Biomedical subjects
Publications and source records attributed to R Favre.
A parasitic origin of rheumatological manifestations is only suspected if the patient returns from an endemic area of the world. We report a young girl who developed without travelling, an isolated hip arthropathy simultaneously with a Toxocara infestation. Pathogenesis is discussed.
A 2116bp segment of the bacteriophage T4 genome encompassing the motA regulatory gene has been sequenced. In addition to motA, five open reading frames were identified in the direction of early transcription. The motA gene encodes a basic protein of 211 amino acids with a predicted molecular weight of 23,559. Measurements of the rate of transcription of motA showed that the promoter of this gene is turned off after only 2 min of T4 development. This early promoter presents a structure which is richer in information than that of a classical constitutive Escherichia coli promoter. In addition to containing conserved sequences centred at -10 and -35, this promoter shares extensive homologies with other subgroups of early promoters in regions centred at +3 and at -55. We discuss the possible role of these different sequence determinants.
Two clinical cases of fetal hydrops are discussed: one of them was caused by diffuse lymphangiectasis and the other was idiopathic. A review of recent literature regarding the management of non-immunological hydrops is presented and gives hope for a new therapeutic approach to fetal hydrops especially in cases of chylothorax. However the mortality remains extremely high because of lung hypoplasia.
The present study has assessed the value of clinical examination of breast cancers in a retrospective study of 2,626 cases of operated mammary lesions. Anatomopathology is used as basic reference. The fiability of the cancer diagnosis is 94%, its sensitivity is 90% and specificity 96%. The total error only amounts to 6%, with 2/3 false negatives and 1/3 false positives. The errors are for the most part due to the anatomopathologic nature of the tumor, its size, the area of the body it is situated in and also to the examiner and to the of the patient. Nevertheless clinical examination still remains the first diagnostic step, and is indispensable in all breast pathology.
Navelbine (NVB) (5'-noranhydrovinblastine) is a new semi-synthetic vincaalkaloid (VA) exhibiting a high affinity for tubulin and considerable anticancer activity in patients. A better hematologic tolerance and a weak neurotoxicity have been reported for this drug as compared to other VA. Moreover, NVB presents a relatively high bioavailability and a good digestive tolerance, thus offering original perspectives for the treatment of ambulatory cancer patients. A clinical pharmacokinetic study of NVB was carried out on 12 patients after oral administration of the drug. The pharmacokinetic parameters were similar to those of intravenous administration and also showed a high interindividual variability. Studies on the in vitro metabolism of NVB using hepatic microsomal fractions from 22 different donors demonstrated the formation of 3 metabolites. The biotransformation rate quantitatively varies from one human liver specimen to another, a fact which could be, in part, at the origin of the interindividual variability of the therapeutic response.
Cardiac complications of mediastinal irradiation usually concern the pericardium, the ventricular myocardium and the coronary arteries. We report the case of a 42-year old woman who experienced a syncopal atrioventricular (AV) block 12 years after irradiation of a mediastinal Hodgkin's lymphoma. Electrophysiological recordings showed infranodal conduction disturbances. A review of the literature yielded only 12 cases of syncopal radiation-induced AV block. This case highlights the risk of syncopal AV blocks occurring a long time after mediastinal irradiation and leading to severe damage of the His bundle and its branches. The presence, as in our patient, of an associated right ventricular outflow tract stenosis confirms the importance and severity of radiation-induced cardiac lesions.
A superior vena cava syndrome developed suddenly in a 36 year old man who had been undergoing chemotherapy via an implanted venous access catheter for 18 months. Venography showed superior vena cava thrombosis extending bilaterally to the subclavian veins. Direct local thrombolysis with low-dose Urokinase resulted in partial recanalisation with an excellent clinical result despite the persistence of an endovenous sequestrum situated at the catheter tip, a sequela of previous thrombosis. This case underlines the importance of direct local thrombolysis in patients with a Port-a-Cath system complicated by a thrombosis.
