[Karl Landsteiner (1868­1943) and the discovery of blood groups]. / Karl Landsteiner (1868­1943) et la découverte des groupes sanguins.

Karl Landsteiner, a Viennese M.D. and pathologist, discovered in the years 1900­1901 the first human blood groups, ABO groups. Furthermore, he made numerous significant contributions to various fields of the biomedical science. In this paper I report on his life and work in Vienna, The Hague and New York.

[Seroprevalence of hepatitis C antibodies among blood donors. Study of second generation ELISA and RIBA tests and surrogate markers]. / Séroprévalence des anticorps contre le virus de l'hépatite c chez les donneurs de sang. Etude des tests ELISA et RIBA de 2e génération et des marqueurs indirects.

Between March and November 1991, prevalence of hepatitis C antibodies was evaluated in 60,960 blood donors from the North-East of France. Using a second generation ELISA, 424 donors (0.69%) were reactive, with no significant difference between males (0.69%) and females (0.70%). Among these 424 donors, respectively 137 (32.3%), 86 (20.3%) and 201 (47.4%) were reactive, indeterminate or nonreactive by a second generation RIBA (RIBA-2) (Recombinant Immunoblot Assay). Donors with a high ELISA ratio (> or = 4) were significantly more likely to have a reactive RIBA-2. Of the 1906 donors with anti-HBc positivity (3.12%), 44 had a reactive ELISA; of these, respectively 27, 12 and 5 had a reactive, indeterminate and nonreactive RIBA. Of the 1201 donors (1.97%) with increased serum ALAT (alanine-amino-transferase) levels (> or = 2N), 42 had a positive ELISA; of these, respectively 35, 2 and 5 had a reactive, indeterminate and nonreactive RIBA. Of the 54 donors with both indirect markers, nine had a reactive ELISA; the same nine donors had a reactive RIBA. These data show that donors with both surrogate markers and a reactive ELISA are very likely to have a positive RIBA. Seventy-seven (18.16%) of the 424 donors with a reactive ELISA had at least one surrogate marker; 67 of these donors (30.04%) were among the 223 donors with a reactive ELISA and a reactive or indeterminate RIBA.

Biliary elimination and pharmacokinetics of vinorelbine in micropigs.

The biliary elimination and pharmacokinetics of vinorelbine (NVB) were investigated in five conscious micropigs provided with a double-terminal choledocal fistula allowing the collection and reinstillation of bile. After the i.v. administration of NVB (0.5 mg/kg), serum and bile samples were collected over a 48-h period. The concentrations of NVB were measured by high-performance liquid chromatography. The serum concentrations decreased rapidly from a maximal value of 208.6 ng/ml (SD, 111.7 ng/ml). The mean half-life was 10.9 h (SD, 8.6 h) and the mean AUC0-48 h was 292.8 ng ml-1 h (SD, 79.4 ng ml-1 h). The bile concentrations were high, amounting to 16.0 micrograms/ml (range, 5.4-27.7 micrograms/ml). The 0- to 48-h biliary excretion of unchanged NVB accounted for 25.8% (SD, 5.7%) of the injected dose, with 21.5% (SD, 4.0%) being eliminated during the 0- to 8-h period. Desacetyl-NVB was found in an inconstant manner and in very low amounts in bile samples. In addition, no glucuronide of NVB could be detected. Thus, in the micropig, biliary excretion represents an important route of elimination for NVB.

The in vitro effect of amodiaquine on bone marrow granulocyte-macrophage progenitor cells from normal subjects.

Amodiaquine is used for antimalarial prophylaxis and treatment and has been associated with neutropenia and agranulocytosis in man. The effect of the drug on the in vitro growth of bone marrow human myeloid progenitor cells (GM-CFU) was tested using the soft agar culture technique: 42 haematologically normal subjects were studied and it was found that amodiaquine, at concentrations tested in vitro (0.005, 0.05 and 0.5 micrograms.ml-1), had no quantitative effect on the colony and cluster growth. Our results argue against direct toxicity of the drug on GM-CFU. Therefore, in cases of amodiaquine-associated neutropenia, alternative mechanisms should be considered: a abnormally sensitive GM-CFU; b) toxic effect of metabolites such as desethyl-amodiaquine; c) immune-mediated toxicity.

