Search PubMed⌕ Search

Biomedical subjects

M George

Publications and source records attributed to M George.

At least 55 records · Page 3Linked to original sources
PubMed2000

Can the light-addressable potentiometric sensor (LAPS) detect extracellular potentials of cardiac myocytes?

The light-addressable potentiometric sensor (LAPS) measures localized photo-induced currents from a silicon wafer, which are dependent on the local surface potential and on the intensity of the light pointer. In this study the ability of the LAPS to record extracellular potentials of adherent cells was investigated. Time dependent LAPS photocurrent signals that correlated in time with contractions were recorded from beating cardiac myocytes cultured on LAPS surfaces. Signals could be recorded both when the LAPS was biased to working points where the photocurrent was maximally sensitive to potential changes and when it was biased to working points where the photocurrent was insensitive to changes in surface potential. Therefore, signals could not be predominantly created by changes in extracellular potential and might be related to mechanical contractions. One possible explanation might be, that the cell-induced modulation of photocurrents arose as a result of cell shape changes. Such alterations in cell shape might have focused and defocused the light pointer and, thus, modulated its intensity. To further test this hypothesis, height changes of beating cardiac myocytes were measured with an atomic force microscope (AFM). They were found to match well with signals derived from LAPS measurements. Therefore, it can be concluded, that LAPS signals were mainly determined by the periodic changes in shape of beating heart cells, and this interference precludes the measurements of extracellular electrophysiological potentials from these cells.

Animals↗
PubMed2000

Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes.

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.

Animals↗
PubMed2000

The safety and tolerability of candesartan cilexetil in CHF.

The management of congestive heart failure (CHF) continues to represent a major therapeutic challenge. The primary goal of any treatment is the improvement of symptoms with a reduction in CHF related morbidity and a neutral or beneficial effect on mortality. The number of hospitalisations is considered an important measure of morbidity and quality-of-life in these patients. This pooled safety analysis was performed on adverse event data from five placebo-controlled studies involving a total of 1893 patients, 1287 of whom received candesartan cilexetil and 606 of whom received placebo. These were the only placebo-controlled phase II and III studies of candesartan safety available at the time of the analysis, and investigated the efficacy and safety of candesartan cilexetil in patients with CHF. None was designed as an endpoint trial. A blinded, independent review of all adverse event data was performed to assess all-cause mortality and unexpected deaths, and hospitalisations for acute deterioration of CHF, chronic progression of CHF, other intercurrent events, or accidental injury/attempted suicide. The descriptive analysis included crude and cumulative incidence rates for mortality and cardiac and non-cardiac morbidity using the Kaplan-Meier method and the log-rank test. The sample population was predominantly (approximately two thirds) male, with a median age of 61 years (range: 20-89 years). The median age for women in the sample population was 66 years (range: 26-86 years). Patients received candesartan cilexetil, 2-32 mg, over a median period of 84 days (range: 1-418 days), or placebo over a median period of 85 days (range: 1-398 days). The results demonstrated a clinically non-significant trend for all relevant events (deaths and hospitalisations, whether related to CHF or not) to occur less frequently in patients receiving candesartan cilexetil than in patients receiving placebo (deaths - candesartan cilexetil: 1.6%, placebo: 1.8%; hospitalisations - candesartan cilexetil: 7.2%, placebo: 10.9%). There was a significant treatment difference in CHF hospitalisations (candesartan cilexetil: 3.0% vs. placebo: 5.6%). The time to event analysis revealed that significantly fewer hospitalisations due to CHF occurred in the group receiving candesartan cilexetil than in the group receiving placebo. This treatment difference persisted throughout therapy (log-rank test; p < 0.028). These results show the safety of candesartan cilexetil, compared with placebo, in the treatment of patients with CHF.

Adult↗
PubMed2000

Metabolic activation stimulates acid production in synovial fibroblasts.

