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Biomedical subjects

C Grandjean

Publications and source records attributed to C Grandjean.

At least 19 recordsLinked to original sources
PubMed2002

Discriminant value of blood and urinary corticoids for the diagnosis of scrapie in live sheep.

The mean (sd) concentration of plasma 20beta-dihydrocortisol in 126 scrapie-affected sheep was 5-5 (7.0) ng/ml compared with 1.1 (0.7) ng/ml in 52 healthy sheep. The mean (sd) concentration of creatinine in the urine of 93 scrapie-affected sheep was 2.43 (1.56) microg/ml compared with 0.94 (0.86) pg/ml in 49 healthy sheep and 1.10 (0-95) pg/ml in 25 sheep with other diseases. These discriminant analyses carried out on healthy and scrapie-affected sheep showed that plasma 20beta-dihydrocortisol and urinary creatinine were the best predictors of the disease, and classified correctly 98 per cent of healthy sheep and 82 per cent of scrapie-affected sheep.

Animals↗
PubMed2001

Novel hyperbranched glycomimetics recognized by the human mannose receptor: quinic or shikimic acid derivatives as mannose bioisosteres.

The mannose receptor mediates the internalization of a wide range of molecules or microorganisms in a pattern recognition manner. Therefore, it represents an attractive entry for specific drug, gene, or antigen delivery to macrophages and dendritic cells. In an attempt to design novel effective synthetic mannose receptor ligands, quinic and shikimic acid were selected as putative mannose mimics on the basis of X-ray crystallographic data from the related rat mannose-binding lectin. As the mannose receptor preferentially binds to molecules displaying several sugar residues, fluorescein-labeled cluster quinic and shikimic acid derivatives with valencies of two to eight were synthesized. Their mannose receptor mediated uptake was assayed on monocyte-derived human dendritic cells by cytofluorimetric analysis. Mannose-receptor specificity was further assessed by competitive inhibition assays with mannan, by confocal microscopy analysis, and by expression of the mannose receptor in transfected Cos-1 cells. Constructs derived from both quinic and shikimic acid were efficiently recognized by the mannose receptor with an optimum affinity for the molecules with a valency of four. As a result, commercially available quinic and shikimic acids appear as stable mannose bioisosteres, which should prove valuable tools for specific cell delivery.

Animals↗
PubMed2001

Tartric acid-based linker for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes.

A novel linker, based on the anchoring of (+)-dimethyl 2,3-O-isopropylidene-D-tartrate to PEGA or PEG-PS solid supports, was developed for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes. Peptide elongation was performed using the 9-fluorenylmethoxycarbonyl/t-Bu chemistry. The peptide and the 1,2-diol were deprotected on the solid phase. Then, a periodic oxidation of the fully deprotected peptidyl-resin led to the simultaneous cleavage of the product from the solid support and to the generation of the alpha-oxo aldehyde moiety. The methodology allowed the distance between the alpha-oxo aldehyde and the peptide to be easily modulated. The C-terminal peptide alpha-oxo aldehydes synthesized in this study were found to be useful partners in hydrazone, thiazolidine, and oxime chemical ligations.

Aldehydes↗
PubMed2001

Synthesis of clustered glycoside-antigen conjugates by two one-pot, orthogonal, chemoselective ligation reactions: scope and limitations.

Major histocompatibility class II antigens have been bound to clustered glycosides for selective targeting of the dendritic cell mannose receptor. Di-, tetra-, and octavalent glycoside-antigen conjugates have been obtained after two, orthogonal, hydrazone/thioether ligations, performed by using thio derivatives of D-mannose, D-galactose, or D(-)-quinic acid, glyoxylyl (or hydrazino)-N-chloroacetylated lysinyl trees, and N-terminal hydrazino (or glyoxylyl) peptide antigens. Successful one-pot condensations have been developed to account for the nature of the antigens and the valency of the trees.

Amino Acid Sequence↗
PubMed2000

Major hypercorticism is an endocrine feature of ewes with naturally occurring scrapie.

