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Ebolaviruses are pathogenic agents associated with a severe, potentially fatal, systemic disease in man and great apes. Four species of ebolaviruses have been identified in west or equatorial Africa. Once the more virulent forms enter the human population, transmission occurs primarily through contact with infected body fluids and can result in major epidemics in under-resourced settings. These viruses cause a disease characterised by systemic viral replication, immune suppression, abnormal inflammatory responses, major fluid and electrolyte losses, and high mortality. Despite recent progress on vaccines, and with no licensed prophylaxis or treatment available, case management is essentially supportive with management of severe multiple organ failure resulting from immune-mediated cell damage. The 2013–16 outbreak was classified by WHO as a Public Health Emergency of International Concern, which drew attention to the challenges of diseases caused by infections with ebolaviruses and questioned scientific, clinical, and societal preparation to handle future epidemics.

Supplemental Digital Content is available in the text.Many genes are now thought to confer susceptibility to autism. Despite the fact that this neuropsychiatric disease appears to be related to several different causes, common cellular and molecular pathways have emerged and point to synaptic dysfunction or cellular growth. Several studies have indicated the importance of the ubiquitin pathway in synaptic function and the aetiology of autism. Here, we focused on the ring finger protein 135 (RNF135) gene, encoding an E3 ubiquitin ligase expressed in the cortex and cerebellum, and located in the NF1gene locus in 17q11.2, a region linked to autism. We carried out a genetic analysis of the coding sequence of RFN135in a French cohort of patients with autism and observed a significantly increased frequency of genotypes carrying the rare allele of the rs111902263 (p.R115K) missense variant in patients (P=0.0019, odds ratio: 4.23, 95% confidence interval: 1.87–9.57). Particularly, three unrelated patients showed a homozygous genotype for K115, a situation not observed in the 1812 control individuals. Further cellular and molecular studies are required to elucidate the role of this gene and the variant K115 in brain development and neuronal function.

AbstractThe aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p < 0.05). This increase was limited to ASD children aged ≤8 years (p < 0.01), and not older (p  0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

Background: Vaccination of asymptomatic human immunodeficiency virus (HIV)-infected patients with a CD4 cell count ® 200/mm3 is strongly suggested prior to travel to a region where yellow fever (YF) is endemic. However, few data describing YF vaccination in such patients are available. Methods: In this retrospective observational study of 23 HIV-infected patients, YF antibody titers, CD4 cell counts, and viral loads were measured before and after vaccination. Serologies were performed retrospectively on samples that had been stored as part of routine hospital procedures. Results: Ninety-three percent of patients (13/14) with no baseline immunity, seroconverted after vaccination. Immunogenicity appeared slowly; only 2 of the 5 patients tested within 5 weeks of vaccination had seroconverted. A booster effect was noted in 3 of the 9 patients with baseline immunogenicity. Finally, due to unawareness of his HIV status, one patient was vaccinated and was found later to have a CD4 cell count < 200/mm3. The YF vaccine was well tolerated and no serious adverse events were reported. The impact of vaccination on immunologic and viral parameters was variable. Both decreases (n 7) and increases (n 5) in CD4 cell counts were recorded. Viral loads became undetectable in 2 patients and doubled or became positive in 3 patients. Conclusions: Yellow fever vaccination was safe and effective in a large majority of this cohort of stable, HIV-infected patients.