OBJECTIVE: In rheumatoid arthritis (RA), synovial fibroblasts express proteases such as collagenases or cathepsins and inflammatory cytokines at elevated levels and so contribute to the inflammatory degradation process. Extracellular matrix degradation and cathepsin activity is dependent upon the presence of an acidic milieu. We examined whether activated synovial fibroblasts secrete acidic components. METHODS: Synovial fibroblasts were isolated and immortalized to study the mechanisms of metabolic activation. Naïve and immortalized fibroblasts were activated with different cytokines. The responses were investigated by immunoblot to detect Egr-1 and by a cytosensor microphysiometer analysis to evaluate acid secretion. Basic gene expression patterns were investigated in naïve and immortalized cells by RT-PCR analysis. RESULTS: We found RA synovial fibroblasts respond to different cytokines associated with the pathomechanisms of RA including interleukin 1, basic fibroblast growth factor, platelet derived growth factor, and tumor necrosis factor-alpha, with metabolic activation and enhanced secretion of acidic components. In addition, naive and SV40 TAg immortalized fibroblasts rapidly release acidic components after stimulation with phorbol ester or ionomycin as well. CONCLUSION: Activated synovial fibroblasts not only express inflammatory cytokines and matrix degrading proteases that are associated with the pathomechanisms of RA, but upon stimulation may release acidic components that lower pH and consequently enhance cathepsin activity and collagen solubilization.

Arthritis, Rheumatoid↗
PubMed1999

Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure (STRETCH) Investigators.

BACKGROUND: The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure (CHF). This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF. METHODS AND RESULTS: In this multicenter, double-blind, parallel-group study, 844 patients with CHF were randomized to 12 weeks' treatment with placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea Fatigue Index score, NYHA functional class, and cardiothoracic ratio were determined. Candesartan cilexetil produced a dose-related improvement in exercise time. For the intention-to-treat population, the increase produced by candesartan cilexetil 16 mg was significantly greater than that produced by placebo (47.2 versus 30.8 seconds, P=0.0463). All doses of candesartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved more frequently in the candesartan cilexetil groups; the differences relative to placebo were not significant. The decrease in cardiothoracic ratio with candesartan 4 to 16 mg was small but statistically significant compared with placebo (all P<0.05). In all candesartan cilexetil groups, plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well tolerated at all doses. CONCLUSIONS: In summary, treatment with candesartan cilexetil demonstrated significant improvements in exercise tolerance, cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.

Adult↗
PubMed1999

Mapping the mechanical pulse of single cardiomyocytes with the atomic force microscope.

The atomic force microscope (AFM) was used to analyse the contractile behaviour of embryonic chicken cardiomyocytes. The mechanical pulsing of cardiomyocytes was analysed by observing active single cells as well as cells in a confluent layer. When embedded in a confluent layer, owing to synchronisation, pulsing of the cells was often found to be very stable in terms of frequency and amplitude of the beat, including negative as well as positive amplitudes. Nevertheless, owing to movements of contraction centres within the layer, a flipping of the sign of the amplitude did sometimes also occur on a time scale of minutes. In contrast, single cells often changed between active periods of pulsing and periods of complete quietness. Also characteristic parameters like beat period and pulse amplitude were observed to be unstable. Finally, we combined the abilities of the AFM to image adherent single cells and to record locally beat amplitudes, to characterise the pulsing behaviour of single cells laterally resolved.

Animals↗
PubMed1999

Electrically excitable normal rat kidney fibroblasts: A new model system for cell-semiconductor hybrids.

In testing various designs of cell-semiconductor hybrids, the choice of a suitable type of electrically excitable cell is crucial. Here normal rat kidney (NRK) fibroblasts are presented as a cell line, easily maintained in culture, that may substitute for heart or nerve cells in many experiments. Like heart muscle cells, NRK fibroblasts form electrically coupled confluent cell layers, in which propagating action potentials are spontaneously generated. These, however, are not associated with mechanical disturbances. Here we compare heart muscle cells and NRK fibroblasts with respect to action potential waveform, morphology, and substrate adhesion profile, using the whole-cell variant of the patch-clamp technique, atomic force microscopy (AFM), and reflection interference contrast microscopy (RICM), respectively. Our results clearly demonstrate that NRK fibroblasts should provide a highly suitable test system for investigating the signal transfer between electrically excitable cells and extracellular detectors, available at a minimum cost and effort for the experimenters.

Action Potentials↗
PubMed1999

[Anesthesia consultation in cardiovascular and thoracic surgery. A survey of patient and physician satisfaction].

