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Objective: To explore the effect and investigate the molecular mechanism of different concentrations of total tanshinones alone and in combination with tyrosine kinase inhibitors (TKIs) on the proliferation inhibition and apoptosis of human myeloid leukemia cell lines. Methods: K562 and Kasumi-1 cell lines were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences, and the TKIs-resistant strain K562/T315I cell line was constructed in Molecular Medicine Research Center, Beijing Lu Daopei Institute of Hematology. Logarithmic growth phase cells were taken and divided into intervention groups with total tanshinone of 0, 2.19, 4.38, 8.75, 17.50 and 35.00 µg/ml intervention groups, which were inoculated in 96-well plates at a density of 1×104 cells/well and exposed to the drug for 24 h, and a control group treated with dimethyl sulfoxide was also set up simultaneously. All experiments were repeated independently 3-5 times. The proliferative activity of the cells was assessed using the CCK-8 assay, the apoptotic rates were measured by flow cytometry, and the expression levels of apoptosis-regulating proteins Bcl-2 and Bax were analyzed by Western blotting. The cell lines treated and untreated with total tanshinone were subjected to transcriptome sequencing and gene set enrichment analysis to identify differentially expressed genes. Results: The half-inhibitory concentration (IC50) values of 8.75 µg/ml total tanshinone at 24 h for K562, K562/T315I and Kasumi-1 cells were (4.11±0.02), (4.95±0.04) and (3.98±0.01) µg/ml, respectively. When combined with 0.25 µmol/L imatinib, 8.75 µg/ml total tanshinone could enhance the induction of apoptosis effects on K562 and K562/T315I cell lines. After being treated with 4.38, 8.75, and 17.50 µg/ml of total tanshinone for 24 h, compared with the control group, total tanshinone upregulated the expression level of Bax protein, downregulated the expression level of Bcl-2 protein, and decreased the Bcl-2/Bax ratio (all P<0.05). Total tanshinone inhibited the proliferation-related signaling pathway and DNA damage repair pathway of myeloid leukemia cell lines, and activated the signaling pathway that induces apoptosis in leukemia cells. Conclusion: Different concentrations of total tanshinoneinhibites proliferation and promote apoptosis in K562, Kasumi-1 and TKIs-resistant K562/T315I cell lines, and further enhance the anti-leukemic effect when combined with TKIs.
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Abietanos , Apoptosis , Proliferación Celular , Leucemia Mieloide , Humanos , Abietanos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células K562 , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , /farmacologíaRESUMEN
Fat deposition is an important economic trait in farm animals. However, it is difficult to genetically improve intramuscular fat deposition via trait-based cattle breeding. The main objectives of this study were to analyze the factors about beef flavor, and to detect functional microRNA (miRNA, miR) associated with intramuscular fat deposition in Yanbian cattle. Longissimus dorsi samples from six steers were separated into high- and low-fat groups (n = 3 each) based on the marbling score, and transcriptomic analysis was performed using miRNA sequencing. A total of 33 miRNAs and 38 genes were found to be differentially expressed in the high- and low-fat groups. Quantitative real-time polymerase chain reaction was performed to validate the sequencing results. Integrated miRNA-mRNA analysis revealed that miRNA-associated target genes were primarily associated with skeletal muscle development. However, some of the miRNAs (miR-424 etc.) and genes (ATF3 etc.) were also associated with fat metabolism. A targeted relationship between miR-22-3p and the WFIKKN2 gene and its involvement in adipocyte differentiation were confirmed experimentally. The study findings may provide potential candidate molecular targets for the selection of cattle with improved meat quality.
