Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent.

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

[Risk factors for human African trypanosomiasis in the Bipindi region of Cameroon]. / Recherche des facteurs de risque de la trypanosomose humaine africaine dans le foyer de Bipindi au Cameroun.

In the course of two surveys carried out at the end of 1998 and beginning of 1999, sleeping sickness was diagnosed in a total of 43 people in the Bipindi region of Cameroon. This observation led us to investigate the mechanisms of transmission of human African trypanosomiasis in the epicentrer of the outbreak. A case-control study showed a particularly high risk of infection associated with hunting activities (Odds-Ratio: 2.87; CI 95%: 0.96-9.52). Interpretation of this finding in the light of local geographical features and current entomological data suggests that the higher risk in hunters is linked to the presence of a perennial vector population and absence of domestic pigs.

Beta-globin gene haplotypes and alpha-thalassemia analysis in Babinga pygmies from Congo-Brazzaville.

We analyzed beta-globin gene cluster haplotypes and deletional alpha+-thalassemia (-alpha3.7kb) in 54 Babinga pygmy subjects from Congo-Brazzaville. The beta(S)-globin gene frequency was 0.065 and that of the deletional alpha-globin gene (-alpha3.7kb) was 0.29. Eighty-five percent of the beta(S) chromosomes and 13% of the beta(A) chromosomes were associated with the Bantu haplotype, 10% of beta(A) chromosomes with the Senegal haplotype, and the remaining beta chromosomes with atypical haplotypes. None of the chromosomes were of the Benin haplotype. These results are clearly of anthropological and evolutionary interest. They also support earlier observations that alpha+-thalassemia is prevalent at a high frequency in African populations.

[The focus of human trypanosomiasis in Campo (Cameroon). History and endemic situation in 1998]. / Le foyer de trypanosomose humaine de Campo (Cameroun). Historique et situation de l'endémie en 1998.

For the first time in the last thirteen years, the human sleeping sickness focus at Campo, spanning the Cameroon-Equatorial Guinea border areas, has been prospected. The screening was carried out simultaneously on both sides of the border. This focus has been known since the beginning of the century but, contrary to what took place in other well-known foci in bordering countries south of Cameroon, either in the 1920s or the 1980s--there has never been an epidemic outbreak in that area. Such an epidemiological situation makes this focus particularly interesting. Though still active, trypanosomiasis is not very manifest. According to passive screening carried out in recent years, the estimated prevalence ranges between 0.2 and 0.5%. For this screening, 5,255 persons were examined on the Cameroonian side of the focus (90.6% of the census population). The serological screenings were carried out with the CATT 1.3, which is the CATT generally used in screening, and with the latex CATT which associates LiTat 1.3, 1.5 and 1.6. The search for trypanosomes was made by testing the lymph nod juice in presence of adenopathy and in the blood by Quantitative Buffy Coat (QBC), the mini anion exchange centrifugation (mAEC), as well as the in vitro culture using the kit for in vitro isolation of trypanosomes (KIVI) for individuals suspected to be serologically positive. 16 patients were identified in Cameroon but none in Equatorial Guinea. The results show that the Campo focus is active only on the Cameroonian side, centred on the village of Ipono with a limited prevalence (0.3%). The persisting epidemic is most likely to be associated with the presence of pigs carrying the Trypanosoma brucei gambiense which was identified during the study in Ipono. The strain that we isolated was studied by isoenzyme electrophoresis on cellulose acetate. Its zymodeme is the same as that of the human strain isolated in Campo. With the collected epidemiological data, a concerted medical and entomological action could be planned within the limits of the village of Ipono to eradicate the disease. This action may be organised by the existing local health structures. During this study, the latex CATT proved to be more cost-effective than the CATT 1.3 since a similar result was reached requiring eight times less work at a lower cost. This remains to be confirmed in a hyperendemic focus.

Detection and identification of trypanosomes by polymerase chain reaction in wild tsetse flies in Cameroon.

