Identification of Mycoviruses in the Pathogens of Fragrant Pear Valsa Canker from Xinjiang in China.

As a common disease, canker seriously affects the yield and quality of fragrant pear due to the lack of effective control measures. Some fungi have been reported to harbor rich reservoirs of viral resources, and some mycoviruses can be used as biocontrol agents against plant diseases. In this study, 199 isolates were obtained from diseased branches of fragrant pear in the main production areas of Xinjiang. Among them, 134 belonged to Valsa spp., identified using morphological and molecular biological techniques, in which V. mali was the dominant species. The mycoviruses in Valsa spp. were further identified using metatranscriptomic sequencing and RT-PCR. The results revealed that a total of seven mycoviruses were identified, belonging to Botourmiaviridae, Endornaviridae, Fusariviridae, Hypoviridae, Mitoviridae, and Narnaviridae, among which Phomopsis longicolla hypovirus (PlHV) was dominant in all the sample collection regions. The Cryphonectria hypovirus 3-XJ1 (CHV3-XJ1), Botourmiaviridae sp.-XJ1 (BVsp-XJ1), and Fusariviridae sp.-XJ1 (Fvsp-XJ1) were new mycoviruses discovered within the Valsa spp. More importantly, compared with those in the virus-free Valsa spp. strain, the growth rate and virulence of the VN-5 strain co-infected with PlHV and CHV3-XJ1 were reduced by 59% and 75%, respectively, and the growth rate and virulence of the VN-34 strain infected with PlHV were reduced by 42% and 55%, respectively. On the other hand, the horizontal transmission efficiency of PlHV decreased when PlHV was co-infected with CHV3-XJ1, indicating that PlHV and CHV3-XJ1 were antagonistic. In summary, the mycoviruses in Valsa spp. were identified in Xinjiang for the first time, and three of them were newly discovered mycoviruses, with two strains yielding good results. These results will offer potential biocontrol resources for managing pear canker disease and provide a theoretical basis for the control of fruit tree Valsa canker disease.

Central lymph nodes in frozen sections can effectively guide extended lymph node resection for papillary thyroid carcinoma.

OBJECTIVES: The scope of lateral neck lymph node dissection (LND) in papillary thyroid carcinoma (PTC) remains controversial. Our research aimed to explore the value of central lymph node metastasis (CLNM) in frozen sections for predicting neck lateral lymph node metastasis (NLLNM) and to guide clinical surgeons in performing surgical lymph node dissection. PATIENTS: A total of 275 patients with PTC with suspected 'Cervical lymph node metastasis (LNM, including CLNM and NLLNM)' underwent unilateral or bilateral thyroidectomy and an intraoperative frozen diagnosis of central lymph nodes (LNs), as well as central and neck lateral LND. Validity indices and consistency of central LNs in frozen sections were calculated. In total, 216 patients then met the inclusion criteria and were enrolled in the follow-up study. The clinical and pathological data of the patients were retrospectively analyzed. The relationship between the number, metastatic diameter, and the ratio of CLNM to NLLNM was investigated. RESULTS: CLNM in frozen and paraffin-embedded sections was associated with NLLNM. Univariate and multivariate analyses revealed the following risk factors for NLLNM metastasis: maximum diameter, total number, and ratio of metastatic LNs. A significant result was obtained when a cut-off value of 2.050 mm for the maximum metastatic diameter, 5.5 in the total number, and 0.5342 for the CLNM ratio level was used. Interaction term analyses showed that the association between the number of CLNM and NLLNM differed according to maximum diameter. CONCLUSION: Central LNs in frozen sections accurately predicted NLLNM. In patients with PTC with >5 CLNMs, ≥2 and ≤5 CLNMs and maximum metastatic diameter > 2 mm, neck lateral LND should be considered. Our findings will facilitate the identification of patients who are likely to benefit from extended lateral neck LND.

Real-Time Nondestructive Viscosity Measurement of Soft Tissue Based on Viscoelastic Response Optical Coherence Elastography.