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Bovinos/genética , Metabolismo de los Lípidos/genética , MicroARNs/genética , Desarrollo de Músculos/genética , ARN Mensajero/genética , Adipocitos , Animales , Células Cultivadas , Masculino , TranscriptomaRESUMEN
Objective: To classify and quantify IKZF1 mutant transcripts in B-cell acute lymphoblastic leukemia (B-ALL) by RNA sequencing (RNA-seq) and bioinformatics analysis. Methods: A cohort of 263 B-ALL cases was enrolled at Hebei Yanda Ludaopei Hospital from September 2018 to September 2020. An integrated bioinformatics pipeline was developed to adapt the classification and quantification of IKZF1 transcripts from RNA-seq and was applied to sequencing data of these cases. The IKZF1 mutant transcripts classified by RNA-seq analysis were compared with the qualitative reverse transcription PCR (RT-PCR). Results: IKZF1 mutant transcripts were identified in 53 B-ALL patients by RT-PCR and Sanger sequencing, among which IK6 and IK10 transcripts accounted for 67.9% (36/53) and 28.3% (15/53) respectively. Additionally, 2 patients were double positive for IK6 and IK10. RNA-seq analysis identified 51 patients with IKZF1 mutant transcripts. Compared with the RT-PCR result, the detection sensitivity and specificity of RNA-seq analysis reached 94.3% (50/53) and 99.5% (209/210), respectively. Among the 50 patients with IKZF1 mutant transcripts both in RNA-seq and RT-PCR analysis, the ratio of mutant transcripts to total IKZF1 transcripts in 6 patients was 0.14 (0.11, 0.35), which was significantly lower than that of the other 44 patients [0.88 (0.35, 0.97), Z=-3.945,P<0.001]. IKZF1 mutations mostly occurred in Ph+and Ph-like B-ALL, characterized by abnormal JAK-STAT pathway, and B-ALL with PAX5 translocation. Conclusions: Through the optimized bioinformatics analysis process, RNA-seq data can be used to classify and quantitatively analyze IKZF1 transcripts in B-ALL. Furthermore, the relative expression of mutant IKZF1 transcripts was found to cluster into two groups, and IKZF1 mutation was found often accompanied with PAX5 translocations.
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Factor de Transcripción Ikaros , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfocitos B/metabolismo , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Isoformas de Proteínas , TranscriptomaRESUMEN
Yanbian yellow cattle are one of the top five largest breeds of cattle in China. We had previously found that bta-miR-1271 is differentially expressed in the longissimus dorsi muscles of Yanbian yellow bulls and steers. However, whether bta-miR-1271 affects bovine fat formation is unclear. In this study, we used target gene prediction, dual-luciferase reporter assay, and transfection-mediated overexpression and inhibition of bta-miR-1271 in a culture of Yanbian yellow cattle preadipocytes to investigate the role of bta-miR-1271 in adipogenesis. We showed that bta-miR-1271 directly targets the 3'-untranslated region (3'-UTR) of the activating transcription factor 3 (ATF3) mRNA and downregulates its expression. Overexpression of bta-miR-1271 enforced by the miRNA mimics promoted triglyceride accumulation and significantly upregulated expression of the adipogenic peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα) genes at both the protein and mRNA levels, as demonstrated by RT-qPCR and Western blot analyses. Conversely, inhibition of bta-miR-1271 expression produced the opposite effect. Our results show that bta-miR-1271 regulates differentiation of Yanbian yellow cattle preadipocytes by inhibiting ATF3 expression, which highlights the importance of microRNA-mediated regulation of adipogenesis. miR-1271 and its target gene(s) may provide a new research direction for investigating biological agents affecting intramuscular fat deposition in cattle.
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Factor de Transcripción Activador 3/genética , Adipocitos/citología , Adipocitos/metabolismo , MicroARNs/metabolismo , Factor de Transcripción 3/metabolismo , Regiones no Traducidas 3' , Factor de Transcripción Activador 3/metabolismo , Adipogénesis/fisiología , Animales , Bovinos , Diferenciación Celular/fisiología , Células Cultivadas , Femenino , Masculino , MicroARNs/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción 3/genéticaRESUMEN
Objective: To explore the application and discovery of genotyping, gene sequencing, and gene expression analysis in the determination of ABO blood group subtypes and antigen expression abnormalities in hematological malignancies patients. Methods: From June 2019 to May 2020, three clinical cases were found with forward and reverse ABO typing discrepancy or atypical serologic agglutination pattern in the laboratory and blood transfusion department of Hebei Yanda Ludaopei Hospital were selected. Sequence-specific primer PCR (PCR-SSP) and Sanger sequencing of ABO gene coding regions were performed to determine the ABO genotypes, and whole transcriptome sequencing was used to analyze ABO and FUT1 gene expression levels. Results: A 12-year-old female acute lymphoblastic leukemia patient was determined as O.01.02 and BA.04 sub-genotype, corresponding to the serological B(A) subtype, and her ABO gene expression was normal (354.80). A 41-year-old female acute myeloid leukemia patient was determined as A1.02 and B.01 genotype, corresponding to the serological A(1)B phenotype, and her ABO gene expression was significantly reduced (45.70). A 42-year-old male with myelodysplastic syndrome and myelofibrosis was determined as A1.02 and A2.05 sub-genotype, corresponding to the serological A(1) and A(2) phenotype, respectively, and his ABO expression was negative. FUT1 expression was in the normal range in all three cases. The clinical blood product infusion strategy was formulated according to the genotype and the corresponding immunological subtype, and no significant transfusion-related adverse reactions occurred. Conclusion: Blood group sub-genotypes or aberrant gene expression can lead to ambiguities in serological blood group determination in hematological malignancies patients. ABO genotyping and gene expression analysis can help in this scenario and escort blood product infusion safety.