The prevalence of various species and subgroups of trypanosomes in infected flies from three sleeping sickness foci in Cameroon was determined by the use of polymerase chain reaction (PCR). The predominant tsetse species found were Glossina palpalis palpalis. Microscopical examination of 943 non-teneral tsetse flies revealed an average infection rate of 10.4%. A total of 90 flies were analyzed for trypanosome identification with primer sets specific for Trypanosoma (Trypanozoon) brucei s.l., T. (Duttonella) vitax, T. (Nannomonas) simiae, and forest type T. (Nannomonas) congolense. PCR succeeded in identifying 52 of the 90 infected flies. Other primers were also tested on microscope positive/PCR-negative infections, and trypanosome subgroups were detected (Kilifi type and savannah type T. congolense). PCR amplification allowed identification of immature infections and revealed mixed-infections. The PCR technique failed to identify 42.2% (38/90) of the parasitologically positive flies and the reasons for this failure are discussed.

Characterization of trypanosome infections by polymerase chain reaction (PCR) amplification in wild tsetse flies in Cameroon.

The polymerase chain reaction (PCR) method was used to characterize trypanosome infections in tsetse flies from 3 sleeping sickness foci in Cameroon. The predominant tsetse species found was Glossina palpalis palpalis. An average infection rate of 12.1% was revealed by microscopical examination of 888 non-teneral tsets flies. PCR amplification analyses for trypanosome identification were carried out on 467 flies, with primer sets specific for Trypanosoma (Trypanozoon) brucei s.1., T. (Duttonella) vivax, T. (Nannomonas) simiae and forest type T. (Nannomonas) congolense. Of 467 flies 93 were positive by microscopical analysis while PCR succeeded in identifying 89 positive flies. Of the PCR-positive flies 34 (38.2%) were negative by microscopical examination. PCR amplification, when compared to the parasitological technique, gave a higher estimate of infection rate of trypanosomes in natural tsetse populations. The PCR technique did, however, fail to identify 40.9% (38/93) of the parasitologically positive flies. The reasons for this failure are discussed. The overall prevalence of mixed infections, assessed by PCR, was 37.1%; the majority (72.7%) involved T. brucei and forest type T. congolense.

Effect of the sickle cell trait status of gametocyte carriers of Plasmodium falciparum on infectivity to anophelines.

Insect-reared Anopheles gambiae were experimentally fed with the blood of naturally infected human volunteers carrying gametocytes of Plasmodium falciparum. Infection of at least one mosquito was successful in 86 experiments. For these gametocyte carriers, the hemoglobin types studied were AA (normal, n = 77), AS (heterozygous sickle cell, n = 8), and SS (homozygous sickle cell, n = 1). The mean of the percentages of infected mosquitoes by gametocyte carriers of AS hemoglobin was almost double that of carriers of AA: 30.4% versus 17.5%. The genetic protection in humans conferred by the beta(s) gene in its heterozygous form seems to be associated with an increasing effect on P. falciparum transmission from humans to mosquitoes. The epidemiologic and evolutionary aspects of this finding are discussed.

Etude de cinq indicateurs de Sante en zone tropicale de foret tropicale sempervirente du Sud-Cameroun

Cette etude presente cinq indicateurs de sante des populations Bantous et pygmees Baka du Canton Bulu du Dja (village principal: Mekas) au sud du Cameroun parmi lesquels: un indicateur de l'etat nutritionnel de la population; statut en vitamine A des enfants de moins de 6 ans; un indicateur genetique ou drepanocytose; le paludisme; les infections par le virus C des hepatites (VHC) et le virus HTLV-1. Ce travail a ete realise du 21 au 30 janvier 1993. Cette etude n'a pas permis de dresser un bilan de sante exhaustif des populations; elle a revele cependant un certain nombre de constatations. Sur le plan nutritionnel; il apparait que les deux populations; Bulu et Pygmee; sont en situation carentielle moderee du fait d'une alimentation trop exclusivement basee sur le manioc. Cet etat pourrait etre ameliore par le changement chez la mere des conduites d'allaitement et par une modification des pratiques de sevrage. L'etude de l'hemoglobine montre plutot une difference entre les deux groupes ethniques

A novel sickle cell mutation of yet another origin in Africa: the Cameroon type.

