A Systematic Review of Statins for the Treatment of Nonalcoholic Steatohepatitis: Safety, Efficacy, and Mechanism of Action.

Nonalcoholic fatty liver disease (NAFLD) is the liver component of a cluster of conditions, while its subtype, nonalcoholic steatohepatitis (NASH), emerges as a potentially progressive liver disorder that harbors the risk of evolving into cirrhosis and culminating in hepatocellular carcinoma (HCC). NASH and cardiovascular disease (CVD) have common risk factors, but compared to liver-related causes, the most common cause of death in NASH patients is CVD. Within the pharmacological armamentarium, statins, celebrated for their lipid-modulating prowess, have now garnered attention for their expansive therapeutic potential in NASH. Evidence from a plethora of studies suggests that statins not only manifest anti-inflammatory and antifibrotic properties but also impart a multifaceted beneficial impact on hepatic health. In this review, we used "statin", "NAFLD", "NASH", and "CVD" as the major keywords and conducted a literature search using the PubMed and Web of Science databases to determine the safety and efficacy of statins in patients and animals with NASH and NAFLD, and the mechanism of statin therapy for NASH. Simultaneously, we reviewed the important role of the intestinal microbiota in statin therapy for NASH, as it is hoped that statins will provide new insights into modulating the harmful inflammatory microbiota in the gut and reducing systemic inflammation in NASH patients.

ScAlN Film-Based Piezoelectric Micromechanical Ultrasonic Transducers with Dual-Ring Structure for Distance Sensing.

Piezoelectric micromechanical ultrasonic transducers (pMUTs) are new types of distance sensors with great potential for applications in automotive, unmanned aerial vehicle, robotics, and smart homes. However, previously reported pMUTs are limited by a short sensing distance due to lower output sound pressure. In this work, a pMUT with a special dual-ring structure based on scandium-doped aluminum nitride (ScAlN) is proposed. The combination of a dual-ring structure with pinned boundary conditions and a high piezoelectric performance ScAlN film allows the pMUT to achieve a large dynamic displacement of 2.87 µm/V and a high electromechanical coupling coefficient (kt2) of 8.92%. The results of ranging experiments show that a single pMUT achieves a distance sensing of 6 m at a resonant frequency of 91 kHz, the farthest distance sensing registered to date. This pMUT provides surprisingly fertile ground for various distance sensing applications.

Artificial neuromuscular fibers by multilayered coaxial integration with dynamic adaption.

Integrating sense in a thin artificial muscle fiber for environmental adaption and actuation path tracing, as a snail tentacle does, is highly needed but still challenging because of the interfacing mismatch between the fiber's actuation and sensing components. Here, we report an artificial neuromuscular fiber by wrapping a carbon nanotube (CNT) fiber core in sequence with an elastomer layer, a nanofiber network, and an MXene/CNT thin sheath, achieving the ingenious sense-judge-act intelligent system in an elastic fiber. The CNT/elastomer components provide actuation, and the sheath enables touch/stretch perception and hysteresis-free cyclic actuation tracing due to its strain-dependent resistance. As a whole, the coaxial structure builds a dielectric capacitor that enables sensitive touchless perception. The key to seamless integration is to use a nanofiber interface that allows the sensing layer to adaptively trace but not restrict actuation. This work provides promising solutions for closed-loop control for future intelligent soft robots.

Critical Role of Osteopontin in Maintaining Urinary Phosphate Solubility in CKD.

Background: Nephron loss dramatically increases tubular phosphate to concentrations that exceed supersaturation. Osteopontin (OPN) is a matricellular protein that enhances mineral solubility in solution; however, the role of OPN in maintaining urinary phosphate solubility in CKD remains undefined. Methods: Here, we examined (1) the expression patterns and timing of kidney/urine OPN changes in CKD mice, (2) if tubular injury is necessary for kidney OPN expression in CKD, (3) how OPN deletion alters kidney mineral deposition in CKD mice, (4) how neutralization of the mineral-binding (ASARM) motif of OPN alters kidney mineral deposition in phosphaturic mice, and (5) the in vitro effect of phosphate-based nanocrystals on tubular epithelial cell OPN expression. Results: Tubular OPN expression was dramatically increased in all studied CKD murine models. Kidney OPN gene expression and urinary OPN/Cr ratios increased before changes in traditional biochemical markers of kidney function. Moreover, a reduction of nephron numbers alone (by unilateral nephrectomy) was sufficient to induce OPN expression in residual nephrons and induction of CKD in OPN-null mice fed excess phosphate resulted in severe nephrocalcinosis. Neutralization of the ASARM motif of OPN in phosphaturic mice resulted in severe nephrocalcinosis that mimicked OPN-null CKD mice. Lastly, in vitro experiments revealed calcium-phosphate nanocrystals to induce OPN expression by tubular epithelial cells directly. Conclusions: Kidney OPN expression increases in early CKD and serves a critical role in maintaining tubular mineral solubility when tubular phosphate concentrations are exceedingly high, as in late-stage CKD. Calcium-phosphate nanocrystals may be a proximal stimulus for tubular OPN production.