Fossel et al. have recently proposed the proton NMR examination of plasmatic lipoproteins--and more precisely the determination of an index obtained from the averaged linewidth of the CH2 and CH3 resonances--as a possible tool for detection of cancer. Many evaluations conducted on an international basis have demonstrated that initial expectations were not met and that the test lacked sensitivity, specificity, and predictive value to be accepted as a screening and diagnostic tool. In our evaluation we have collected plasma from healthy subjects, from patients with various kinds of cancer at different stages of evolution and therapy, and from patients suffering from a variety of pathologies, including benign tumors. In accordance with Chmurny et al., we observed that the linewidth index (LWI) is precise and reproducible when care is taken in the handling and storage of samples and in the fasting of subjects. After finding no predictive value to the test, we have reanalyzed the spectra and studied the variations of the ratio defined by the methylene signal area over the methyl signal area. This ratio is significantly increased in cancer. Furthermore, it offers a better separation of statistical populations permitting a more precise discrimination between cancer, other pathologies and controls. We have also found that malignant tumors arising from mesenchyma (sarcoma, leukemia, lymphoma) induce less important variations in the CH2/CH3 ratio than adenocarcinoma or glioma, when such differences cannot be documented using the LWI. These observations are particularly interesting since they might bring new information on the metabolic modifications of the LWI and the CH2/CH3 ratio might reflect the embryologic origin of the tumors and raise the issue of the heterogeneity of cancer disease.
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A case of carcinoid cardiopathy (C.C.) of the right heart, related to liver metastases secondary to a bronchial tumor, is reported. Non-invasive investigative methods have enabled an easy diagnosis of C.C.: liver metastases by scan and abdominal sonogram, restrictive myocardiopathy with typical tricuspid lesions by echocardiography and MRI, magnitude of the tricuspid regurgitation by cardiac Doppler. These extremely performing methods must allow an early diagnosis at a stage when the patient may be still operable, since C.C. is the most frequent cause of death in patients with carcinoid tumors.
The use of a protocol of induction in Ewing's sarcoma based on the sequential association of Cyclophosphamide (150 mg/m2 for 7 days) and Adriamycin (35 mg/m2 on day 8) has shown that: 1. The clinical and radiological response (scan + MRI) even when complete is not predictive of the quality of the histological response. 2. For the histological response to be predictive, it must be evaluated on a complete monobloc resection. 3. A sustained, complete remission is more frequent after systematic extratumoral monobloc surgery and appropriate postoperative chemotherapy. When these conditions are respected, a complete remission rate of 88% at 30 months can be expected.
Three therapeutic protocols were used successively for the treatment of osteogenic osteosarcoma since 1978. The first protocol associated initial surgery and 12 months of chemotherapy and was applied to 41 patients with good results in adults but poor results in children. A protocol introducing adjuvant chemotherapy based on the association of adriamycin-cisplatinum gave very disappointing results first in children and then in adults. The protocol based on HD MTX gave much more encouraging results: the long version (3 months preoperative chemotherapy) was effective in good responders but did not influence the course of poor responders. The shortened version of this protocol, derived from the T 10 Rosen protocol (1 month preoperative chemotherapy conservative surgery and appropriate peri- and postoperative chemotherapy) seems to transform the prognosis of osteosarcoma. Our current results indicate a complete primary remission rate of 89% at one year, and 83% at 33 months.
We have identified a nucleolytic activity in Escherichia coli infected by bacteriophage T4 that introduces cuts in the ribosome binding site of at least two T4 mRNAs. Cutting takes place specifically in the GGAG sequences that are complementary to the 3' end of 16S rRNA (Shine-Dalgarno sequence). The nature of this nucleolytic cut has been investigated by reverse transcriptase mapping, anti-mRNA mapping, utilization of the vaccinia virus guanylyltransferase, and labeling by polynucleotide kinase. We have compared the sequences of target mRNAs with an mRNA of similar sequence but that is not a substrate for the nuclease. This allowed us to narrow down the possibilities for sequence elements that determine nuclease recognition. We hypothesize that this nuclease plays a physiological role in the inhibition of expression of a class of phage proteins.