The aim of this study was to identify the origin of scrapie-induced hypercortisolism. Cortisol and ACTH kinetics and production rate were measured in 14 ewes (6 healthy and 8 scrapie-affected). It was shown that cortisol plasma clearance remained unmodified but that cortisol production rate and plasma concentrations of free cortisol were increased by a factor of 5, whereas the total cortisol plasma concentrations were only doubled. The apparent discrepancy between adrenal secretion rate and the corresponding total cortisol plasma levels was attributable to the scrapie-induced lower corticosteroid-binding globulin (CBG) binding capacity, which altered the ratio of free-to-bound cortisol. The secretion rate of ACTH from diseased ewes was increased by a factor of 1.5, in comparison with healthy ewes, and 4 of the 8 scrapie-affected ewes exhibited a decreased response to a low dexamethasone suppression test. The administration of tetracosactide induced a 2-fold increase in the cortisol production in diseased ewes, compared with that of healthy ewes, but the pituitary sensitivity to ovine CRF was not modified by the prion disease. In conclusion, natural scrapie displays a syndrome of hypercorticism associated with increased ACTH secretion, hyperresponsiveness of the adrenals, and lower CBG binding capacity, which leads to overexposure to CBG-free cortisol.

Adrenal Glands↗
PubMed1998

Synthesis of the two monomethyl esters of the disaccharide 4-O-alpha-D-galacturonosyl-D-galacturonic acid and of precursors for the preparation of higher oligomers methyl uronated in definite sequences.

Methyl (alpha-D-galactopyranosyluronic acid)-(1-->4)-D-galactopyranuronate and methyl alpha-D-galactopyranosyl-uronate-(1-->4)-D-galactopyranuronic acid have been synthesized by coupling methyl (benzyl 2,3-di-O-benzyl-beta-D-galactopyranosid)uronate (3) or benzyl (benzyl 2,3-di-O-benzyl-beta-D-galactopyranosid)uronate (4) with benzyl (phenyl 2,3,4-tri-O-benzyl-1-thio-beta-D-galactopyranosid)uronate and methyl (phenyl 2,3,4-tri-O-benzyl-1-thio-beta-D-galactopyranosid)uronate, respectively, using N-iodosuccinimide and trifluoromethanesulphonic acid as promoters, followed by removal of the benzyl groups. The 4'-OH unprotected dimers benzyl (methyl 2,3-di-O-benzyl-alpha-D-galactopyranosyluronate)-(1-->4)-(benzyl 2,3-di-O-benzyl-beta-D-galactopyranosid)uronate and methyl (benzyl 2,3-di-O-benzyl-alpha-D-galactopyranosyluronate)-(1-->4)-(benzyl 2,3-di-O-benzyl-beta-D-galactopyranosid)uronate were prepared from methyl (phenyl 2,3-di-O-benzyl-1-thio-4-O-trimethylsilyl-beta-D-galactopyranosid) uronate and benzyl (phenyl 2,3-di-O-benzyl-1-thio-4-O-trimethylsilyl-beta-D-galactopyranosid) uronate and acceptors 4 or 3, respectively. These compounds have been designed to serve as precursors for the preparation of higher-membered D-galacturonic acid oligomers methyl esterified in definite positions.

Esters↗
PubMed1998

Melatonin and prolactin secretion profile in naturally occurring scrapie in ewe.

The 24 hr pattern of melatonin secretion was determined in scrapie-affected ewes during the clinical course of the disease. The melatonin response to a night interruption by a 1 hr period of illumination was also measured. Fourteen ewes (seven control and seven scrapie-affected ewes) were subjected to artificial short days (9L:15D). Four 24 hr blood sampling sessions separated by about 10 days were performed. Ewes were sacrificed when clinical signs had progressed to irreversible recumbency and the scrapie diagnosis was confirmed by histopathology. Plasma melatonin was assayed in all samples and prolactin was analysed in samples obtained during the second sampling session using RIA methods. The instantaneous amplitude of elevation of plasma melatonin concentrations was calculated for each ewe and each sampling session and the within-ewe repeatability of this parameter was evaluated. The within-ewe repeatability of instantaneous amplitude of melatonin secretion was apparently greater in control than in scrapie-affected ewes (72% vs. 39%). The light stimulus induced an abrupt decrease of night melatonin concentrations in all ewes. Prolactin secretion was not affected by the disease. It was concluded that the 24 hr pattern of melatonin secretion was maintained in scrapie-affected ewes. The retino-hypothalamic tract transducing light information remained functional in diseased ewes despite some evidence of histopathological changes of the pineal gland. The instability of melatonin secretion during the clinical course of scrapie could reflect a disturbance of pineal function. However, whether this effect exists or not, it could not be used to discriminate scrapie-affected ewes from control ones.

