[Metabolic, cerebral and neuropsychological characterization of Parkinson syndromes].
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Atrophy↗
Biomedical subjects
M George
Publications and source records attributed to M George.
Safety and efficacy of l-leucovorin rescue following high-dose methotrexate for osteosarcoma.
High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patients, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate.
Adolescent↗
Taenia crassiceps: cloning and mapping of mitochondrial DNA and its application to the phenetic analysis of a new species of Taenia from Southeast Asia.
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Animals↗
Burn-induced nitric oxide release in humans.
Nitric oxide (NO) generation in a series of 20 burn patients was studied with a novel anion exchange high-performance liquid chromatographic method for the simultaneous determination of nitrite (NO2-) and nitrate (NO3-), the stable metabolic endproducts of NO. The NO values within our survivor group (n = 17) were significantly altered at days 1, 6, and 12 postburn in contrast to controls (n = 23) (p < or = 0.03). NO2- values were significantly depressed in both plasma and urine, whereas NO3- values were significantly elevated in contrast to control values (p < or = 0.03). The ratio of NO2-:NO3- was significantly lower for burn patients versus controls in both plasma and urine (p < 0.01). The NO generation seemed in part to be dependent on the percentage of total body surface area burn, most dramatically elevated in patients with burns of 10 to 40% total body surface area. In subjects who did not survive beyond 36 hours postinjury because of irreversible shock (n = 3), the production of NO was significantly depressed in contrast to survivors and controls (p < 0.0001). However, the NO2-:NO3- ratio (0.001) was relatively unchanged, with reflection of a global depression in NO formation with no change in the individual component release. Burn injury resulted in an increased release/production of NO that in the first postburn week is maximally elevated immediately postinjury. NO release, although decreased at day 6 relative to the day 1 values, remained elevated into the second week postinjury when there was evidence for a further increase in NO production. The enhanced NO3- formation may well result from NO reacting with oxygen-free radicals counteracting superoxide anion-induced destruction of tissue, thereby potentially functioning as a protectant molecule.
Anion Exchange Resins↗
PeaceHealth's Marsha George drives down costs. Interview by Damon Braly.
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Alaska↗
The role of hematopoietic growth factors in support of ifosfamide/carboplatin/etoposide chemotherapy.
The ifosfamide/carboplatin/etoposide (ICE) combination represents an active chemotherapy regimen across a wide variety of disease types. The most common limiting toxicity for all three of these agents individually and in combination is myelosuppression. Thus, this regimen represents an ideal model to evaluate the role of hematopoietic growth factor support in amelioration of hematologic toxicity, maintenance of dose intensity, and dose escalation. While chemotherapy strategies using colony-stimulating factors have abrogated neutropenia, cumulative thrombocytopenia is common with many chemotherapy regimens, including ICE chemotherapy. In preclinical and phase II trials, monotherapy with recombinant human interleukin-6 (IL-6) has demonstrated substantial thrombopoietic activity, but with little enhancement of neutrophil recovery. Thus, this study was designed to evaluate combination cytokine therapy with both recombinant IL-6 and granulocyte colony-stimulating factor (G-CSF) after ICE chemotherapy. Previously untreated patients with inoperable non-small cell lung cancer are eligible. Treatment includes two monthly cycles of ifosfamide 2,000 mg/m2 with mesna 1,600 mg/m2 intravenously on days 1, 2, and 3, carboplatin 350 mg/m2 intravenously on day 1 only, and etoposide 75 mg/m2 intravenously on days 1, 2, and 3. All patients then receive G-CSF at a dose of 5 micrograms/kg/d subcutaneously beginning on day 4 until a postnadir absolute neutrophil count of more than 10 x 10(9)/L. Cohorts of patients (n = 15) are randomized to receive 0, 1, 2.5, or 5 micrograms/kg/d of IL-6 subcutaneously on days 4 to 13 in successive cohorts. This study has now reached its target accrual in all cohorts. The final data analysis is in progress. It is hoped that this trial will define the safety and tolerability of the simultaneous administration of IL-6 and G-CSF following ICE chemotherapy in patients with non-small cell lung cancer. In addition, this trial should determine the biologic activity and hematopoietic recovery observed during the simultaneous administration of these two cytokines in this setting.
Antineoplastic Combined Chemotherapy Protocols↗
Changing socio-cultural values: impact on family.
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Adult↗
[Role of urapidil in the treatment of acute hypertension].
