ABSTRACT
AIM: To define the predictive factors of severe retinopathy of prematurity (ROP) and develop a nomogram for predicting severe ROP in southeast China. METHODS: Totally 554 infants diagnosed with ROP hospitalized in the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University and hospitalized in Taizhou Women and Children's Hospital were included. Clinical data and 43 candidate predictive factors of ROP infants were collected retrospectively. Logistic regression model was used to identify predictive factors of severe ROP and to propose a nomogram for individual risk prediction, which was compared with WINROP model and Digirop-Birth model. RESULTS: Infants from the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (n=478) were randomly allocated into training (n=402) and internal validation group (n=76). Infants from Taizhou Women and Children's Hospital were set as external validation group (n=76). Severe ROP were found in 52 of 402 infants, 12 of 76 infants, and 7 of 76 infants in training group, internal validation group, and external validation group, respectively. Birth weight [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.996-0.999; P<0.001], multiple births (OR, 1.885; 95%CI, 1.013-3.506; P=0.045), and non-invasive ventilation (OR, 0.288; 95%CI, 0.146-0.570; P<0.001) were identified as predictive factors for the prediction of severe ROP, by univariate analysis and multivariate analysis. For predicting severe ROP based on the internal validation group, the areas under receiver operating characteristic curve (AUC) was 78.1 (95%CI, 64.2-92.0) for the nomogram, 32.9 (95%CI, 15.3-50.5) for WINROP model, 70.2 (95%CI, 55.8-84.6) for Digirop-Birth model. In external validation group, AUC of the nomogram was also higher than that of WINROP model and Digirop-Birth model (80.2 versus 51.1 and 63.4). The decision curve analysis of the nomogram demonstrated better clinical efficacy than that of WINROP model and Digirop-Birth model. The calibration curves demonstrated a good consistency between the actual severe ROP incidence and the predicted probability. CONCLUSION: Birth weight, multiple births, and non-invasive ventilation are independent predictors of severe ROP. The nomogram has a good ability to predict severe ROP and performed well on internal validation and external validation in southeast China.
ABSTRACT
Metal-organic frameworks (MOFs) show tremendous promise for drug delivery due to their structural and functional versatility. However, MOFs are usually used as biologically inert carriers in most cases. The creation of intrinsically immunostimulatory MOFs remains challenging. In this study, a facile and green synthesis method is proposed for the preparation of a manganese ion (Mn2+)-based immunostimulatory MOF (ISAMn-MOF) for cancer metalloimmunotherapy. ISAMn-MOF significantly facilitates the activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) related genes and signaling pathways in bone-marrow-derived dendritic cells (BMDCs). BMDCs treated with ISAMn-MOF secrete 4-fold higher type I interferon and 2- to 16-fold higher proinflammatory cytokines than those treated with equivalent MnCl2. ISAMn-MOF alone or its combination with immune checkpoint antibodies significantly suppresses tumor growth and metastasis and prolongs mouse survival. Mechanistic studies indicate that ISAMn-MOF treatment facilitates the infiltration of stimulatory immune cells in tumors and lymphoid organs. This study provides insight into the design of bioactive MOFs for improved cancer metalloimmunotherapy.
Subject(s)
Metal-Organic Frameworks , Neoplasms , Mice , Animals , Metal-Organic Frameworks/pharmacology , Manganese/pharmacology , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism , Neoplasms/drug therapyABSTRACT
Enabling macrophages to phagocytose tumor cells holds great potential for cancer therapy but suffers from tremendous challenges because the tumor cells upregulate antiphagocytosis molecules (such as CD47) on their surface. The blockade of CD47 alone is insufficient to stimulate tumor cell phagocytosis in solid tumors due to the lack of "eat me" signals. Herein, a degradable mesoporous silica nanoparticle (MSN) is reported to simultaneously deliver anti-CD47 antibodies (aCD47) and doxorubicin (DOX) for cancer chemo-immunotherapy. The codelivery nanocarrier aCD47-DMSN was constructed by accommodating DOX within the mesoporous cavity, while adsorbing aCD47 on the surface of MSN. aCD47 blocks the CD47-SIRPα axis to disable the "don't eat me" signal, while DOX induces immunogenic tumor cell death (ICD) for calreticulin exposure as an "eat me" signal. This design facilitated the phagocytosis of tumor cells by macrophages, which enhanced antigen cross-presentation and elicited efficient T cell-mediated immune response. In 4T1 and B16F10 murine tumor models, aCD47-DMSN generated a strong antitumor effect after intravenous injection by increasing tumor-infiltration of CD8+ T cells. Taken together, this study offers a nanoplatform to modulate the phagocytosis of macrophages for efficacious cancer chemo-immunotherapy.
