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BACKGROUND: Normal bile is sterile. Studies have shown that cholangitis after liver transplantation (LT) was associated with a relatively poor prognosis. It remains unclear whether the bacteriobilia or fungibilia impact the patient outcomes in LT recipients, especially with donation after circulatory death (DCD) allografts, which was correlated with a higher risk of allograft failure. METHODS: This retrospective study included 139 LT recipients of DCD grafts from 2019 to 2021. All patients were divided into two groups according to the presence or absence of bacteriobilia or fungibilia. The prevalence and microbial spectrum of postoperative bacteriobilia or fungibilia and its possible association with outcomes, especially hospital stay were analyzed. RESULTS: Totally 135 and 171 organisms were isolated at weeks 1 and 2, respectively. Among all patients included in this analysis, 83 (59.7%) developed bacteriobilia or fungibilia within 2 weeks post-transplantation. The occurrence of bacteriobilia or fungibilia (ß = 7.43, 95% CI: 0.02 to 14.82, P = 0.049), particularly the detection of Pseudomonas (ß = 18.84, 95% CI: 6.51 to 31.07, P = 0.003) within 2 weeks post-transplantation was associated with a longer hospital stay. However, it did not affect the graft and patient survival. CONCLUSIONS: The occurrence of bacteriobilia or fungibilia, particularly Pseudomonas within 2 weeks post-transplantation, could influence the recovery of liver function and was associated with prolonged hospital stay but not the graft and patient survival.
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Linusorbs (LOs), significantly influence oil quality and sensory properties of flaxseed oil. Trp-containing LOs exhibit distinct oxidative behavior when γ-tocopherol (γ-T) is present. Polar fractions of crude flaxseed oil were stripped via silica absorption, and reintroduced (LO and γ-T) separately into the oil matrix to investigate their interaction during storage. Compared with crude oil, LOs account for 18.49% reduction of p-anisidine value, while LOs with γ-T contributed to most of the endogenous antioxidant effect in crude oil. γ-T was found to suppress oxidation of Trp-containing LO at early stage (Met form), while facilitate oxidation while at their mid-stage (MetO form, Methionine sulfoxide). In vitro oxidation shows that CLD more likely cleaved into peptide fragments, while few products retain intact ring structures. LC-MS/MS analysis and silicon simulation revealed proximity between MetO and Trp residues, facilitating inter- or intra-molecular reactions and ring structure rupture. Remarkably, the presence of γ-T facilitate these phenomena.
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Óleo de Semente do Linho , Triptofano , gama-Tocoferol , Triptofano/química , Óleo de Semente do Linho/química , gama-Tocoferol/química , Oxirredução , Antioxidantes/química , Espectrometria de Massas em Tandem , Linho/químicaRESUMO
Linusorbs (LOs, cyclolinopeptides) are a class of naturally occurring cyclic hydrophobic peptides found in flaxseed oil, whose oxidation states indicate the oxidative stability and bitterness of flaxseed oil. Subjected to 63 °C accelerated oxidation, most Met-containing LOs in cold-pressed flaxseed oil entirely depleted by the 6th day except CLP, and MetO2-containing LOs became the dominant ones. However, no MetO2 form of Trp-containing LOs, such as CLD, CLF and CLG, were detected. Given their oxidative kinetics, methionine sulfoxide (MetO) residue in some LOs was less sensitive toward oxidation in the presence of Trp (Tryptophan) group, and the oxidative stability of Met-containing LOs was CLP < CLB < CLL ≈ CLM < CLO, as compared to MetO-containing LOs: CLD < CLE < CLC < CLF ≈ CLG. When antioxidant was added into cold-pressed flaxseed oil to assess the additives' antioxidant effect, no significant difference was observed on oil oxidative indices in early stage except α-tocopherol, where they vary dramatically in suppressing Met oxidation of LOs: L-AP (L-ascorbyl palmitate) > TBHQ (tert-butyl hydroquinone) > γ-tocopherol > carnosic acid > α-tocopherol. Besides its ability to suppress oxidation of Trp-containing LOs, L-AP also exhibits superior antioxidant effect on non-Trp-containing LOs due to its amphiphilic property. Due to the prooxidative effects of both α- and γ-tocopherol on LOs that contain Trp, it has been suggested that tocopherols may repair Trp residue on LOs, leading to increased tendency of MetO residues to oxidize. The findings of this research are critical for elucidating the antioxidative mechanism of LOs, which can further lead to the establishment of strategies in suppressing bitter after taste to produce high-quality flaxseed oil.