OBJECTIVE: To assess the quality of the preadmission anaesthetic consultation prior to cardiovascular and thoracic surgery with a satisfaction inquiry. STUDY DESIGN: Prospective study with a questionnaire, extended over a period of two months. PERSONS: Patients and anaesthetists of the cardiothoracic surgical service. METHODS: The inquiry, which took place after completion of the consultation was achieved by a person non member of the staff. Anaesthetists were questioned on the medical content, its exhaustive character and its value for the patient's perioperative care. RESULTS: Out of the 273 patients included in the study, 121 agreed to answer the questionnaire. Participation in the study was more significant in older patients (58 +/- 20 vs 51 +/- 24 years) and following shorter waiting time (WT) [15 +/- 13 (0-60) vs 25 +/- 18 (0-66) min]. The duration of the consultation (DC) was not different between the two groups [29 +/- 12 (8-70) vs 31 +/- 14 (6-75) min]. However patients' participation increased when the DC exceeded by 0.6 the sum of DC and WT [DC > 0.6 (DC + WT)]. The analogic score (AS) assessing reduction in preoperative anxiety was 8.4 +/- 1.5 (2-10). Finally, 108 patients out of 121 considered to have been well informed about the anaesthetic [AS = 8.7 +/- 1.2 (4-10)], 113 considered the preadmission consultation as a useful procedure [AS = 8.6 +/- 1.5 (2-10)]) and for 41 a personalized follow-up by the same anaesthetist was valuable. Only three operations had to be postponed the day before surgery. One third of the anaesthetists considered that the consultation improved the clinical and therapeutic management of the patients. CONCLUSION: This inquiry showed that the preadmission anaesthesia consultation was considered as benefitful by patients and anaesthetists. However the participation of patients in this study was poor. Subsequently to the inquiry information forms have been produced and handed to the patient prior to the consultation.

Adolescent↗
PubMed1999

Structure elucidation of the adducts formed by fjord-region Dibenzo[a,l]pyrene 11,12-dihydrodiol 13,14-epoxides and deoxyadenosine.

Model adducts to be used in the identification of biologically formed adducts were synthesized by reaction of fjord-region dibenzo[a,l]pyrene 11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE) and deoxyadenosine (dA). The (+/-)-anti-DB[a,l]PDE was reacted with dA in dimethylformamide at 100 degrees C for 30 min to give four DB[a, l]PDE-14-N(6)dA adducts: (-)-anti-trans (26%), (+)-anti-trans (26%), (-)-anti-cis (17%), and (+)-anti-cis (17%). The (+/-)-syn-DB[a,l]PDE was reacted with dA under the same conditions to yield four DB[a, l]PDE-14-N(6)dA adducts and one N7Ade adduct: (+)-syn-cis (19%), (+)-syn-trans (13%), (-)-syn-cis (19%), (-)-syn-trans (13%), and (+/-)-syn-DB[a,l]PDE-14-N7Ade (22%). The structures of the eight stereoisomers of DB[a,l]PDE-14-N(6)dA were unequivocally assigned by reacting optically pure (-)-anti-DB[a,l]PDE and (+)-syn-DB[a,l]PDE with dA and by a combination of NMR, circular dichroism, and fast atom bombardment mass spectrometry. Reactions at 100 degrees C yielded mainly the trans-opened adducts at the benzylic C-14 position for both (+/-)-anti-DB[a,l]PDE and (-)-anti-DB[a,l]PDE, whereas (+/-)-syn-DB[a,l]PDE and (+)-syn-DB[a,l]PDE afforded mainly cis-opened adducts. At room temperature, however, only trans-opened adducts were obtained from (+/-)-anti-DB[a,l]PDE and only cis-opened adducts from (+/-)-syn-DB[a,l]PDE. Steric hindrance created by the fjord region may be an important factor for the stereoselectivity observed at room temperature.

Chromatography, High Pressure Liquid↗
PubMed1999

Structure elucidation of the adducts formed by fjord region Dibenzo[a,l]pyrene-11,12-dihydrodiol 13,14-epoxides with deoxyguanosine.

(+/-)-anti-Dibenzo[a,l]pyrene-11,12-dihydrodiol 13,14-epoxide {(+/-)-anti-DB[a,l]PDE} was reacted with deoxyguanosine (dG) in dimethylformamide at 100 degrees C for 30 min, and two sets of adducts were isolated: a mixture of (+/-)-anti-cis- & -trans-N(2)dG (43%) and a mixture of (+/-)-anti-cis- & -trans-N7Gua (45%). Both are mixtures of four stereoisomers that cannot be separated by HPLC. Similarly, (+/-)-syn-DB[a,l]PDE was reacted with dG under the same conditions, and (+/-)-syn-cis- & -trans-N(2)dG (38%) and (+/-)-syn-cis- & -trans-N7Gua (59%) were obtained. The structures of the adducts were determined by a combination of NMR and fast atom bombardment mass spectrometry. By reacting (-)-anti-DB[a,l]PDE or (+)-syn-DB[a,l]PDE with dG under the same conditions, however, optically pure N(2)dG and N7Gua isomers were obtained: (-)-anti-cis-N(2)dG (12%), (-)-anti-trans-N(2)dG (17%), (-)-anti-trans-N7Gua (43%), (+)-syn-cis-N(2)dG (7%), (+)-syn-trans-N(2)dG (3%), (+)-syn-cis-N7Gua (36%), and (+)-syn-trans-N7Gua (22%). The structures of the optically pure adducts were assigned by NMR. syn- and anti-DB[a,l]PDE-N(2)dG adducts can be distinguished by fluorescence line-narrowing spectroscopy (FLNS). Moreover, distinction between cis- and trans-stereochemistry of the adducts is also straightforward by FLNS, because the FLN spectra for the four DB[a,l]PDE-N(2)dG adducts, anti-cis, anti-trans, syn-cis, and syn-trans, are spectroscopically unique.

