A monoclonal antibody to the human platelet glycoprotein IIb/IIIa complex induces platelet activation

The platelet glycoprotein (GP) IIb/IIIa complex functions as the receptor for fibrinogen on activated platelets. The effects of two anti-GPIIb/IIIa monoclonal antibodies on platelet function were studied. These antibodies, 6C9 and C17, recognized different epitopes, which were exclusively present on the undissociated GPIIb/IIIa complex. Whereas C17 inhibited the binding of fibrinogen to platelets and platelet aggregation induced by adenosine diphosphate (ADP) or collagen, 6C9 caused irreversible aggregation of platelets, both in the presence and absence of extracellular fibrinogen. When incubated with unstirred (non-aggregating) platelets, 6C9 induced release of alpha and dense granule-constituents as well as binding of 125I-fibrinogen to platelets. The latter was evidently mediated in part by platelet-derived ADP, since it was inhibited to a large extent by apyrase, the ADP-hydrolyzing enzyme. F(ab')2 fragments of 6C9 did not induce platelet-release reactions but caused (slow) aggregation of platelets in the presence of extracellular fibrinogen. These results indicate that binding of an antibody to a specific site on the platelet GPIIb/IIIa complex may cause fibrinogen-mediated aggregation. The Fc part of the platelet-bound antibody appears to be involved in the induction of platelet release.     

Different Regiospecificity in the Hydroxylation of the Antidepressant Desmethylimipramine Between Rat Brain and Liver

Abstract: Incubation of the tricyclic antidepressant desmethylimpramine (DMI) with rat liver or brain microsomes in the presence of NADPH or t-butyl-hydroperoxide (TBH) revealed different regiospecificities in the hydroxylation reactions between the tissues. In brain preparations 10-OH-DMI was formed in reactions supported by NADPH or TBH, whereas in the latter case also an unidentified metabolite could be detected. Inclusion of exogenous NADPH-cytochrome P450 reductase in the brain preparations caused a 10-fold higher rate of 10-hydroxylation but no 2-OH-DMI could be detected. By contrast, liver microsomal preparations in the presence of NADPH catalyzed formation of both 2- and 10-OH-DMI, whereas only 10-OH-DMI was formed in TBH-supported reactions. The results indicate that antidepressant drugs can be metabolized in brain with different stereospecificity as compared to liver.     

Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR(-) rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR(-) rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR- rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR- rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.     

Behavioural Problems in Children with Infantile Hydrocephalus

The occurrence of behavioural problems in a population-based series of children with infantile hydrocephalus (non-spina bifida) was analysed, using parent questionnaires. Children with both infantile hydrocephalus and mental retardation had significantly more behavioural problems compared with those with no mental retardation and controls. Inattentiveness and hyperactivity were particularly typical. No differences were found between children with infantile hydrocephalus and no mental retardation and the control group.     

Holographic analysis of displacement of the bovine cornea after disruption of intact structures]

Displacement of the surface of the cornea of bovine eyes after disruption of intact structures was investigated by means of holographic interferometry. Double-T-incisions of different depths were made with a diamond knife. Starting at about 80% of the incision depth there is a change in the central holographic interference fringe pattern. These effects can be clearly demonstrated by means of double-exposure holographic interferometry and real-time holographic interferometry. The stability of an existing corneal scar was analyzed by double-exposure holographic interferometry. The region of the scar showed a higher density of holographic interference fringes compared with the non-affected corneal areas, indicating a higher degree of elasticity. All eyes were investigated at an intraocular pressure of 1340 Pa (about 10 mmHg) and an intraocular pressure change of 10 Pa and 20 Pa. Further potential ophthalmic applications of holographic interferometry are discussed.     

Growth of Hodgkin cell lines in severely combined immunodeficient mice.

No animal model exists for the in vivo growth of Hodgkin's-lymphoma-derived cells. Neither unmanipulated Hodgkin's-disease(HD)-derived cell lines nor primary biopsy tissue could be grown in nude mice. Since the severe combined immunodeficient (SCID) mouse has been reported to be a better recipient for transplanted human lymphatic tissue than the nude mouse, we tested whether SCID mice provide suitable conditions for the in vivo growth of HD cell lines. Tumorigenicity of HD cells was tested in untreated and pre-treated SCID mice and in another combined immunodeficient mouse strain, beige/nude/X-linked immunodeficient (BNX) mouse. SCID mice supported in vivo growth of the 6 HD cell lines tested (L428, L540, L591, DEV, HD-LM2, KM-H2). Only one of the 6 lines (DEV) was tumorigenic in BNX mice. No HD cell line proliferated in T-cell-deficient nude mice. Thus, in vivo growth of HD cell lines appeared to be related to the degree of host immunodeficiency. Additional growth supportive treatments such as fibrosarcoma co-transplantation, intraperitoneal mineral oil injection or immunosuppressive pre-treatment (anti-asialo-GMI-antibody injection) permitted growth of 3 additional HD cell lines in BNX mice. The immunophenotype and karyotype of explanted graft cells were identical to the original cell lines. Our experiments describe an effective and reproducible xenograft model for growth of Hodgkin's-disease-derived cell lines. This may be of value for elucidating the growth characteristics of Hodgkin's-lymphoma-derived cells as well as for testing new therapeutic regimens.     

Implantation of antibiotic-releasing carriers and in situ reconstruction for treatment of mycotic aneurysm.

Four patients with mycotic aneurysm of the extracranial carotid artery, the innominate artery, the ascending aorta, and the infrarenal aorta were treated with local implantation of antibiotic-releasing carriers after resection of the aneurysm, excision of all infected tissue, and in situ reconstruction by prosthetic graft replacement in two patients and patch plasty in two patients. The patient with a mycotic aneurysm of the ascending aorta was operated on again 1 month after the first operation because of a second mycotic aneurysm located on the aortic arch. No early or late signs of recurrent infection were seen on clinical and laboratory postoperative follow-up done between 9 and 16 months or on duplex scan or computed tomography done at these times. Implantation of antibiotic-releasing carriers after débridement of all infected tissue and in situ reconstruction for treatment of mycotic aneurysm was performed successfully in four patients with this life-threatening condition.