Subject(s)
Nanoparticles , Neoplasms , Mice , Animals , Calreticulin , CD8-Positive T-Lymphocytes , Phagocytosis , Neoplasms/metabolism , Immunotherapy , CD47 Antigen/metabolismABSTRACT
Cancer vaccines have received tremendous attention in cancer immunotherapy due to their capability to induce a tumor-specific immune response. However, their effectiveness is compromised by the insufficient spatiotemporal delivery of antigens and adjuvants in the subcellular level to induce a robust CD8+ T cell response. Herein, a cancer nanovaccine G5-pBA/OVA@Mn is prepared through multiple interactions of manganese ions (Mn2+), benzoic acid (BA)-modified fifth generation polyamidoamine (G5-PAMAM) dendrimer, and the model protein antigen ovalbumin (OVA). In the nanovaccine, Mn2+ not only exerts a structural function to assist OVA loading as well as its endosomal escape, but works as an adjuvant of stimulator of interferon genes (STING) pathway. These collaboratively facilitate the orchestrated codelivery of OVA antigen and Mn2+ into cell cytoplasm. Vaccination with G5-pBA/OVA@Mn not only shows a prophylactic effect, but also significantly inhibits growth against B16-OVA tumors, indicating its great potential for cancer immunotherapy.
Subject(s)
Cancer Vaccines , Nanoparticles , Neoplasms , Humans , Animals , Mice , Manganese , Antigens , Adjuvants, Immunologic/therapeutic use , Neoplasms/therapy , Immunotherapy , Mice, Inbred C57BL , Nanoparticles/chemistry , Dendritic CellsABSTRACT
In Asian rice systems, Cyrtorhinus lividipennis Reuter is an important predator that preys on rice planthopper eggs and young nymphs, as a primary food source. Alanine aminotransferase (ALT) acts in many physiological and biochemical processes in insects. We cloned the full-length complementary DNA of C. lividipennis ClALT. Expression analysis showed higher expression in the fat body and midgut compared to other tissues. It is expressed in all C. lividipennis developmental stages and at least four organs. Silencing of ClALT by RNA interference significantly decreased the ClALT enzyme activity and ClALT expression compared to dsGFP-treated controls at 2 days after emergence (DAE). Silencing of ClALT influenced free hemolymph amino acid compositions, resulting in a reduction of Aspartic acid (Asp) and Alanine (Ala) proportions, and increased Cysteine (Cys) and Valine (Val) proportions in females at 2 DAE. dsClALT treatments led to decreased soluble total protein concentrations in ovary and fat body, and to lower reduced vitellogenin (Vg) expression, body weight, and the numbers of laid eggs. The double-stranded RNA viruse treatments also led to prolonged preoviposition periods and hindered ovarian development. Western blot analysis indicated that silencing ClALT also led to reduced fat body Vg protein abundance at 2 DAE. These data support our hypothesis that ClALT influences amino acid metabolism and fecundity in C. lividipennis.
Subject(s)
Alanine Transaminase , Amino Acids/metabolism , Fertility , Heteroptera , Alanine Transaminase/genetics , Alanine Transaminase/metabolism , Amino Acids/genetics , Animals , Hemolymph/metabolism , Heteroptera/genetics , Heteroptera/metabolism , Heteroptera/physiology , Insect Proteins/metabolism , RNA Interference , Vitellogenins/metabolismABSTRACT
Granulomatous inflammation is rare in the musculoskeletal system and difficult to diagnose. Here we describe a case of a 62-year-old woman with a history of being stabbed by a fishbone presented with a soreness, swelling, and limitation of movement of her right palm and wrist for 4 months. Surgery was done and the histopathology of specimens demonstrated granulomatous lesion, which was negative for acid-fast bacilli. This case demonstrates the diagnosis of granulomatous tenosynovitis on MRI, ultrasound, and surgical examination under anesthesia.