Viscoelasticity of the soft tissue is an important mechanical factor for disease diagnosis, biomaterials testing and fabrication. Here, we present a real-time and high-resolution viscoelastic response-optical coherence elastography (VisR-OCE) method based on acoustic radiation force (ARF) excitation and optical coherence tomography (OCT) imaging. The relationship between displacements induced by two sequential ARF loading-unloading and the relaxation time constant of the soft tissue-is established for the Kelvin-Voigt material. Through numerical simulation, the optimal experimental parameters are determined, and the influences of material parameters are evaluated. Virtual experimental results show that there is less than 4% fluctuation in the relaxation time constant values obtained when various Young's modulus and Poisson's ratios were given for simulation. The accuracy of the VisR-OCE method was validated by comparing with the tensile test. The relaxation time constant of phantoms measured by VisR-OCE differs from the tensile test result by about 3%. The proposed VisR-OCE method may provide an effective tool for quick and nondestructive viscosity testing of biological tissues.

Treatment With Small Molecule Inhibitors of Advanced Glycation End-Products Formation and Advanced Glycation End-Products-Mediated Collagen Cross-Linking Promotes Experimental Aortic Aneurysm Progression in Diabetic Mice.

Background Although diabetes attenuates abdominal aortic aneurysms (AAAs), the mechanisms by which diabetes suppresses AAAs remain incompletely understood. Accumulation of advanced glycation end- (AGEs) reduces extracellular matrix (ECM) degradation in diabetes. Because ECM degradation is critical for AAA pathogenesis, we investigated whether AGEs mediate experimental AAA suppression in diabetes by blocking AGE formation or disrupting AGE-ECM cross-linking using small molecule inhibitors. Methods and Results Male C57BL/6J mice were treated with streptozotocin and intra-aortic elastase infusion to induce diabetes and experimental AAAs, respectively. Aminoguanidine (AGE formation inhibitor, 200 mg/kg), alagebrium (AGE-ECM cross-linking disrupter, 20 mg/kg), or vehicle was administered daily to mice from the last day following streptozotocin injection. AAAs were assessed via serial aortic diameter measurements, histopathology, and in vitro medial elastolysis assays. Treatment with aminoguanidine, not alagebrium, diminished AGEs in diabetic AAAs. Treatment with both inhibitors enhanced aortic enlargement in diabetic mice as compared with vehicle treatment. Neither enhanced AAA enlargement in nondiabetic mice. AAA enhancement in diabetic mice by aminoguanidine or alagebrium treatment promoted elastin degradation, smooth muscle cell depletion, mural macrophage accumulation, and neoangiogenesis without affecting matrix metalloproteinases, C-C motif chemokine ligand 2, or serum glucose concentration. Additionally, treatment with both inhibitors reversed suppression of diabetic aortic medial elastolysis by porcine pancreatic elastase in vitro. Conclusions Inhibiting AGE formation or AGE-ECM cross-linking enhances experimental AAAs in diabetes. These findings support the hypothesis that AGEs attenuate experimental AAAs in diabetes. These findings underscore the potential translational value of enhanced ECM cross-linking as an inhibitory strategy for early AAA disease.

Mechanisms and efficacy of metformin-mediated suppression of established experimental abdominal aortic aneurysms.

Objective: Metformin treatment attenuates experimental abdominal aortic aneurysm (AAA) formation, as well as reduces clinical AAA diameter enlargement in patients with diabetes. The mechanisms of metformin-mediated aneurysm suppression, and its efficacy in suppressing established experimental aneurysms, remain uncertain. Methods: Experimental AAAs were created in male C57BL/6J mice via intra-aortic infusion of porcine pancreatic elastase. Metformin alone (250 mg/kg), or metformin combined with the 5' AMP-activated protein kinase (AMPK) antagonist Compound C (10 mg/kg), were administered to respective mouse cohorts daily beginning 4 days following AAA induction. Further AAA cohorts received either the AMPK agonist AICA riboside (500 mg/kg) as positive, or vehicle (saline) as negative, controls. AAA progression in all groups was assessed via serial in vivo ultrasonography and histopathology at sacrifice. Cytokine-producing T cells and myeloid cellularity were determined by flow cytometric analyses. Results: Metformin limited established experimental AAA progression at 3 (-85%) and 10 (-68%) days following treatment initiation compared with saline control. Concurrent Compound C treatment reduced this effect by approximately 50%. In metformin-treated mice, reduced AAA progression was associated with relative elastin preservation, smooth muscle cell preservation, and reduced mural leukocyte infiltration and neoangiogenesis compared with vehicle control group. Metformin also resulted in reduced interferon-γ-, but not interleukin-10 or -17, producing splenic T cells in aneurysmal mice. Additionally, metformin therapy increased circulating and splenic inflammatory monocytes (CD11b+Ly-6Chigh), but not neutrophils (CD11b+Ly-6G+), with no effect on respective bone marrow cell populations. Conclusions: Metformin treatment suppresses existing experimental AAA progression in part via AMPK agonist activity, limiting interferon-γ-producing T cell differentiation while enhancing circulating and splenic inflammatory monocyte retention.

