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Biomedical subjects

F Thomas

Publications and source records attributed to F Thomas.

At least 37 records · Page 2Linked to original sources
PubMed1995

Carboxyl-terminal domain truncation alters apolipoprotein A-I in vivo catabolism.

Apolipoprotein A-I (apoA-I), the major protein of high density lipoproteins, facilitates reverse cholesterol transport from peripheral tissue to liver. To determine the structural motifs important for modulating the in vivo catabolism of human apoA-I (h-apoA-I), we generated carboxyl-terminal truncation mutants at residues 201 (apoA-I201), 217 (apoA-I217), and 226 (apoA-I226) by site-directed mutagenesis. ApoA-I was expressed in Escherichia coli as a fusion protein with the maltose binding protein, which was removed by factor Xa cleavage. The in vivo kinetic analysis of the radioiodinated apoA-I in normolipemic rabbits revealed a markedly increased rate of catabolism for the truncated forms of apoA-I. The fractional catabolic rates (FCR) of 9.10 +/- 1.28/day (+/- S.D.) for apoA-I201, 6.34 +/- 0.81/day for apoA-I217, and 4.42 +/- 0.51/day for apoA-I226 were much faster than the FCR of recombinant intact apoA-I (r-apoA-I, 0.93 +/- 0.07/day) and h-apoA-I (0.91 +/- 0.34/day). All the truncated forms of apoA-I were associated with very high density lipoproteins, whereas the intact recombinant apoA-I (r-apoA-I) and h-apoA-I associated with HDL2 and HDL3. Gel filtration chromatography revealed that in contrast to r-apoA-I, the mutant apoA-I201 associated with a phospholipid-rich rabbit apoA-I containing particle. Analysis by agarose gel electrophoresis demonstrated that the same mutant migrated in the pre-beta position, but not within the alpha position as did r-apoA-I. These results indicate that the carboxyl-terminal region (residue 227-243) of apoA-I is critical in modulating the association of apoA-I with lipoproteins and in vivo metabolism of apoA-I.

Animals↗
PubMed1995

Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues.

Somatostatin receptor scintigraphy (SRS) is positive in approximately 80% of all patients who have been found to have neuroendocrine (NE) gastroenteropancreatic (GEP) tumors. The reasons for negative results are unclear. The aim of the present study was identification of the specific somatostatin receptor (SSTR) subtypes that are responsible for the in vivo binding of the widely used somatostatin (SST) analogues octreotide and lanreotide in human neuroendocrine gastroenteropancreatic tumors. Ten patients were subjected to SRS with radiolabeled octreotide. Following surgical resection, tumor tissues were analyzed for SSTR subtype mRNA expression by the reverse transcription-polymerase chain reaction (RT-PCR). In addition, SSTR subtype transcripts were investigated by Northern blot analysis and RT-PCR in neuroendocrine tumor cell lines. Expression of SSTR at the protein level was studied by chemical cross-linking experiments. Three patients were negative by SRS. However, RT-PCR revealed most prominently SSTR 2 expression in all tumor specimens. In addition, all tumor tissues analyzed by chemical crosslinking exhibited SST-14 binding sites, indicating that at least some NE tumors were false-negative on SRS.

Animals↗
PubMed1995

Evidence of two genetic entities in Bothriocephalus funiculus (Cestoda) detected by arbitrary-primer polymerase chain reaction random amplified polymorphic DNA fingerprinting.

The genetic diversity of two samples of Cestoda (Bothriocephalus funiculus, Renaud and Gabrion, 1984) parasitizing two sympatric teleostean species was assessed using random amplified polymorphic DNA (RAPD). A total of 72 Bothriocephalus were analyzed individually, and electrophoretic analysis of the amplification products of 65 primers among the 68 tested revealed monomorphic patterns, reflecting the close genetic relatedness within and between the parasites of the two samples. However, 3 primers showed polymorphic patterns at 6 RAPD sites. Analysis of the distribution of these genomic fragments, assuming random mating, showed strong linkage disequilibria (only 8 genetic combinations were observed among the 32 expected). Two genetic entities displaying a high degree of host specificity were evidenced within our two samples of funiculus. This powerful molecular technique can be used as a diagnostic tool in studies concerning the biodiversity of related genetic entities and could have broad applications in parasitology.