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Antioxidantes , Óleo de Semente do Linho , Antioxidantes/química , Hidroquinonas , Óleo de Semente do Linho/química , Peptídeos Cíclicos , Tocoferóis , Triptofano , alfa-Tocoferol , gama-TocoferolRESUMO
A convenient synthesis of methylene-bridged pyrrolo[2,1-a]isoquinolines has been developed. Treatment of pyrroloisoquinolines with acetyl chloride and dimethylsulfoxide (DMSO) at ambient temperature afforded bispyrroloisoquinolylmethanes in 17-85% yields. This reaction system can also be expanded to the synthesis of bispyrrolylmethanes (34-94% yields). Easy chemical transformation of methylene-bridged pyrroloisoquinoline provided an unsymmetric acid and amide possessing a privileged framework.
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Isoquinolinas , Pirróis , Acetatos , Cloretos , Dimetil SulfóxidoRESUMO
BACKGROUND: Ceftobiprole is a novel ß-lactam cephalosporin with activity against Gram-positive and -negative bacteria. The aim of the present study was to investigate the pharmacokinetics (PK), pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerance of ceftobiprole in Chinese participants, to evaluate this dosage regimen for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) in China. METHODS: The use of ceftobiprole was investigated in a single-center, open-label, single- and multiple-dose study using 12 healthy Chinese participants (6 males and 6 females). Ceftobiprole plasma and urine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK/PD characteristics of 500 mg ceftobiprole every 8 h at 1.5-, 2-, 3-, or 4-h infusion time were analyzed by Monte Carlo simulations (MCS). RESULTS: The maximum plasma concentration of ceftobiprole was observed 2 h after dosage; its terminal half-life was about 3 h. Ceftobiprole was predominantly eliminated in urine, and the cumulative excretion in 24 h was >90%. There was no accumulation after multiple dosing. Both single and multiple doses were well tolerated, with no severe or serious adverse events (AEs). PK/PD analysis indicated that Staphylococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) were sensitive to ceftobiprole. About half of extended-spectrum ß-lactamase (ESBL) non-producing Enterobacteriaceae are sensitive to ceftobiprole, according to PK/PD results of ceftobiprole. For Pseudomonas aeruginosa (P. aeruginosa), no regimen was found to be effective against strains. CONCLUSIONS: The PK/PD results indicated that 500 mg ceftobiprole every 8 h at 2-h infusion time is expected to achieve good microbiological efficacy in the treatment of CAP and HAP in China.
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Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell-targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell-targeting and pH-sensitive nano-micelles. The results showed a critical P14-micelle concentration of 1.758 mg l-1and an average particle size of micelles of 121.64 nm, with entrapment and drug-loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 h in pH 4.5 medium, and the drug cumulative release profile of micelles can be described by the first-order model. Compared with free DOX, the micelles exhibited an increased ability to inhibit tumor cell growth and cause tumor apoptosisin vitro, with IC50values of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06µg ml-1, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.
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Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Nanoestruturas/química , Peptídeos/metabolismo , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Doxorrubicina/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Cinética , Células MCF-7 , Micelas , Terapia de Alvo Molecular , Nanoestruturas/ultraestrutura , Peptídeos/síntese químicaRESUMO
PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.
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Antibacterianos/farmacocinética , Colistina/farmacocinética , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/química , Colistina/administração & dosagem , Colistina/química , Estudos Cross-Over , Composição de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Medical students have high rates of depression, anxiety, and burnout that have been found to affect their empathy, professional behaviors, and performance as a physician. While studies have examined predictors for burnout and depression in the United States (US), no study, to our knowledge, has compared depression in medical students cross-culturally, or has attempted to examine the effect of factors influencing rates including burnout, exercise, stress, unmet mental health needs, and region. AIM: To examine rates of depression in three international cohorts of medical students, and determine variables that may explain these differences. METHODS: Convenience samples of medical students from three countries (US, China, and a Middle Eastern country whose name remains anonymous per request from the school) were surveyed in this observational study. Using the Patient Health Questionnaire-2 (PHQ-2) and a modified Maslach Burnout Inventory, depression and burnout were examined among medical students from the three cohorts (n = 473). Chi-square test and analysis of variance were used to examine differences in demographics, behavioral, and psychological variables across these three schools to identify potentially confounding descriptive characteristics. Analysis of covariance compared depression and the emotional exhaustion component of burnout identified through Principal Component Analysis across countries. Multiple linear regression was used to analyze the impact of demographic, behavioral, and psychological variables on screening positive for depression. RESULTS: Medical students from the Middle Eastern country had the highest rates of positive depression screens (41.1%), defined as a PHQ-2 score of ≥ 3, followed by China (14.1 %), and then the US (3.8%). More students in the Middle Eastern school had unmet mental health needs (50.8%) than at the medical school in China (34.8%) or the school in the US (32.8%) (Pearson chi-square significance < 0.05). Thus, PHQ-2 scores were adjusted for unmet mental health needs; however, the Middle Eastern country continued to have the highest depression. Adjusting for PHQ-2 score, medical students from the US scored the highest on emotional exhaustion (a measure of burnout). Demographic variables did not significantly predict medical student depression; however, lack of exercise, unmet mental health needs, stress, and emotional exhaustion predicted nearly half of depression in these cohorts. In comparison to the US, coming from the Middle Eastern country and China predicted higher levels of depression. CONCLUSION: Depression rates differ in three international cohorts of medical students. Measured factors contributed to some observed differences. Identifying site-specific prevention and intervention strategies in medical student mental health is warranted.
