Biomedical subjects
Publications and source records attributed to J Roux.
Arterial endofibrosis is a rare disease usually affecting the external iliac artery in highly trained athletes. We report a case of bilateral external iliac endofibrosis in a 44-year-old cyclist. Microscopic examination of the resection specimen showed an isolated thickening of the arterial intima, and confirmed the diagnosis of this entity of unknown etiology.
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In 1994 in Madagascar a woman died after eating a sardine, Herklotsichthys quadrimaculatus. Two heads removed, respectively, from a toxic and a nontoxic fish before cooking were retrieved, kept frozen, and used for toxin analysis. The causative toxin was identified as palytoxin or its analogs based on its cytotoxicity, delayed hemolysis, neutralization with an anti-palytoxin antibody, chromatographic properties on different columns, and MS data. The gill and esophagus of the fish contained large amount of bottom sediments indicating that the fish had fed on the bottom and thus probably obtained the toxin from a benthic organism. The benthic dinoflagellate Ostreopsis siamensis that produces palytoxin and its analogs was inferred as the probable toxin source. This is the first study to shed light on clupeotoxism, a highly fatal form of human intoxication due to ingestion of clupeoid fish.
Anopheles funestus and Anopheles gambiae s.l. have been considered until now the major vectors of malaria everywhere in Madagascar. Anopheles mascarensis, a mosquito native to Madagascar, has been identified in Sainte-Marie island as a secondary vector only. In 1997, an entomological study was carried out to identify the malaria vectors in the area of Fort-Dauphin, South-East of Madagascar. Every month, mosquitoes were collected from landing catches on human volunteers (from 7:00 am to 5:00 pm inside dwellings and from 7:00 am to 0:00 pm outside) and from knockdown spray-collections indoors. An mascarensis was the most abundant mosquito, the average number of An. mascarensis bites per man/night was 7.6. The sporozoite index was 0.89%. Despite the presence of An. funestus and An. gambiae s.l., An. mascarensis was found to be responsible for 2/3 of the infectious bites (25 infectious bites per man/year). An. mascarensis is widely distributed ih Madagascar but only specimens from the east coast have been found to carry sporozoites of human malaria. Further arguments are thus advanced for the hypothesis according to which a sibling species of An. mascarensis is present in Madagascar.
Increased serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1, CD54) and of soluble E- (CD62E), but not soluble P- (CD62P) and L- (CD62 L) selectins, were detected in Malagasy patients living in an hyperendemic focus of Schistosoma mansoni. Levels of sICAM-1 remained elevated for several months after treatment with praziquantel. Serum levels of ICAM-1, but not of other markers, were significantly correlated with the disease severity, as indicated by ultrasonographical data, and with some circulating fibrosis markers (at least hyaluronic acid). sICAM-1 level may reflect endothelial inflammatory reactions, probably harmful, in the liver and may be useful for monitoring morbidity evolution in schistosomiasis mansoni.
The pharmacokinetics of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5-isopropyl-2-methyl phenyl acetate, CAS 54-32-0, moxisylyte, Carlytène) were studied in female hairless rats following different administration routes: oral, intravenous or percutaneous. After percutaneous administration, the half-life of elimination of 14C-thymoxamine and its metabolites was longer (t 1/2 = 15 h) than after oral or intravenous administration (t 1/2 = 9 h). The penetration/resorption phenomenon of thymoxamine base mainly located in the horny layer could explain the high value of the pseudo half-life of elimination observed after percutaneous administration. Due to the absorption slower than elimination, this special pharmacokinetics had to be considered as a flip-flop model. The type and proportions of thymoxamine metabolites recovered in plasma varied according to the route of administration. The unconjugated metabolites, desacetyl-thymoxamine (DAT) + desacetyl-desmethyl-thymoxamine (DMAT), were observed only after intravenous or percutaneous administration, they represented 12% and 15%, respectively. They were never observed after oral administration suggesting the existence of a hepatic first-pass metabolism. The other metabolites observed were sulphate conjugates and glucuronides of DAT + DMAT. The values of sulfoconjugates were constant with each administration route (21%), whereas glucuronides increased with oral administration. In conclusion, the pharmacokinetics of percutaneous thymoxamine presented two main features: the drug absorption was high and durable (t 1/2 = 15 h); the cutaneous application allowed to avoid the hepatic first-pass metabolism.