Fibulin-1: a novel biomarker for predicting disease activity of the thyroid-associated ophthalmopathy.

PURPOSE: This study was designed to investigate the association between fibulin-1(FBLN1) and thyroid-associated ophthalmopathy (TAO). METHOD: The plasma FBLN1 levels were measured in 80 participants, including 30 active TAO patients, 25 inactive TAO patients, and 25 Graves disease (GD) patients without TAO using enzyme-linked immunosorbent assay (ELISA). RESULTS: TAO patients had significantly higher TRAb level than GD patients (p < 0.05). The active TAO patients consumed more tobacco and had higher CAS than inactive TAO patients (all p < 0.05). No significant differences were found in age, sex, and the level of FT3, FT4, and TSH between TAO and GD patients, and between the active and inactive TAO patients (all p > 0.05). The plasma FBLN1 level in TAO patients was higher than that in GD patients, and that in active patients was higher than that in inactive patients (all p < 0.05). Furthermore, the plasma FBLN1 level showed strong association with clinical activity score (CAS) of TAO (r = 0.67, p < 0.01). By receiver operator characteristic (ROC) curve analysis, FBLN1 demonstrated good efficiency for predicting disease activity at the cut-off value > 625.33 pg/ml with a sensitivity of 93.3% and a specificity of 88.0% (AUC:0.92, p < 0.01). CONCLUSION: The plasma FBLN1 levels correlated with TAO activity and a value >625.33 pg/ml was associated with active disease. Our results suggest that the plasma FBLN1 level could be a novel biomarker for predicting disease activity of TAO.

The HIF1α polymorphism rs2301104 is associated with obesity and obesity-related cytokines in Han Chinese population.

AIMS: To evaluate the association between genetic polymorphisms of HIF1α and obesity and obesity-related cytokines in the Han Chinese population. METHODS: The study consisted of 160 subjects with obesity and 166 age- and gender-matched healthy controls. We genotyped three tag single nucleotide polymorphisms (SNPs) of HIF1α by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based genotyping technology. Plasma cytokine concentrations were determined on the Luminex platform. The genetic associations were analysed statistically. RESULTS: Obese subjects had significant obesity-related metabolic abnormalities, including hyperglycaemia, insulin resistance, and abnormalities in blood lipids, liver enzymes, and uric acid levels. SNP analysis of HIF1α revealed that the allele and genotype frequencies of rs2301104 were significantly associated with obesity. Our results suggest that the minor allele C of rs2301104 might be a protective mutation of obesity, and CC/CG genotypes of rs2301104 could be protective genotype of obesity. We also found that subjects with CC/CG genotypes of rs2301104 had significantly lower levels of IL-6, TNF-α, IL-1ß, IL-8, and IL-10 than subjects with GG genotypes. CONCLUSIONS: This is the first study to report an association between HIF1α polymorphisms and obesity and obesity-related cytokines in a Han Chinese population. These results require replication in larger populations but suggest that HIF1α may play an important role in obesity development.

Type I Interferon Receptor Subunit 1 Deletion Attenuates Experimental Abdominal Aortic Aneurysm Formation.