Animals↗
PubMed1996

Preparation and in vitro antibacterial activity of 9-O-glycosyloxime derivatives of erythromycin A, a new class of macrolide antibiotics.

9-O-Glycosyloxime derivatives of erythromycin A have been synthesized and their in vitro antibacterial activity compared with that of erythromycin A (1). This new class of macrolide antibiotics showed reduced antibacterial spectrum. However, some derivatives were as or more active than erythromycin A (1) against strains, responsible for respiratory track infections, such as Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Anti-Bacterial Agents↗
PubMed1990

Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega-3 fatty acids.

A "marginally deficient" essential fatty acid state was produced in male Sprague-Dawley rats by dietary supplementation with omega 3 fatty acids. Animals fed diets containing the highest amounts of these fatty acids (10% menhaden fish oil) demonstrated a 70% maximum decrease in the linoleic and arachidonic acid content of articular cartilage, a 30-40% decrease in cartilage hexosamine content, with little effect on hydroxyproline levels, and a 32% inhibition of proteoglycan synthesis. Histologic analysis revealed an occasional surface irregularity and localized depletion of Safranin O and toluidine blue staining of articular cartilage on the femoral heads from animals taking the higher doses. Electron microscopic analysis revealed a marked decrease in "dark-staining" chondrocytes relative to "light-staining" cells in all animals fed menhaden fish oil. The cartilaginous changes noted in this study reflect a causal relationship between chondrocyte metabolism and an altered unsaturated fatty acid content. The observed responses of chondrocytes to omega 3 fatty acids may be similar to those commonly associated with the development of early osteoarthrosis. It is not known whether similar changes are induced in other species, including humans, but these observations suggest that some caution must be taken in the long-term administration of menhaden fish oil or other omega 3 fatty acid-containing preparations in rheumatoid arthritis patients.

Animals↗
PubMed1980

Carcinogenicity of N-nitrosomethyl(2-oxopropyl)amine in Syrian hamsters.

7-Methylguanine was found in hydrolysates of liver and pancreas DNA from Syrian golden hamsters given a single dose of N-[1-14C]nitrosobis(2-oxopropyl)amine (BOP). This led us to examine the carcinogenicity of a potential methylating metabolite of BOP, N-nitrosomethyl(2-oxopropyl)amine (MOP). MOP was found to be a potent pancreatic carcinogen by either single or weekly s.c. injections. A single MOP treatment (25 mg/kg body weight) induced ductular adenomas and/or adenocarcinomas in 80% of the hamsters. A higher incidence of these neoplasms was found in 93% and 87% of animals receiving, respectively, 3.5 and 1.75 mg MOP per kg body weight weekly for life. However, the lower dose (0.87 mg/kg body weight) was less effective, resulting in a 33% tumor incidence. Compared with the known potent pancreatic carcinogen BOP, MOP seemed to have a greater affinity for the pancreas since considerably lower doses were required to induce similar incidences of equivalent pancreatic tumors. Like BOP, MOP caused tumors of the liver (7 to 100% incidence), kidneys (7 to 80% incidence), and vascular system (7 to 27% incidence). However, in contrast to BOP, which was noncarcinogenic to the upper respiratory tract, MOP-treated animals developed a high incidence of nasal cavity tumors (40% after a single treatment and 27 to 100% after weekly injections). The mutagenesis studies using hamster liver cell-mediated V79 cells confirmed the stronger effect of MOP compared to BOP. The assumption that MOP might be a proximate carcinogenic metabolite of BOP could not be substantiated by our methods for determining the in vivo and in vitro metabolites of BOP.