Molecular characterization and phylogeny of Shiga toxin-producing Escherichia coli derived from cattle farm.

Shiga toxin-producing Escherichia coli (STEC) is an important food-borne pathogen, which can cause diseases such as diarrhea, hemorrhagic enteritis, and hemolytic uremic syndrome in humans. Twelve STEC isolates were collected from beeves and feces of commercial animals in China between 2019 and 2020 for this study. In addition to the determination of serotype and Shiga toxin subtype, whole-genome sequencing (WGS) was used for determining phylogenetic relationships, antimicrobial resistance (AMR), virulence genes, and sequence type (ST) of isolates. A total of 27 AMR genes were detected, and each STEC isolate carried more than 10 AMR genes. Eight STEC isolates from ground beef and four STEC isolated from feces were screened. A total of seven serotypes were identified, and one isolate ONT:H10 was undetermined by SeroTypeFinder. Three O157:H7 strains were confirmed and the remaining five serogroups were confirmed as O26:H11, O81:H31, O105:H8, O178:H19, and O136:H12. The phylogenetic analysis showed that STEC isolates of the same serotype or ST were clustered together based on cgMLST. The comparison of the genomes of 157 STEC reference isolates worldwide with our local STEC isolates showed that STEC isolates screened in China represented various collections and could not form a separate cluster but were interspersed among the STEC reference collection, which suggested that several STEC isolates shared a common ancestor irrespective of STEC serotype isolates. cgMLST revealed that isolates of the same O serotype clustered irrespective of their H type. Further investigation is required to determine the pathogenic potential of other serotypes of STEC, particularly in regard to these rare serotypes.

Influencing factors of the supply-demand relationships of carbon sequestration and grain provision in China: Does land use matter the most?

The provision of ecosystem services (ESs) such as carbon sequestration and grain provision are critical components to sustainable development. Reaching carbon neutrality generally requires the growing carbon sequestration of forest land, and feeding a growing population needs an expansion of cultivated land. However, limited land resources may lead to a contradiction between the carbon sequestration and grain provision. China has proposed long-term and large-scale land use programs, and exploring whether these land use policies are effective for ES sustainable provision would be instructive for future policy implications. This study integrated multi-source data in the socioecological dimension to determine the extent by which land use and land use change influence the supply-demand mismatches of carbon (carbon sequestration and emission) and grain (grain provision and consumption) in China at the provincial level. The result showed that the total quantity of carbon emissions surpassed carbon sequestration and the grain provision could cover the consumption from 2000 to 2015. Spatially, southeastern coastal provinces had higher grain deficits and northeast provinces had higher carbon deficits. This study further detected the influencing factors of the mismatches between the supply and demand of the two ESs. Excluding land use factors, our results showed that social factors contributed 38% and 47% to the supply-demand mismatches of carbon and grain, respectively, and natural factors contributed 39% and 15%, respectively. During 2000-2005, 2005-2010, and 2010-2015, cropland changes significantly affected grain balance, while forest land changes did not significantly affect carbon balance. These results indicated that cropland protections are vital to food safety, and carbon emission reductions should be the focus for carbon balance. Finally, this study makes policy suggestions for land use and ecosystem management, and a future research framework was proposed to help mitigate ES supply-demand imbalance.

Genotyping Based on CRISPR Loci Diversity and Pathogenic Potential of Diarrheagenic Escherichia coli.