OBJECTIVE: Type I interferon receptor signaling contributes to several autoimmune and vascular diseases such as lupus, atherosclerosis and stroke. The purpose of this study was to assess the influence of type I interferon receptor deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). METHODS: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1)-deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysmal abdominal aortae. The initiation and progression of experimental AAAs were assessed via ultrasound imaging prior to (day 0) and days 3, 7 and 14 following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. RESULTS: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA induction, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1-deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1-deficient mice in comparison to wild type mice. CONCLUSION: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest an important role for IFNAR1 activity in AAA pathogenesis.

Glucocorticoid therapy reduces ocular hypertension in active moderate-severe thyroid-associated orbitopathy.

PURPOSE: Ocular hypertension (OHT) is an important clinical feature of thyroid-associated orbitopathy (TAO).While the prevalence and outcome of OHT in TAO remains unclear. This study investigates this in moderate-severe active TAO. METHODS: Sixty-eight patients with active moderate-severe TAO were recruited, 49 of whom were treated with 12-week GC therapy.The clinical and biochemical parameters were collected.Treatment outcomes were evaluated after GC therapy. RESULTS: The prevalence of OHT was 44.85% in moderate-severe active TAO patients,including 81.97% of mild hypertension, 13.11% of moderate hypertension and 4.92% of severe hypertension. Clinical and biochemical parameters had no significant difference between OHT patients and non-OHT patients,such as age, sex distributions, smoking status, the kind and the duration of thyroid disease,the duration of eye symptoms and the level of FT3,FT4,TSH, TR-Ab, and Tpo-Ab, Tg-Ab(all P > 0.05). After GC therapy,the intraocular pressure(IOP) in OHT eyes decreased significantly (P < 0.05), while IOP in non-OHT eyes remained unchanged (P > 0.05).There was no significant difference in CAS and the effective rate of GC therapy between OHT eyes and non-OHT eyes (P > 0.05). CONCLUSION: In moderate-severe active TAO, the prevalence of OHT was 44.85%, most of which were mild hypertension.OHT was relieved by GC therapy,which had no effect on the efficacy of GC therapy.Our results will enhance physicians' confidence in GC therapy.

Analysis of HIF2α polymorphisms in infertile women with polycystic ovary syndrome or unexplained infertility.

Objective: To evaluate HIF2α polymorphisms and glucose metabolism in a group of women with polycystic ovary syndrome (PCOS) or unexplained infertility (UI). Patients: The infertile group (n=148) consisted of 96 women with PCOS, 52 women with UI, and176 women without infertility as a healthy control group. Intervention: We genotyped 29 single nucleotide polymorphisms (SNPs) of HIF2α by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based genotyping technology. The genetic associations were analyzed statistically. Main outcome measures: Allele frequency, genotype distribution and haplotype analyze of the HIF2α polymorphisms were performed. Body mass index (BMI), waist circumference, uric acid (UA), high-sensitivity C-reactive protein (hsCRP), lipids, glucose and insulin tolerance - were also measured. Results: Infertile women with PCOS had a higherBMI and waist circumference, elevated hsCRP and uric acid (UA) levels, impaired glucose tolerance, and increased levels of plasma insulin compared to UI patients and healthy women. SNP analysis of HIF2α revealed that the allele and genotype frequencies of rs4953361 were significantly associated with infertile women with PCOS. Haplotype analysis of the HIF2α polymorphism identified haplotypes TGG and TGA as being associated with infertile women with PCOS. Women with the AA genotype of rs4953361 had a significantly higher BMI and post load plasma glucose and insulin levels than those of women with the GG genotype. Conclusion: Infertile women with PCOS more commonly have metabolic disturbances than those with UI. This is the first study to report an association between HIF2α polymorphisms (rs4953361) and the risk of infertile women with PCOS, not UI, in Han Chinese population. These results require replication in larger populations.In this observational study, we did not report the results of a health care intervention on human participants. The study was approved by the Human Research Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. Clinical data and peripheral blood samples were collected only after explaining the objectives of the study and obtaining a signed informed consent form.

Effect of nickel (II) on the performance of anodic electroactive biofilms in bioelectrochemical systems.

