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11.
Electrophysiological effects of amrinone and milrinone in an isolated canine cardiac tissue model of ischemia and reperfusion 总被引:2,自引:0,他引:2
The purpose of this study was to determine if amrinone or milrinone after the electrophysiological responses of canine ventricular tissues to "ischemia" or reperfusion. Isolated canine Purkinje tissue-papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 10 min with a solution that mimicked ischemia (hypoxia, acidosis, elevated lactate levels and zero substrate). Reperfusion with normal Tyrode's solution was then instituted for 60 min. Next, tissues were equilibrated with amrinone (5.3 X 10(-4) M) or milrinone (2.5 X 10(-4) M) for 15 min and the protocol was repeated with drug in all solutions. Without drug, ischemic conditions resulted in moderate depolarization of Purkinje and muscle tissues. Reperfusion caused a rapid hyperpolarization in Purkinje tissue. This was followed by a phase of mild depolarization associated with enhanced pacemaker activity. All preparations recovered by 45 min of reperfusion. With amrinone or milrinone present, the changes in membrane potential induced by conditions of ischemia and reperfusion were not different from control. However, an early phase of very rapid ectopic activity was seen during reperfusion with amrinone or milrinone. This ectopic activity had a constant cycle length during the pauses in stimulation. However, irregular patterns of spontaneous and driven beats were observed when electrical stimulation was superimposed on the ectopic activity. Amrinone and milrinone also increased pacemaker activity in Purkinje tissue but this occurred later in reperfusion. This study demonstrates that amrinone and milrinone sensitize isolated canine ventricular tissues to the arrhythmogenic effects of reperfusion. The mechanism underlying the arrhythmic activity elicited by the bipyridines is not clear, but may involve re-entry or abnormal automaticity. 相似文献
12.
Bartkova J Rajpert-De Meyts E Skakkebaek NE Lukas J Bartek J 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2003,111(1):252-266
Deregulated cell cycle and defective genome-integrity checkpoints are among the hallmarks of cancer.Here we summarize our recent studies of key components of the GI/S machinery in normal human spermatogenesis, and their abnormalities in testicular germ cell tumours (TGCTs), with special emphasis on carcinoma in situ lesions (CIS). Our combined immunohistochemical and immunoblotting analyses of normal human adult and fetal testes, CIS, seminomas, embryonal carcinomas, and teratomas, revealed an 'unorthodox' spectrum of defects within the so-called RB pathway in TGCTs. The early aberrations included lack of expression of the retinoblastoma tumour suppressor (pRB) and the CDK inhibitor pl9ink4d, and overexpression of cyclin D2. Progression from CIS to invasive TGCTswas associated with loss of another two CDK inhibitors and tumour suppressors: pl6ink4a and pl8ink4c. We also found the lack of pRB and pl9ink4d in fetal gonocytes, the candidate target cell for all types of TGCTs. These findings, together with the status of the Chk2-p53 DNA-integrity checkpoint, are considered in relation to the origin, biology and pathogenesis of TGCTs, and potential implications of the GI/S defects for the curability of these tumours. 相似文献
13.
Fat in the intestine as a regulator of appetite--role of CCK 总被引:1,自引:0,他引:1
The present review summarizes the appetite-suppressing effects of intestinal fat in the regulation of food intake in humans, with a special focus on the role of cholecystokinin (CCK). Current evidence supports a role for intestinal fat (especially long-chain free fatty acids) acting via the peptide CCK as a physiological satiety pathway. The regulation of satiety is, however, complex and it is not surprising that multiple control systems exist. It is interesting to note that nutrients, such as hydrolysis products of fat in the small intestine, stimulate the release of satiety peptides, such as CCK or PYY, that serve as satiety signals. CCK, released from the gastrointestinal tract by the local action of digested food, exerts various functions: stimulation of gallbladder contraction and exocrine pancreatic secretion, inhibition of gastric emptying, and inhibition of appetite. CCK functions therefore (1) as a positive feedback signal to stimulate digestive processes and (2) as negative feedback signal to limit the amount of food consumed during an individual meal. 相似文献
14.
15.
Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression 总被引:11,自引:0,他引:11
Karamessinis PM Tzinia AK Kitsiou PV Stetler-Stevenson WG Michael AF Fan WW Zhou B Margaritis LH Tsilibary EC 《Laboratory investigation; a journal of technical methods and pathology》2002,82(8):1081-1093
Thickening of the tubular basement membrane (TBM) occurs in diabetic nephropathy, but the effects of high glucose on the functional aspects of proximal tubular epithelial cells are not clearly understood. In the present study, we examined the effects of elevated glucose concentrations on (a) integrin expression by human proximal tubular epithelial cells (HK-2) and integrin-mediated interactions with type IV collagen (colIV) and laminin, major components of TBM; (b) the expression of matrixins/matrix metalloproteinases (MMPs), which is regulated by integrins; and (c) the expression of tissue inhibitors of metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose underwent a reduction of the expression of alpha3, beta1, alpha(v)beta3, and alpha5 integrin subunits, with a concomitant increase of the alpha2 subunit, compared with cells grown in 5 mM glucose. Adhesion experiments demonstrated that high glucose led to increased cell adhesion on either colIV or laminin. Experiments of competition of adhesion using anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used mainly alpha(v)beta3 and alpha5beta1 integrins to adhere to colIV, whereas in 25 mM glucose they additionally used alpha2beta1. In the case of laminin, a beta1-mediated adhesion was observed when HK-2 cells were in 5 mM glucose, whereas in 25 mM glucose, alpha2beta1 and alpha(v)beta3 were also involved. Elevated glucose concentrations resulted in decreased expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a decrease in TIMP-2 expression were observed. We also examined which integrins mediated the expression and secretion of matrixins MMP-2 and MMP-9. Ligation of alpha3beta1 with mAbs resulted in induction of MMP-2 expression and secretion, whereas antibody ligation of alpha(v)beta3 led to down-regulation of MMP-9. The above data implicate integrins of proximal tubular epithelial cells in the regulation of MMPs and in the development of TBM thickening in diabetic nephropathy. 相似文献
16.
Hunziker L Recher M Macpherson AJ Ciurea A Freigang S Hengartner H Zinkernagel RM 《Nature immunology》2003,4(4):343-349
Polyclonal hypergammaglobulinemia is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. Here we have studied hypergammaglobulinemia in mice infected with lymphocytic choriomeningitis virus (LCMV), which induces nonspecific immunoglobulins as a result of switching natural IgM specificities to IgG. The process is dependent on help from CD4+ T cells that specifically recognize LCMV peptides presented by B cells on major histocompatibility complex class II molecules. Thus, hypergammaglobulinemia may arise when specific helper T cells recognize B cells that have processed viral antigens irrespective of the B cell receptor specificity. This nonspecific B cell activation may contribute to antibody-mediated autoimmunity. 相似文献
17.
In Hypocrea jecorina (anamorph: Trichoderma reesei) multiple gene deletions are limited by the number of readily available selection markers. We have therefore constructed
a blaster cassette which enables successive gene knock-outs in H. jecorina. This 3.5 kb pyr4 blaster cassette contains the H. jecorina pyr4 marker gene encoding orotidine-5′-monophosphate (OMP) decarboxylase flanked by two direct repeats of the Streptoalloteichus hindustanus bleomycin gene (Sh ble), which facilitate the excision of the blaster cassette by homologous recombination after each round of deletion. Functionality
of this pyr4 blaster cassette was demonstrated by deletion of the glk1 encoding glucokinase and hxk1 encoding hexokinase. 1.4–1.8 kb of the non-coding flanking regions of both target genes were cloned into the respective blaster
cassettes and transformation of a pyr4 negative H. jecorina strain with the two cassettes resulted in 10–13% of the transformants in the deletion of one of the two kinase genes. For
excision of the pyr4 blaster cassettes, Δglk1 strains were selected for growth in the presence of 5-fluoroorotic acid. Recombination between the two Sh ble elements resulted in uridine auxotrophic strains which retained their respective glucokinase negative phenotype. Subsequent
transformation of one of these auxotrophic Δglk1 strains with the hexokinase blaster cassette resulted in pyr4 prototrophic strains deleted in both glk1 and hxk1. Δglk1 strains showed reduced growth on d-glucose and d-fructose whereas Δhxkl strains showed reduced compact growth on d-glucose but were unable to grow on d-fructose as carbon source. The double Δglk1Δhxk1 deletion strain was completely unable to grow on either d-glucose or d-fructose.
Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under the accession numbers DQ068384 (H. jecorina glk1) and DQ068385 (H. jecorina hxk1). 相似文献
18.
Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure 总被引:9,自引:0,他引:9
Yancy CW Fowler MB Colucci WS Gilbert EM Bristow MR Cohn JN Lukas MA Young ST Packer M;U.S. Carvedilol Heart Failure Study Group 《The New England journal of medicine》2001,344(18):1358-1365
BACKGROUND: The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure. METHODS: In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. RESULTS: As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses). CONCLUSIONS: The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure. 相似文献
19.
Coamplification of simple repetitive DNA fingerprint fragments and the EGFR gene in human gliomas. 总被引:3,自引:0,他引:3
P Nürnberg H Zischler E Fuhrmann G Thiel T Losanova D Kinzel G Nisch R Witkowski J T Epplen 《Genes, chromosomes & cancer》1991,3(2):79-88
DNA fingerprints were generated by the oligonucleotide probe (GTG)5 from surgically removed tissue and/or primary cell culture of 36 intracranial tumors (31 gliomas, 1 medulloblastoma, 4 metastatic carcinomas) and compared with the constitutional banding pattern obtained from the peripheral blood leukocytes of each patient. A multitude of somatic changes was detected and found to reflect the chromosome alterations identified by parallel karyotype analysis. Gain and/or loss of bands or significant band intensity shifts could be demonstrated in the fingerprints of more than 80% of the tumors investigated. This included a highly amplified fingerprint fragment in five independent gliomas (four of them had double minutes, dmin) which appeared not individual- but tumor-specific (2.4 kilobases, kb, after HaeIII digestion). Rehybridization with the oligonucleotide probes (GT)8 and (GATA)4, respectively, revealed additional amplified fingerprint fragments in the tumor DNA of these patients. While a (ca/gt)n fragment (2.6 kb. HaeIII) was also found to be amplified in all five cases, one band detected with (GATA)4 (1.4 kb, HaeIII) represented a unique feature for one of these tumors only. Amplification of the epidermal growth factor receptor (EGFR) gene via Southern blot hybridization was revealed only in those tumors showing the amplified DNA fingerprint fragments as well. Thus in many gliomas the amplification unit harbors two simple repetitive DNA fingerprint loci, (cac/gtg)n and (ca/gt)n, in addition to the EGFR gene. 相似文献
20.
Harder A Jendroska K Kreuz F Wirth T Schafranka C Karnatz N Théallier-Janko A Dreier J Lohan K Emmerich D Cervós-Navarro J Windl O Kretzschmar HA Nürnberg P Witkowski R 《American journal of medical genetics》1999,87(4):311-316
We present a novel large German kindred of fatal familial insomnia (FFI) consisting of three branches and comprising more than 800 individuals of 12 generations, the largest pedigree of any familial prion disease known today. There is a wide spectrum of clinical presentations leading to misdiagnoses of Olivo-Ponto-Cerebellar Atrophy (OPCA), Parkinson's or Alzheimer's disease in addition to Creutzfeldt-Jakob disease (CJD) and Gerstmann-Str?ussler-Scheinker (GSS) syndrome. Molecular genetic analysis of the prion protein gene (PRNP) confirmed the mutation D178N segregating with methionine at the polymorphic codon 129 of PRNP in all 7 patients examined. This polymorphism at codon 129 is supposed to discriminate between familial CJD (fCJD) and FFI; the 129M allele determines FFI and 129V fCJD. Furthermore, heterozygosity at this site appears to induce prolonged disease duration as compared to the homozygous condition. The variability of the clinical and pathological findings documented for our patients indicates the difficulty in establishing the diagnosis of FFI on clinical and on pathological grounds alone. In three cases (IX-97, XI-21, V-2) followed up by us prospectively insomnia was an early and severe symptom; however, in case notes analyzed retrospectively this symptom was frequently missed. In contrast to previous reports and in agreement with recent studies we cannot confirm a clear relationship between the status of the M/V polymorphism at codon 129 and the age-of-onset of this disease. 相似文献