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Tipificación y Pruebas Cruzadas Sanguíneas , Neoplasias Hematológicas , Sistema del Grupo Sanguíneo ABO/genética , Adulto , Alelos , Niño , Genotipo , Neoplasias Hematológicas/genética , Humanos , Masculino , FenotipoRESUMEN
The article "MiR-1294 acts as a tumor suppressor in clear cell renal cell carcinoma through targeting HOXA6", by W. Pan, L.-J. Pang, H.-L. Cai, Y. Wu, W. Zhang, J.-C. Fang, published in Eur Rev Med Pharmacol Sci 2019; 23 (9): 3719-3725-DOI: 10.26355/eurrev_201905_17797-PMID: 31114997 has been retracted by the Editor in Chief. Following some concerns raised on PubPeer regarding a possible manipulation in Figures 2 and 3, the Editor in Chief has started an investigation to assess the validity of the results as well as possible figure manipulation. The authors have been informed about the journal's investigation but remained unresponsive. The journal investigation revealed duplications in panels miR-1294 mimic - Caki01 and Caki01 of Figure 2D and in the Western blots of Figure 3 with previously published articles. Consequently, the Editor in Chief mistrusts the results presented and has decided to retract the article. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/17797.
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OBJECTIVE: Renal cancer represents about 3% of all human cancers. Clear cell renal cell carcinoma (ccRCC) is the main type of renal cancer. MicroRNAs (miRNAs) have been reported to play crucial roles in the carcinogenesis of human cancers. This study was aimed to investigate the expression of miR-1294 and the mechanisms underlying miR-1294-mediated ccRCC progression. MATERIALS AND METHODS: The miR-1294 expression levels in ccRCC cell lines were analyzed by quantified real time-PCR (qRT-PCR). The effect of the miR-1294 expression on the overall survival of ccRCC patients was analyzed by the Kaplan-Meier Plotter. Cell proliferation, colony growth, and cell invasion were examined by cell counting kit-8 assay, colony formation assay, and transwell invasion assay, respectively. The luciferase activity reporter assay and Western blot assay were conducted to validate the connection between miR-1294 and homeobox A6 (HOXA6). RESULTS: MiR-1294 was downregulated in ccRCC cell lines and correlated with the poor overall survival of ccRCC patients. The overexpression of miR-1294 inhibits ccRCC cell proliferation, colony growth, and cell invasion. HOXA6 was validated as a target of miR-1294 and negatively regulated by miR-1294. The overexpression of HOXA6 attenuated the miR-1294-mediated effects on ccRCC cellular functions. CONCLUSIONS: Our results indicated that miR-1294 functions as a tumor suppressor in ccRCC. MiR-1294 suppressed cell proliferation, colony formation, and invasion in ccRCC partially via targeting HOXA6.
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Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Genes Supresores de Tumor , Proteínas de Homeodominio/genética , MicroARNs/genética , Carcinoma de Células Renales/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Homeodominio/metabolismo , Humanos , Estimación de Kaplan-Meier , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Xestia c-nigrum granulovirus (XcGV) was tested for its ability to increase Spodoptera litura nucleopolyhedrovirus (SINPV) infection in larvae of S. litura (F.). The interaction of XcGV with peritrophic matrix and SINPV in S. litura also was studied to account for the synergism. In dose-response bioassays with a constant XcGV concentration of 5-mg/ ml capsules and SINPV concentration that varied from 10(3) to 10(7) polyhedral inclusion bodies (PIB) per larva, XcGV increased the virulence of SINPV infection in fifth instars of S. litura. The lethal concentration of 50% individuals (LC50) of SINPV combined with XcGV was 3.35 x 10(5)PIB/ml, which was significantly lower than that of SINPV alone (2.17 x 10(6)). Compared with 10(7) PIB/ml SINPV alone, the lethal time of 50% individuals (LT50) of 10(7) PIB/ml SINPV combined with XcGV was not significantly shortened. In addition, no significant improvement in the activity and killing speed of SINPV progeny was noted after propagation with XcGV, indicating that native characters of SINPV associated with viral potency were not altered by XcGV. Investigation via environmental scanning electronic microscopy showed that the peritrophic matrix (PM) of S. litura exposed to XcGV or XcGV enhancin, or the combination treatment, was markedly disrupted. The outer surface of the PM was loose, or ruptured, which potentially facilitated the passage of virions through the PM. Therefore, it is reasonable to conclude that the synergy between XcGV and SINPV was closely associated with the disruption of the PM in S. litura.
