) is a poison well-known to cause delayed mortality due to acute kidney injuries (AKI). This study examines the changes in serum amino acids (AAs) metabolite profiles as surrogate markers of renal cell metabolism and function after paraquat poisoning. METHODS: To identify the metabolic profiling of free serum AAs and its metabolites, serum from 40 paraquat-poisoned patients with or without AKI is collected. LC-MS/GC-MS is performed to analyze AA molecules. A Cox proportional hazard model was used to assess for incidence of AKI. Receiver operating characteristic (ROC) curve is applied to evaluate AKI occurrence and prognosis. RESULTS: A total of 102 serum AAs and its metabolites were identified. Compared with non-AKI patients, 37 varied significantly in AKI patients. The univariate Cox proportional hazard model analysis revealed that the estimated PQ amount, plasma PQ concentration, urine PQ concentration, APACHE, SOFA scores and 16 amino acids correlated with the incidence of AKI. Further analyses revealed that 3-methylglutarylcarnitine, 1-methylimidazoleacetate, and urea showed higher cumulative hazard ratios for the occurrence of AKI during follow-up (P < 0.05). The area under the curve (AUC) of 3-methylglutarylcarnitine, 1-methylimidazoleacetate and urea were 0.917, 0.857, 0.872, respectively. CONCLUSION: 3-methylglutarylcarnitine, 1-methylimidazoleacetate and urea were associated with AKI in patients with paraquat intoxication.

Mechanical Behaviors of Flax Fiber-Reinforced Composites at Different Strain Rates and Rate-Dependent Constitutive Model.

Flax fiber-reinforced composites (FFRCs) exhibit excellent environmentally friendly qualities, such as light weight, low cost, recyclability, and excellent mechanical properties. Understanding the dynamic mechanical behavior of FFRCs could broaden their potential applications in lightweight, crashworthy, and impact-critical structures. This study presents a study on the fabrication of FFRCs by vacuum-assisted resin infusion. The dynamic stress⁻strain responses of the fabricated specimens at strain rates ranging from 0.006 s-1 to 2200 s-1 were evaluated using quasi-static tests and the Split⁻Hopkinson pressure bar (SHPB). The results indicated that the FFRC exhibited superior strain rate sensitivity. Final deformation photographs and scanning electron micrographs clearly revealed the damage evolution of the FFRC specimens, as well as various failure mechanisms, including fiber⁻matrix debonding, fiber pull-out, and fiber fracture at different strain rates. On the basis of the experimental results, a simplified Johnson⁻Cook model was established to describe the strain-rate dependent constitutive model of FFRC. The validation of the suggested constitutive model was embedded in the finite element simulations and could well repeat the strain wave observed from the experiment results. Finally, the quasi-static compression and drop-hammer impact of pyramidal lattice structures with FFRC cores were investigated both numerically and experimentally, proving the effectiveness of the simplified Johnson⁻Cook model. This study could potentially contribute to a deeper understanding of the dynamic mechanical behavior of FFRCs and provide fundamental experimental data for future engineering applications.

Metabolic Profiling of Amino Acids Associated with Mortality in Patients with Acute Paraquat Poisoning.

BACKGROUND Paraquat is a major cause of fatal poisoning after ingestion in many parts of Asia and the Pacific nations. However, optimal prognostic indicators to evaluate patient mortality have not been unequivocally established. Following acute paraquat poisoning, a number of amino acids (AA), are abnormally expressed in metabolic pathways. However, the alterations in AA metabolite levels after paraquat poisoning remain unknown in humans. MATERIAL AND METHODS In the present study, 40 patients were enrolled, of whom 16 survived and 24 died. A metabolomics approach was used to assess changes in AA metabolites in plasma and its potential prognostic value following paraquat poisoning. Mass spectrometry (MS) based on metabolite identification was conducted. RESULTS Twenty-five AA levels in plasma were abnormally expressed in non-survivor patients. Among them, creatinine, indolelactate, and 3-(4-hydroxyphenyl)lactate were found to be highly correlated with paraquat death prediction. It was noted that the intensity levels of these 3 AA metabolites in the non-survivor group were substantially higher than in the survivor group. Furthermore, we examined receiver operating characteristic (ROC) curves for clinical validation. ROC results showed that 3-(4-hydroxyphenyl)lactate had the highest AUC of 0.84, while indolelactate and creatinine had AUCs of 0.75 and 0.83, respectively, suggesting that they can be used to predict the clinical outcome (although this methodology is expensive to implement). CONCLUSIONS Metabolic profiling of AA levels could be a reliable tool to identify effective indicators for the early high precision prognosis of paraquat poisoning.