ABSTRACT
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Sorafenib (sfb) is widely used in clinics for advanced HCC therapy. However, the therapeutic efficacy of sfb is suboptimal due to its poor water solubility, low bioavailability, and side effects. Here, we employed a clinically safe polymer poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) to prepare a nanoparticle (NP)-based sfb formulation (NP-sfb) and tested its antitumor effect in multiple HCC models. NP-sfb could achieve effective drug loading and remain stable under physiological conditions. NP-sfb could be taken up by HepG2, Hepa1-6, and H22 cells and could efficiently inhibit cell proliferation and/or promote cell apoptosis. In vivo studies indicated that NP-sfb showed significantly improved therapeutic efficacy compared with free-sfb at the same dose or even higher doses. Mechanistic studies demonstrated that NP-sfb not only inhibited tumor proliferation and angiogenesis but also stimulated the tumor microenvironment by reducing the infiltration of immunosuppressive myeloid cells and increasing the ratio of cytotoxic T cells. This study demonstrates that the NP-based formulation is a promising strategy to improve the clinical application of sfb.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , Antineoplastic Agents/therapeutic use , Biological Availability , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Humans , Liver Neoplasms/drug therapy , Polymers/therapeutic use , Sorafenib , Tumor MicroenvironmentABSTRACT
The predatory mirid bug, Cyrtorhinus lividipennis Reuter, feeds on brown planthopper (BPH) eggs that are deposited on rice and gramineous plants surrounding rice fields. The development and reproduction of C. lividipennis are inhibited by feeding on BPH eggs from gramineous species, and the underlining regulatory mechanism for this phenomenon is unclear. In the present study, HPLC-MS/MS analysis revealed that the concentrations of six amino acids (AAs:Ala, Arg, Ser, Lys, Thr, and Pro) were significantly higher in rice than in five gramineous species. When C. lividipennis fed on gramineous plants with BPH eggs, expression of several genes in the target of rapamycin (TOR) pathway (Rheb, TOR, and S6K) were significantly lower than that in the insects fed on rice plants with BPH eggs. Treatment of C. lividipennis females with rapamycin, dsRheb, dsTOR, or dsS6K caused a decrease in Rheb, TOR, and S6K expression, and these effects were partially rescued by the juvenile hormone (JH) analog, methoprene. Dietary dsTOR treatment significantly influenced a number of physiological parameters and resulted in impaired predatory capacity, fecundity, and population growth. This study indicates that these six AAs play an important role in the mediated-TOR pathway, which in turn regulates vitellogenin (Vg) synthesis, reproduction, and population growth in C. lividipennis.
ABSTRACT
The mirid bug, Cyrtorhinus lividipennis Reuter, is an important predator of rice planthoppers in Asia. In a previous study, C. lividipennis fed on gramineous weeds with brown planthopper (BPH) eggs had reduced development compared to those fed on rice with BPH eggs. In the current study, the concentrations of selected amino acids (AAs) were higher in rice than five gramineous species, which might explain the enhanced growth of C. lividipennis on rice. When C. lividipennis was fed on AA-deprived artificial diets, the Wnt/ß-catenin pathway was inhibited. Furthermore, C. lividipennis females silenced for expression of Frizzled 2 (Fz2) showed a significant reduction in the Wnt/ß-catenin and target of rapamycin (TOR) pathways. Silencing Fz2 led to decreased expression of the vitellogenin gene (Vg), lower Vg accumulation in oocytes, reduced soluble protein in ovaries and fat bodies, reduced titers of juvenile hormone, prolonged preoviposition periods, and lower predation capacity, body weight, and egg numbers as controlled to controls. Fz2 silencing resulted in undeveloped ovaries and the inhibition of oocyte growth in the ovarioles, resulting in decreased numbers of offspring and reduced hatching rates. The silencing of Fz2 also resulted in aberrant embryos with undeveloped eyespots and organs, suggesting that Fz2 is an essential gene for embryonic development, oogenesis, and egg maturation. In summary, this study established a potential link between Wnt and TOR pathways, which interact synergistically to regulate C. lividipennis reproduction in response to AA signals. These results provide valuable new information that can be applied to large-scale rearing of C. lividipennis predators, which is important for reducing planthopper damage in rice fields.