The impact of nickel (Ni2+) on the performance of anodic electroactive biofilms (EABs) in the bioelectrochemical system (BES) was investigated in this study. Although it has been reported that Ni2+ influences microorganisms in a number of ways, it is unknown how its presence in the anode of a BES affects extracellular electron transfer (EET) of EABs, microbial viability, and the bacterial community. Results revealed that the addition of Ni2+ decreased power output from 673.24 ± 12.40 mW/m2 at 0 mg/L to 179.26 ± 9.05 mW/m2 at 80 mg/L. The metal and chemical oxygen demand removal efficiencies of the microbial fuel cells (MFCs) declined as Ni2+ concentration increased, which could be attributed to decreased microbial viability as revealed by SEM and CLSM. FTIR analysis revealed the involvement of various microbial biofilm functional groups, including hydroxyl, amides, methyl, amine, and carboxyl, in the uptake of Ni2+. The presence of Ni2+ on the anodic biofilms was confirmed by SEM-EDS and XPS analyses. CV demonstrated that the electron transfer performance of the anodic biofilms was negatively correlated with the various Ni2+ concentrations. EIS showed that the internal resistance of the MFCs increased with increasing Ni2+ concentration, resulting in a decrease in power output. High-throughput sequencing results revealed a decrease in Geobacter and an increase in Desulfovibrio in response to Ni2+ concentrations of 10, 20, 40, and 80 mg/L. Furthermore, the various Ni2+ concentrations decreased the expression of EET-related genes. The Ni2+-fed MFCs had a higher abundance of the nikR gene than the control group, which was important for Ni2+ resistance. This work advances our understanding of Ni2+ inhibition on EABs, as well as the concurrent removal of organic matter and Ni2+ from wastewater.

Dynamic follow-up of the effects of programmed death 1 inhibitor treatment on thyroid function and sonographic features in patients with hepatocellular carcinoma.

Objective: Programmed cell death protein-1 (PD-1) inhibitors are widely used for the treatment of hepatocellular carcinoma (HCC). Thyroid dysfunction is common in patients treated with this therapy, although the dynamic changes in thyroid function and sonographic features remain unclear. Methods: We analyzed 38 patients with HCC who received anti-PD-1 therapy at our hospital. Demographic, clinical, laboratory, and ultrasound data were extracted from electronic medical records. The grading of thyroid nodules was based on the American College of Radiology Thyroid Imaging Reporting and Data System classification. Statistical analyses were performed using GraphPad Prism 5.0. Results: Fifteen patients (40%) had hypothyroidism, among which six had hypothyroidism at baseline, three had overt hypothyroidism, and six had subclinical hypothyroidism after anti-PD1 therapy. The proportion of patients with euthyroid function and thyroid antibody positivity was significantly lower than that of patients with thyroid dysfunction (10% vs 39%, P < 0.05). Nine patients (24%) had irregular echo patterns on sonographic imaging, six of whom had irregular echo patterns present during the treatment, but only one had them persist until the end of treatment. At baseline, the classification of most thyroid nodules was grade 3, with a significant increase in grade 4A and 4B classifications during treatment, though most nodules remained grade 3 at the end of treatment. There were no significant differences in survival rates between the euthyroid and thyroid dysfunction groups. Conclusion: Anti-PD-1 therapy-induced thyroid dysfunction was accompanied by changes in thyroid function, antibodies, and ultrasonography. Therefore, in patients receiving anti-PD-1 therapy, close, dynamic monitoring of thyroid function, antibodies, and ultrasonographic characteristics is necessary.

Enhancing microbial fuel cell performance using anode modified with Fe3O4 nanoparticles.

Low electricity generation efficiency is one of the key issues that must be addressed for the practical application of microbial fuel cells (MFCs). Modification of microbial electrode materials is an effective method to enhance electron transfer. In this study, magnetite (Fe3O4) nanoparticles synthesized by co-precipitation were added to anode chambers in different doses to explore its effect on the performance of MFCs. The maximum power density of the MFCs doped with 4.5 g/L Fe3O4 (391.11 ± 9.4 mW/m2) was significantly increased compared to that of the undoped MFCs (255.15 ± 24.8 mW/m2). The COD removal efficiency of the MFCs increased from 85.8 ± 2.8% to 95.0 ± 2.1%. Electrochemical impedance spectroscopy and cyclic voltammetry tests revealed that the addition of Fe3O4 nanoparticles enhanced the biocatalytic activity of the anode. High-throughput sequencing results indicated that 4.5 g/L Fe3O4 modified anodes enriched the exoelectrogen Geobacter (31.5%), while control MFCs had less Geobacter (17.4%). Magnetite is widely distributed worldwide, which provides an inexpensive means to improve the electrochemical performance of MFCs.