The sickle cell mutation (beta s) arose as at least three independent events in Africa and once in Asia, being termed the Senegal, Benin, Bantu and Indian types respectively. An investigation in Cameroon was carried out to determine whether the atypical sickle genes observed in the neighboring countries are the result of recombination or the presence of a sickle cell mutation of a different genetic origin. It was conducted on 40 homozygous SS patients followed at the Blood Transfusion Center in the capital city of Yaoundé. On 80 beta s chromosomes, 13 exhibited a novel polymorphic pattern that was observed three times in the homozygous state. This chromosome contains an A gamma T gene. The restriction fragment length polymorphism haplotype is different from all the other beta s chromosomes in both the 5' and 3' regions, but has previously been reported in sporadic cases. The (AT)8(T)5 sequence in the -500 region of the beta gene is specific and different from that of the Senegal, Benin, Bantu or Indian beta s genes. All the carriers of this specific chromosome belong to the Eton ethnic group and originate from the Sanaga river valley. This observation strongly argues for yet another independent origin of the sickle cell mutation in Africa, here referred to as the "Cameroon type". The Benin haplotype and a Benin/Bantu recombinant haplotype have been observed in the other studied populations: Ewondo, Bamiléké, Bassa, Yambassa and Boulou.

[Comparative study on the chemical modification of sulfhydryl groups of glyceraldehyde-3-phosphate dehydrogenases from yeast and rabbit muscle. The relationship between structure and chemical reactivity]. / Etude comparative de la modification chimique des groupes sulfhydryles des glycéraldéhyde-3-phosphate déshydrogénases de lavure et de muscle de lapin. Relation structure-réactivité chimique.

Chemical modification of cystein 149 residues from yeast apo-glyceraldehyde-3-phosphate dehydrogenase either by iodoacetamidonaphtol or N-(4-dimethylamino-3,5-dinitrophenyl) maleimide results in the disappearance of free sulfhydryl groups according to "full sites reactivity", whereas loss of the dehydrogenase activity occurs following "half of the sites reactivity". Chemical modification of the same cystein residues of the rabbit muscle apoenzyme by N-(4-dimethylamino-3,5-dinitrophenyl) maleimid shows that both loss of activity and disappearance of the sulphydryl groups may be described as "full sites reactivity" phenomena. After chemical modification by iodoacetamidonaphtol both processes follow "half of the sites reactivity".

Structure and reactivity relationship in glyceraldehyde-3-phosphate dehydrogenase. Dinitrophenylation of cysteine residues of yeast and rabbit muscle enzymes.

Dinitrophenylation of rabbit muscle and yeast glyceraldehyde-3-phosphate dehydrogenases modifies only SH groups. The rabbit muscle apoenzyme loses 75% of its original activity upon dinitrophenylation of two SH groups per tetramer whereas the yeast apoenzyme is totally inactivated under the same conditions. Dinitrophenylation of the active-site cysteine-149 of rabbit muscle and yeast holoenzymes results in an loss of activity corresponding to a 'half-of-the-sites' and a 'full-sites' reactivity, respectively. Determination of the sulphydryl content of the modified enzymes shows an unmasking of the cysteine residues of the dinitrophenylated rabbit muscle apoenzyme which is not observed for the yeast protein. However, conformational changes are revealed for both dinitrophenylated apoenzymes by differential absorption spectroscopy or by limited proteolysis. Sulphydryl group unmasking is not observed after modification of the cysteine residues of the rabbit muscle holoenzyme but it does occur when dinitrophenylation is performed in the presence of two moles NAD+/mole rabbit muscle enzyme. Although the apoenzyme is sensitive to an induced conformational change, our results favour symmetrical structures for both yeast apo and holo enzymes. The bis-dinitrophenylated rabbit muscle apoenzyme presents all the characteristics of an asymmetrical structure; however, it is not possible to deduce whether this symmetry is due to the chemical modification or whether it preexists in the native apoenzyme. The results of the dinitrophenylation of the rabbit holoenzyme, however, indicate that this enzyme possesses an asymmetrical structure.