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BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlighted the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX)-10 has a regulatory function in endolysosomal trafficking and stabilisation. Here, we investigated the roles of SNX10 in CMA activation and in the pathogenesis of alcohol-induced liver injury and steatosis. METHODS: Snx10 knockout (Snx10 KO) mice and their wild-type (WT) littermates fed either the Lieber-DeCarli liquid alcohol diet or a control liquid diet, and primary cultured WT and Snx10 KO hepatocytes stimulated with ethanol, were used as in vivo and in vitro ALD models, respectively. Activation of CMA, liver injury parameters, inflammatory cytokines, oxidative stress and lipid metabolism were measured. RESULTS: Compared with WT littermates, Snx10 KO mice exhibited a significant amelioration in ethanol-induced liver injury and hepatic steatosis. Both in vivo and in vitro studies showed that SNX10 deficiency upregulated lysosome-associated membrane protein type 2A (LAMP-2A) expression and CMA activation, which could be reversed by SNX10 overexpression in vitro. LAMP-2A interference confirmed that the upregulation of Nrf2 and AMPK signalling pathways induced by SNX10 deficiency relied on CMA activation. Pull-down assays revealed an interaction between SNX10 and cathepsin A (CTSA), a key enzyme involved in LAMP-2A degradation. Deficiency in SNX10 inhibited CTSA maturation and increased the stability of LAMP-2A, resulting in an increase in CMA activity. CONCLUSIONS: SNX10 controls CMA activity by mediating CTSA maturation, and, thus, has an essential role in alcohol-induced liver injury and steatosis. Our results provide evidence for SNX10 as a potential promising therapeutic target for preventing or ameliorating liver injury in ALD. LAY SUMMARY: Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Recent studies highlight the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Our study reveals that deficiency of sorting nexin (SNX) 10 increases the stability of LAMP-2A by inhibiting cathepsin A maturation, resulting in the increase of CMA activity and, thus, alleviates alcohol-induced liver injury and steatosis.
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Fígado Gorduroso/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatopatias Alcoólicas/complicações , Estresse Oxidativo , RNA/genética , Nexinas de Classificação/genética , Animais , Autofagia , Western Blotting , Modelos Animais de Doenças , Etanol , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hepatócitos/patologia , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Nexinas de Classificação/biossínteseRESUMO
In response to changes in microenvironment, macrophages polarize into functionally distinct phenotypes, playing a crucial role in the pathogenesis of inflammatory bowel disease (IBD). Here, we investigated the effects of sorting nexin 10 (SNX10), a protein involved in endosomal trafficking and osteoclast maturation, on regulation of macrophage polarization and progression of mouse colitis. Our results revealed that SNX10 deficiency increased the population of M2-type monocytes/macrophages, and protected against colonic inflammation and pathological damage induced by dextran sulfate sodium (DSS). By in vitro study, we showed that deficiency of SNX10 polarized macrophages derived from mouse bone marrow or human peripheral blood mononuclear cells (PBMCs) towards an anti-inflammatory M2 phenotype, which partially reversed by SNX10 plasmid transfection. Adoptive transfer of SNX10(-/-) macrophages ameliorated colitis in WT mice. However, transfer of WT macrophages exacerbated colitis in SNX10(-/-) mice. Our data disclose a crucial role and novel function for SNX10 in macrophage polarization. Loss of SNX10 function may be a potential promising therapeutic strategy for IBD.