ABSTRACT
Selenoproteins serve in anti-oxidant and cellular redox functions in almost all organisms. A recent study characterized a selenoprotein F-like (SPF-L) in the brown plant hopper's (BPH), Nilaparvata lugens, male accessory glands (MAGs), raised the question of whether the SPF-L is associated with female fecundity. In this study, SPF-L mRNA was found to be enriched in the internal reproductive organ (IRO) of virgin males, also expressed relatively stably in virgin males and females, and dietary dsSPF-L-treatments led to reduced MAG protein and Arginine content. Knockdown of NlSPF-L in unmated males did not influence juvenile hormone (JH) III and ecdysteroid titers, however, dsSPF-L-treated mated males had increased JH III titer, and reduced ecdysteroid titer compared to controls. After mating with dsSPF-L-treated males, female partners had reduced fat body and ovary soluble proteins and JH III tier and vitellogenin (Vg) mRNA levels, but no alterations in ecdysteroid titer, body weight or longevity. The experimental females had prolonged pre-oviposition periods and they laid fewer eggs, which suffered reduced hatching rates and population growth index (PGI). Such mating also led to impaired IRO development in males and females, which was confirmed by immunofluorescence staining. We infer that SPF-L affects reproductive success of males and their partners.
ABSTRACT
The antibiotic jinggangmycin (JGM) is broadly applied in Chinese rice producing regions to control rice blight, a fungal disease. Aside from protecting rice plants from the disease, JGM leads to the unexpected action of stimulating brown planthopper (BPH; Nilaparvata lugens; Hemiptera: Delphacidae) reproduction to the extent it can influence population sizes. The JGM-induced BPH population growth has potential for severe agricultural problems and we are working to understand and mitigate the mechanisms of the enhanced reproduction. UDP-glucuronosyltransferases (UGTs) are multifunctional detoxification enzymes responsible for biotransformation of diverse lipophilic compounds. The biological significance of this enzyme family in insect fecundity is not fully understood, however, upregulated UGT12 in JGM-treated BPH, may influence fecundity through metabolism of developmental hormones. This idea prompted our hypothesis that NlUGT12 is a positive modulator of BPH reproductive biology. JGM treatment led to significant increases in accumulations of mRNA encoding NlUGT12, numbers of eggs laid, oviposition period, juvenile hormone III titers, and fat body, and ovarian protein contents. dsUGT12 treatment suppressed NlUGT12 expression and reversed JGM-enhanced effects, resulting in under-developed ovaries and reduced expression of juvenile hormone acid methyltransferase and the JH receptor, methoprene tolerant. Application of the JH analog, methoprene, on dsUGT12 treated-females partially reversed the dsUTG12 influence on vitellogenin synthesis and on NlUGT12 expression. These results represent an important support for our hypothesis.
ABSTRACT
BACKGROUND: Inherited retinal dystrophy (IRD) is a group of retinal disorders that are both clinically and genetically diverse, typically with loss of photoreceptor function. Herein, we aimed to identify the underlying genetic defect in IRD patients with mutations in the SLC7A14 gene. METHODS: A targeted exome capture panel was applied for mutational screening of SLC7A14. Targeted exome sequencing (TES) was performed on 200 non-syndromic and unrelated autosomal recessive or sporadic IRD families. Candidate variants were validated by direct sequencing and further examined using bioinformatics analyses for determination of their potential effect. RESULTS: We identified compound heterozygous missense mutations (c.988G>A, p.G330R; c.1970G>A, p.R657Q) in an autosomal recessive retinitis pigmentosa (RP) case and a homozygous mutation (c.988G>A, p.G330R) in a simplex case with Leber congenital amaurosis (LCA) in the SLC7A14 gene. Both G330R and R657Q were deleterious based on in silico predictive tools. Our proposed topological model of the SLC7A14 polypeptide suggested that both G330R and R657Q affected evolutionarily highly conserved amino acid residues in SLC7A14 that occurred in transmembrane helixes. Structural modeling revealed a broken arginine and aspartic acid connection between residues 657 and 406. CONCLUSIONS: We applied TES to the molecular diagnosis of patients with IRD and for the first time identified SLC7A14 mutations in two unrelated families with RP and LCA separately. Our findings uniquely add the knowledge of the phenotypic variability of SLC7A14 mutations.