Animals↗
PubMed1995

A clinical and genetic study of familial cases of Parkinson's disease.

We assessed a group of patients with a family history of Parkinson's disease (PD) in order to see if they differed clinically from sporadic cases and to study their genetic characteristics. Index cases were selected on the basis of clinically typical PD, and at least one affected relative. Fourteen families including 110 first degree and 40 second degree relatives were ascertained. A total of 31 individuals (17 females and 14 males) were found to be affected. This group was compared for selected clinical parameters to 31 age matched patients with sporadic PD. No statistical difference was found between the two groups. In familial cases, both the clinical parameters studied and the course of the disease varied within and between families, as observed in sporadic cases. The genetic transmission was compatible with an autosomal dominant model. The total segregation ratio of 0.25 suggested an incomplete penetrance, which increased with age, from 0 below the age of 30 to 0.43 over the age of 70. Age at onset was earlier in children than in their parents in the 8 multigeneration kindreds studied (mean difference 26 +/- 4.6 years, p = 0.01), whereas it was identical within a generation (mean difference 4.7 +/- 5.7 years, p = 0.1). Although we cannot exclude an ascertainment bias, our results are compatible with an anticipation phenomenon, which deserves further studies for confirmation.

Adult↗
PubMed1995

Administration of a gonadotropin-releasing hormone agonist during pregnancy: follow-up of 28 pregnancies exposed to triptoreline.

OBJECTIVE: To evaluate the teratogenic or fetal risk of a long-acting GnRH agonist (GnRH-a) triptoreline acetate (Decapeptyl; Ipsen-Biotech, Inc., Paris, France), inadvertently administrated in the first weeks of pregnancy. DESIGN: Prospective follow-up of exposed pregnancies and case reports. SETTING: Teratology information service of a public hospital and pharmacovigilance department of the firm. PATIENTS: Inadvertent pregnant women receiving a treatment, mainly for endometriosis or IVF. INTERVENTIONS: Case by case, individual estimations of the risks have been provided. MAIN OUTCOME MEASURE: Each pregnancy issue has been analyzed. RESULTS: No teratogenic or fetal toxic effect has been noted. CONCLUSION: No specific hazard has been observed among newborns after inadvertent exposures to a GnRH-a during the first 20 weeks of pregnancy.

Abnormalities, Drug-Induced↗
PubMed1995

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers.

Flurbiprofen is a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID) used widely in the treatment of rheumatism and non-arthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two-part, open study involving healthy adult volunteers. In the first (cross-over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen-containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen-containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high-performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (Cmax) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean +/- SD: 43 +/- 16 ng/ml versus 5999 +/- 1300 ng/ml, respectively). After repeated application of the topical patch, Cmax increased only slightly to 103 +/- 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3.5 +/- 1.7%, calculated from plasma area under the curve data and 4.4 +/- 2.8% from urinary excretion data.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Marked prolongation of incompatible class I deficient heart allografts: paradoxical effects between primarily and secondarily vascularized allografts.

These studies argue strongly against the widespread use of skin grafts for rejection testing. Primarily vascularized grafts of a clinically grafted organ would seem to be much more relevant to future studies. These results suggest that the elimination of either class I or class II antigens in grafts or techniques to modulate these antigens or reduce the degree of incompatibility of these antigens by tissue typing should be actively pursued for solid organ grafting in the future.

Animals↗
PubMed1995

Improved large burn therapy with reduced mortality following an associated septic challenge by early excision and skin allografting using donor-specific tolerance.

