Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile.

Numerous reports have highlighted the central role of regulatory T cells in long-term allograft tolerance, but few studies have investigated the B-cell aspect. We analyzed the B-cell response in a rat model of long-term cardiac allograft tolerance induced by a short-term immunosuppression. We observed that tolerated allografts are infiltrated by numerous B cells organized in germinal centers that are strongly regulated in their IgG alloantibody response. Moreover, alloantibodies from tolerant recipients exhibit a deviation toward a Th2 isotype and do not activate in vitro donor-type endothelial cells in a pro-inflammatory way but maintained expression of cytoprotective molecules. Interestingly, this inhibition of the B-cell response is characterized by the progressive accumulation in the graft and in the blood of B cells blocked at the IgM to IgG switch recombination process and overexpressing BANK-1 and the inhibitory receptor Fcgr2b. Importantly, B cells from tolerant recipients are able to transfer allograft tolerance. Taken together, these results demonstrate a strong regulation of the alloantibody response in tolerant recipients and the accumulation of B cells exhibiting an inhibited and regulatory profile. These mechanisms of regulation of the B-cell response could be instrumental to develop new strategies to promote tolerance.

Structure-activity relationships in platelet-activating factor (PAF). 7. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors. Synthesis and PAF-antagonistic activity.

2,5-Disubstituted tetrahydrofuran derivatives present a dual activity: they are effective PAF antagonists and acetylcholinesterase inhibitors. In this paper their synthesis and in vitro PAF-antagonistic effect are described. Introduction in position 2 of a long aliphatic chain bearing a carbamate group and a pyridinium moiety appears to be required for potent platelet aggregation inhibition. Substitution in position 5, or cis-trans isomerism do not induce any increase in activity. No correlation can be established between global lipophilicity and the anti-aggregant activity. Structural requirements for a potent activity are discussed and are consistent with the hypothesis we have proposed for the PAF receptor considered as a multipolarized structure with alternants of electropositive, electronegative and hydrophobic areas.

Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < sigma f < 7) are the main features required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity.

The murG gene of Escherichia coli codes for the UDP-N-acetylglucosamine: N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase involved in the membrane steps of peptidoglycan synthesis.

Physiological properties of the murG gene product of Escherichia coli were investigated. The inactivation of the murG gene rapidly inhibits peptidoglycan synthesis in exponentially growing cells. As a result, various alterations of cell shape are observed, and cell lysis finally occurs when the peptidoglycan content is 40% lower than that of normally growing cells. Analysis of the pools of peptidoglycan precursors reveals the concomitant accumulation of UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylmuramyl-pentapeptide (UDP-MurNAc-pentapeptide) and, to a lesser extent, that of undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide (lipid intermediate I), indicating that inhibition of peptidoglycan synthesis occurs after formation of the cytoplasmic precursors. The relative depletion of the second lipid intermediate, undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)GlcNAc, shows that inactivation of the murG gene product does not prevent the formation of lipid intermediate I but inhibits the next reaction in which GlcNAc is transferred to lipid intermediate I. In vitro assays for phospho-MurNAc-pentapeptide translocase and N-acetylglucosaminyl transferase activities finally confirm the identification of the murG gene product as the transferase that catalyzes the conversion of lipid intermediate I to lipid intermediate II in the peptidoglycan synthesis pathway. Plasmids allowing for a high overproduction of the transferase and the determination of its N-terminal amino acid sequence were constructed. In cell fractionation experiments, the transferase is essentially associated with membranes when it is recovered.

Roxithromycin in skin and soft tissue infections.

In a double blind randomised investigation in 76 patients, roxithromycin (150 mg bd) and doxycycline (200 mg once daily) were compared in two groups of patients who were well-matched for age, sex, body weight, diagnosis, duration and severity of disease and associated pathological conditions, with infected skin conditions. Clinical effectiveness was 92% for roxithromycin and 82% for doxycycline, and bacteriological effectiveness also 92% and 82% respectively, the differences not being statistically significant.

