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Biomedical subjects

W Hancock

Publications and source records attributed to W Hancock.

At least 19 recordsLinked to original sources
PubMed2001

Ibutilide: efficacy and safety in atrial fibrillation and atrial flutter in a general cardiology practice.

BACKGROUND: Published experience with ibutilide (IB) in randomized clinical trials reveals that conversion to sinus rhythm (SR) occurs in 31% of patients with atrial fibrillation (AF) and in 63% of patients with atrial flutter. HYPOTHESIS: The study was undertaken to test the efficacy and safety of IB in patients with AF and with atrial flutter and to compare them with those reported in previous studies. METHODS: In a general cardiology practice, 54 consecutive patients with AF or atrial flutter, no contraindication to IB, and a normal QTc interval, were treated with intravenous IB (0.4-2.0 mg). Duration of arrhythmia, left atrial (LA) size, ejection fraction (EF), time to conversion, QTc interval, and adverse drug events were determined. Patients were observed for a minimum of 6 h. Successful cardioversion was defined as arrhythmia termination within 6 h. RESULTS: Twenty-four of 34 (70.6%) patients with AF and 15 of 20 (75%) patients with atrial flutter converted to SR. Conversion of AF to SR was more likely to occur if duration of AF was approximately 96 h compared with > 96 h (81 vs. 17%, respectively; p = 0.006). The mean time to arrhythmia termination was 68.8 min. Left atrial size, determined by echocardiogram, was 44 +/- 13 mm in 43 patients. Patients with LA size approximately 45 mm had a conversion rate of 55% in both AF and flutter, compared with a conversion rate of 72% in patients with LA size < 45 mm. Ejection fraction was not a predictor of drug success. The QTc intervals were significantly prolonged after IB administration, with a mean change of 47.1 ms for successfully treated patients. Sustained polymorphic ventricular tachycardia occurred in one patient within 1 min of IB infusion, requiring electrical cardioversion to SR. This patient's serum electrolytes and QTc interval were normal prior to IB infusion; however, the QTc increased by 160 ms (from 387 to 547 ms) during drug infusion. No systemic or pulmonary emboli occurred. CONCLUSION: The efficacy of IB for conversion of AF to SR in this prospective observational study was considerably better than previously reported. Duration of AF remains an important predictor of conversion to SR. Complications are rare and without long-term adverse effects.

Aged↗
PubMed2000

Interleukin-2 and interferon-gamma double knockout mice reject heterotopic cardiac allografts.

BACKGROUND: Several studies suggest that MHC-mismatched allografts reject with a Th1 or Th2 immune response, but these models all have low-level expression of the Th1 cytokines interleukin (IL)-2 and interferon-gamma (IFN-gamma). METHODS: We interbred mice with single targeted gene disruptions for IL-2 and IFN-gamma to establish IL-2 + IFN-gamma double knockout (DKO) mice. Heterotopic cardiac allografts from DBA/2j (H2d) donors were transplanted WT, IL-2 knockout (KO), IFN-gamma KO, and DKO recipients (C57BL/6x129; H2b). Cytokine transcripts from allografts and DKO splenocytes were analyzed by reverse transcription polymerase chain reaction. RESULTS: DKO mice had a cytokine profile and IgG1/ IgG2a isotype ratio characteristic of Th2 deviation. DKO recipients rejected heterotopic cardiac allografts faster than IL-2 KO mice, but significantly slower than WT and IFN-gamma KO mice (P<0.01). Analysis of the rejecting DKO recipients showed intragraft Th2 cytokine expression. CONCLUSION: The combined absence of IL-2 and IFN-gamma in the setting of Th2 deviation does not prevent allograft rejection.

Animals↗
PubMed2000

Use of on-line mass spectrometric detection in capillary electrochromatography.

Capillary electrochromatography (CEC) is a liquid phase analytical separation technique that is generally carried out with packed capillary columns by electroosmotically driven mobile phase at high electric field strength. The analytes are separated by virtue of the differences in their distribution between the mobile and stationary phases and, if charged in their electrophoretic mobilities as well. It is thus considered a hybrid of liquid chromatography and capillary electrophoresis and is expected to combine the high peak efficiency of capillary zone electrophoresis (CZE) with the versatility and loading capacity of HPLC. This review explores the potential use of on-line mass spectrometric detection for CEC. It discusses key design issues that focus on the physical and electrical arrangement of the CEC column with respect to the electrospray orifice inlet. The salient features of the sheathless, sheath flow and liquid junction interfaces that are frequently employed while coupling a CEC column to an electrospray ionization mass spectrometry system are also highlighted. Possible configurations of the CEC column outlet that would obviate the need for pressurizing the capillary column are also presented. While coupling CEC with MS both the nature of the interface and the configuration of the column outlet will determine the optimal arrangement. The review also discusses bandspreading that occurs when a connecting tube is employed to transfer mobile phase from the column outlet to the atmospheric region of the electrospray source with a concomitant loss in sensitivity. Selected examples that highlight the potential of this technique for a wide range of applications are also presented.

Electrophoresis, Capillary↗
PubMed1999

Integrated approach to the multidimensional analysis of complex biological samples by microseparation techniques. Analysis of glycoprotein factor associated with cancer cachexia.

