Monoclonal antibody against sialylated Lewis(a) antigen

We isolated hybridoma cells, which secreted monoclonal antibody (MAb) 121 SLE, an IgM showing the following reactivities: (1) by immunodiffusion, MAb 121 SLE and MAb NS 19-9 (a monoclonal antibody directed against a sialylated Lewis(a) antigen called CA 19-9) showed an identical precipitin line with mucin preparation containing this CA 19-9; (2) by immunoradiometric assay, MAb 121 SLE totally inhibited fixation of radiolabelled MAb NS 19-9; (3) by immunoperoxidase, MAb 121 SLE stained the normal gastrointestinal mucosa of Le-positive individuals exclusively, and this staining disappeared after neuraminidase treatment, as observed using MAb NS 19-9. However, the pattern of the staining obtained with MAb 121 SLE differed slightly from that given by MAb 19-9 on the different positive areas of the gastrointestinal mucosae. These differences principally concerned the number of positive epithelial cells and the intensity of their staining; (4) moreover, antibodies against idiotype determinant of NS 19-9 antibody did not react with the antibody 121 SLE. We concluded that MAb 121 SLE is different from the MAb NS 19-9. However, both these antibodies were associated with the same molecular sialylated Lewis(a) structure.     

Naphthalimido derivatives as antifolate thymidylate synthase inhibitors

A new series of N-(substituted)benzyl-1,8-naphthalimides 4, structurally related to the previously reported thymidylate synthase (TS) inhibitor naphthaleins 3, were synthesized and compounds tested for their inhibition of several species of TS. Moreover, their in vitro cytotoxicity together with antimycotic and antibacterial properties were assayed. While no activity was detected in the antibacterial tests, the m-nitro (4ae) and the p-nitro (4af) derivatives were found able to partially inhibit TS at low micromolar concentrations. Introduction of nitro or (substituted)-amino groups in position 4 of the naphthalic ring always led to less active compounds.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Extra-intracranial shunts by venous grafts interposed on the carotid system

Patients with occlusive arterial diseases, tumors invading the vascular structures of the skull base or giant aneurysms may benefit from an EICB. Most of the time this can be achieved using a scalp artery. But in cases of a thrombotic ECA, excessively short or thin scalp branches or destruction of those by prior cranial surgery, an interposed venous graft is needed. In the author's series, which consists of 16 patients, the bypass was performed for ICA occlusive diseases in 5, before complete removal of cavernous sinus tumours in 4 and prior to cervical internal carotid ligation for giant aneurysms in 7. The grafts were always harvested from the internal saphenous vein. The proximal site of implantation was CCA (2 cases), ECA (6 cases), ICA (1 case), superior thyroid A (2 cases)--i.e. 11 long grafts--and the trunk of the occipital A--i.e. short grafts in 5 cases. In this series, there was no mortality and no morbidity related to revascularization. The early patency rate, checked with arteriography, was 62.5% (10 cases) and the late one 56.2% (9 cases). Causes of failure, partially related to technical difficulties in 2 cases, were almost always due to an insufficient extra-intracranial pressure gradient (4 cases). Excepted in one case, there was no correlation between patency and the use or not of anti-aggregant and/or heparin. Literature data are summarized and discussed. They all confirm the importance--besides the absence of technical errors--of a sufficient extra-intracranial gradient for obtaining a good patency rate.     

Epidermal growth factor receptor regulates normal urothelial regeneration

Members of the epidermal growth factor (EGF) family and their receptors are involved in many cellular processes, including proliferation, migration, and differentiation. We have previously reported that these growth factors are expressed and have specific regulatory functions in an organ-like culture model of normal human urothelial cells. Here, we used this model to investigate the involvement of EGF receptor (EGFR) in human urothelial regeneration. Three 4-mm-diameter damaged areas were made in confluent normal human urothelial cell cultures with a biopsy punch. Regeneration was measured, on fixed stained cultures, with an image analyzer, at 4, 24, and 48 hours after injury. Cell proliferation was assessed by 5-bromo-2-deoxyuridine incorporation. To identify EGF family factors potentially involved in the healing process, we studied the effect of these factors on damaged confluent cultures and the level of expression of mRNAs extracted from these cultures. EGFR inhibition of the proliferation and migration of urothelial cells was tested with (1). a specific tyrosine kinase inhibitor (AG1478) and (2). a blocking anti-EGFR antibody (LA22). Exogenously added amphiregulin, EGF, transforming growth factor-alpha and heparin-binding EGF (HB-EGF) stimulated urothelial regeneration. The damaged areas were repaired by regrowth within 48 hours. Both AG1478 and LA22 inhibited the repair (by 50% and 30%, respectively), as well as proliferation and migration. This regeneration was accompanied by increased HB-EGF mRNA expression in cultures of cells from four of six subjects, but no corresponding change in EGFR protein level was observed. These results indicate that the EGFR signaling pathway is involved in urothelial regeneration. Our data support an autocrine role of HB-EGF in this process and suggest that the EGFR pathway is a potential therapeutic target for modulating urothelial cell proliferation.     

Critical ovarian hyperstimulation syndrome in a coasted in-vitro fertilization patient

We report an instance of critical ovarian hyperstimulation syndrome in a highly responsive in-vitro fertilization patient despite the preventive measure of a 4 day 'coast' interval during which no gonadotrophins were administered while gonadotrophin-releasing hormone agonist therapy continued until serum oestradiol concentrations fell below 3000 pg/ml.      

High risk for unbalanced segregation of some reciprocal translocations: A large pedigree containing distal 4q trisomy from t(4;7)(q28;p22)

We report on a familial t(4;7)(q28;p22) with 2:2 adjacent‐1 unbalanced segregation producing duplication of 4q28→qter in multiple offspring. Within the large four‐generation pedigree, a carrier had a reproductive outcome that was approximately equal for 1) the balanced translocation, 2) normal chromosomes, and 3) viable 4q trisomy or pregnancy loss. The three individuals with chromosomal confirmation of trisomy 4q28→qter (comprising approximately 1.8% of the haploid autosomal length) had similar mental and developmental retardation, hypotonia, restricted speech, seizures, and facial anomalies but no cardiac, renal, or skeletal anomalies. It is suggested that these latter severe malformations, associated with the classic 4q2 to 3 group of anomalies, were from an imbalance outside 4q28→qter and were not necessarily related to the relatively large size of the trisomic segment. Multiple different chromosomes are reported to be rearranged with 4q in the production of distal 4q trisomy. The incidence of 4q rearrangement remains unexplained, but once it is present in a family, viability of a large trisomy in 4q seems to explain the number of affected individuals reported. © 2001 Wiley‐Liss, Inc.