Linear cutaneous neuromas (dermatoneurie en stries): a limited phakomatosis with striated pigmentation corresponding to cutaneous hyperneury (featuring multiple endocrine neoplasia syndrome?).

A 60-year-old woman developed a progressive linear pigmentation on the trunk. Skin biopsy demonstrated an increase in the number and size of neural fibers in the dermis. Clinical and paraclinical investigations of this unusual disease showed findings similar to the hereditary type of Sipple syndrome (multiple endocrine neoplasia syndrome, Type 2b). Such findings as Marfanoid habitus, abnormal electromyography and hypertrophy of the corneal nerves suggest that our patient's disease and Sipple syndrome are identical. However, such other symptoms of Sipple syndrome as presence of endocrine tumors are absent. Questions of long-term prognosis and physiopathogenicity are raised, since no nerve growth factor was detected in this patient. The name of linear cutaneous neuromas is suggested for the patient's lesions, and a possible association with the pigmentation and cutaneous neuromas of the MEN 2b syndrome.

Thaumetopoein: an urticating protein from the hairs and integument of the pine processionary caterpillar (Thaumetopoea pityocampa Schiff., Lepidoptera, Thaumetopoeidae).

Hairs of the Thaumetopoea pityocampa caterpillar (Lepidoptera) cause a cutaneous reaction in man and animals. The irritating fraction extracted from hairs contains soluble proteins which were separated by various electrophoretic and immunoelectrophoretic techniques. Some of these proteins are present also in cuticle and haemolymph. One protein of 28,000 mol. wt is hair specific and caused a reaction in pig skin identical to that produced by hair extract. It is therefore an urticating protein which we have named thaumetopoein. This protein is formed of two subunits of molecular weights 13,000 and 15,000. It is present in large quantities in the glands producing urticating hairs.

[Cerebral lesions in a case of Degos' disease]. / Lésions cérébrales dans un cas de maladie de Degos.

The central nervous system may be involved in Degos disease, but neuropathologic observations are still few. We report a typical case with cerebral involvement. The diagnosis was suggested by the characteristic skin lesions and vascular damage. In the central nervous system, occlusive changes of small arteries were responsible for areas of ischaemic necrosis. These foci of infarction were of varying size, age and distribution. Intestinal lesions were discrete and death was due to several cerebral infarcts.

Bowenoid papulosis. Demonstration of human papillomavirus (HPV) with anti-HPV immune serum.

Two cases of bowenoid papulosis (BP) occurred. The presence of human papillomavirus was demonstrated in one patient. In the other patient, condyloma acuminatum developed after initial spontaneous improvement in his lesions. The discovery of a possible oncogenic virus in BP and the epidemiologic behavior of carcinoma in situ and multicentric carcinomas suggest the need for a very careful follow-up evaluation of such lesions. Bowenoid papulosis may be a chronic dysplasia with a variable long-term prognosis linked to a cocarcinogenic factor.

[French Guiana "papillonite" (lepidopterism). Clinical and epidemiological study]. / La papillonite de Guyane Française. Etude clinique et épidémiologique.

Clinical studies by Dr R. Pradinaud (Cayenne) has given prominence to the symptoms of "papillonite": its primary and secondary cutaneous lesions, their localisation and evolution as well as its accompanying symptoms such as respiratory pathology. Epidemiologic survey shows a parallelism between the occurrence of papillonite and the presence of the moth Hylesia urticans. The urticant apparatus of this moth was studied with the scanning electron microscope. "Arrow" (fléchettes) were found and they more or less resemble the urticant apparatus of Thaumetopoea pityocampa Schiff caterpillar. The mechanism of action has been studied in the animal and in humans. Extracts prepared from the "arrows" have been rested in vivo guinea-pigs (bleu Evans, Liacopoulos et al.). The findings seem to incriminate an histamino-liberation.