Comparison of the clinical characteristics of primary thyroid lymphoma and diffuse sclerosing variant of papillary thyroid carcinoma.

Objective: Both primary thyroid lymphoma (PTL) and diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) are two rare malignant tumours with different therapies and prognoses. This study compared their clinical features. Methods: From a retrospective review of the pathologic database at our institute between January 2015 and August 2020, 52 PTL patients and 40 DSVPTC patients were included. Demographic, clinical, laboratory and ultrasound data were extracted from electronic medical records. Statistical analyses were performed using GraphPad Prism 5.0. Results: Both PTL and DSVPTC were more likely to occur in women (83.7 and 67.5%, respectively), but DSVPTC patients were younger (median age: 36 vs 64.5), had fewer compressive symptoms, and more frequently had neck lymph node metastasis than PTL patients. The prevalence of Hashimoto's thyroiditis (HT) and hypothyroidism was significantly higher in PTL patients than in DSVPTC patients (31% vs 17.5%). Hyperthyroidism could only be found in DSVPTC patients, which accounted for 7.5%. Heterogeneous echogenicity and irregular edges were frequently observed in both PTL and DSVPTC. However, compared with PTL, DSVPTC exhibited smaller lesion sizes, higher frequencies of diffuse sonographic patterns and calcification and lower frequencies of hypoechoic features and internal blood flow signal. The overall survival rate with PTL was 77.23%, which was lower than that with DSVPTC (90.91%), but this difference was not significant (P = 0.096). Conclusion: Clinical characteristics such as age, compression symptoms, and sonographic features such as a large mass with heterogeneous echogenicity, hypoechoic, irregular edges, and calcification are helpful for impression diagnosis of PTL and DSVPTC before surgery.

Recovery of heavy metals from industrial wastewater using bioelectrochemical system inoculated with novel Castellaniella species.

Water pollution is a global issue that has drastically increased in recent years due to rapid industrial development. Different technologies have been designed for the removal of pollutants from wastewater. However, most of these techniques are expensive, generate new waste, and focus solely on metal removal instead of metal recovery. In this study, novel facultative exoelectrogenic strains designated Castellaniella sp. A5, Castellaniella sp. B3, and Castellaniella sp. A3 were isolated from a microbial fuel cell (MFC). These isolates were utilized as pure and mixed culture inoculums in a bioelectrochemical system (BES) to produce bioelectricity and treat simulated industrial wastewater. A single-chamber MFC inoculated with the mixed culture attained the highest electricity generation (i.e., 320 mW/m2 power density and 3.19 A/m2 current density), chemical oxygen demand removal efficiency (91.15 ± 0.05%), and coulombic efficiency (54.81 ± 4.18%). In addition, the BES containing biofilms of the mixed culture achieved the highest Cu, Cr, and Cd removal efficiencies of 99.89 ± 0.07%, 99.59 ± 0.53%, and 99.91 ± 0.04%, respectively. The Cr6+ and Cu2+ in the simulated industrial wastewater were recovered via microbial electrochemical reduction as Cr3+ and Cu0, respectively. However, Cd2+ precipitated as Cd (OH)2 or CdCO3 on the surface of the cathodes. These results suggest that a mixed culture inoculum of Castellaniella sp. A5, Castellaniella sp. B3, and Castellaniella sp. A3 has great potential as a biocatalyst in BES for heavy metals recovery from industrial wastewater.

Treatment with the Prolyl Hydroxylase Inhibitor JNJ Promotes Abdominal Aortic Aneurysm Progression in Diabetic Mice.