These studies demonstrate clearly that the creation of donor-specific tolerance in animals permits the long-term survival of incompatible skin grafts placed following a burn with early eschar excision. Furthermore, the studies demonstrate graphically that such replacement can be done without any increase in the septic mortality in these animals and strongly suggest that such a treatment would be potentially efficacious as a therapy for large body burns that could not be successfully covered with autografts. When animals were observed either in the potentially septic milieu of a large 30% body burn or in a situation of a deliberate attempt to create a septic state using the septic challenge of CLP, the placement of a full-thickness skin graft that survived was clearly beneficial to the animal in reducing mortality. In addition, the donor-specific tolerance technique described permits long-term survival of these skin grafts, which in some of the earlier laboratory studies were able to survive permanently and might well achieve permanent survival in a clinical situation. However, a prolonged graft survival of 90 to 100 days, considering the ability to develop new split thickness skin grafts providing dermal cover at 20- to 25-day intervals, would provide opportunity for a least four "croppings" of the skins. Thus, for example, a small area of remaining autograft skin of 20% in an 80% burn patient could potentially be cropped four times to achieve close to 80% coverage. Coverage would be easier and more successful in the more common burns of less than 70% of TBSA. It is of interest to us that there is virtually no well-developed literature on the use of donor-specific tolerance to aid skin graft survival. There would seem to be a reasonable rationale for considering such therapy since septic problems should not be significantly increased during induction of skin graft tolerance. Once the skin grafting has produced a significant increase in functionally covered skin, the risk of sepsis should decrease markedly. Because sepsis is currently the major factor in 75% of burn deaths, donor-specific tolerance for skins grafts appears to be eminently reasonable for future consideration. Expanded animal studies are probably necessary before clinical trials are undertaken, although skin grafting with immunosuppression has already been tried in patients.

Animals↗
PubMed1995

A gene transfer method for the study of chimerism derived from donor bone marrow in organ transplant recipients.

Transduction of DBMC with the neo gene did not negatively affect the viability of DBMC or the graft-prolonging effect of DBMC infusion and provided a sensitive method to monitor DBMC-derived chimerism at a microchimeric level for at least 6 months by molecular and immunohistochemical techniques. Selection of neo-transduced DBMC with G418 prior to infusion will enable more uniform neo expression and will provide novel opportunities to further investigate chimerism in primates.

Animals↗
PubMed1995

Role of natural killer and killer cells in concordant xenograft rejection.

This study was designed to test the alternative hypothesis to the T-cell cytotoxicity as a primary element in concordant xenograft rejection. Two sets of studies were done with one involving the known NK- and K-cell deficient Be mouse and another in which a normal mouse was induced with high levels (3 to 5 times normal) of LAK cell killing by a constant Osmolar Mini-Pump infusion of rIL-2. In the Be animals the CXR of skin and cardiac CXR grafts was slightly prolonged and the graft survived for a longer time than normal grafts, indicating the NK- and K-cell mechanisms are operative in CXR. These studies suggest that the NK and K cells act as ancillary mechanisms in cytotoxicity in CXR. In the second portion of these studies, the increasing of LAK cell activity by infusions of rIL-2 failed to delay rejection beyond that in the Be mouse but did delay rejection beyond controls. These results suggest that the NK- and K-cell killing acts as an ancillary mechanism in CXR. Because these animals had only a slight rise in ADCC shortly after transplantation with maximum titers of 1:256 in this model, it would be presumptive to assume that cell killing was not important in CXR because many xenograft models show extraordinarily high levels of ADCC after transplantation, especially in a late transplant period. As in human allografting, the vasculitis seen with ADCC antibody could be expected to represent a significant pathology long after transplantation and this mechanism of cytotoxicity involving NK and K cells may be important in a later phase after xenografting when chronic vasculitis develops in the long surviving xenografts. Techniques for immunomodulation of the NK and K activity are now being actively pursued in our laboratory.

Animals↗
PubMed1995

Deoxyspergualin is a unique immunosuppressive agent with selective utility in inducing tolerance to pancreas islet xenografts.

