A novel humanized anti-human death receptor 5 antibody CS-1008 induces apoptosis in tumor cells without toxicity in hepatocytes.

BACKGROUND: The antitumor activity of CS-1008, a humanized agonistic anti-human death receptor (DR) 5 antibody, was investigated in preclinical models. MATERIALS AND METHODS: Cytotoxicity of CS-1008 was evaluated in a several human tumor cell lines as well as primary human hepatocytes in vitro. To evaluate antitumor efficacy, athymic nude mice were inoculated with human colorectal tumor COLO 205, pancreatic tumor MIA PaCa-2 or non-small-cell lung carcinoma NCI-H2122 and CS-1008 was i.v. administered. The combination effects of CS-1008 with gemcitabine or docetaxel (Taxotere) against MIA PaCa-2 or NCI-H2122 were evaluated in vivo, respectively. RESULTS: CS-1008 inhibited the growth of tumor cell lines with DR5 expression, including COLO 205, NCI-H2122, MIA PaCa-2 and renal cell adenocarcinoma ACHN in vitro with antibody cross-linkage. Using COLO 205, apoptosis induction was confirmed by annexin V staining. Weekly administration of CS-1008 resulted in the inhibition of COLO 205 tumor growth as well as MIA PaCa-2 in vivo. CS-1008 in combination with gemcitabine or docetaxel demonstrated enhanced antitumor activity against MIA PaCa-2 or NCI-H2122 cells, respectively. Unlike tumor necrosis factor-related apoptosis-inducing ligand, CS-1008 did not induce cell death in human primary hepatocytes. CONCLUSION: CS-1008 has a selective toxicity toward tumor cells expressing DR5 and the potential for antitumor efficacy in human malignancies.

[Multiple Ebola virus haemorrhagic fever outbreaks in Gabon, from October 2001 to April 2002]. / Plusieurs epidémies de fièvre hémorragique due au virus Ebola au Gabon, d'octobre 2001 a avril 2002.

Outbreaks of Ebola virus haemorrhagic fever have been reported from 1994 to 1996 in the province of Ogooué Ivindo, a forest zone situated in the Northeast of Gabon. Each time, the great primates had been identified as the initial source of human infection. End of November 2001 a new alert came from this province, rapidly confirmed as a EVHV outbreak. The response was given by the Ministry of Health with the help of an international team under the aegis of WHO. An active monitoring system was implemented in the three districts hit by the epidemic (Zadié, Ivindo and Mpassa) to organize the detection of cases and their follow-up. A case definition has been set up, the suspected cases were isolated at hospital, at home or in lazarets and serological tests were performed. These tests consisted of the detection of antigen or specific IgG and the RT-PCR. A classification of cases was made according to the results of biological tests, clinical and epidemiological data. The contact subjects were kept watch over for 21 days. 65 cases were recorded among which 53 deaths. The first human case, a hunter died on the 28th of October 2001. The epidemic spreads over through family transmission and nosocomial contamination. Four distinct primary foci have been identified together with an isolated case situated in the South East of Gabon, 580 km away from the epicenter. Deaths happened within a delay of 6 days. The last death has been recorded on the 22nd of March 2002 and the end of the outbreak was declared on the 6th of May 2002. The epidemic spreads over the Gabon just next. Unexplained deaths of animals had been mentionned in the nearby forests as soon as August 2001: great primates and cephalophus. Samples taken from their carcasses confirmed a concomitant animal epidemic.

[First major epidemic caused by Neisseria meningitidis serogroup W135 in Africa?]. / Premiere epidemie de garnde amplier provoquee par Neisseria meningitidis W135 en Afrique?

Neisseria meningitidis serogroup W 135 (N.m. W 135) has caused sporadic infections and small epidemics such as those that occurred during religious pilgrimages in Saudi Arabia in 2000 and in 2001. It is routinely isolated from specimens coming from African countries. The first major epidemic involving N.m. W 135 occurred in Burkina Faso between January and May 1992. There were more than 1300 cases including 1500 deaths. Enhanced surveillance of circulating strains showed that N.m. W 135 accounted for 83% of the 203 positive cerebrospinal fluid specimen cultures. The offending organism was identical to the strain that caused the smaller epidemic in Saudi Arabia in 2000. Due to the shortage of tetravalent meningococcal vaccine against N.m. W 135, the Health Ministry based its response to the epidemic on treatment of symptomatic patients using chloramphenicol and ampicillian. These drugs were distributed free. The emergence of N.m. W135 has impacted public health in Africa. Repeated identification of this serogroup in Burkina Faso during 2002 raises the risk that similar outbreak will occur in the meningitis belt during the next epidemic season. The high cost of tetravalent meningococcal vaccine compounded with the only progressive increase in production capacity underline the need to reinforce surveillance of circulating strains and available treatment facilities. Control strategy for epidemic meningitis is currently the focus of close collaboration between the WHO and the health authorities and corresponding institutions in the countries involved.

Early detection and response to meningococcal disease epidemics in sub-Saharan Africa: appraisal of the WHO strategy.