After a thirty year period of successful control, bubonic plague showed the first signs of return in Madagascar where a fatal outbreak occurred in Antananarivo in 1978. A second outbreak was observed in Mahajanga in 1991 after more than a half century. In 1997, 459 confirmed or presumptive cases were reported, as compared to 150 to 250 cases during the last years. However the actual extent of this recrudescence must be placed in the perspective of a more efficient control program that has led to better reporting of suspected cases and availability of more accurate diagnostic techniques. Recent research has led to the development of highly effective immunological diagnostic tools (detection of antibodies and F1 antigen) allowing not only better surveillance of the disease in man and animals but also renewed study of the epidemiological cycle in the current environment. In this regard the capacity of several endemic fleas as vectors and the role of the rat Rattus norvegicus and the musk shrew Suncus murinus are currently under investigation. Genetic study of strains collected from 1936 to 1996 has demonstrated the appearance of 3 new ribotypes of Yersinia pestis since 1982 in the zones of strongest plague activity in Madagascar. A strain showing multiresistance to standard therapeutic antibiotic agents was isolated in 1995. Bubonic plaque is a priority health problem in Madagascar but remains a major concern for the rest of the world.
Analysis of the interaction of proteins with either DNA or RNA sequences by in vivo footprinting involves two steps: (i) the in situ modification of nucleic acids by the footprinting reagent and (ii) the visualization of the footprints. Ligation-mediated PCR (LM-PCR) procedures provide a level of sensitivity and specificity that is suitable for visualization of footprints of single-copy genes or low-abundance mRNAs in higher eukaryotes. In this article, we discuss several of the technical aspects of these multistep procedures that contribute to the quality of the results, particularly the parameters that affect the specificity and fidelity of the reactions: (i) the design of the primers, which is important to achieve optimal specificity; (ii) the choice of polymerases so that the amplified material represents faithfully the initial nucleic acid population; and (iii) the impact of the plateau effect within the PCR on the interpretation of the data. We then discuss aspects of in vivo nucleic acid manipulation that may affect the quality of the footprinting image, in particular the choice of the footprinting reagent and its condition of use (e.g., on intact or permeabilized cells or prepared nuclei) and the extent of nucleic acid modification. Finally, we provide detailed experimental procedures corresponding to the techniques we have developed or modified: LM-PCR, reverse ligation-mediated PCR, and nuclease treatment of RNAs in vivo.
Intestinal ultrasound, a frequently applied diagnostic tool in industrialized nations, has recently also been introduced in tropical regions. This study attempts to describe the anatomical and sonographical features of Ascaris lumbricoides in the human intestine. In the course of a schistosomiasis morbidity study in Madagascar, 581 inhabitants of a rice-farming village on the high plateau of the island had their stools examined by means of a modified Kato-Katz thick smear technique (four slides per sample); 53% had eggs of Ascaris lumbricoides in their stools. Twenty-two individuals underwent intestinal ultrasound examination and, in six cases, Ascaris lumbricoides was visualized. All six patients showed eggs upon stool examination. At ultrasound, the parasite was seen as a large, curved echogenic strip (4-6 mm in diameter) with an inner, anechoic, longitudinal canal. The image resembled a winding highway, the central structure representing the pseudocoel of the parasite. Patients were treated with mebendazole. The excreted worms of one patient were scanned under water, showing the same characteristics as in vivo. We conclude that Ascaris lumbricoides has a characteristic sonographical appearance and should not be a confounding factor in studies using intestinal ultrasound.
To assess the impact of cysticercosis on public health in Madagascar, we compared patients > 15 years with late-onset epilepsy to non-epileptic controls in a matched case-control study. The association between epilepsy and cysticercosis was studied by enzyme-linked immunoelectrotransfer blot (EITB) assay for antibodies specific to Taenia solium. The EITB assay was performed on 104 pairs of sera specimens and on 95 pairs of cerebrospinal fluid (CSF) specimens. Depending on whether we consider the results obtained from sera or from CSF, we obtain for the population attributable risk percent of cysticercosis in late-onset epilepsy two slightly different estimates: 22.3% and 17.6%. Therefore cysticercosis is a major aetiological factor of late-onset epilepsy in Madagascar. In the control group, the frequency of positive results, especially in CSF specimens (7.4%), confirms the existence of asymptomatic cases of neurocysticercosis.