Diarrheagenic Escherichia coli (DEC) can cause epidemic diarrhea worldwide. The pathogenic potential of different strains is diverse and the continuous emergence of pathogenic strains has brought serious harm to public health. Accurately distinguishing and identifying DEC with different virulence is necessary for epidemiological surveillance and investigation. Clustered regularly interspaced short palindromic repeats (CRISPR) typing is a new molecular method that can distinguish pathogenic bacteria excellently and has shown great promise in DEC typing. The purpose of this study was to investigate the discrimination of CRISPR typing method for DEC and explore the pathogenicity potential of DEC based on CRISPR types (CT). The whole genome sequences of 789 DEC strains downloaded from the database were applied CRISPR typing and serotyping. The D value (Simpson's index) with 0.9709 determined that CRISPR typing had a higher discrimination. Moreover, the same H antigen strains with different O seemed to share more identical spacers. Further analyzing the strains CRISPR types and the number of virulence genes, it was found that there was a significant correlation between the CRISPR types and the number of virulence genes (p < 0.01). The strains with the largest number of virulence genes concentrated in CT25 and CT56 and the number of virulence genes in CT264 was the least, indicating that the pathway potential of different CRISPR types was variable. Combined with the Caco-2 cell assay of the laboratory strains, the invasion capacity of STEC strains of different CRISPR types was different and there was no significant difference in the invasion rate between different CRISPR type strains (p > 0.05). In the future, with the increase of the number of strains that can be studied experimentally, the relationship between CRISPR types and adhesion and invasion capacities will be further clarified.

Kidney stone formation in a novel murine model of polycystic kidney disease.

Individuals with autosomal dominant polycystic kidney disease have a higher incidence of stone formation than the general population. However, there are no cystic animal models known to develop stones. Cystic mice compound heterozygous for hypomorphic Pkd1V and Pkd1RC alleles develop cystic kidneys within a few weeks of birth but live beyond 20 wk of age, allowing for the study of cystic comorbidities including stone formation. Cystic Pkd1V/RC mice were euthanized at 3, 13, or 26 wk of age, and their kidneys were analyzed by microcomputed tomography (µCT) for stone formation. Mice had occasional mineral aggregates that could be detected by µCT analysis at 3 wk of age. At 13 or 26 wk of age, numerous white masses were visible beneath the kidney surface. µCT analysis confirmed the masses to be large mineral stone deposits throughout the renal cortex, with mineral content increasing with age. Staining of histological sections with alizarin red and von Kossa suggested that the stone deposits were composed primarily of calcium and phosphate. Microdissection confirmed stones localized within cyst lumens. Analysis of individual stones by µCT and infrared spectroscopy confirmed apatite mineral composition. Urinalysis revealed elevated levels of phosphate and citrate at 3 wk of age and lower pH and elevated levels of calcium and citrate at 13 wk of age, suggesting altered phosphate and calcium homeostasis as a potential cause of mineralization and renal stone formation. This is the first animal model exhibiting overt kidney stone formation in the context of cystic kidney disease.NEW & NOTEWORTHY Compound heterozygous Pkd1V/RC mice were found to form calcium phosphate-containing stones within cysts of the renal cortex by 13 wk of age. This is the first polycystic kidney disease animal model exhibiting spontaneous stone formation. A growing body of evidence suggests a link between renal stone formation and cystic kidney disease. This mouse model may be useful for studying the interplay between stone and cyst formation and the functional role of polycystins in mineral homeostasis.

The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity.

Cyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METTL3, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.

[Application of CRISPR in evolution analysis, detecting and typing, virulence and antibiotic resistance regulation in food-borne pathogens].

Clustered regularly interspaced short palindromic repeats (CRISPR) and its associated protein gene system can limit the horizontal gene transfer, thereby effectively preventing the invasion of foreign gene elements such as bacteriophages. CRISPR arrays of different bacteria are diverse. Based on the differences in the CRISPR system, this review summarizes the application of CRISPR in food-borne pathogen evolution analysis, detection and typing, virulence and antibiotic resistance in recent years. We also address bacterial detection typing method developed based on the characteristics of CRISPR arrays and the association of CRISPR with virulence and drug resistance of food-borne pathogens. The shortcomings of CRISPR in evolution, detection and typing, virulence and resistance applications are analyzed. In addition, we suggest standardizing CRISPR typing methods, improving and expanding the CRISPR database of pathogenic bacteria, and further exploring the co-evolution relationship between phages and bacteria, to provide references for further exploration of CRISPR functions.

Prognostic Value of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. METHODS: We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. RESULTS: Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of -1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03). CONCLUSION: FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers.

Using Artificial Intelligence to Detect COVID-19 and Community-acquired Pneumonia Based on Pulmonary CT: Evaluation of the Diagnostic Accuracy.