Microanalytical separation techniques including capillary liquid chromatography, capillary electrophoresis and capillary electrochromatography are suitable for detection of diagnostically important changes in the metabolic profiles of biological fluids. A prototype instrument was employed to serve as an integrated platform for the analysis of urine sample from patients suffering from cancer cachexia. The instrument provides for convenient, rapid and efficient multidimensional approach towards method development which would facilitate simultaneous analysis of complex biological mixtures by the above techniques.

Cachexia↗
PubMed1999

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

INTRODUCTION: To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. METHODS: Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. RESULTS: Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. CONCLUSION: These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Animals↗
PubMed1999

Investigation of the potential of capillary electrophoresis with off-line matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for clinical analysis: examination of a glycoprotein factor associated with cancer cachexia.

The potential of capillary electrophoresis (CE) with offline matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has been demonstrated for the examination of a glycoprotein factor associated with cancer cachexia. A comparison of CE profiles of a healthy volunteer and a cancer patient shows the presence of additional peaks in the electropherogram of the cancer patient that could be associated with cachexia. Micropreparative CE was performed with 180-micron fused silica capillary columns with tapered ends to collect CE fractions for further identification by MALDI-TOF-MS. The analysis of crude urine samples of cancer patients exhibiting cachexia, as well as CE fractions, with MALDI-TOF-MS using ferulic acid as the matrix shows a number of characteristic ions at m/z values of approximately 24 and approximately 67 kDa. The 24-kDa peak may be identified as the cachectic factor, a glycoprotein, whereas the peak at 67 kDa is identified as albumin, which is present in urine of most patients, and to which the cachectic factor is noncovalently bound. The combined use of CE and MALDI-TOF-MS was successful in detecting cachexia in all of the patients in this study, including one patient that was in an early phase of the disease.

Blood Proteins↗
PubMed1998

p53 gene therapy in a rat model of hepatocellular carcinoma: intra-arterial delivery of a recombinant adenovirus.

p53 tumor suppressor gene therapy has been proposed for cancers characterized by inactivation of p53 function, and successful therapy will require efficient strategies for gene delivery. To maximize transgene expression in tumors, a clinical strategy has been proposed to treat neoplasms in the liver via hepatic artery administration of a recombinant adenovirus encoding wild-type p53 (rAd-p53). We have developed a syngeneic rat model using a p53mut hepatocellular carcinoma cell line (McA-RH7777) that results in multifocal liver tumor nodules to provide experimental support for this strategy. Treatment of McA-RH7777 cells with rAd-p53 in vitro resulted in efficient transgene expression, growth suppression, and apoptosis. Intrahepatic artery dosing with rAd-p53 or an adenovirus encoding beta-galactosidase (rAd-betagal) increased transgene expression in tumor tissue and decreased systemic exposure when compared with i.v. dosing. Daily hepatic artery dosing of rAd-p53 suppressed tumor growth when compared with untreated rats or animals treated with rAd-betagal. These data demonstrate the potential for arterial gene delivery to tumors using recombinant adenoviruses, and support continued investigation of rAd-p53 gene therapy for liver malignancies.

Adenoviridae↗
PubMed1996

Adenovirus-mediated p53 gene transfer suppresses growth of human glioblastoma cells in vitro and in vivo.

Alterations in the p53 tumor-suppressor gene occur in 35-60% of human glioblastomas, and re-introduction of p53 can suppress neoplastic growth. To evaluate the potential for p53 gene therapy of glioblastoma, we have analyzed the response of human glioblastoma cell lines in vitro and in vivo to experimental therapy with replication-deficient recombinant adenoviruses encoding wild-type p53 (rAd-p53). Western blot analyses showed high-level expression of p53 protein after treatment with rAd-p53, and transgene expression was dependent on promoter strength. A p53-specific dose-dependent inhibition of in vitro cellular proliferation was observed in 5 of 6 cell lines, and growth inhibition corresponded to adenovirus-mediated gene transfer and expression. p53-specific cell death was quantitated by release of the lactate dehydrogenase enzyme. Fragmentation of DNA into nucleosomal oligomers and the occurrence of a hypodiploid cell population detected by flow cytometry provided evidence for apoptosis. Studies in nude mice demonstrated that ex vivo infection with rAd-p53 suppressed the tumorigenic potential of human glioblastoma cells. Furthermore, direct injection of rAd-p53 into established s.c. xenografts inhibited tumor growth. Our observations suggest that re-introduction of wild-type p53 may have potential clinical utility for gene therapy of glioblastoma.

Adenoviridae↗
PubMed1994

Chronic rejection in experimental cardiac transplantation in a rat model.

The most significant pathologic finding in chronically rejected organ grafts is diffuse concentric intimal proliferation in the arterial system. To develop a reproducible model of chronic vascular rejection in cardiac grafts which we could then use to study the pathogenesis and therapy of this disease process, we exchanged heterotopic cardiac allografts across minor histocompatibility barriers using commercially available Lewis rats as donors and F-344 rats as recipients. We found that all long-term surviving allografts developed diffuse graft arteriosclerotic lesions which were virtually identical in appearance to those seen in chronically rejected human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions and are made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of continuous series of rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 probably underlies early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR and immunocytochemistry confirms MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF and IL-1 beta in vascular lesions suggests these factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts, as they, along with protein S, were closely associated with sites of intimal hyperplasia and smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