Adenocarcinoma↗
PubMed1979

In vivo studies in Syrian golden hamsters: a transplacental bioassay of ten nitrosamines.

The carcinogenic effects of low doses of 10 nitrosamines were determined in pregnant Syrian golden hamsters and their offspring. Compounds studied included dimethylnitrosamine, di-n-propylnitrosamine, di-n-butylnitrosamine, nitrosopiperidine, nitrosohexamethyleneimine, 2-dydroxypropyl-propyl-nitrosamine, 2-oxopropyl-propyl-nitrosamine, methylpropylnitrosamine, di(2-hydroxypropyl) nitrosamine, and 4-hydroxybutyl-butyl-nitrosamine. Tumor incidences of all organ systems were almost always higher and latencies shorter in the mothers than in the offspring. Exceptions occurred in the respiratory system in which several compounds induced a low incidence of tumors in the offspring but none in the mothers. Fetal susceptibility appeared greatest toward the end of gestation. For purposes of bioassay, transplacental exposure was less efficient than conventional adult treatment.

Animals↗
PubMed1978

Carcinogenicity and metabolic profiles of 6-substituted benzo[a]pyrene derivatives on mouse skin.

The ability was tested of appropriate substituents of benzo[a]pyrene (BP) at C-6 to decrease or suppress the carcinogenic activity for these BP derivatives relative to the parent compound. 8-week-old female Swiss mice in 9 groups of 30 were treated on the back with 0.2 mumol of compound in acetone 4 times weekly for 20 weeks. The following compounds were administered: BP, 6-methylbenzo[a]pyrene (BP-6-CH3), 6-hydroxymethylbenzo[a]pyrene (BP-6-CH2OH), benzo[a]pyrene-6-carboxaldehyde (BP-6-CHO), benzo[a]pyrene-6-carboxylic acid, 6-methoxybenzo[a]pyrene, 6-acetoxybenzo[a]pyrene, 6-bromobenzo[a]pyrene, and 6-iodobenzo[a]pyrene. Two additional groups received BP or BP-6-CH3 twice weekly for 20 weeks at a total dose 25% of that above. In addition, the metabolism of selected 6-substituted BP derivatives was studied, using mouse skin homogenates in vitro and mouse skin in vivo. Only four compounds were carcinogenic; the order of potency was BP greater than BP-6-CH3 greater than BP-6-CH2OH and BP-6-CHO. The difference in carcinogenicity between BP-6-CH2OH and BP-6-CHO could not be assessed by this experiment. In a further tumorigenesis experiment the carcinogenicity of BP-6-CH2OH was compared to that of BP-6 CHO, BP-6-CH3 and 6-hydroxymethylbenzo[a]pyrere sulfate ester (BP-6-CH2OSO3Na) on mouse skin. 9-week-old female Swiss mice in groups of 28 were treated at three dose levels with 0.8, 0.2 and 0.05 mumol of compounds in dioxane--dimethyl sulfoxide (75 : 25) twice weekly for 40 weeks. After 40 experimental weeks BP-6-CH2OSO3Na proved to be a more potent carcinogen than BP-6-CH2OH, which, in turn was more active than BP-6-CHO. The greater carcinogenicity of BP-6-CH3 relative to BP-6-CH2OH and BP-6-CHO is confirmed, suggesting that BP-6-CH2OH is not a proximate carcinogenic metabolite for BP-6-CH3. Since BP-6-CHO is a weaker carcinogen than BP-6-CH2OH and is efficiently reduced metabolically to BP-6-CH2OH, the latter compound may be a common proximal carcinogenic metabolite. The stronger potency of BP-6-CH2OSO3Na, compared to its alcohol, suggests that an ester of BP-6-CH2OH might be the ultimate alkylating compound reacting with cellular nucleophiles.

Animals↗
PubMed1978

Carcinogenicity and metabolic profiles of 3-methylcholanthrene oxygenated derivatives at the 1 and 2 positions.