OBJECTIVE: To assess the sensitivity, specificity and predictive value positive of the WHO threshold strategy for detecting meningococcal disease epidemics in sub-Saharan Africa and to estimate the impact of the strategy on an epidemic at district level. METHODS: Data on meningitis cases at the district level were collected weekly from health ministries, WHO country and regional offices, and nongovernmental organizations in countries where there were epidemics of meningococcal disease in 1997. An epidemic was defined as a cumulative district attack rate of at least 100 cases per 100,000 population from January to May, the period of epidemic risk. The sensitivity, specificity and predictive value positive of the WHO threshold rate were calculated, and curves of sensitivity against (1 - specificity) were compared with alternatively defined threshold rates and epidemic sizes. The impact of the WHO strategy on a district epidemic was estimated by comparing the numbers of epidemic cases with cases estimated to have been prevented by vaccination. FINDINGS: An analysis was made of 48 198 cases reported in 174 districts in Benin, Burkina Faso, the Gambia, Ghana, Mali, Niger, and Togo. These cases were 80.3% of those reported from Africa to WHO during the 1997 epidemic period. District populations ranged from 10,298 to 573,908. The threshold rate was crossed during two consecutive weeks in 69 districts (39.7%) and there were epidemics in 66 districts (37.9%). Overall, the sensitivity of the threshold rate for predicting epidemics was 97%, the specificity was 95%, and the predictive value positive was 93%. Taken together, these values were equivalent or better than the sensitivity, specificity and predictive value positive of alternatively defined threshold rates and epidemics, and remained high regardless of district size. The estimated number of potential epidemic cases decreased by nearly 60% in the age group targeted for vaccination in one district where the guidelines were followed in a timely manner. CONCLUSION: The use of the WHO strategy was sensitive and specific for the early detection of meningococcal disease epidemics in countries of sub-Saharan Africa during 1997 and had a substantial impact on a district epidemic. Nevertheless, the burden of meningococcal disease in these countries remains formidable and additional control measures are needed.

[Detection of meningococcal meningitis epidemics in Africa: a new recommendation]. / Mieux détecter les épidémies de méningite à méningocoque en Afrique: une nouvelle recommandation.

In sub-Saharan Africa, the control of meningococcal meningitis epidemics relies on early epidemic detection and mass vaccination. However, experience shows that interventions are often initiated too late to have a significant impact on the epidemic. A new recommendation drafted by participants of a consensus meeting proposes an alert threshold and an epidemic threshold based on the weekly number or incidence of meningitis cases, according to the population size and the epidemic risk, resulting in indicators with high sensitivity and specificity for the detection of an emerging epidemic. Meningitis outbreak investigations must include an assessment of the quality of epidemiologic surveillance. The new recommendation is published in English and French in the Weekly Epidemiologic Record [12]. The success of this consensus meeting shows the value of integrating results from surveillance, field experience and operational research for designing new health strategies.

Risk factors of malaria infection during pregnancy in Burkina Faso: suggestion of a genetic influence.

A cohort of 570 untreated pregnant women from Burkina Faso was studied to assess the influence of epidemiologic factors on malaria infection, which was quantified as the mean of serial, season-adjusted parasitemia measurements (mean parasite density [MPD]) carried out during the last five months of gestation. A significant effect of the area of maternal residence on the MPD was found (P < 0.003) and was probably due to geographic differences in mosquito transmission conditions. The strong relationship observed between parity and malaria infection (P < 0.0001), with MPD levels decreasing as the number of gestations increased, confirms that primigravidae are a high-risk group whose protection should be a priority. After adjustment for two relevant epidemiologic factors (i.e., area of residence and parity), the residual MPD values fitted a mixture of two distributions. This result supports the view that a major gene is involved in the determination of malaria infection intensities and is consistent with the results of a recent familial study in Cameroon.

Detection of meningitis epidemics in Africa: a population-based analysis.

Portions of sub-Saharan Africa are subject to major epidemics of meningococcal meningitis that require early detection and rapid control. We evaluated the usefulness of weekly meningitis rates derived from active surveillance data in Burkina Faso for detecting a meningitis epidemic. By analysing the rates of disease in 40 x 40km2 areas within a study region of Burkina Faso, we found that a threshold of 15 cases/100,000/week averaged over 2 weeks was 72-93% sensitive and 92-100% specific in detecting epidemics exceeding 100 cases/100,000/year. During epidemic periods, the positive predictive value of this threshold approached 100% for detecting local epidemics. Additionally, meningitis incidence was proportional to village size, with villages greater than 8000 having the highest disease rates during a major group A meningococcal epidemic in 1983-1984. Despite the rudimentary nature of surveillance data available in many developing countries, these data can be used to detect the early emergence of meningitis epidemics. Additional studies are needed to determine the relevance of this approach for detecting epidemics.

Effect of chloroquine chemoprophylaxis during pregnancy on birth weight: results of a randomized trial.