Treatment Outcome of Combined Continuous Venovenous Hemofiltration and Hemoperfusion in Acute Paraquat Poisoning: A Prospective Controlled Trial.

OBJECTIVES: To investigate whether combined continuous venovenous hemofiltration and hemoperfusion among paraquat-poisoned patients would improve survival. DESIGN: Prospective, controlled interventional study over 4 years. SETTING: Single, tertiary, academic medical center. PATIENTS: We recruited patients admitted to Shanghai Tenth People's Hospital within 48 hours after paraquat ingestion. Exclusions were under 14 years old, ingestion of paraquat with other toxicants, pregnant, a history of chronic pulmonary disease, psychosis, hyperthyroidism, or diabetes with impaired liver or renal function. INTERVENTIONS: All patients were assigned to receive continuous venovenous hemofiltration with hemoperfusion therapy (continuous venovenous hemofiltration group) and to receive conventional therapy (conventional group). The study outcomes were death from any cause within 90 days after paraquat ingestion and the frequencies of hypoxia, acute kidney injury, or adverse events. MEASUREMENTS AND MAIN RESULTS: Of the 110 enrolled patients, 59 were assigned to continuous venovenous hemofiltration group and 51 to conventional group. The two groups had similar baseline demographics and clinical features. At 90 days after paraquat ingestion, 19 of 59 patients (32.2%) in the continuous venovenous hemofiltration group and 29 of 51 patients (56.9%) in the conventional group had died (hazard ratio, 0.43; 95% CI, 0.24-0.76; p = 0.004). In multivariable Cox proportional hazard models controlling for baseline characteristics, combined continuous venovenous hemofiltration and hemoperfusion was independently associated with reduced risk of death compared with conventional therapy (adjusted hazard ratio, 0.35; 95% CI, 0.19-0.64; p = 0.001). Patients in the continuous venovenous hemofiltration group, as compared to the conventional group, had a reduced occurrence rate of hypoxia (40.7% vs 72.5%; p = 0.001) and of acute kidney injury (59.3% vs 78.4%; p = 0.03). Hypophosphatemia and thrombocytopenia were more common in the continuous venovenous hemofiltration group (p < 0.05). CONCLUSIONS: In patients with paraquat poisoning, treatment with combined continuous venovenous hemofiltration and hemoperfusion significantly improved 90-day survival rates.

Oxylipin profiling of human plasma reflects the renal dysfunction in uremic patients.

INTRODUCTION: Nearly all the enzymes that mediate the metabolism of polyunsaturated fatty acids (PUFAs) are present in the kidney. However, the correlation of renal dysfunction with PUFAs metabolism in uremic patients remains unknown. OBJECTIVES: To test whether the alterations in the metabolism of PUFAs reflect the renal dysfunction in uremic patients. METHODS: LC-MS/MS-based oxylipin profiling was conducted for the plasma samples from the uremic patients and controls. The data were analyzed by principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The receiver operating characteristic (ROC) curves and the correlation of the estimated glomerular filtration rate (eGFR) with the key markers were evaluated. Furthermore, qPCR analysis of the whole blood cells was conducted to investigate the possible mechanisms. In addition, a 2nd cohort was used to validate the findings from the 1st cohort. RESULTS: The plasma oxylipin profile distinguished the uremic patients from the controls successfully by using both PCA and OPLS-DA models. 5,6-Dihydroxyeicosatrienoic acid (5,6-DHET), 5-hydroxyeicosatetraenoic acid (5-HETE), 9(10)-epoxyoctadecamonoenoic acid [9(10)-EpOME] and 12(13)-EpOME were identified as the key markers to discriminate the patients from controls. The excellent predictive performance of these four markers was validated by ROC analysis. The eGFR significantly correlated with plasma levels of 5,6-DHET and 5-HETE positively but with plasma 9(10)-EpOME and 12(13)-EpOME negatively. The changes of these markers may account for the inactivation of cytochrome P450 2C18, 2C19, microsome epoxide hydrolase (EPHX1), and 5-lipoxygenase in the patients. CONCLUSION: The alterations in plasma metabolic profile reflect the renal dysfunction in the uremic patients.

Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3ß signaling.

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3ß (GSK3ß) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3ß phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3ß phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3ß phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

A modified nontransposed brachiobasilic arteriovenous fistula versus brachiocephalic arteriovenous fistula for maintenance hemodialysis access.

OBJECTIVE: With the growing need for reliable and durable upper arm hemodialysis access, we sought to compare the performance of a novel modified nontransposed brachiobasilic arteriovenous fistula (mNT-BBAVF) with that of the more traditional brachiocephalic arteriovenous fistula (BCAVF). METHODS: Briefly, to construct an mNT-BBAVF, an incision is made on the ulnar side of the elbow. The brachial artery and basilic vein are then isolated, and a side-to-side anastomosis is performed without transposition of the basilic vein. Next, the proximal basilic vein and the perforating veins within the surgical field are ligated. In this study, we retrospectively reviewed the medical records of all patients who underwent either an mNT-BBAVF or a BCAVF between January 2011 and October 2014 to compare 1-year primary unassisted patency, cumulative patency, and complications. We also examined hemodynamic parameters of vessels in each fistula type. RESULTS: We identified a total of 84 patients: 45 had a BCAVF, and 39 had an mNT-BBAVF. The two groups were well matched for baseline characteristics. Maturation rates at 1 month were 97% for mNT-BBAVF and 96% for BCAVF. The 1-year primary unassisted patency was significantly higher in the mNT-BBAVF group than that in the BCAVF group (87% vs 67%; hazard ratio, 2.86; 95% confidence interval, 1.11-6.40; P = .03), although cumulative patency did not differ (90% vs 73%; hazard ratio, 2.80; 95% confidence interval, 0.98-6.96 ; P = .06). There were no differences in thrombosis, failure of maturation, bleeding, steal syndrome, arm swelling, aneurysm, and stenosis between the two groups during the 12-month study. Importantly, diameters and blood flow volumes of the proximal cephalic vein, distal cephalic vein, and distal basilic vein in patients who received an mNT-BBAVF increased significantly after 12 months. All three vessels met the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria for fistula maturation and were available for dialysis cannulation, whereas only the proximal cephalic vein in the BCAVF group met the maturation criteria and could be used for cannulation. CONCLUSIONS: mNT-BBAVF appeared to be an effective alternative to BCAVF for upper arm hemodialysis access.

Identification of apoptosis and macrophage migration events in paraquat-induced oxidative stress using a zebrafish model.

AIMS: Paraquat (PQ) is a pesticide highly toxic to human beings, and a well-known trigger of oxidative stress. Although several animal models of PQ poisoning have been developed, some disadvantages limit their application in vivo. A zebrafish model was used in the present study to better define mechanisms of oxidative stress injury induced by PQ. MAIN METHODS: The toxicity of PQ was evaluated in the AB strain of zebrafish, and apoptosis was assessed by acridine orange staining. Macrophage migration was identified using the TG (zlyz:EGFP) transgenic strain, and angiogenesis was observed using the fli1a-EGFP casper strain. Following the validation of gene changes by zebrafish-based in vivo quantitative real-time PCR, network analysis was performed using the Ingenuity Pathway Analysis software. KEY FINDINGS: We first established the LC50 of PQ in the zebrafish model, and then found that robust oxidative stress and antioxidant genes were activated after PQ exposure. Moreover, apoptosis and distinct macrophage activation and migration were identified for the first time in PQ-exposed zebrafish. Utilizing this model, both extrinsic and intrinsic pathways involved in PQ-induced apoptosis were elucidated. We further demonstrated that macrophage migration was specifically induced by PQ, and that Rho family members and JNK-MMP13 signaling participated in this process. SIGNIFICANCE: Zebrafish is a promising tool for investigating the mechanisms of oxidative stress injury induced by PQ, and for screening effective anti-oxidant drugs.