During the study of chemotherapy responsiveness of twenty nine human tumors by 6 day subrenal capsule assay (SRCA), we measured, after cisplatinum regimen, the total platinum in human tumor implants and in mice plasma and renal tissue. The plasmatic (m = 0.36 +/- 0.13 microgram/ml) and renal (m = 16.1 +/- 6.4 ng/ml) total platinum concentrations are correlated. In human tumor implants the total platinum is measurable in only ten cases (above the minimum value of 7 ng/mg). There are no correlation between the tumor total platinum concentrations and the tumor cisplatinum chemosensitivity. The study is an example of anti-cancer drugs dosage in SRCA.
The pharmacokinetic studies of anticancer drugs still go on after they are out on the market. The therapeutic protocol is then more precise and depends on the dosage results of these drugs. Some examples of dosage adjustment according to their plasmatic level are reported here for high-dose methotrexate infusion and for CDDP infusion over five days. The test dose and the bayesian method (pharmacokinetic population) are used to predict the adapted individualized dosage for each patient.
Eleven patients with advanced cancer received navelbine (15 mg/m2) as a single i.v. bolus injection. At least 1 week later, the patients were given a 2-fold increased dose of navelbine (30 mg/m2) and, for seven of them, the 30-mg/m2 dose was repeated after a delay longer than a week. After each administration, plasma and urine were collected for 72 h and monitored for navelbine concentration by radioimmunoassay. The comparison of dose-normalized plasma level profiles showed significant time dependence (P less than 0.05) in four of the seven assessable patients. Some patients also exhibited significant (P less than 0.05) nonlinear (dose dependent) kinetic profiles. Only 3 of the 10 appreciable patients were characterized by both time independent and linear profiles. However, the plasma concentration decay curves presented a triphasic shape similar to that obtained with other antitumor Vinca alkaloids and the data were consistent with a three-compartment pharmacokinetic model. The dose and/or time dependence evidenced for most of the patients did not result in marked changes in pharmacokinetic parameters among courses. The pharmacokinetics of navelbine were characterized by a high plasma clearance (0.27 to 1.49 liter.h-1.kg-1), a large distribution volume (8.2 to 48.2 liter.kg-1), and a long terminal half-life (22.1 to 67.8 h). Urine excretion was low (less than 7.9%). Thus, navelbine pharmacokinetics resembles that of other antitumor Vinca alkaloids.
The time-related changes of dopamine (DA) and norepinephrine (NE) pools were investigated in heart, superior cervical ganglion (SCG) and urine in rats treated chronically with guanethidine (50 mg/kg i.p. five days each week). The efficiency of sympathectomy was assessed by the great loss of NE in heart and superior cervical ganglion (SCG) (-96% and -76% respectively of control values on day 18) together with the ready reduction of NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine. The pattern of changes was quite different for DA, which was less readily affected and at a lesser extent than NE in heart and SCG thus suggesting the presence of norepinephrine-independent DA stores. Similarly the urinary excretion of free DA, free 3,4-dihydroxyphenylacetic acid (DOPAC) and free homovanillic acid (HVA) was slightly decreased only from the 9th day, whereas urinary conjugated DA remained unaltered. These results indicate that the greatest portion of urine free and conjugated DA, free DOPAC and free HVA derives from peripheral pools located outside noradrenergic neurons. Alternatively, the time-course of DA sensitivity to guanethidine suggests that a portion of urine DA may originate from DA stored independently from NE in noradrenergic neurons.
The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m2) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 X 10(-4) M methotrexate (infusion rates greater than 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotrexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant (P less than 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.