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Polaridade Celular/imunologia , Colo/imunologia , Doenças Inflamatórias Intestinais/imunologia , Macrófagos/imunologia , Nexinas de Classificação/imunologia , Transferência Adotiva , Animais , Polaridade Celular/genética , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Macrófagos/patologia , Macrófagos/transplante , Camundongos , Camundongos Knockout , Nexinas de Classificação/genéticaRESUMO
OBJECTIVE: Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice. METHODS: The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10(-/-) mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10(-/-) mice. RESULTS: SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1ß and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10(-/-) osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10(-/-) osteoclasts causing an inhibition of integrin ß3-Src-PYK2 signalling. CONCLUSIONS: Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.
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Artrite Experimental/complicações , Reabsorção Óssea/prevenção & controle , Fatores de Transcrição NFATC/metabolismo , Nexinas de Classificação/fisiologia , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Integrina beta3/fisiologia , Masculino , Camundongos Knockout , Osteoclastos/patologia , Osteoclastos/fisiologia , Osteogênese/fisiologia , Transdução de Sinais/fisiologia , Nexinas de Classificação/deficiência , Membrana Sinovial/patologia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To explore natural herbs to maintain the bactericidal activity of hydrogen peroxide (H). METHODS: Eighteen extracts of Chinese herbs were prepared complying with the standard protocol. Each of the solutions was then mixed with 1% H2O2. The mixtures were handled with two approaches: autoclaved daily for one, two or three times; stored at room temperature from one through five years. Then the bactericidal activity were evaluated by assaying the minimal bactericidal concentration (MBC) and minimal inhibitory concentration (MIC) against Gram positive (Staphylococcus aureus, ATCC25923) and Gram negative (Escherichia coli, ATCC12421) bacteria. RESULTS: While mixed with 1% H2O2, 10 out of 18 kinds of assessed Chinese herbs displayed MBC values at 1:12800 or higher after three times of autoclaving, and 8 of them preserved such level of MBC value after stored at room temperature for three years. Some Chinese herbs, i.e. R. Scutellariae, R. Coptidis, R. Bupleuri, H. Epimedii, C. Phelledendri and F. Chrysanthemi, can significantly maintain the bactericidal activity of diluted H2O2. CONCLUSIONS: Certain Chinese herbs can effectively stabilize the bactericidal activity of H2O2 undergoing autoclave or long-term storage. This paper reported a brandnew pharmaceutical function of Chinese herbs and provided experimental data for the potential enhancement of H2O2 usage while its stability level is promoted.
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Antibacterianos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Peróxido de Hidrogênio/farmacologia , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Esterilização , Fatores de TempoRESUMO
OBJECTIVE: To explore an approach to rapidly and accurately identify the compounds as biomarkers of Chinese medicine (CM) syndromes. METHOD: The Fourier transform infrared (FT-IR) spectrometry was applied to investigate the characteristic components of a mice model of Kidney (Shen)-yang deficiency syndrome (KDS), and the remedial effect of a typical CM formula Shenqi Pill (). Thirty-six females and 18 males of Balb/c mice were randomly divided into KDS, Shenqi or control group. The females and males of the same group freely were mated for 96 h, and the males were taken out and only the female mice were raised. Females of the KDS group were threatened by a ferocious cat every other day for 14 d. After delivery, the KDS, or gestational threatened, offspring were raised at standard condition for 11 weeks. Then 10 male offspring were randomly selected, anaesthetized and their representative organs, i.e. testes, kidneys, lungs and feet were collected, for the FT-IR scan. Mice of the Shenqi group were intragastric administered Shenqi Pill; while mice in the KDS and control groups were given the same volume of saline. RESULTS: The attenuated birth outcomes of the KDS group were displayed. The remarkable FT-IR differences of all organs between KDS mice and healthy control were mainly at 1,735-1,745 cm(-1) (indicating the increased levels of lipids) and at 1,640-1,647 cm(-1) and 1,539-1,544 cm(-1) (displaying the decreased proteins). No statistic FT-IR difference between Shenqi and control mice was observed. CONCLUSION: In accordance with major traits of KDS, prenatal stress extensively impaired the building up of proteins and resulting in the excessive lipid storage, and FT-IR could effectively identify the biomarkers of KDS.