[Serum antibodies to hepatitis C virus: analysis of risk factors of seropositivity in a population of blood donors in metropolitan France]. / Anticorps sériques contre le virus de l'hépatite C: analyse des facteurs de risque de séropositivité dans une population de donneurs de sang de France métropolitaine. Le Groupe "Hepatites Virales" de la Société Nationale de Transfusion Sanguine.

Risk factors were analyzed in a group of 117 blood donors seropositive for hepatitis C virus antibody. One risk factor, at least, was found in 63 (53.8%) subjects. Frequently encountered risk factors were 1) travels in developing countries (31/117); 2) blood transfusions (20/117); 3) health care works (10/117); 4) intravenous drug addiction (8/117); 5) homosexual or multiple heterosexual contacts (3/67). Our study emphasizes the high percutaneous transmission of hepatitis C in contrast with the low sexual transmission. No risk factor could be found in 54 (46.2%) of the 117 seropositive subjects: the route of transmission in these cases is an intriguing issue which certainly deserves further epidemiological investigations.

[Serum antibodies against hepatitis C: study of 4,100 blood donors from the northeast of France]. / Anticorps sériques contre le virus de l'hépatite C: étude de 4,100 donneurs de sang du nord-est de la France.

Between June 1989 and February 1990 the prevalence of antibodies to hepatitis C virus (anti-HCV) was studied in blood donations from 4,100 donors tested in north east France. 37 samples were found reactive for anti-HCV (prevalence of anti-HCV: 0.90%) without any significant difference in sex (males: 0.94%; females: 0.87%) and age distributions. 178 (4.34%) of the 4,100 donors were found anti-HBc positive, 5 of these donors being anti-HCV positive (13.51% of all anti-HCV positive donors). 52 donors (1.27%) had raised alanine aminotransferase (ALT) levels (greater than or equal to 2 N: 2 times the M +/- 2 SD value): 3 were found anti-HCV positive (8.11% of all anti-HCV positive donors). Association of the 2 surrogate markers is poorly sensitive since it detects only 8 (21.62%; males: 4, females: 4) of all anti-HCV positive donors. Furthermore, it appears weekly specific since it discards 230 blood samples of which 222 (96.52%) were anti-HCV negative. The 2 surrogate markers are complementary to one another and none of the anti-HCV positive donors had both anti-HBc antibodies and raised ALT. The mean ALT level is significantly higher in anti-HCV positive donors as compared to seronegative (M +/- 1 SD: 51 +/- 82 U/l versus 24 +/- 17 U/l). In anti-HCV positive donors, a marginal (r = 0.34) though statistically significant (p less than 0.05) positive correlation was found between ALT level and anti-HCV ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

[Familial hypobetalipoproteinemia. Familial study of 4 cases]. / L'hypobêtalipoprotéinémie familiale. Etude familiale de 4 cas.

A familial study of four cases with hypobetalipoproteinemia is reported. Three members are heterozygous and one is homozygous. This congenital fat malabsorption in homozygous state is commonly associated with an absence of serum apoprotein B and LDL. Neuromuscular and ophthalmological signs are absent in this case. The major role of upper digestive endoscopy in the diagnostic procedure is emphasized. Histochemical and immunoenzymatic stains of enterocytes and intestinal organ culture show defective synthesis apo B in the homozygous patient. Studies of DNA polymorphism in the homozygous patient have shown that the apo B gene doesn't certain major insertions or deletions. These results are discussed.

[Epidemiologic study of HIV serology in blood donors from 5 departments in northeastern France (1985-1989)]. / Etude épidémiologique de la sérologie VIH des donneurs de sang dans cinq départements du nord-est de la France (1985-1989).

Between July 1985 and June 1989, the prevalence of HIV antibody was studied in 503,019 blood donations tested in 5 administrative areas ("departments") of north east France: 91 seropositive donations (donors) were detected (prevalence: 0.18%). The prevalence was 0.41% in 1985, 0.22% in 1986, 0.14% in 1987, 0.10% in 1988 and 0.11% in 1989: in each year, it was found lower than the national prevalence. 14 (15.4%) of the 91 seropositive donors were females, and the prevalences of HIV antibody in blood donations from female and male donors were 0.07% and 0.26% respectively. All seropositive donors were younger than 50 and 83 (91.2%) younger than 40. The prevalence of HIV antibody was higher in blood units at first donation (occasional donors) as compared with blood units collected from regular donors (0.60% versus 0.09%). The prevalence of HIV antibody was higher in blood donations from military donors as compared with donations from civilian donors (0.49% versus 0.07% in 1987, 1988 and 1989). Most seropositive military donors were young male recruits of the national armed forces conscription system. We believe that these recruits are subjects with risk factors which must be taken into account for the determination of national blood supply policies.