To determine the effect of chloroquine chemoprophylaxis during pregnancy on birth weights, a randomized trial was carried out in 1987 and 1988 in Banfora, Burkina Faso (West Africa). Seven hundred forty-five randomly selected women treated with chloroquine sulfate were compared to with 719 controls who received no treatment. In spite of an unquestionable effect of chloroquine in preventing placental infection (4.1% infected placentas in the treated group versus 19.0% in the controls), the mean difference in birth weights between the two groups (6 g) was not significant. The difference in the proportion of low birth weight (LBW) newborn babies in two groups (16.3% versus 16.4%) was also not significant. However, there was a strong relationship between placental infection and birth weight (the mean birth weight difference between infected and uninfected placentas was 113 g, and the proportion of LBW babies was 26.0% in infected placentas versus 14.8% in uninfected placentas). The small difference in birth weights observed between the two groups may be due to the fact that the prevalence rate of placental infection is low and that prophylaxis is effective only on a portion of the subjects in the treated group. It may also indicate that malaria is only one of several risk factors responsible for LBW. The relatively small increase in birth weight, the expected poor acceptance of mass prophylaxis, and the spreading of chloroquine-resistant Plasmodium strains should be considered before extending malaria chemoprophylaxis to all pregnant women. It might be worth considering to limit prophylaxis to primigravidae.

[Comparison of 2 field methods for urinary assay of chloroquine]. / Comparaison de deux méthodes de dosage de la chloroquine dans les urines sur le terrain.

Two methods of urinary chloroquine assay were tested in pregnant women in the town of Banfora (Burkina Faso): the method with bromothymol blue (Bergqvist) and the method with methyl-orange (Haskins and Mount or HMM II). Urinary assay of chloroquine was performed with both methods in 45 women chosen at random whether or not under chemoprophylactic treatment (21 taking a weekly prophylaxis of 300 mg of chloroquine, and 24 controls). The HMM II method proved to be more sensitive (100%) and more specific (91.7%) than the Bergqvist method (80.9% and 83.3% respectively); it was also more reliable with regard to positive (91.3% versus 80.9%) and negative (100% versus 91.3%) predictive values. Moreover, the quantitative appreciation of the levels of chloroquine excretion proved to be superior with the HMM II method. Finally, this method is faster to perform, easier to use and cheaper, making it the method of choice for field assay of chloroquine in urine.

Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine.

Sequential case-control studies were used to monitor changes in the clinical protection induced by group A meningococcal polysaccharide vaccine over a 3-year period. Overall, vaccine efficacy declined from 87% 1 year after vaccination to 70% and 54% at 2 and 3 years, respectively. When stratified by age at time of vaccination the data showed that, although vaccine efficacy remained high in children greater than or equal to 4 years of age (vaccine efficacy 85%, 74%, and 67% at 1, 2, and 3 years after vaccination, respectively), it declined dramatically in those less than 4 years of age at time of vaccination (vaccine efficacy 100%, 52%, and 8%, respectively, at 1, 2, and 3 years after vaccination). Thus, a single dose of group A meningococcal vaccine does not yield lasting clinical protection in children less than 4 years of age.

[Extent of endemic yaws in Upper Volta in 1981]. / Niveau de l'endémie pianique en Haute-Volta en 1981.

This yaws investigation has been realized in the South West of Upper-Volta, in 1981, in areas around Gaoua, Niangoloko, N'Dorola; this investigation concerns 15 villages, chosen at random, and a sample of 1540 persons older than 4 years. The clinical prevalence (infectious cases) is 0.6%; the higher prevalence is observed around Gaoua (1.5%). Infectious contagious lesions are found especially in the 5-14 years old group. This investigation shows a low prevalence (under 5%) of active yaws. The serological prevalence (Kline-test) is 5.8% and we observe also around Gaoua the highest prevalence (8%). Periodical screening surveys of the population, during years 1952-1957, had shown a low prevalence of yaws, with a medium prevalence of yaws around Gaoua. Yaws treatment campaigns had been realized from 1957 to 1960 in South-West of Upper-Volta with very good results (prevalence: 0.06% - 1960). Now, in 1981, we note a resurgence of endemic foci, especially around Gaoua, from where the infection is spreading again, this, threatening the gains made by previous mass treatment campaigns. Taking in account the present result, it is necessary to treat contagious cases and contact sick persons (selective mass treatment or S.M.T., recommended in areas of low prevalence, by the WHO scientific group on treponemal infections).

Epidemic group C meningococcal meningitis in Upper Volta, 1979.

Group C meningococci were isolated during an epidemic of meningococcal meningitis which occurred between January and May 1979 in eastern Upper Volta, an area previously associated with endemic and epidemic group A disease. A total of 539 cases of meningitis, 55 of which were fatal, were reported, giving an attack rate of 517 cases per 100 000 inhabitants. Attack rates were higher for children under 15 years of age. Clinical and bacteriological data suggested that the group C meningococci were sulfonamide-resistant. The last meningococcal epidemic in Upper Volta occurred in 1970 and was nationwide. Epidemic cycles of group A meningococcal meningitis have occurred at 10-15 year intervals in the sub-Saharan region, raising concern that the current increase in activity may presage more wide-spread disease in the next dry season.