Background Coronavirus disease 2019 (COVID-19) has widely spread all over the world since the beginning of 2020. It is desirable to develop automatic and accurate detection of COVID-19 using chest CT. Purpose To develop a fully automatic framework to detect COVID-19 using chest CT and evaluate its performance. Materials and Methods In this retrospective and multicenter study, a deep learning model, the COVID-19 detection neural network (COVNet), was developed to extract visual features from volumetric chest CT scans for the detection of COVID-19. CT scans of community-acquired pneumonia (CAP) and other non-pneumonia abnormalities were included to test the robustness of the model. The datasets were collected from six hospitals between August 2016 and February 2020. Diagnostic performance was assessed with the area under the receiver operating characteristic curve, sensitivity, and specificity. Results The collected dataset consisted of 4352 chest CT scans from 3322 patients. The average patient age (±standard deviation) was 49 years ± 15, and there were slightly more men than women (1838 vs 1484, respectively; P = .29). The per-scan sensitivity and specificity for detecting COVID-19 in the independent test set was 90% (95% confidence interval [CI]: 83%, 94%; 114 of 127 scans) and 96% (95% CI: 93%, 98%; 294 of 307 scans), respectively, with an area under the receiver operating characteristic curve of 0.96 (P < .001). The per-scan sensitivity and specificity for detecting CAP in the independent test set was 87% (152 of 175 scans) and 92% (239 of 259 scans), respectively, with an area under the receiver operating characteristic curve of 0.95 (95% CI: 0.93, 0.97). Conclusion A deep learning model can accurately detect coronavirus 2019 and differentiate it from community-acquired pneumonia and other lung conditions. © RSNA, 2020 Online supplemental material is available for this article.

Randomized, Placebo-Controlled Trial of Rifaximin Therapy for Lowering Gut-Derived Cardiovascular Toxins and Inflammation in CKD.

BACKGROUND: Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1ß), and change in composition and diversity of fecal microbiota. RESULTS: A total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera. CONCLUSIONS: Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rifaximin Therapy in Chronic Kidney Disease, NCT02342639.

Surgical treatment is better than non-surgical treatment for primary patellar dislocation: a meta-analysis of randomized controlled trials.

BACKGROUND: At present, the best treatment for primary patellar dislocation (PPD) has not been unified. Moreover, meta-analyses comparing the non-surgical and surgical treatments of PPD are lacking. Thus, we aimed to compare the clinical efficacy of surgical or non-surgical treatment of PPD. METHODS: Randomized controlled studies of surgical and non-surgical treatments of PPD from 1966 to 2018 were retrieved from the following databases: PubMed, EMBASE, Cochrane Library, Wanfang Database, China Knowledge Network, Google Scholar, and Weipu Database. We screened for literature that met the inclusion criteria and extracted useful data for our meta-analysis. RESULTS: Nine studies, involving 492 patients, met the inclusion criteria and were analyzed in this study. The recurrence rate of patellar dislocation in the surgical group was lower than that in the non-surgical group (P = 0.04]). Subgroup analysis according to the follow-up time showed that the Kujala score (P < 0.001) and lower recurrence rate of dislocation (P = 0.05) than the non-surgical group in the short term. Subgroup analysis according to surgical year showed that the surgical group get higher Kujala score (P < 0.001) and lower recurrence rate of dislocation (P = 0.01) than the non-surgical group in recent years. CONCLUSION: Surgical treatment can provide better clinical results in a short period of time, and patients may achieve good results within 10 years owing to the advances in surgical techniques and instruments. Thus, we recommend surgical treatment as the preferred treatment for primary patellar dislocation.

Dietary phosphate restriction attenuates polycystic kidney disease in mice.

Studies in rodents with reduced nephron mass have suggested a strong positive correlation between dietary phosphate consumption and CKD progression. Prior work by our group demonstrated that dietary phosphate restriction can prevent tubular injury and microcyst formation in rodents with glomerulonephritis. Tubular injury and cystic dilation of tubules are key contributors to kidney function decline in polycystic kidney disease (PKD). Here, we determined whether dietary phosphate restriction slows renal cyst growth and fibrosis in a mouse model of PKD. Pcy/pcy mice received a normal phosphate (0.54%) or a phosphate-restricted (0.02%) diet (n = 10/group) from 7 to 20 wk of age. All of the other major dietary constituents, including protein source and content, were comparable between the two diets. At 20 wk, body weight, kidney weight-to-body weight ratio (KW/BW), cystic area, cyst number, and kidney fibrosis were quantified. Pcy/pcy mice fed a phosphate-restricted diet had lower serum phosphate, fibroblast growth factor 23, and parathyroid hormone levels, along with elevated serum calcium levels and increased kidney Klotho gene expression compared with mice that consumed the control diet. Dietary phosphate restriction resulted in a 25% lower KW/BW ratio and reduced the cyst number, cystic index, and gene expression for the tubular injury markers neutrophil gelatinase-associated lipocalin and interleukin-18. Mice fed the phosphate-restricted diet exhibited lower kidney expression for pathways involved in collagen deposition and myofibroblast activation (collagen type I-α1, phosphorylated SMAD3, and α-smooth muscle actin); however, histological differences in kidney fibrosis were not appreciated. Dietary phosphate restriction slows cystogenesis and inhibits the activation of key pathways in the generation of kidney fibrosis in PKD mice.