A strong malaria epidemic with a high mortality rate occurred on the Madagascar Highlands in 1986-88. Vector control and free access to antimalaria drugs controlled the disease. The authors have searched for the causes of the epidemic to propose a strategy avoiding such events. The Highlands on Madagascar were known as malaria free. In 1878 a very severe epidemic flooded all the country. Development of irrigated ricefields which house both An. arabiensis and An. funestus had created a new anthropic environment. Moreover manpower imported from malarious coastal areas for rice cultivation and also for building large temples, could have brought P. falciparum. After several outbreaks the disease became endemic up to 1949. In 1949 a malaria eradication programme based on DDT spraying and drug chemoprophylaxis and chemotherapy was launched. By 1960 malaria was eliminated and DDT spraying cancelled. Only 3 foci were kept under surveillance with irregular spraying until 1975. The prophylaxis and treatment centres ("centres de nivaquinisation") were kept open up to 1979. The catholic dispensary of Analaroa, 100 km N.E. of Tananarive, opened in 1971 and worked without interruption up to now. The malaria diagnosis has always been controlled by microscopy. Its registers are probably the more reliable source of information on malaria in the area. They show that malaria was already present on the Highlands in 1971 but at a low prevalence; in 1980 when the "centres de nivaquinisation" were closed the number of cases increased by three times the progressive increase of the number of cases became exponential from 1986 to 1988 which was the peak of the epidemic; malaria remained at a high level until the end of 1993; yearly DDT spraying since 1993 have decreased the number of malaria cases among the dispensary attendants by 90%. The epidemic peak of 1988 was well documented by the Pasteur Institute of Madagascar around Tananarive. Before the epidemic started it was observed a come back of An. funestus which had been previously eliminated of most of the villages by DDT spraying. More than an epidemic the malaria increase in 1988 was a reconquest by malaria of the land from which it had been eliminated in the years 1950. This episode became dramatic because the lack of immunity of the population and the shortage of medicaments. The global warming which was advocated to explain the epidemic has no responsibility because the temperature on the Madagascar Highlands has not changed during the last 30 years. Also the cyclones do not seem to have played any role. It is very likely that the gradual decline of control measures, first DDT spraying, later drug distributions, had the main responsibility in the Highlands drama. Everywhere An. funestus reached a high level during the time where the parasite reservoir was rebuilding. They synergised each other. These findings should be taken in account in drawing the strategy planning for the next years.
Azelastine (CAS 37932-96-0) nasal spray (Allergodil, Rhinolast, Astelin) was investigated in acute experiments in guinea pigs and after a 26-week local application period with daily repeated administration for effects on ciliary beat activity (acute experiments) and morphology of nasal mucosa. The commercially available spray did not inhibit ciliary beat activity in guinea pigs nor did it cause any inflammatory or atrophic changes after 26-week daily local application on nasal mucosa in rats and dogs.
Neurocysticercosis (i.e. cerebral localization of the metacestode larvae of Taenia solium) is believed to be a major cause of late onset epilepsy in non-Muslim developing countries. To define its role in childhood epilepsy in Madagascar, analysis of serological markers of cysticercosis was performed in 256 children with unexplained epilepsy and in 113 controls. Sera were considered positive when high titres in ELISA were present together with at least one of the bands 13, 14, 18, 21, 24 or 32 kD on Western blot. Altogether, 17.6% of the patients versus none of the controls were seropositive using these criteria. When analysing the bands of the Western blot, those of 13, 14 and 18 were significantly more frequently detected in sera of epileptic children than in sera of controls. Neurocysticercosis can be considered the main cause of secondary childhood epilepsy in our country, Madagascar being one of the most important foci in the world.
In November 1993, 188 people were admitted to hospital after eating the meat from a single shark (Carcharhinus leucas) in Manakara, a medium-sized town on the south-east coast of Madagascar. This shark and its meat had no unusual characteristics. The attack rate was about 100%. The first clinical signs appeared within 5-10 hr after ingestion. The patients presented with neurological symptoms almost exclusively, the most prominent being a constant, severe ataxia. Gastrointestinal troubles, like diarrhoea and vomiting, were rare. The overall case mortality ratio was close to 30% among the 200 poisoned inhabitants. There were no reports of previous similar poisonings in this area, and fishermen in Manakara usually eat this kind of shark without problems. Bacteriological and chemical causes were eliminated. Two liposoluble toxins were isolated from the liver and tentatively named carchatoxin-A and -B, respectively. They were distinct from ciguatoxin in their chromatographic properties.