Urapidil is a vasodilator acting on peripheral vessels by alpha-1 adrenoceptor blockade, and on central nervous system by alphaadrenoceptor blockade on the tractus solitarius nuclei and stimulation of serotoninergic receptors. Its hepatic metabolism and central action explain the absence of rebound effect when treatment is stopped. Urapidil is an arterial and venous vasodilator in systemic and pulmonary circulation. Therefore urapidil decreases systemic and pulmonary arterial pressures and left and right ventricular preload. These effects are accompanied by moderate effects on heart rate, and increased cardiac output in patients with heart failure. Some adverse effects observed with other vasodilators are absent (increased intracranial pressure and intrapulmonary shunt, negative inotropic effect, tachycardia). IV urapidil is used to treat systemic arterial hypertension perioperatively and hypertensive emergencies. Moreover urapidil has been administered to treat pulmonary artery hypertension in chronic pulmonary disease. Its haemodynamic effects seem proportional to the basal activity of alpha-adrenoceptors. Therefore, wide individual variations in active doses are observed from 12.5 to 50 mg as i.v. bolus in adults. Thereafter i.v. continuous administration or oral treatment may be necessary, depending on the cause of hypertension.
Acute Disease↗
Induction of cytochrome P4504A by the peroxisome proliferator perfluoro-n-octanoic acid.
The influence of a single dose of the peroxisome proliferator, perfluoro-n-octanoic acid (PFOA) on hepatic and renal mixed-function oxidase activities has been examined in rats. Peroxisome proliferation was confirmed by increases in peroxisomal palmitoyl-CoA oxidation and carnitine acetyl transferase activity, particularly in liver. The liver was also more susceptible than the kidney to PFOA-dependent induction of the 12-hydroxylation of lauric acid, suggesting induction of the CYP4A sub-family. This was further confirmed by Western blot analyses, wherein an anti-CYP4A1 antibody revealed a substantial PFOA-dependent induction of CYP4A1 in a pattern similar to that observed for the classical peroxisome proliferator, clofibrate. In addition, using a cDNA probe to CYP4A1 in Northern blot analysis, PFOA treatment resulted in a marked increase in the steady state level of CYP4A1 mRNA, again more extensively in liver than in kidney. Taken collectively, our data provide compelling evidence that PFOA, like other peroxisome proliferators, is also an inducer of the CYP4A subfamily.
Animals↗
Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated.
Previous studies demonstrated that cigarette smoking is associated with high elevations in levels of both cytochrome P450 1A1 (CYP1A1) and DNA adducts in human placenta. To date, the identity of the smoking related DNA adducts is not known. The DNA adducts identified in placenta of smokers could result from chemicals present in cigarette smoke, substances formed by CYP 1A1 metabolic activation of endogenous compounds, noncigarette related exposures or a combination of these processes. Exposure to contaminated rice oil containing large doses of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) also resulted in massive elevation of CYP 1A1 in human placenta but formation of DNA adducts directly from this exposure has not previously been reported. The purpose for comparing the two populations was to test the hypothesis that if CYP 1A1 induction results in the metabolic activation of endogenous compounds, then DNA adducts should also be present in PCB/PCDF exposed tissues exhibiting high CYP 1A1 activity and some of the adducts detected in the placental DNA from smokers may be identified as those derived from the metabolic activation of endogenous compounds. To test this hypothesis, we measured DNA adducts using 32P-postlabeling to analyze placental DNA from women exposed to PCB/PCDF and from cigarette smokers where levels of CYP 1A1 were similarly elevated. There was no evidence of DNA adducts among specimens obtained from PCB/PCDF exposed individuals. These data suggest that CYP 1A1 induction alone (in the absence of cigarette smoking) does not induce the formation of DNA adducts detectable by this approach, and that smoking related adducts are not a consequence of CYP 1A1 induction mediated activation of endogenous compounds or xenobiotics other than cigarette smoke.
Aryl Hydrocarbon Hydroxylases↗
Regulation of glycogen synthase activity in isolated rat adipocytes by levamisole.
The effect of levamisole on glycogen synthase activity in isolated adipocytes was studied. The addition of levamisole to these cells resulted in an acute concentration-dependent increase in glycogen synthase activity. In contrast, epinephrine, dibutyryl cyclic AMP (DcAMP) and cysteamine decreased glycogen synthase activity. The stimulatory effect of levamisole on the activity of the enzyme was not affected by the presence of epinephrine but was diminished when either DcAMP or cysteamine was present. The results of this study suggest that levamisole increases adipocyte glycogen synthase activity by a mechanism that can be reversed by the elevation of cAMP.
Adipocytes↗
Induction of the CYP4A subfamily by perfluorodecanoic acid: the rat and the guinea pig as susceptible and non-susceptible species.