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Granulovirus/metabolismo , Nucleopoliedrovirus/metabolismo , Spodoptera/virología , Proteínas Virales/metabolismo , Animales , Granulovirus/clasificación , Larva/virología , Control Biológico de Vectores/métodos , Unión ProteicaRESUMEN
BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.
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Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Endotelina-1/fisiología , Vasoconstricción/fisiología , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Antagonistas de los Receptores de Endotelina , Humanos , Persona de Mediana Edad , Análisis Multivariante , Nitroglicerina/farmacología , Péptidos Cíclicos/farmacología , Receptor de Endotelina A , Vasoconstricción/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation. METHODS AND RESULTS: We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3(+) T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3(+) T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3(+) T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively; P<0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P=0.01). CONCLUSIONS: The presence of CXCR3(+) T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3-IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.
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Quimiocinas CXC/biosíntesis , Rechazo de Injerto/metabolismo , Trasplante de Corazón , Receptores de Quimiocina/biosíntesis , Transcripción Genética , Adulto , Biopsia , Complejo CD3/análisis , Quimiocina CXCL10 , Quimiocinas/biosíntesis , Quimiocinas/genética , Quimiocinas CXC/genética , Estudios Transversales , Femenino , Rechazo de Injerto/genética , Rechazo de Injerto/patología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , ARN Mensajero/biosíntesis , Receptores CXCR3 , Receptores de Quimiocina/genética , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.
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Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/fisiología , Sistema Vasomotor/fisiología , Vitamina E/sangre , Acetilcolina , Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitroglicerina , Triglicéridos/sangre , Sistema Vasomotor/efectos de los fármacosRESUMEN
The binding of glycosaminoglycans to a synthetic peptide (SKAQKAQAKQAKQAQKAQKAQAKQAKQW-CONH(2)), consisting of a hybrid consensus heparin binding sequence, is studied using circular dichroism, fluorescence anisotropy and nuclear magnetic resonance techniques. The results unveil certain novel features, most importantly, the peptide binds preferentially to iduronic acid containing glycosaminoglycans and the dissociation constant for the peptide-heparin complex was found to be 30 nM. Interestingly, higher order intermolecular association(s)/aggregation was not observed, especially at saturating concentrations of the ligand. The helical structure of the peptide backbone, induced upon binding to a particular glycosaminoglycan is directly related to their binding affinity. In our opinion, studies on such unconventional hybrid peptide sequences containing low density basic amino acid residues would lead to the design of sequence specific glycosaminoglycan binding peptides.
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Glicosaminoglicanos/química , Péptidos/química , Secuencia de Aminoácidos , Conformación de Carbohidratos , Dicroismo Circular , Secuencia de Consenso , Polarización de Fluorescencia , Heparina/química , Lisina , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos/síntesis química , Conformación Proteica , Pliegue de ProteínaRESUMEN
Numerous trials have demonstrated that cholesterol-lowering therapy leads to marked reductions in cardiovascular and overall mortality and in the need for coronary revascularization. Angiographic regression trials have shown that cholesterol lowering can reduce progression and, in some instances, achieve regression of coronary atherosclerotic lesions. However, recent studies have contradicted the traditional view that the clinical course of coronary artery disease is closely linked to the severity of coronary artery stenosis. It is now apparent that stenoses responsible for myocardial infarction or unstable angina are typically mild rather than severe. These observations suggest that regression may not be the principal mechanism by which cholesterol lowering affects cardiovascular risk. Two mechanisms---plaque stabilization and improved endothelial function-have been examined in this regard. Basic studies suggest that cholesterol lowering favorably alters those features of atherosclerosis that promote plaque stability. Recent clinical studies have clearly established that aggressive lipid-lowering therapy improves endothelial function and reduces myocardial ischemia in patients with hypercholesterolemia.
