Corin, a transmembrane serine protease that can cleave pro‐atrial natriuretic peptide (Pro‐ANP) into smaller bioactive molecule atrial natriuretic peptide, has been shown to be involved in the ...pathophysiology of hypertension, cardiac hypertrophy. We sought to examine the associations of corin genetic variations with salt sensitivity, blood pressure (BP) changes and hypertension incidence. We studied participants of the original Baoji Salt‐Sensitive cohort, recruited from 124 families from seven Chinese villages in 2004 who sequentially received a usual baseline salt diet, a 7‐day low salt diet (3 g/day) and a 7‐day high salt diet (18 g/day), respectively. They were followed up for 8 years (in 2009, 2012) to evaluate the development of hypertension. Corin SNP rs3749584 was significantly associated with diastolic BP (DBP) and mean arterial pressure (MAP) response to low‐salt diet, while rs4695253, rs17654278 were associated with pulse pressure (PP) response to low‐salt diet. SNPs rs4695253, rs12509275, rs2351783, rs2271036, rs2271037 were significantly associated with systolic BP (SBP), DBP, and MAP responses to high‐salt diet. In addition, SNPs rs12641823, rs6834933, rs2271036, and rs22710367 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP over 8 years of follow‐up. SNP rs73814824 was significantly associated with the incidence of hypertension over 8 years. Gene‐based analysis showed that corin gene was significantly associated with longitudinal BP changes and hypertension incidence after 8‐year follow‐up. This study suggests that corin may play a role in salt sensitivity, BP progression, and development of hypertension.
Neural precursor cell expressed developmentally downregulated 4‐like (NEDD4L), a member of the E3 ubiquitin‐protein ligases, encoded by NEDD4L gene, was found to be involved in in salt sensitivity by ...regulating sodium reabsorption in salt‐sensitive rats. The authors aimed to explore the associations of NEDD4L genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in Chinese adults. Participants from 124 families in Northern China in the Baoji Salt‐Sensitive Study Cohort in 2004, who received the chronic salt intake intervention, including a 7‐day low‐salt diet (3.0 g/day) and a 7‐day high‐salt diet (18 g/day), were analyzed. Besides, the development of hypertension over 14 years was evaluated. NEDD4L single nucleotide polymorphism (SNP) rs74408486 was shown to be significantly associated with systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) responses to low‐salt diet, while SNPs rs292449 and rs2288775 were significantly associated with pulse pressure (PP) response to high‐salt diet. In addition, SNP rs4149605, rs73450471, and rs482805 were significantly associated with the longitudinal changes in SBP, DBP, MAP, or PP at 14 years of follow‐up. SNP rs292449 was significantly associated with hypertension incidence over the 14‐year follow‐up. Finally, this gene‐based analysis found that NEDD4L was significantly associated with longitudinal BP changes and the incidence of hypertension over the 14‐year follow‐up. This study indicated that gene polymorphism in NEDD4L serve an important function in salt sensitivity, longitudinal BP change and development of hypertension in the Chinese population.
The function of cholinergic anti-inflammatory pathway (CAP) in acute liver failure (ALF) with inflammatory storm remains indefinite. The liver-gut axis has been proved to be crucial for liver ...homeostasis. Investigation about CAP regulation on liver-gut axis would enrich our understanding over cholinergic anti-inflammatory mechanism.
Co-injection of lipopolysaccharide and D-galactosamine was used to establish the model of ALF. PNU-282987 was used to activate the CAP. Histological staining, real-time polymerase chain reaction, Western blotting, RNA sequencing, and flow cytometry were conducted. Liver biopsy specimens and patients' serum from patients with liver failure were also analyzed.
We confirmed that activating the CAP alleviated hepatocyte destruction, accompanied by a significant decrease in hepatocyte apoptosis, pro-inflammatory cytokines, and NLRP3 inflammasome activation. Moreover, hepatic MAdCAM1 and serum MAdCAM1 levels were induced in ALF, and MAdCAM1 levels were positively correlated with the extent of liver damage and the expression of pro-inflammatory markers. Furthermore, activating the CAP mainly downregulated ectopic expression of MAdCAM1 on endothelial cells, and inhibition of NF-κB p65 nuclear translocation was partly attributed to the decreased MAdCAM1. Notably, in ALF, the aberrant hepatic expression of MAdCAM1 subsequently recruited gut-derived α4β7+ CD4+T cells to the liver, which exhibited an augmented IFN-γ-secreting and IL-17-producing phenotype. Finally, we revealed that the levels of serum and hepatic MAdCAM1 were elevated in patients with liver failure and closely correlated with clinical course. Increasing hepatic infiltration of β7+ cells were also confirmed in patients.
Activating the CAP attenuated liver injury by inhibiting MAdCAM1/α4β7 -mediated gut-derived proinflammatory lymphocytes infiltration, which provides a potential therapeutic target for ALF.
Background Bradykinin （BK） acts mainly on two receptor subtypes： B1 and B2, and activation of B2 receptor mediates the most well-known cardioprotective effects of angiotensin converting enzyme ...inhibitors （ACEi）, however, the role that B1 receptor plays in ACEi has not been fully defined. We examined the role of B1 receptor in the inhibitory effect of ACE inhibitor captopril on rat cardiomyocyte hypertrophy and cardiac fibroblast proliferation induced by angiotensin Ⅱ （Ang Ⅱ） and explored its possible mechanism.
Methods Neonatal cardiomyocytes and cardiac fibroblasts （CFs） were randomly treated with Ang Ⅱ, captopdl, B2 receptor antagonist （HOE-140） and B1 receptor antagonist （des-Arg^10, Leu^9-kallidin） alone or in combination. Flow cytometry was used to evaluate cell cycle, size and protein content. Nitric oxide （NO） and intracellular cyclic guanosine monophosphate （cGMP） level were measured by colorimetry and radioimmunoassay.