Subject(s)
Amino Acid Transport System y+/genetics , Leber Congenital Amaurosis/genetics , Mutation, Missense , Retinitis Pigmentosa/genetics , Biological Variation, Population , DNA Mutational Analysis , Evoked Potentials, Visual/physiology , Exome/genetics , Female , Humans , Pedigree , Polymorphism, Single Nucleotide , Retinitis Pigmentosa/physiopathology , Exome SequencingABSTRACT
Quantitative magnetic resonance image (MRI) in individual muscles may be useful for monitoring disease progression in Duchenne muscular dystrophy (DMD). The purpose of this study was to measure T2 relaxation time of thigh muscles in children with DMD and healthy boys, and to correlate the T2 relaxation time of muscles with the fat fraction (FF) at quantitative magnetic resonance and results of clinical assessment. Thirty-two boys with DMD and 18 healthy boys were evaluated with T2 mapping and three-point Dixon MRI. Age, body mass index (BMI), muscle strength assessment, timed functional tests (time to walk or run 10 metres, rise from the floor and ascend four stairs), and the North Star Ambulatory Assessment (NSAA) were evaluated. Spearman's correlation was used to assess the relationships between FF and clinical assessments and T2 relaxation time. The mean T2 relaxation time of thigh muscles in DMD was significantly longer than that in the control group (P<0.05), except for the gracilis (P=0.952). The gracilis, sartorius and adductor longus were relatively spared by fatty infiltration in DMD patients. The T2 relaxation time was correlated significantly with the mean FF in all muscles. Age, BMI, total muscle strength score, timed functional tests and NSAA were significantly correlated with the overall mean T2 relaxation time. T2 mapping may prove clinically useful in monitoring muscle changes as a result of the disease process and in predicting the outcome of DMD patients.
Subject(s)
Adipose Tissue/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Muscular Dystrophy, Duchenne/diagnostic imaging , Thigh/diagnostic imaging , Adolescent , Body Mass Index , Case-Control Studies , Child , Child, Preschool , Disease Progression , Humans , Magnetic Resonance Imaging , Male , Prospective StudiesABSTRACT
Hexokinase is a rate-limiting enzyme that plays pivotal roles in glucose homeostasis and energy metabolism via glucose (Glc) phosphorylation and Glc signaling mediation. Previous investigations have revealed the modulatory role of Hexokinase (Hex) genes involved in proper glucose regulation during insect diapause and embryo development, whereas whether it functions in insect fecundity remains largely unknown. We aimed to explore the relationship between Triazophos (TZP)-induced Hex-1 and fecundity of female Nilaparvata lugens. In this study, Hex-1 expression were characterized at different developmental stages and in various tissues of N. lugens, with the highest expression registered in brain tissues and 5th instar nymph. The present findings indicated that TZPâ¯+â¯dsHex-1 silencing significantly reduced protein synthesis, including the fat body and ovarian protein content of female adults. Meanwhile, the glycometabolism with respect to the soluble sugar, trehalose and glucose content in female adults were strikingly influenced as a result of Hex-1 knockdown. The relative transcript level of Hex-1, vitellogenin (NlVg) and vitellogenin receptor (NlVgR) considerably decreased in TZPâ¯+â¯dsHex-1 treated females compared to TZP and TZPâ¯+â¯dsGFP-treated groups. More importantly, TZPâ¯+â¯dsHex-1 silencing led to reduced number of eggs laid and vitellogenin (Vg) accumulation as well as retarded ovary development compared with TZP-treated and TZPâ¯+â¯dsGFP-treated groups. Taken together, it is proposed that Hex-1 implicates in N. lugens fecundity by exerting profound effects on glycometabolism, protein sythesis and NlVg expression.
Subject(s)
Fertility/drug effects , Hemiptera/drug effects , Hexokinase/genetics , Insect Proteins/genetics , Insecticides/toxicity , Organothiophosphates/toxicity , Triazoles/toxicity , Animals , Female , Fertility/genetics , Hemiptera/physiology , Insect Proteins/metabolism , Male , RNA InterferenceABSTRACT
Pyruvate kinase (PYK) operates in the glycolytic pathway, responsible for regulating the balance between glycolysis and gluconeogenesis. The previous work indicates PYK acts in development of Drosophila embryos and in embryonic muscle growth, from which it may be inferred that PYK acts in insect fecundity. More to the point, as a central enzyme in the glycolytic pathway, PYK acts in many energy-spending functions in most organisms. On the background findings that triazophos (TZP) stimulates fecundity via increase activities of several genes in brown planthoppers, Nilaparvata lugens, we investigated the combined influence of TZP and silencing a N. lugens PYK (NlPYK) on reproduction-linked biological performance parameters. Here, we report that TZP+dsNlPYK treatments led to reduced (by 26%) ovarian, but not fat body, protein content relative to controls. Ovarian (35%) and fat body (54%) soluble sugar contents were reduced. TZP+dsNlPYK treatments also led to reduced (by about 24%) fecundity, expressed as numbers of eggs laid. These data show directly that NlPYK acts in insect fecundity, probably via increases in glucose metabolism.