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Nefropatias/patologia , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Deficiência da Energia Yang/patologia , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Nefropatias/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Deficiência da Energia Yang/tratamento farmacológicoRESUMO
We have performed an analysis of a family with kidney-yang deficiency syndrome (KDS) in order to determine the structural genomic variations through a novel approach designated as "copy number variants" (CNVs). Twelve KDS subjects and three healthy spouses from this family were included in this study. Genomic DNA samples were genotyped utilizing an Affymetrix 100 K single nucleotide polymorphism array, and CNVs were identified by Copy Number Algorithm (CNAT4.0, Affymetrix). Our results demonstrate that 447 deleted and 476 duplicated CNVs are shared among KDS subjects within the family. The homologus ratio of deleted CNVs was as high as 99.78%. One-copy-duplicated CNVs display mid-range homology. For two copies of duplicated CNVs (CNV(4)), a markedly heterologous ratio was observed. Therefore, with the important exception of CNV(4), our data shows that CNVs shared among KDS subjects display typical Mendelian inheritance. A total of 113 genes with established functions were identified from the CNV flanks; significantly enriched genes surrounding CNVs may contribute to certain adaptive benefit. These genes could be classified into categories including: binding and transporter, cell cycle, signal transduction, biogenesis, nerve development, metabolism regulation and immune response. They can also be included into three pathways, that is, signal transduction, metabolic processes and immunological networks. Particularly, the results reported here are consistent with the extensive impairments observed in KDS patients, involving the mass-energy-information-carrying network. In conclusion, this article provides the first set of CNVs from KDS patients that will facilitate our further understanding of the genetic basis of KDS and will allow novel strategies for a rational therapy of this disease.
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Objective. To explore the genetic traits of Kidney-yang deficiency syndrome (KDS). Design. Twelve KDS subjects and three spouses from a typical KDS family were recruited. Their genomic DNA samples were genotyped by Affymetrix 100K single-nucleotide polymorphism (SNP) arrays. The linkage disequilibrium (LD) SNPs were generated using GeneChip DNA analysis software (GDAS, Affymetrix). Genes located within 100 bp of the flanks of LD SNPs were mined via GeneView. 29 exons of the doublecortin domain containing 5 (DCDC5), a representative gene within the flank of an LD SNP, were resequenced. Results. Five LD SNPs display midrange linkage with KDS. Two genes with established functions, DCDC5 and Leucyl-tRNA synthetase, were mined in the flanks of LD SNPs. Resequencing of DCDC5 revealed a nonsynonymous variation, in which 3764T/A was replaced by C/G. Accordingly, the Ser(1172) was substituted by Pro(1172). The S1172P substitution effect was evaluated as "possibly damaging" by PolyPhen. Conclusion. We have identified a genomic variation of DCDC5 based on the LD SNPs derived from a KDS family. DCDC5 and other genes surrounding these SNPs display some relationships with key symptoms of KDS.
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OBJECTIVE: To improve the diagnosis and management of Duchenne/Becker muscular dystrophy(DMD/BMD). METHODS: Clinical features of 90 cases of DMD/BMD were collected. Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes, and multiplex ligation-dependent probe amplification (MLPA) was applied to detect DMD gene to identify genetic mutation. For those patients whose deletion/duplication mutation was not identified, FKRP gene mutation analysis was performed using PCR-DNA direct sequence. All the cases were followed up. RESULTS: Among the 90 cases of clinically diagnosed DMD/BMD, exons deletion of DMD was detected in 58 cases (64.44%), and exons duplication in 9 (10.00%). Among the 34 mothers with an affected boy but without previous genetic conformation, 17 were confirmed to be carriers with gene deletion/duplication. None of the 23 cases, without detected DMD gene deletion/duplication, carried FKRP gene mutation. Fourteen children were given short-term intermittent prednisone therapy (0.75 mg/kg daily during the first 10 days of each month). The course was not long enough and the sample size was too small to conclude any benefits or side effects. Prenatal diagnosis was provided for one mother in her next pregnancy detecting a female carrier fetus. CONCLUSION: DMD gene deletions mainly occurs between exons 45 and 54, while duplications mostly at 5'-terminus. Identification of the characteristics and types of gene mutation may facilitate the recognition and prognosis prediction of DMD/BMD. MLPA is a non-complex and quick diagnostic tool for DMD/BMD and its carriers, and also helpful in genetic counseling.