Hepatocyte nuclear factor 3 (HNF3) recognizes two apparently distinct classes of sequence. However, a detailed mutational analysis of a representative binding site of each class reveals that these sequences display common features. We propose a unified consensus sequence for HNF3-binding sites. The basis of the sequence specificity of the interaction of HNF3 with DNA is analyzed in light of the recently determined structure of an HNF3-DNA complex (Clark et al., Nature 364, 412-420, 1993). Particularly, our study reveals that the DNA site used for this structural analysis is too short to account for all HNF3-DNA interactions. The better knowledge of the sequence determinant recognized by HNF3 has allowed us to analyze its function in the glucocorticoid response of the rat tyrosine aminotransferase (TAT) gene. This response is mediated through a complex array of neighboring and overlapping transcription factor binding sites. Selective inactivation of the HNF3-binding sites in this glucocorticoid response unit (GRU) allows us to demonstrate unambiguously that they play a major role in the amplitude of the glucocorticoid response. Furthermore, HNF3 beta overexpression results in a stimulation of the glucocorticoid response that is dependent on the integrity of its binding sites. We also show that the relative level of HNF3 determines the extent of the contribution of one of the glucocorticoid receptor binding sites. Our results indicate that HNF3 accounts for most of the liver-specific activity of this GRU.
The rat tyrosine aminotransferase gene is a model system to study transcriptional regulation by glucocorticoid hormones. We analyzed transcription factor binding to the tyrosine aminotransferase gene glucocorticoid-responsive unit (GRU) at kb -2.5, using in vivo footprinting studies with both dimethyl sulfate and DNase I. At this GRU, glucocorticoid activation triggers a disruption of the nucleosomal structure. We show here that various regulatory pathways affect transcription factor binding to this GRU. The binding differs in two closely related glucocorticoid-responsive hepatoma cell lines. In line H4II, glucocorticoid induction promotes the recruitment of hepatocyte nuclear factor 3 (HNF3), presumably through the nucleosomal disruption. However, the footprint of the glucocorticoid receptor (GR) is not visible, even though a regular but transient interaction of the GR is necessary to maintain HNF3 binding. In contrast, in line FTO2B, HNF3 binds to the GRU in the absence of glucocorticoids and nucleosomal disruption, showing that a "closed" chromatin conformation does not repress the binding of certain transcription factors in a uniform manner. In FTO2B cells, the footprint of the GR is detectable, but this requires the activation of protein kinase A. In addition, protein kinase A stimulation also improves the recruitment of HNF3 independently of glucocorticoids and enhances the glucocorticoid response mediated by this GRU in an HNF3-dependent manner. In conclusion, the differences in the behavior of this regulatory sequence in the two cell lines show that various regulatory pathways are integrated at this GRU through modulation of interrelated events: transcription factor binding to DNA and nucleosomal disruption.
The pharmacokinetics of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5- isopropyl-2-methyl phenyl acetate hydrochloride) (moxisylyte, Carlytène) was studied on female hairless rats. Animals received 5 mg/kg of thymoxamine-HCl (CAS 964-52-3) intravenously or orally. 14C-thymoxamine was both rapidly and entirely absorbed after oral administration, Tmax value was observed at 0.25 h. The decrease of the total radioactivity followed a biexponential mode. After intravenous and oral administration, the apparent half-live of distribution were 0.20 and 0.31 h, respectively, whereas the apparent half-live of elimination were 9.6 (i.v.) and 8 h (p.o.). The nature and proportions of thymoxamine metabolites recovered in the plasma varied according to the route of administration. After intravenous administration, desacetyl-thymoxamine (DAT) + desacetyl-desmethyl-thymoxamine (DMAT), sulphate conjugates and glucuronides of DAT + DMAT represented 12, 21 and 63%, respectively. After oral administration, the values were 0, 21 and 79%, respectively. These results underlined the importance of the hepatic first-past effect which induced the disappearance of DAT and DMAT, and increased the levels of glucuronides when thymoxamine was orally administered. The level of sulphate conjugates for DAT and DMAT seems always constant.
A survey was undertaken in April 1993 to compare the respective benefits of 2 regimens containing either streptomycin (SHRZ) or ethambutol (EHRZ) in the first two months of treatment of smear-positive pulmonary tuberculosis in Madagascar. This operational research was justified by the risks related to the use of parenteral streptomycin in a country where single use material is rare and its purpose was to provide arguments for an eventual recommendation to replace this drug by oral ethambutol which is also less expensive. 907 patients were included. The compliance was not significantly different between the 2 groups, although it was traditionally assumed to be better with streptomycin. The frequency of side effects was significantly lower with EHRZ. Overall treatment failure rates were not significantly different, but all of 6 patients who were negative at 5 months and were again positive at 8 months had received EHRZ. This point obliged to be careful before concluding, because 24% of patients were lost for follow-up. A 2 years surveillance will be necessary to compare the frequency of recurrences.