Bifunctional S, N-Codoped carbon dots-based novel electrochemiluminescent bioassay for ultrasensitive detection of atrazine using activated mesoporous biocarbon as enzyme nanocarriers.

A novel and ultrasensitive electrochemiluminescent (ECL) bioassay has been developed for the detection of atrazine (ATZ), whereby bifunctional S, N-codoped carbon dots (S, N-CDs) and activated mesoporous bicarbons (BCs) have been innovatively integrated to synergistically amplify the ECL signal. When endogenous dissolved O2 is used as a coreactant, its sluggish reduction hinders the enhancement of ECL intensity of the luminophore, thus restricting its further application in bioanalysis. Here, bifunctional S, N-CDs severe as not only the ECL luminophore but the coreaction accelerator of dissolved O2 to generate more intermediates to boost the coreaction without using any other coreactant and coreaction accelerator. The as-formed nanoarchitectures of BCs possess enlarged surface area as the nanocarriers. They could provide adequate active sites for immobilization of tyrosinase (Tyr), which greatly prompts the ECL bioassay applications. Such a smart integration of bifunctional S, N-CDs, activated mesoporous BCs and the enzyme inhibition reaction achieves a unique and attractive high-performance signal-on ECL bioassay, realizing ultrasensitive detection of ATZ. Under the optimal condition, this bioassay exhibits two linear ranges, from 0.0001 to 0.01 µg L-1 and 0.01-20 µg L-1 with a detection limit of 0.08 ng L-1 at signal to noise ratio of 3. The as-fabricated assay is sensitive and economical, opening a new way for the enhancement of ECL signal output and a versatile strategy for ultrasensitive ECL bioanalysis.

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden.

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r(2)=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 µM [54.8-133.0 µM] for dialysis-dependent patients versus 3.3 µM [3.1-6.0 µM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 µM [29.2-189.7 µM] pretransplant versus 11.4 µM [8.9-20.2 µM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 µM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.

[One case report of overseas imported quartan malaria].

This paper reports one case of overseas imported quartan malaria and the diagnosis and treatment process. By using dihydroartemisinin combined with piperaquine, the treatment results are satisfactory.

Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.

BACKGROUND AND OBJECTIVES: Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters. RESULTS: Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis. CONCLUSIONS: Patients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability.

Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunction and arterial stiffness in chronic kidney disease (CKD) patients; however, the direct effects of FGF23 on endothelial function are unknown. We hypothesized that FGF23 directly impairs endothelial vasorelaxation by hindering nitric oxide (NO) bioavailability. We detected expression of all four subtypes of FGF receptors (Fgfr1-4) in male mouse aortas. Exogenous FGF23 (90-9,000 pg/ml) did not induce contraction of aortic rings and did not relax rings precontracted with PGF2α. However, preincubation with FGF23 (9,000 pg/ml) caused a ∼36% inhibition of endothelium-dependent relaxation elicited by acetylcholine (ACh) in precontracted aortic rings, which was prevented by the FGFR antagonist PD166866 (50 nM). Furthermore, in FGF23-pretreated (9,000 pg/ml) aortic rings, we found reductions in NO levels. We also investigated an animal model of CKD (Col4a3(-/-) mice) that displays highly elevated serum FGF23 levels and found they had impaired endothelium-dependent vascular relaxation and reduced nitrate production compared with age-matched wild types. To elucidate a mechanism for the FGF23-induced impairment, we measured superoxide levels in endothelial cells and aortic rings and found that they were increased following FGF23 treatment. Crucially, treatment with the superoxide scavenger tiron reduced superoxide levels and also restored aortic relaxation to ACh. Therefore, our data suggest that FGF23 increases superoxide, inhibits NO bioavailability, and causes endothelial dysfunction in mouse aorta. Together, these data provide evidence that high levels of FGF23 contribute to cardiovascular dysfunction.