Amodiaquine-induced agranulocytosis: report of a case with in vitro studies of granulocyte-macrophage progenitor cells.

We report a case of amodiaquine-induced agranulocytosis in a 60-year-old woman. Four months after the agranulocytosis episode we investigated the effect of the drug using in vitro agar culture techniques. Amodiaquine at increasing concentrations (0.005, 0.05 and 0.5 microgram/ml) displayed an inhibitory effect, probably dose-dependent, on the growth of the patient's bone marrow GM-CFU colonies in the absence of autologous serum. In contrast, no effect was found on the colony and cluster growth of bone marrow samples from 13 healthy controls. Though it has been shown in several cases that amodiaquine-induced agranulocytosis occurs via immune-mediated mechanisms, our data are in support of a direct toxic effect of the drug on abnormally sensitive myeloid progenitor cells.

Toxicity of HPA-23 (ammonium-21-tungsto-9-antimoniate) for normal human myeloid progenitor cells (GM-CFU) in vitro.

HPA-23 is a competitive inhibitor of the RNA-dependent DNA polymerase (reverse transcriptase) of the human immunodeficiency virus (HIV). It may therefore potentially benefit patients with HIV infection. This study aimed at defining the haematopoietic toxicity of this drug and particularly its effects on the normal human granulocyte-macrophage progenitor cells (GM-CFU). Our in vitro studies, in semi-solid agar, have shown an inhibitory effect of increasing concentrations of HPA-23 on colony and cluster formation. This effect is probably dose-dependent. An almost complete inhibition of colony formation was observed at doses of more than 20 micrograms/ml. Regarding cluster formation, a similar although much more progressive inhibitory effect was found. Our experimental data should be extrapolated with caution to clinical situations. However, they must be kept in mind for optimal design of HPA-23 therapy in HIV infected patients.

Analysis of blood CD4+ and CD8+ T-lymphocyte subsets with monoclonal antibodies. Comparison of the Genetic Systems CD4/CD antigen typing kit with conventional indirect immunofluorescence microscopy and the automated Technicon-H1 Enzyme Immunoassay (EIA).

The Genetic Systems Technique (GS: direct immunofluorescence microscopy with ethidium bromide counterstaining of nuclei) was tested for quantitative analysis of T-lymphocyte subsets in human peripheral blood. The monoclonal antibodies anti-CD4 and anti-CD8 were used for detection of T-helper and T-suppressor cells respectively and the results compared to those obtained by conventional indirect immunofluorescence microscopy and the Technicon Enzyme Immunoassay (EIA) with automated reading. The GS technique provided results correlating well with both indirect immunofluorescence and EIA techniques. Moreover, this method has two advantages: it is less time-consuming than the indirect immunofluorescence microscopy and necessitates less expensive and more commonly available equipment than the automated EIA technique.

Amodiaquine-induced immune agranulocytosis.

This report describes two patients who developed agranulocytosis while receiving prophylactic amodiaquine treatment. The neutrophil counts returned to normal in one after stopping the drug while the other died of sepsis. Amodiaquine-dependent circulating neutrophil IgG antibodies were demonstrated in both patients using the indirect granulocyte immunofluorescence test. The antineutrophil antibody activity was enhanced with the use of the major amodiaquine metabolite, mono-desethyl amodiaquine. Additional studies showed the activity of the sera to be nondialysable, heat stable, active against autologous as well as allogenic cells, and absent from the convalescent sera. There was no growth inhibition of allogenic myeloid committed progenitor cells (CFU-GM) following incubation with the patients' sera, complement and amodiaquine. These results indicate that agranulocytosis can be mediated by a drug-dependent antibody which affects mature blood cells.

Haematological adverse effects of histamine H2-receptor antagonists.

Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration. These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption. 85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors such as underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists. Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450. Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretion by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.