Chromatography, High Pressure Liquid↗
PubMed1999

Oral and systemic immunoglobulin G-subclass antibodies to Actinobacillus actinomycetemcomitans leukotoxin.

Salivary, gingival crevicular fluid and serum-specific immunoglobulin G (IgG)-subclass antibodies to Actinobacillus actinomycetemcomitans leuktoxin were quantified by enzyme-linked immunosorbent assay. Samples were taken from six patients with periodontal pockets > or = 5 mm, harboring A. actinomycetemcomitans in subgingival plaque and from six healthy, sex- and age-matched controls, who did not harbor A. actinomycetemcomitans. In individuals suffering from periodontitis, the median values of specific IgG1- and IgG2-subclass antibodies in saliva, gingival crevicular fluid and serum were, respectively IgG1 147 ng/ml, 5226 ng/ml and 7318 ng/ml and IgG2 4.8 ng/ml, 934 ng/ml and 860 ng/ml. In the patients, specific IgG3 antibodies were detected in one out of six individuals in saliva, in two individuals in gingival crevicular fluid and in five out of six patients in serum with a median value of 561 ng/ml. The median values of specific IgG4 antibodies in saliva, gingival crevicular fluid and serum were below detectable levels. The median values of the total IgG subclasses in saliva and serum were 14622 ng/ml and 10.3 g/l respectively. Individuals with periodontitis had, compared with controls, a higher ratio of specific IgG1 antibodies to total IgG1 in saliva (P < 0.05) and in serum (P < 0.05) and a higher ratio of specific IgG antibodies to total IgG in saliva (P < 0.05) and in serum (P < 0.01). The results show an elevation of both oral and systemic specific antibodies to A. actinomycetemcomitans leukotoxin.

Adult↗
PubMed1999

Influence of temperature on tracheal tube cuff pressure during cardiac surgery.

BACKGROUND: Lateral wall pressure may cause tracheal injury by affecting tracheal capillary blood flow. Damage to the trachea is less severe when lateral wall pressure exerted by the endotracheal tube cuff does not exceed the mean capillary perfusion pressure of the mucosa. The purpose of this study was to determine the effects of hypothermic and normothermic cardiopulmonary bypass (CPB) on tracheal tube cuff pressure dynamics. METHODS: Twenty-two patients were studied during normothermic CPB (pulmonary artery blood temperature in the CPB period between 36 and 35 degrees C), and 22 patients during hypothermic CPB (pulmonary artery temperature in the CPB period between 32 and 28 degrees C). A Mallinckrodt Medical Lo-Contour Murphy tracheal tube, with high-volume, low-pressure cuff was used without lubricant. Intracuff pressure (ITCP) was recorded at end-expiration before, during and after cardiopulmonary bypass. RESULTS: ITCP measurements were different between groups during CPB at aortic cross-clamping (13.9 +/- 0.8 mmHg in the normothermic group versus 11.3 +/- 0.4 mmHg in the hypothermic group, P < 0.05), and respectively during CPB after aortic declamping (15.3 +/- 0.8 mmHg and 12.6 +/- 0.8 mmHg, P < 0.05) and after CPB at the end of surgery (16.8 +/- 0.7 mmHg and 18.6 +/- 0.3 mmHg, P < 0.05). CONCLUSION: We conclude that the ITCP is higher in normothermic CPB than in hypothermic CPB; however, the clinical significance of this observation needs further investigation.

Aged↗
PubMed1999

Molecular characterization of U937-dependent T-cell co-stimulation.