OBJECTIVE: Prolyl hydroxylase domain containing proteins (PHD) rigorously regulate intracellular hypoxia inducible factor-1 (HIF-1) protein expression and activity. Diabetes impairs PHD activity and attenuates abdominal aortic aneurysm (AAA) progression. The extent to which dysregulated PHD activity contributes to diabetes mediated AAA suppression remains undetermined. METHODS: AAAs were induced in diabetic and non-diabetic male C57BL/6J mice via intra-aortic elastase infusion. A PHD inhibitor (JNJ-42041935, aka "JNJ", 150 mmol/kg) or vehicle alone was administered daily starting one day prior to AAA induction for 14 days. Influences on AAA progression was assessed via ultrasonography and histopathology. Expression of aortic HIF-1α, three of its target genes and macrophage derived mediators were assayed via quantitative reverse transcription polymerase chain reaction. Aneurysmal sections from AAA patients with and without diabetes (two patients in each group) were immunostained for HIF-1α and vascular endothelial growth factor (VEGF)-A. RESULTS: Expression of HIF-1α target genes (erythropoietin, VEGF-A, and glucose transporter-1) was reduced by 45% - 95% in experimental diabetic aortas. Diameter enlargement was similarly limited, as were mural elastin degradation, leukocyte infiltration, and neo-angiogenesis (reduced capillary density and length) on histopathology. Pre-treatment with JNJ prior to AAA initiation augmented aortic HIF-1α target gene expression and aneurysm progression in diabetic mice, along with macrophage VEGF-A and matrix metalloproteinase 2 mRNA expression. No differences were noted in HIF-1α or VEGF-A expression on aortic immunohistochemical staining of human aortic tissue as a function of diabetes status. CONCLUSION: Small molecule PHD inhibitor treatment reduces or offsets impairment of experimental AAA progression in hyperglycemic mice, highlighting the potential contribution of dysregulated PHD activity to diabetes mediated aneurysm suppression.

Recombinant Interleukin-19 Suppresses the Formation and Progression of Experimental Abdominal Aortic Aneurysms.

Background Interleukin-19 is an immunosuppressive cytokine produced by immune and nonimmune cells, but its role in abdominal aortic aneurysm (AAA) pathogenesis is not known. This study aimed to investigate interleukin-19 expression in, and influences on, the formation and progression of experimental AAAs. Methods and Results Human specimens were obtained at aneurysm repair surgery or from transplant donors. Experimental AAAs were created in 10- to 12-week-old male mice via intra-aortic elastase infusion. Influence and potential mechanisms of interleukin-19 treatment on AAAs were assessed via ultrasonography, histopathology, flow cytometry, and gene expression profiling. Immunohistochemistry revealed augmented interleukin-19 expression in both human and experimental AAAs. In mice, interleukin-19 treatment before AAA initiation via elastase infusion suppressed aneurysm formation and progression, with attenuation of medial elastin degradation, smooth-muscle depletion, leukocyte infiltration, neoangiogenesis, and matrix metalloproteinase 2 and 9 expression. Initiation of interleukin-19 treatment after AAA creation limited further aneurysmal degeneration. In additional experiments, interleukin-19 treatment inhibited murine macrophage recruitment following intraperitoneal thioglycolate injection. In classically or alternatively activated macrophages in vitro, interleukin-19 downregulated mRNA expression of inducible nitric oxide synthase, chemokine C-C motif ligand 2, and metalloproteinases 2 and 9 without apparent effect on cytokine-expressing helper or cytotoxic T-cell differentiation, nor regulatory T cellularity, in the aneurysmal aorta or spleen of interleukin-19-treated mice. Interleukin-19 also suppressed AAAs created via angiotensin II infusion in hyperlipidemic mice. Conclusions Based on human evidence and experimental modeling observations, interleukin-19 may influence the development and progression of AAAs.

Volatile Organic Compounds to Identify Infectious (Bacteria/Viruses) Diseases of the Central Nervous System: A Pilot Study.