Trapping of 3-methylcholanthrene (MC) radical cation by nucleophilic compounds occurs specifically at the 1-carbon atom. With the purpose of providing more evidence for the hypothesis that the critical mechanism of activation of MC is one-electron oxidation, the carcinogenicity of MC was compared to that of 1-hydroxy-3-methylcholanthrene (MC-1-OH), 3-methylcholanthrene-1-one (MC-1-one), 2-hydroxy-3-methylcholanthrene (MC-2-OH), 3-methylcholanthrene-2-one (MC-2-one) and 3-methylcholanthrylene (MCL) by repeated application on mouse skin. Seven-week-old female Swiss mice in 6 groups of 30 were treated on the back with 0.2 mumol of compound in acetone twice weekly for 20 weeks. In addition, the metabolism of MC and its derivatives was studied using mouse skin homogenates. The compounds tested were classified according to carcinogenicity in 4 groups: MC and MC-2-OH, the strongest carcinogens; MC-2-one and MCL, weaker than MC and MC-2-OH; MC-1-OH, the weakest carcinogen; and MC-1-one, non-carcinogenic. These results support the hypothesis that one-electron oxidation for MC, MC-2-OH and MC-1-one might be the critical mechanism of carcinogenic activation, with C-1 the binding site to cellular nucleophiles. The carcinogenic effect of MC-1-OH is speculated to be the formation of an ester bearing a good leaving group, which might be the ultimate alkylating compound in the in vivo reaction. The lack of carcinogenic activity for MC-1-one may be attributed to absence of nucleophilic trapping at C-1 via the radical cation pathway as well as the inability of mouse skin to reduce MC-1-one to the carcinogenic MC-1-OH.

Animals↗
PubMed1978

Carcinogenic effect of subcutaneously administered N-nitroso-2,6-dimethylmorpholine in Syrian golden hamsters.

N-Nitroso-2,6-dimethylmorpholine (DMNM) was examined in Syrian golden hamsters in a comparative study of N-N-dipropylnitrosamine (DPN) metabolites. DMNM was administered sc, and the results were compared with those of a previous study in which the compound was given intragastrically. DMNM was more toxic when administered sc, and the respiratory tract was the main target organ (with a 100% tumor incidence). With an sc administration, neoplasms occurred earlier in the hamsters than with an intragastric administration, and fewer tumors of the pancreas and biliary tract were found. However, neoplasms of the upper digestive tract and vagina were seen only with sc treatment. These studies indicated the importance of the treatment route but did not substantiate the role of common metabolites, such as DMNM, formed by beta-oxidation from DPN, with regard to induction of a given tumor type.

Animals↗
PubMed1977

The effect of 1-methoxypropylpropylnitrosamine in Syrian golden hamsters.

The carcinogenicity of the alpha-dipropylnitrosamine (DPN) methyl-ether, 1-methoxypropylpropylnitrosamine (1-MPPN), was investigated in Syrian hamsters for comparison with the effect of the alpha-DPN acetylester, 1-acetoxypropylpropylnitrosamine (1-APPN). It seemed possible that 1-MPPN, 1-APPN and DPN could form a common intermediate. However, contrary to the effect of 1-APPN, no tumors were found at the injection site after subcutaneous 1-MPPN treatment. The main target organ for 1-MPPN was the respiratory tract (as with DPN) and the lungs were greatly affected. In addition, pharyngeal and forestomach tumors occurred, and these were not observed after DPN administration. The results of 1-MPPN treatment, relative to DPN and 1-APPN, are discussed.

Animals↗
PubMed1977

Carcinogenicity of 1-oxopropylpropylnitrosamine (N-nitroso-N-propyl-proprionamide) in Syrian hamsters.

The effect of 1-oxopropylpropylnitrosamine (1-OPPN) was examined in Syrian hamsters. The subcutaneous (s.c.) LD50 was 308 mg/kg b.w. Animals treated s.c. once with a high dose of 1-OPPN had subcutaneous sarcomas and vaginal papillomas. Weekly s.c. injections for life led to high incidences of sarcomas at the injection site. In addition, 1-OPPN had a systemic effect. Neoplasms developed in the nasal cavity, larynx, trachea, lungs forestomach, and vagina. The results are discussed in connection with those found with other DPN derivatives substituted in the alpha-position.

Animals↗