Subject(s)
Hemiptera/enzymology , Ovum/growth & development , Pyruvate Kinase/metabolism , Animals , Carbohydrate Metabolism , Female , Fertility , Insect Proteins/metabolism , Male , Organothiophosphates , RNA Interference , Reproduction , TriazolesABSTRACT
Lipase-displaying yeast cells are a promising alternative to the conventional immobilised lipases for organic bioconversions. However, the hydrophilic characteristics of the yeast cell surface may impede efficient immobilisation. Herein, we tested three methods to enhance the hydrophobicity of the surface of Candida antarctica lipase B-displaying Pichia pastoris cells, co-displaying a fungal hydrophobin, coating with ionic liquids, and adding decane as a hydrophobic carbon source during fermentation. Modified cells showed higher surface hydrophobicity and superior esterification of C6-C18 saturated fatty acids in hydrophobic solvents. When used for biodiesel synthesis, modified cells exhibited an improved initial reaction rate and equilibrium fatty acid methyl ester yield. We systematically discuss the influence of cell surface hydrophobicity on the catalytic properties, and the results provide guidance for improving the catalytic efficiency and operational characteristics of lipase-displaying yeast cells for organic bioconversions.
Subject(s)
Candida/enzymology , Lipase/metabolism , Pichia/enzymology , Catalysis , Esterification , Fermentation , Hydrophobic and Hydrophilic Interactions , Substrate Specificity , Surface PropertiesABSTRACT
Citrus essential oils (CEOs) are important flavors in the food and confectionary industries. A lipase process was proposed for enhancing the flavor profiles and increasing the proportions of esters in CEOs. The effects of the enzymatic process were explored by detecting the constituents of the CEOs of American sweet orange oil (ASO) and Brazil mandarin oil (BMO) through GC/MS and sensory evaluation by a trained panel, and positive effects were confirmed by both methods. A further eleven kinds of CEOs were treated via the lipase process and increments of 10 - 1170% were achieved in the proportions of esters, which were mostly ethyl esters. Enhancement in fruity odor, especially the top note, was demonstrated by all CEOs after enzymatic processing. All CEOs were tested for antimicrobial activities, and only ASO displayed fairly ideal antimicrobial activities. Meanwhile, modified ASO showed a certain increase in antimicrobial activities. This methodology might be considered a sustainable route for acquiring 'natural' essential oils with enhanced flavor profiles and simultaneously enhancing the comprehensive utilization of citrus fruits.