Male Wistar rats and male Duncan Hartley guinea pigs were treated with one i.p. dose of perfluorodecanoic acid (PFDA) resulting in pronounced hepatomegaly in the rat but not the guinea pig. PFDA treatment also resulted in a 4-fold induction of lauric acid 12-hydroxylase activity in the rat but not the guinea pig, indicating induction of the CYP4A subfamily of isoenzymes. Consistent with this latter conclusion, Western blot analysis of rat liver microsomes using an antibody to CYP4A1 and Northern blot analysis of RNA extracts using a CYP4A1 cDNA probe, revealed PFDA-dependent induction of the CYP4A subfamily in the rat but not the guinea pig. Taken collectively, our data has demonstrated that PFDA, like other peroxisome proliferators, is also a CYP4A inducer and conforms to the well-documented species specificity in induction for this class of compound.
Animals↗
Phase II trial for intraperitoneal cisplatin plus intravenous sodium thiosulphate in advanced ovarian carcinoma patients with minimal residual disease after cisplatin-based chemotherapy--a phase II study of the EORTC Gynaecological Cancer Cooperative Group.
On the basis of its efficacy against ovarian carcinoma and its safe peritoneal administration, cisplatin administered by the intraperitoneal route was studied in a phase II multicentric trial. 34 patients with good performance status and residual disease less than 1 cm were treated with a 90 mg/m2 dose (60 mg/m2 at first cycle), administered in the abdominal cavity every 3 weeks for at least four cycles. In case of haematological or renal toxicity, intravenous sodium thiosulphate was perfused simultaneously with intraperitoneal cisplatin with protective intent. 25 patients were evaluable for response: 3 patients had pathological complete response and 1 patient had a microscopic disease (16% response rate in evaluable patients). Systemic toxicity was mild, and sodium thiosulphate clearly protected against leucopenia (6 patients) and renal toxicity (8 patients). Local side-effects were evaluable in 34 patients with 2 cases of infectious peritonitis, 1 of wound infection and 2 of haemorrhage. Of the 147 evaluable chemotherapy cycles, nine resulted in partial and one in total inflow obstruction, for which 4 patients needed surgical procedures for catheter-related complications, and 1 patient died of acute abdominal complications after such a procedure. We conclude that 90 mg/m2 intraperitoneal cisplatin has activity in pretreated patients with minimal residual disease, and that thiosulphate protects against haematological and renal toxicities. Only a randomised study can demonstrate a true benefit, which will have to be balanced with the toxicity of intraperitoneal drug administration.
Aged↗
Formation of DNA adducts in rat lung following chronic inhalation of diesel emissions, carbon black and titanium dioxide particles.
Exposure of rats to diesel emissions results in the development of lung tumors. The objective of this study was to determine whether the polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs or other polycyclic organic matter adsorbed to diesel particles induces the formation of DNA adducts in the lung when compared to particles with little or no adsorbed organic matter. Rats were exposed to diesel emissions containing particles with over 30% solvent-extractable adsorbed organic matter and to particles with < 0.1% adsorbed organic matter (carbon black particles and TiO2). Wistar rats were exposed to diesel emissions (7.5 mg/m3) for 2 months, 6 months and 2 years and for 2 years to carbon black (11.3 mg/m3) and TiO2 particles (10.4 mg/m3) to compare tumorigenic response and DNA adduct formation in the lung. Two versions of the 32P-postlabeling assay for the detection of DNA adducts were used to tentatively identify nitrated-amine or arylamine adducts formed relative to other nitro PAH based on the demonstrated sensitivity of these adducts to nuclease P1 treatment. Total adduct levels were determined for peripheral lung tissue DNA as detected in a diagonal radioactive zone. One major adduct which migrated outside this region (adduct 1) and a nuclease P1-sensitive adduct (adduct 2) were quantitated separately. Adduct 1 increased significantly over time in the filtered air exposed animals but decreased markedly at the 2 year time points regardless of particle type, presumably as a result of adduct dilution through de novo cell synthesis or cell proliferation invoked in response to particle loading and/or effect on the endogenous synthesis or degradation of DNA reactive moieties. The nuclease sensitive adduct (adduct 2), possibly resulting from exposure to nitro-PAHs, was detected in diesel-exposed rats but was not detected in the rats exposed to TiO2 and carbon black. No significant elevation in PAH-derived adducts, relative to the filtered air controls, was observed in the rodents exposed to diesel emission. Our data suggest that long-term contact with these particles may result in a cell proliferative response, enhanced degradation of I-compounds not related to cell proliferation, and/or synthesis of I-compounds, irrespective of the differences in organic content associated with the three particle types. This response may be an important factor in explaining the reported similarity in tumorigenic response in rodents exposed to diesel emissions, carbon black and TiO2 particles.
Administration, Inhalation↗
Enoximone and acute left ventricular failure during weaning from mechanical ventilation after cardiac surgery.