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Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/fisiopatología , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/fisiopatología , Hipolipemiantes/uso terapéutico , Acetilcolina/farmacología , Constricción Patológica , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Humanos , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: CD40 is expressed by a wide variety of cells in the immune system, including endothelial cells. It binds to CD40 ligand ([CD40L] CD154), which was originally reported to be restricted in its expression to early-activated T cells. We report here the expression of CD40 and CD40L in human cardiac allografts. METHODS: A total of 123 consecutive biopsies from 11 human cardiac allograft recipients were analyzed by immunohistochemistry for the expression of CD40 and CD40L. The expression of CD40L was also examined in vitro in homogeneous cultures of umbilical vein endothelial cells by reverse transcriptase-polymerase chain reaction and by flow cytometry. RESULTS: CD40 was expressed at low levels, and CD40L was minimal or absent in histologically normal biopsies in the absence of CD3+ T-cell infiltrates. In rejection, the expression of CD40 increased on vascular endothelial cells and on graft-infiltrating leukocytes throughout biopsy specimens. Induced expression of CD40 was strongly associated with the presence of CD3+ T-cell infiltrates, acute rejection, and ischemic injury (P<0.05). CD40L was expressed in biopsies with rejection and was prominent on a subset of infiltrating leukocytes as well as on microvascular endothelial cells. In contrast to CD40, staining of endothelial CD40L was focal in most biopsies. Overall, the expression of CD40L correlated with the presence of CD3+ T-cell infiltrates and rejection (P<0.05), but not ischemic injury (P=0.9). To confirm that the endothelium can synthesize CD40L, we also evaluated the expression of endothelial CD40L in vitro. Cultured endothelial cells were found to express little constitutive CD40L that markedly increased after 24 hr of treatment with supernatants from phytohemagglutinin-activated peripheral blood mononuclear cells or by the cytokines tumor necrosis factor-alpha, interleukin-1a, interleukin-4, or interferon-gamma. CONCLUSION: Both CD40 and CD40L are expressed in vivo on infiltrating leukocytes and on microvascular endothelium in human cardiac allograft rejection. We suggest that endothelial cell CD40 and CD40L play a role in human cell-mediated immune responses such as cardiac allograft rejection.
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Antígenos CD40/metabolismo , Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Glicoproteínas de Membrana/metabolismo , Biopsia , Antígenos CD40/genética , Ligando de CD40 , Células Cultivadas , Endotelio Vascular/metabolismo , Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Glicoproteínas de Membrana/genética , Microcirculación , ARN Mensajero/genéticaRESUMEN
We sought to explore the relation between Chlamydia pneumoniae, cytomegalovirus (CMV), and cardiac transplant-associated arteriosclerosis. Serologic evidence of past Chlamydia pneumoniae infection was investigated in 3 patient groups at the time of cardiac catheterization: cardiac transplant recipients (n=49), patients having coronary artery bypass grafting (CABG) (n=39), and a control group free of angiographic coronary artery disease (n=21). High Chlamydia pneumoniae immunoglobulin G titers (> or =1:160) were more frequently observed in cardiac transplant recipients (odds ratio[OR] 13.7; 95% confidence intervals [CI] 1.6 to 117.4, p <0.05) and CABG patients (OR 21.7; 95% CI 1.6 to 287.0, p <0.05) than in controls. However, high Chlamydia pneumoniae titers did not distinguish between cardiac transplant recipients with or without angiographic transplant-associated arteriosclerosis or CABG patients with or without bypass vein graft disease. Furthermore, there was no significant relation between elevated Chlamydia pneumoniae titers and the presence or progression of transplant-associated arteriosclerosis in the subgroup of patients who were also CMV positive. Yet, analysis of the same angiograms demonstrated an association between CMV infection and the recent progression of transplant-associated arteriosclerosis. Thus, patients with cardiac transplantation have evidence of past Chlamydia pneumoniae and CMV infection but Chlamydia pneumoniae does not appear to have an independent role or synergistic relation to CMV in the development of transplant-associated arteriosclerosis.