Recent studies of DSG have demonstrated that this agent has a unique ability among immunosuppressive drugs to induce long-term survival and functional tolerance of discordant islet xenografts from pig to the Lewis rat. In addition, DSG was found to be nontoxic to islet cells in culture and without any inhibitory effect upon insulin secretion in contrast to azathioprine, FK 506, and CyA. The long-term functional tolerance seen with these islets appears to involve a stable block of antidonor humoral immunity, although more testing is necessary to characterize the precise state producing functional tolerance in this model. Other studies presented at this meeting demonstrate the ability of DSG and RATG immunosuppression to produce long-term discordant islet survival in the NOD mouse, which suffers from a virulent autoimmune condition that destroys transplanted islets in most NOD models shortly after transplantation, even when the islets are microencapsulated. The functional tolerance is especially difficult to achieve with a discordant xenograft and thus the ability of RATG and DSG to achieve this impressive. Long-term studies using DSG and total lymphoid irradiation suggest that RATG is not essential to long-term survival but clearly it is quite synergistic with DSG and also has the advantage of being nontoxic. In fact, all animals receiving the DSG/RATG therapy were essentially free of toxicity and no deaths were observed that could be attributed to the drug therapy. This short-term course of administration of the drugs helped achieve this lack of toxicity. The high levels of synergism of ATG in this model could be related to the numerous monoclonal reactivities seen in polyclonal ATG with demonstrated titers of 1 to 4000 or greater for a number of specificities associated with B cells and macrophages, which could well be contributing to the block of humoral antibody previously demonstrated in DSG/RATG treated animals. The DSG, however, is especially effective in synergizing an antihumoral antibody response and can be shown to result in a striking decrease in early humoral antibody production following transplantation. Overall, these studies demonstrate a high potential of this immunosuppressive therapy to promote long-term discordant islet xenograft survival and functional tolerance without chronic rejection or the islet toxicity common to the currently used immunosuppressive agent. DSG may have a wide potential utility in islet transplantation but it appears to have its strongest effect in islet xenografting.

Animals↗
PubMed1995

[Hypoxemic nosocomial pneumonia developing in excavation in a patient with Cushing disease].

Multifocal alveolar hypoxaemic pneumonia caused by sporadic nosocomial infection led to acute respiratory failure and development of cavitations. Legionella pneumophilia type I was isolated. The patient was not in a state of immunosuppression other than that due to Cushing's disease recently treated surgically followed by corticosteroids. Specific clinical and radiological signs of Legionellosis (particularly the development of cavitation) and their mode of infection (community acquired or noscomial, sporadic or epidemic, immunocompetence or immunodepression) are discussed.

Adult↗
PubMed1994

Expression of a bacterial gene in transgenic plants confers resistance to the herbicide phenmedipham.

Tobacco plants were genetically engineered to express a detoxifying pathway for the herbicide phenmedipham. A gene from Arthrobacter oxidans strain P52 that encodes an enzyme catalysing the hydrolytic cleavage of the carbamate compound phenmedipham has recently been cloned and sequenced. The coding sequence was fused with a cauliflower mosaic virus 35S promoter and introduced into tobacco plants by Agrobacterium-mediated gene transfer. Transgenic plants expressing high levels of phenmedipham hydrolase exhibited resistance when sprayed with the herbicide at up to ten times the usual field application rate.

Arthrobacter↗
PubMed1994

Characterization of somatostatin receptors and growth inhibition by the somatostatin analogue BIM23014 in small cell lung carcinoma xenograft: SCLC-6.

Human small cell lung cancer (SCLC) is a neuroendocrine tumour with a very poor prognostic. Receptors for somatostatin-14 and its synthetic analogue BIM23014 (Lanreotide) were characterized in 3 human SCLC xenografts (SCLC-6, SCLC-10 and SCLC-75) transplanted in nude mice. The binding activity of both iodinated ligands was tested by cross-linking assay. One major complex of 57kDa was identified by both ligands in all 3 tumours. Two other minor complexes were only detected by the natural ligand: 90kDa in all 3 tumours and 70kDa in 2 out of the 3 tumours (SCLC-6 and SCLC-75). Analysed by Northern hybridization, the expression of the gene encoding for the receptor subtype I was detected in all 3 tumours whereas the expression of the receptor subtype II was only detected in 2 out of the 3 tumours (SCLC-6 and SCLC-75). No receptor subtype III transcript was observed. The relative quantification of the detected messengers and of the cross-linked complexes determined by densitometry suggested that SCLC-6 contained a large amount of somatostatin receptors. SCLC-6 growing in nude mice was used to evaluate the antiproliferative effect of BIM23014. BIM23014 (250 micrograms, b.i.d. for 5 days) significantly inhibited tumor growth and had an additive effect with cis-platinum (1.5 mg/kg/day for 2 days) when given concomitantly. Values of the relative tumour volume as compared to control were: BIM23014 alone 57%, cis-platinum alone 57% and BIM23014 + cis-platinum: 78%. These experimental data suggest that BIM23014 given alone or in combination with cis-platinum could have a therapeutic potential in the treatment of somatostatin receptor positive SCLCs.

Amino Acid Sequence↗