Results After the CFs and cardiomyocytes were incubated with 0.1 μmol/L Ang Ⅱ for 48 hours, the percentage of CFs in the S stage, cardiomyocytes size and protein content significantly increased （both P 〈0.01 vs control）, and these increases were inhibited by 10 μmol/L captopril. However, NO and cGMP levels were significantly higher than that with Ang Ⅱ alone （both P 〈0.01）. 1 μmol/L HOE-140 or 0.1 pmol/L des-Arg^10, Leu^9-kallidin attenuated the effects of captopril, which was blunted further by blockade of both B1 and B2 receptors.
Conclusions Acting via B2 receptor, BK contributes to the antihypertrophic and antiproliferative effects of captopril on cardiomyocytes and CFs. In the absence of B2 receptor, B1 receptor may act a compensatory mechanism for the B2 receptor and contribute to the inhibition of cardiomyocyte hypertrophy and CFs proliferation by captopril. NO and cGMP play an important role in the effect of B1 receptor.
Acute liver failure （ALF） is a life-threatening illness. The extracorporeal cell-based bioartiflcial liver （BAL） system could bridge liver transplantation and facilitate liver regeneration for ALF ...patients by providing met- abolic detoxification and synthetic functions. Previous BAL systems, based on hepatoma cells and non-human hepatocytes, achieved limited clinical advances, largely due to poor hepatic functions, cumbersome preparation or safety concerns of these cells. We previously generated human functional hepatocytes by lineage conversion （hiHeps）. Here, by improving functional maturity of hiHeps and producing hiHeps at clinical scales （3 billion cells）, we developed a hiHep-based BAL system （hiHep-BAL）. In a porcine ALF model, hiHep-BAL treatment restored liver functions, corrected blood levels of ammonia and bilirubin, and prolonged survival. Importantly, human albumin and a-l-antitrypsin were detectable in hiHep-BAL-treated ALF pigs. Moreover, hiHep-BAL treatment led to attenuated liver damage, resolved inflammation and enhanced liver regeneration. Our findings indicate a promising clinical application of the hiHep-BAL system.
Ectopic Cushing＇s syndrome caused by pheochromocytoma is rare. We reported a 15-year-old female patient who was admitted to hospital with typical Cushing＇s syndrome. She had not started menstruation. ...Her plasma adrenocorticotropic hormone （ACTH） and 24-hour urinary free cortisol levels were extremely high. Gonadal and progestational hormone levels were also abnormal. Abdominal computed tomography scans and enhanced scans revealed multiple irregular tumors in the right adrenal. Pelvic echogram showed an infantile uterus, while the ovaries were at an immature stage of development. Retroperitoneal laparoscopic right adrenalectomy was performed without intraoperative complications. Histology and immunohistochemistry of the tumor were consistent with pheochromocytoma. Retroperitoneal laparoscopic adrenalectomy is a safe procedure with satisfactory outcomes and allows for rapid recovery.
This communication demonstrates the feasibility of the gel-clot method for the analysis of bacterial endotoxins in water extracts of perfluorocarbon which is a water insoluble liquid medical device. ...Perfluorocarbon （10 mL） was shaken with 10 mL water for 15 min at 2000 r/min and the endotoxin present was extracted to the aqueous phase without interference inhibition/enhancement of the product and the recovery of endotoxin added to perfluorocarbon was determined, A validation study confirmed that endotoxins presented in perfluorocarbon pass over into the aqueous phase at concentrations of 20, 10 and 5EU/mL with recoveries from 86.8% to 96.8%. Therefore, the gel-clot test is suitable for detecting bacterial endotoxins in perfluorocarbon which is a water insoluble medical device.
Objective: To evaluate the safety and efficacy of sofosbuvir-based therapy in end-stage renal disease patients undergoing hemodialysis complicated with acute hepatitis C. Methods: Totally 33 subjects ...who met the inclusion criteria received a half dose of sofosbuvir (200mg) and a full dose of daclatasvir (90mg) daily for 24 weeks. Then we detected the levels of HCV RNA, ALT, and TBil at 0, 4, 8, 12, 16, 20, 24, 28, 32 and 36 weeks respectively and evaluated the adverse drug reactions. Results: All the patients made a sustained virological response at 12 weeks after the end of treatment, and there were no drug-related serious adverse events. Conclusion: A half dose of sofosbuvir (200mg once daily) plus a full dose of daclatasvir (90mg once daily) was safe and effective for treatment of acute HCV infection in patients who were undergoing ESRD and were on hemodialysis.
Given the multilevel internal SSD parallelism at the different four levels: channel-level, chip-level, die-level, and plane-level, how to exploit these levels of parallelism will directly and ...significantly impact the performance and endurance of SSDs, which is in turn primarily determined by three internal factors, namely, advanced commands, allocation schemes, and the priority order of exploiting the four levels of parallelism. In this paper, we analyze these internal factors to characterize their impacts, interplay, and parallelism for the purpose of performance and endurance enhancement of SSDs through an in-depth experimental study. We come to the following key conclusions: 1) Different advanced commands provided by Flash manufacturers exploit different levels of parallelism inside SSDs, where they can either improve or degrade the SSD performance and endurance depending on how they are used; 2) Different physical-page allocation schemes employ different advanced commands and exploit different levels of parallelism inside SSDs, giving rise to different performance and endurance impacts; 3) The priority order of using the four levels of parallelism has the most significant performance and endurance impact among the three internal factors. The optimal priority order of using the four levels of parallelism in SSDs is found to be: 1) the channel-level parallelism; 2) the die-level parallelism; 3) the plane-level parallelism; and 4) the chip-level parallelism.
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