Subject(s)
Citrus/chemistry , Citrus/enzymology , Esters/analysis , Lipase/metabolism , Oils, Volatile/analysis , Oils, Volatile/metabolism , Anti-Infective Agents/chemistry , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Citrus/metabolism , Esters/chemistry , Esters/metabolism , Flavoring Agents/metabolism , Gas Chromatography-Mass Spectrometry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Oils, Volatile/pharmacology , Principal Component AnalysisABSTRACT
This study aimed to assess coronary microvascular dysfunction (CMD) differences in hypertrophic cardiomyopathy (HCM) patients using cardiac magnetic resonance (CMR) first-pass perfusion and late gadolinium enhancement imaging. Forty-seven patients with HCM and twenty-one healthy volunteers underwent CMR at rest. Imaging protocols included short axis cine, first-pass myocardial perfusion, and late gadolinium enhancement (LGE). Left ventricular end-diastolic wall thickness (EDTH), LGE, time to peak (Tpeak), maximal up-slope (Slopemax), and peak signal intensity (SIpeak) were assessed for each myocardial segment. The HCM myocardial segments were grouped by the degree of LGE and hypertrophy. Tpeak, SIpeak, Slopemax and EDTH in multiple groups were assessed and compared by ANOVA test/Kruskal-Wallis test. The Spearman correlation test was used to determine the relationships between EDTH, LGE and perfusion parameters (Tpeak, Slopemax and SIpeak). Compared to control group segments, Tpeak increased while Slopemax and SIpeak decreased in non-LGE/non-hypertrophic segments and LGE/hypertrophic segments in the HCM group, while Tpeak increased more significantly in LGE/hypertrophic segments (all p < 0.05). Tpeak statistically increased with increasing degrees of myocardial LGE (p < 0.01). Differences in Tpeak, SIpeak and EDTH were observed between segments with and without hypertrophy (p < 0.05). EDTH and LGE were positively correlated with Tpeak (r = 0.279, p = 0.031 and r = 0.237, p < 0.001). 3.0 T magnetic resonance myocardial perfusion imaging identifies abnormal perfusion in non-LGE and non-hypertrophic segments of HCM patients, and it may be helpful in the early diagnosis of coronary microvascular dysfunction in HCM. This abnormal perfusion is associated with the severity of myocardial fibrosis and the degree of hypertrophy.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Coronary Circulation , Coronary Vessels/diagnostic imaging , Magnetic Resonance Imaging, Cine , Microcirculation , Microvessels/diagnostic imaging , Myocardial Perfusion Imaging/methods , Adult , Aged , Cardiomyopathy, Hypertrophic/physiopathology , Case-Control Studies , Contrast Media/administration & dosage , Coronary Vessels/physiopathology , Female , Fibrosis , Gadolinium DTPA/administration & dosage , Humans , Image Interpretation, Computer-Assisted , Male , Microvessels/physiopathology , Middle Aged , Myocardium/pathology , Predictive Value of Tests , Prognosis , Reproducibility of Results , Severity of Illness Index , Ventricular Function, Left , Ventricular RemodelingABSTRACT
Objective To investigate the inhibitory effect of T ubacin,a selective inhibition of histone deacetylase 6 (HDAC6),on the release of inflammatory mediators in lipopolysaccharide (LPS) activated microglias and its underlying mechanism.Methods BV-2 microglias were divided into control group (conventional culture),LPS group (100 ng/mL LPS),Tubacin treatment group (1 μmol/L Tubacin) and experimental group (LPS 100 ng/mL+Tubacin 1 μmol/L).The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by enzyme linked immunosorbent assay (ELISA).The production of nitric oxide (NO) was assayed by Griess reagent and the expression of inducible nitric oxide synthase (iNOS) was measured by Western blotting.The oxidative stress levels of BV-2 cells were determined by reactive oxygen species (ROS) and superoxide dismutase (SOD) assays.Results As compared with those in the control group,the productions of IL-6,TNF-α and NO were notably increased,the iNOS protein expression was significantly up-regulated,the ROS level was apparently elevated and the SOD activity was significantly decreased in the LPS group (P<0.05).As compared with those in the LPS group,the productions of IL-6,TNF-α and NO were notably decreased,the iNOS protein expression was significantly down-regulated,the ROS level was apparently lessened and the SOD activity was significantly increased in the experiment group (P<0.05).Conclusion Tubacin curbs the release of inflammatory mediators in activated microglial cells induced by LPS,whose effect may be achieved through decreasing oxidative stress levels in LPS activated microglial cells.
ABSTRACT
Usher syndrome (USH) is an autosomal recessive (AR) multi-sensory degenerative disorder leading to deaf-blindness. USH is clinically subdivided into three subclasses, and 10 genes have been identified thus far. Clinical and genetic heterogeneities in USH make a precise diagnosis difficult. A dominantlike USH family in successive generations was identified, and the present study aimed to determine the genetic predisposition of this family. Wholeexome sequencing was performed in two affected patients and an unaffected relative. Systematic data were analyzed by bioinformatic analysis to remove the candidate mutations via stepwise filtering. Direct Sanger sequencing and cosegregation analysis were performed in the pedigree. One novel and two known mutations in the USH2A gene were identified, and were further confirmed by direct sequencing and cosegregation analysis. The affected mother carried compound mutations in the USH2A gene, while the unaffected father carried a heterozygous mutation. The present study demonstrates that wholeexome sequencing is a robust approach for the molecular diagnosis of disorders with high levels of genetic heterogeneity.