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Deleção de Genes , Distrofia Muscular de Duchenne/genética , Mutação , Técnicas de Amplificação de Ácido Nucleico , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Masculino , Fenótipo , Adulto JovemRESUMO
OBJECTIVE: The study was designed to explore the value of the New York University Pediatric Heart Failure Index (NYU PHFI) for diagnosing and grading chronic heart failure in children. METHODS: Totally 105 children with chronic heart failure or structural heart disease but without signs and symptoms of heart failure were enrolled. They were diagnosed using modified Ross score, NYU PHFI and NT-proBNP, respectively. According to modified Ross score as the referent criteria, the diagnostic value of NYU PHFI in quantifying chronic heart failure severity in children was studied. Furthermore, according to the grading of heart failure using modified Ross score, the area under the ROC curves of NYU PHFI was examined, respectively, in order to find out the optimal cut-off point. RESULTS: NYU PHFI score was positively correlated with the modified Ross score (r = 0.909, P = 0.000). According to modified Ross score, NYU PHFI scores in different severity of heart failure in children differed significantly (F = 80.034, P = 0.000). A significantly positive correlation was found between plasma NT-proBNP and modified Ross score, and between NT-proBNP and NYU PHFI score. Correlation coefficients between plasma NT-proBNP and modified Ross score, and between plasma NT-proBNP and NYU PHFI score were 0.752 and 0.918, respectively. The correlation between NYU PHFI and plasma NT-proBNP was superior to that between modified Ross score and plasma NT-proBNP. According to modified Ross scores of 0 - 2 as being without heart failure, 3 - 6 as mild degree of heart failure, 7 - 9 as moderate degree of heart failure and 10 - 12 as severe degree of heart failure, the areas under the ROC curve of the NYU PHFI diagnosing if heart failure was present, differentiating moderate from mild and severe from moderate heart failure were 0.982, 0.942 and 0.918, respectively, and the sum of sensitivity and specificity was favorite when 6, 10 and 13 scores were set as cut-off value diagnosing the presence of heart failure, differentiating moderate from mild, and severe from moderate heart failure, respectively. According to above classification of heart failure based on NYU PHFI score, plasma NT-proBNP concentration was significantly different in different degree of heart failure (F = 53.31, P < 0.001). Plasma NT-proBNP concentration in those without heart failure was significantly lower than that of mild heart failure, and it was also significantly lower in mild heart failure than that of severe heart failure. CONCLUSION: NYU PHFI was highly valuable for diagnosing chronic heart failure in children and 0 - 6 scores as being without heart failure, 7 - 10 scores as mild degree, 11 - 13 scores as moderate degree and 14 - 30 scores as severe degree of heart failure could be used as the reference criteria of different severities of heart failure.
Assuntos
Insuficiência Cardíaca/diagnóstico , Índice de Gravidade de Doença , Adolescente , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , MasculinoRESUMO
OBJECTIVE: To examine the diagnostic value of head-up tilt test in children with unexplained syncope (UPS). METHODS: A total of 379 children (171 males, 208 females) aged 3-18 years, mean age (12 +/- 3) years with unexplained syncope from Beijing, Hunan, Hubei and Shanghai and undergoing baseline head-up tilt tests (BHUTT) or head-up tilt tests potentiated with nitroglycerine (SNHUTT) under a quiet circumstance were selected as the syncope group. Ten healthy children (5 males, 5 females) aged 9-15 years with a mean age of (11.4 +/- 2.1) years, were recruited as the control group. SPSS 10.0 software was used for data analysis. RESULTS: In 379 children with unexplained syncope, 67 (17.7%) were of postural orthostatic tachycardia syndrome (POTS), 157 (41.4%) of vasovagal syncope vasoinhibitory pattern, 14 (3.7%) of vasovagal syncope cardioinhibitory pattern, 47 (12.4%) of vasovagal syncope mixed pattern, 1 (0.3%) of orthostatic hypotension (OH) and 93 children (24.5%) of UPS. In syncope group and control group, the positive rate of BHUTT was 55.9% and 0 respectively and it was 75.5% and 20.0% respectively for SNHUTT. During BHUTT, the mean time of positive response occurrence was (16 +/- 12) minutes, and the posture when positive response appeared was at a tilt angle of 60 degrees. For SNHUTT, the mean time of positive response occurrence was (6 +/- 4) minutes and the posture was at a tilt angle of 60 degrees when potentiated with nitroglycerine. CONCLUSION: HUTT is an objective diagnostic tool of UPS. With a high diagnostic positive rate, SNHUTT can improve the diagnostic positive rate of BHUTT. Meanwhile the time of positive response occurrence during SNHUTT is markedly shorter than BHUTT.