U937 cells provide a co-stimulatory signal for CD3-mediated T-cell activation which is independent of the CD28/CD80/CD86 interaction. This study set out to identify which molecules contribute to this co-stimulatory activity. Monoclonal antibodies (mAb) to the known accessory molecules CD11a, CD18, CD54 and CD45, all inhibited T-cell proliferation. Although CD11a/18 mAb inhibited U937/T-cell cluster formation as well as proliferation, CD45 enhanced the size of the clusters formed, suggesting that this was not the only mechanism of inhibition. The alternative co-stimulatory pathway provided by U937 cells preferentially stimulated a response in the CD18+ T-cell population, and this reflected the reduced sensitivity of CD8+ T cells to CD28-mediated activation. Monoclonal antibodies to three molecules, CD53, CD98 and CD147, also inhibited U937-dependent T-cell proliferation. The mAb to CD98 and CD147 were inhibitory when prepulsed on to the U937 cells, suggesting an effect mediated by these molecules on the antigen-presenting cell.

Antibodies, Monoclonal↗
PubMed1999

Severe morbidity after coronary artery surgery: development and validation of a simple predictive clinical score.

AIMS: To develop a predictive clinical risk score of post-operative morbidity after coronary artery bypass grafting. METHODS AND RESULTS: Data were collected retrospectively from 679 patients undergoing emergency or planned bypass surgery between 1 January and 31 December 1996. The incidence of morbidity was 23%. Multivariate stepwise logistic regression analysis on two-thirds of the patients identified eight independent risk factors for severe morbidity. Six of these were pre-operative: symptomatic right heart failure, previous ventricular arrhythmias, previous coronary bypass surgery, chronic pulmonary disease, ST changes on pre-operative electrocardiogram, body mass index <24 kg. m-2, and two were intra-operative factors: the surgeon who operated, and the cardiopulmonary bypass time. A predictive clinical risk score was developed with the six pre-operative risk factors. The negative predictive value of the model is 87% and the area under the receiver operating characteristic curve is 0.77. When tested on the remaining patients not used for developing the model, the area under the curve is 0.65. CONCLUSION: This pre-operative risk score provides a simple method of risk stratification for patients undergoing coronary artery surgery. However, as for all predictive models, the performance of the score decreases when applied to a population other than that used to develop it.

Adult↗
PubMed1999

Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.

Argatroban is a peptidomimetic inhibitor of thrombin that is currently undergoing extensive clinical trials as a heparin substitute for thrombotic complications. Argatroban is readily metabolized into a major derivative, M1, that has pharmacological characteristics distinct from its parent compound. The currently available clot-based assays measure the cumulative anticoagulant effect of argatroban and its metabolite(s). Available HPLC methods do not differentiate between argatroban and M1-metabolite. A modified method was developed to simultaneouly quantitate M1-metabolite and argatroban in biological fluids. Initial validation studies for the method included clinical trials of argatroban in patients with heparin-induced thrombocytopenia, (ARG 911 Study) and coronary interventional procedures (ARG 310 Study). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. Calibration curves were prepared by running known standards of argatroban and M1-metabolite in normal human plasma. Ultraviolet detection was made at 320 nm. The retention times for argatroban and M1-metabolite peaks were found to be 10.5 +/- 0.3 minutes and 3.9 +/- 0.1 minutes, respectively. The extraction efficiency was > 95% (r2 = 0.99). In heparin-induced thrombocytopenia patients with major bleeding complications (n = 30), the relative increase in M1-metabolite compared to argatroban varied widely (two- to eight-fold). The mean concentration of argatroban during the steady infusion period was found to be 0.7 +/- 0.35 microgram/mL, and for M1-metabolite, it was 5.5 +/- 2.8 micrograms/mL. Proportionate results were not seen when higher dosages of argatroban were administered (coronary angioplasty studies). Argatroban and M1-metabolite levels also compared well with the results in global clotting assays. Owing to the simultaneous quantitation of argatroban and M1-metabolite, this method provides a rapid assessment of the pharmacokinetics and pharmacodynamics of argatroban. The differential quantitation may be useful in the assessment of relative metabolic turnover of argatroban that can be related to the hepatic and renal functions in a given patient.

Anticoagulants↗
PubMed1999

Thoracoscopic sympathectomy: indications and complications.

In 1942,Hughes performed the first thoracoscopic removal of sympathetic ganglia. Two years later Goetz and Marr reported on cases that had undergone thoracoscopic sympathectomy. In the 1950s, Kux performed more than 1,400 thoracoscopic sympathectomies and vagotomies. Interest in thoracoscopic sympathectomy increased in the 1980s and now it is the treatment of choice for severe axillary and palmar hyperhidrosis.

Journal Article↗