BACKGROUND: Central nervous system (CNS) infectious diseases are common diseases in emergency rooms and neurology departments. CNS pathogen identification methods are time consuming and expensive and have low sensitivity and poor specificity. Some studies have shown that bacteria and viruses can produce specific volatile organic compounds (VOCs). The aim of this study is to find potential biomarkers by VOC analysis of cerebrospinal fluid (CSF) in patients with bacterial and viral meningitis/encephalitis (ME). METHODS: CSF samples from 16 patients with bacterial ME and 42 patients with viral ME were collected, and solid-phase microextraction combined with gas chromatography-mass spectrometry was used to analyze the metabolites in the CSF. RESULTS: There are 2 substances (ethylene oxide and phenol) that were found to be different between the 2 groups. Ethylene oxide was significantly greater in the group of bacterial ME patients than in the viral ME group of patients (p < 0.05). In addition, phenol was remarkably increased in the group of ME patients compared with the bacterial ME patients (p < 0.05). CONCLUSIONS: Ethylene oxide and phenol may be potential biomarkers to distinguish bacterial ME and viral ME. VOC analysis of CSF may be used as a supporting tool for clinical diagnosis.

Effects of continuous intravenous infusion of propofol on intestinal flora in rats.

Under normal circumstances, the gut microbiota, host, and external environment establish a dynamic ecological balance and maintain human health. Once this balance is broken, the intestinal flora dysregulation will form, manifested by changes in the diversity, richness, proportion, location and biological characteristics of the gut microbiota. The hypothesis that propofol alters gut microbes was tested in a rat model with continuous intravenous infusion of propofol. Eight male wistar rats underwent tail vein puncture and catheterization respectively, and were continuously pumped with propofol for 3 h. Feces were collected from each rat before and on the 1 st, 3rd, 7th and 14th days after intervention. Finally, the effect of continuous intravenous infusion of propofol on the intestinal flora of rats was analyzed by high-throughput 16S rRNA gene amplification sequencing. Through high-throughput 16S rRNA gene amplicon sequencing analysis, we found that continuous intravenous infusion of propofol had little effect on intestinal flora in rats. Analysis of Alpha (shannon diversity index) showed that group A-7 was different from group P and group A-1 (P = 0.034), and recovered on the 14th day. Although the species diversity analysis showed a significant difference among the five groups (P = 0.049), the distribution of most fecal samples in the PCoA showed a clustered distribution, indicating similarity. In addition, no significant difference was found in the statistical KEGG difference pathway through LEfSe analysis.

Body fat distribution and circulating adipsin are related to metabolic risks in adult patients with newly diagnosed growth hormone deficiency and improve after treatment.

OBJECTIVE: The relationships between body fat distribution, the adipokine adipsin and metabolic risks were assessed in patients with adult growth hormone deficiency (AGHD) before and after growth hormone (GH) treatment. METHODS: Sixty newly diagnosed AGHD patients were included in our study, 24 of whom were evaluated after at least one year of GH treatment. Anthropometric parameters, glucolipid metabolism and the adipokine adipsin were measured. Visceral adipose tissue (VAT) and body composition were evaluated using a dual-energy X-ray-absorptiometry (DXA) scanner. RESULTS: At baseline, the higher VAT group had worse glucolipid metabolism parameters. Basal GH was negatively associated with VAT (r=-0.277, p = 0.045), while minimal correlations were found with fat mass depots, such as limbs and trunk fat (all p > 0.05). Adipsin was correlated with total body fat (r = 0.543, p < 0.001), VAT (r = 0.563, p < 0.001) and insulin resistance (r = 0.353, p = 0.006). The effect of GH administration on fat distribution was mainly reflected in the reduction in VAT. Partial improvements were found in lipid profiles, including increased high-density lipoprotein (HDL) and decreases in triglycerides (TGs) and lipoprotein(a), while glucose metabolism showed little change. The adipsin level also decreased significantly. The best predictors of VAT at baseline were trunk fat and IGF-I, and after treatment, VAT was predicted by decreased adipsin and an increase in lean mass. CONCLUSIONS: (1) VAT is an important metabolic risk factor for AGHD patients. (2) GH treatment decreased body fat predominantly in the visceral and central fat depots. (3) The lipid profiles partially improved after treatment, while glucose metabolism showed little change.