OBJECTIVE: To evaluate enoximone, a phosphodiesterase III inhibitor, in the treatment of left ventricular failure during the weaning of patients from mechanical ventilation after heart surgery. DESIGN: Open label, prospective, weaning trial. SETTING: Cardiothoracic surgical intensive care unit (ICU) in a university hospital. PATIENTS: Nine patients were studied after one or more unsuccessful attempts at weaning from mechanical ventilation due to left ventricular dysfunction. INTERVENTION: For each patient, two respiratory weaning attempts were studied: the first one as a control and the second one with enoximone infused at a rate of 30 micrograms/kg/min for 30 mins, then at a rate of 10 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements were performed at the following interval times: baseline during mechanical ventilation; during spontaneous ventilation with a T-piece for a minimum of 10 mins; during mechanical ventilation after the enoximone infusion for 30 mins; during spontaneous ventilation for a minimum of 10 mins with an enoximone infusion running. During spontaneous ventilation, enoximone increased cardiac index by 34% but mean artery, right atrial, and pulmonary artery occlusion pressures did not change. Despite an increase in venous admixture due to augmented cardiac index and inhibition of hypoxic vasoconstriction, no oxygen debt occurred because oxygen delivery increased. Seven of nine patients were weaned successfully from mechanical ventilation. CONCLUSION: Because of its positive inotropic and vasodilatory properties, enoximone is helpful for respiratory weaning of patients with left ventricular failure after cardiac surgery.
Aged↗
[Automatic implantable defibrillators; subdiaphragmatic insertion].
Although the material and techniques of implantation of the electrodes of implantable defibrillators have been improved, the abdominal implantation of the generator remains widely used as described by Mirowski in 1980. Despite a progressive reduction in their size, the generators remain bulky and a source of local complications. The risks and discomfort of implantation in the abdominal wall led the authors to try subdiaphragmatic implantation in 22 patients. There was no morbidity with perfect healing in all 22 cases. The mean follow-up period was 11 months. The patients felt very comfortable, a significant advance with respect to abdominal implantations.
Adolescent↗
[Implantation of automatic defibrillators by means of video-thoracoscopy. Authors' experience].
The implantable cardioverter-defibrillator represents an effective option for some potentially lethal ventricular arrhythmias. Nowadays defibrillation electrodes are often endoluminal only. In some patients, however, the presence of high defibrillation thresholds mandates the implantation of a subcutaneous patch. If the subcutaneous patch does not allow a sufficient decrease in defibrillation threshold, then two epicardial patches are generally implanted by different surgical approaches. Nevertheless surgical trauma could be a serious hazard in unstable patients. In 6 patients in whom endoluminal electrodes did not allow a safe defibrillation threshold, an extrapericardial patch has been implanted by means of a video-thoracoscopic approach: a left subcostal incision is performed and the subdiaphragmatic extraperitoneal space is reached; a patch electrode is then introduced into the left pleural cavity by blunt dissection of the diaphragm. This patch is positioned under thoracoscopic control in contact to the left pericardial surface and fixed by single stitches sutures. The impulse generator is finally implanted into the subdiaphragmatic pocket. In all the patients the patch electrode configuration sufficiently decreased defibrillation thresholds. In one of the patients a stellectomy was thoracoscopically performed to treat the long QT syndrome which was the cause of the ventricular fibrillation episodes. Defibrillation thresholds were confirmed after 8 day and 2 months postoperatively. In conclusion, the thoracoscopic implantation of an extrapericardial patch has allowed a significant reduction of defibrillation thresholds, without recurring to a major surgical procedure.
Defibrillators, Implantable↗
Chlorotrifluoroethylene trimer and tetramer are inducers of the CYP4A subfamily.
Male Wistar albino rats were treated for a 7 day period with equimolar doses of the trimer and tetramer oligomers of chlorotrifluoroethylene (CTFE), resulting in significant hepatomegaly for both compounds. In addition, both trimer and tetramer significantly induced the peroxisomal beta-oxidation of fatty acids as assessed by increases in palmitoyl-coenzyme A (CoA) oxidation, thus confirming these oligomers as peroxisome proliferators. Consistent with these conclusions, both trimer and tetramer increased the hydroxylation of lauric acid indicating that the CTFEs were inducers of the CYP4A subfamily, a conclusion further supported by substantial increases in the steady-state levels of the cognate CYP4A1 mRNA as determined by northern blotting. The liver appeared to be more susceptible to induction than the kidney and the CTFE tetramer was more potent than the trimer. These results are discussed with respect to both the differential hepatotoxicity, and biotransformation/disposition of the two polyhalogenated oligomers.
Animals↗