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Infecciones por Chlamydia/complicaciones , Chlamydophila pneumoniae/aislamiento & purificación , Enfermedad de la Arteria Coronaria/microbiología , Infecciones por Citomegalovirus/complicaciones , Citomegalovirus/aislamiento & purificación , Trasplante de Corazón , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Infecciones por Chlamydia/inmunología , Chlamydophila pneumoniae/inmunología , Puente de Arteria Coronaria , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios SeroepidemiológicosRESUMEN
Recipient-to-donor atrioatrial conduction across a suture line has been rarely reported after orthotopic heart transplantation. The relation of such conduction to symptomatic arrhythmias and its prevalence are not known. Recipient-to-donor atrioatrial conduction was demonstrated in a 28-year-old woman with paroxysmal supraventricular tachycardia 7 years after orthotopic heart transplantation. Atrial tachycardia in the recipient atria conducted 2:1 to the donor atria and was eliminated by radiofrequency catheter ablation of a left-sided atrioatrial electrical connection. The electrocardiogram at rest and during exercise, recorded before ablation of the recipient-to-donor connection, showed frequent atrial premature complexes, with variable coupling to the preceding sinus beats, and a change in P-wave morphology during exercise, which reverted to normal during the recovery period. These findings were eliminated by ablation of the recipient-to-donor connection. To determine the prevalence of recipient-to-donor atrioatrial conduction late after transplantation, we evaluated the exercise electrocardiograms of 50 subjects > 5 years after heart transplantation for these features of recipient-to-donor conduction. At least 1 feature was present in 5 subjects, and both were present in 1 subject. Electrical conduction can occur across surgical suture lines in the atria. Recipient-to-donor atrioatrial conduction may occur in < or = 10% of patients late after heart transplantation. It is a potential cause of arrhythmias that can be effectively treated with radiofrequency catheter ablation.
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Función Atrial , Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Trasplante de Corazón , Adulto , Anciano , Factores de Confusión Epidemiológicos , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , DescansoRESUMEN
A cross-sectional study was conducted in an urban population 25 years of age and older to determine the prevalence of diabetes mellitus (DM), impaired glucose tolerance (IGT), and associated risk factors. A total of 13,940 subjects was surveyed (7,042 male, 6,898 female). The prevalence (DM 2.33%, IGT 1.30) was much higher than in a 1978 study. Age-standardised prevalence was not statistically different between males and females: respectively 2.54% and 2.14% for DM and 1.42% and 1.31% for IGT. Most diabetic patients were well-educated and performed mildly intensive labour. More patients showed a family history of diabetes during youth and risk factors associated with diabetes in old age, e.g. hypertension and an overweight condition. Microalbuminuria was found in 20.26% of newly diagnosed diabetic patients, i.e. a much higher proportion than in the normal population.
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Diabetes Mellitus/epidemiología , Salud Urbana , Adulto , Anciano , China/epidemiología , Estudios Transversales , Femenino , Intolerancia a la Glucosa/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
The effects of diazepam on several tests of memory were investigated in a double-blind study of 24 healthy young adults. Following a single oral administration of 0.3 mg/kg diazepam or placebo, subjects in the diazepam group showed marked impairment in immediate free recall of words as compared to placebo control subjects. However, diazepam-treated subjects demonstrated performance benefits from prior exposure to the same words on tests of memory priming using word completion and category-generation tasks. The two types of memory tests differ in their demand for conscious recollection. Tests of free recall have explicit (declarative) memory demands whereas the priming test places only implicit (procedural) demands upon memory. The results demonstrate that diazepam spares some forms of memory as does amnesia induced by neurological impairment.
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Diazepam/farmacología , Memoria/efectos de los fármacos , Adolescente , Adulto , Amnesia/psicología , Método Doble Ciego , Femenino , Humanos , Masculino , Recuerdo Mental/efectos de los fármacos , Pruebas PsicológicasRESUMEN
Gastro-oesophageal reflux disease (GERD) is the most common peptic acid disease in the western world and is the commonest indication for acid suppression therapy. Major advances have been made over the past 30 years in the understanding of lower oesophageal sphincter function and the mechanism of acid secretion. Developments in surgical and pharmacological therapy have paralleled these advances. Pharmacotherapy for GERD has evolved from antacids to H2-receptor antagonists (H2RAs) to prokinetics to proton pump inhibitors (PPIs). The H2RAs, while modestly effective in symptom relief and healing of GERD, are limited by pharmacological tolerance. The prokinetics (metoclopramide and cisapride) are limited by low efficacy, pharmacological tolerance and toxicity. The PPIs have emerged as the most effective therapy for symptom relief, healing and long-term maintenance. They have also proved to be remarkably safe and cost-effective in long-term therapy. This review evaluates the pharmacology, efficacy, tolerability, safety and cost-effectiveness of the four currently available PPIs, lansoprazole, omeprazole, pantoprazole and rabeprazole, in the treatment of GERD.