Engagement of surface receptors contributes to the antimicrobial activity of human immune cells. We show here that infection of human monocyte-derived macrophages (MDM) with live Mycobacterium avium induced the expression of CD23 on their membrane. Subsequent cross-linking of surface CD23 by appropriate ligands induced a dose-dependent antibacterial activity of MDM and the elimination of most infected cells. The stimulation of inducible nitric oxide synthase-dependent generation of NO from MDM after CD23 activation played a major role during their anti-M. avium activity. CD23 activation also induced tumor necrosis factor alpha (TNF-) production from MDM. Mycobacteria reduction was partially inhibited by the addition of neutralizing anti-TNF- antibody to cell cultures without affecting NO levels, which suggested the role of this cytokine for optimal antimicrobial activity. Finally, interleukin-10, a Th2 cytokine known to downregulate CD23 pathway, is shown to decrease NO generation and mycobacteria elimination by macrophages. Therefore, (i) infection with M. avium promotes functional surface CD23 expression on human macrophages and (ii) subsequent signaling of this molecule contributes to the antimicrobial activity of these cells through an NO- and TNF--dependent pathway. This study reveals a new human immune response mechanism to counter mycobacterial infection involving CD23 and its related ligands.

RNA interference strategies using small interfering RNA is one of the most important discoveries in biology in recent years. This technology alongside antisense oligonucleotides is very promising and our group has focused its work on the targeting of junction oncogenes with these molecules. We have taken, as first example, papillary thyroid carcinoma. But there is a great need in delivery methods for these molecules in the treatment of cancers. Indeed, many studies have shown that small interfering RNA and antisense oligonucleotides are made efficient by various innovative delivery methods and, under these conditions, offer a powerful new therapeutic tool in cancer treatment.

Overexpression of RhoA in cancer indicates a poor prognosis, because of increased tumor cell proliferation and invasion and tumor angiogenesis. We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways. This study reports the efficacy and lack of toxicity of intravenously administered encapsulated anti-RhoA siRNA in chitosan-coated polyisohexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancers (MDA-MB-231). The siRNA was administered every 3 days at a dose of 150 or 1500 µg/kg body weight in nude mice. This treatment inhibited the growth of tumors by 90% in the 150-µg group and by even more in the 1500-µg group. Necrotic areas were observed in tumors from animals treated with anti-RhoA siRNA at 1500 µg/kg, resulting from angiogenesis inhibition. In addition, this therapy was found to be devoid of toxic effects, as evidenced by similarities between control and treated animals for the following parameters: body weight gain; biochemical markers of hepatic, renal, and pancreatic function; and macroscopic appearance of organs after 30 days of treatment. Because of its efficacy and the absence of toxicity, it is suggested that this strategy of anti-RhoA siRNA holds significant promise for the treatment of aggressive cancers.

The cytogenetic abnormality of Ewing's sarcoma is related to the presence of a balanced t(11;22) translocation expressing the EWS-Fli1 chimeric fusion protein. Oligonucleotides (ODNs) are specific compounds that inhibit gene expression at the transcriptional level. They possess a poor bioavailability and are degraded by nucleases very rapidly. Therefore, there is a strong need for the development of ODN drug delivery systems. In the present study, polyisobutylcyanoacrylate nanocapsules entrapping ODNs in their aqueous core were prepared, with high encapsulation yield (99%). Previous studies have demonstrated that such complexes were able to inhibit tumor growth in mice. Nevertheless, no information was available about their mode of action at the cellular level. The aim of this study was to investigate the efficacy of these ODN nanocapsules on cultured tumor cells. We found that nanocapsules were capable of protecting ODN against degradation. Using confocal microscopy, we observed that cell uptake and nuclear accumulation of ODNs were importantly enhanced when ODNs were associated with these nanocapsules. Consequently, a specific cellular growth inhibition and suppression of EWSFli1 fusion gene expression was noticed. In conclusion, it was demonstrated that nanocapsules as nonviral vectors show great potential for the delivery of ODNs to cells.

The EWS–Fli1fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS–Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS–Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivoon a mice xenografted EWS–Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS–Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.The EWS–Fli1fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS–Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS–Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivoon a mice xenografted EWS–Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS–Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.

The genetic hallmark of the Ewing sarcoma family of tumours (ESFT) is the presence of the t(11;22)(q24;q12) translocation, present in up to 85% of cases of ESFT, which creates the EWS/FLI1 fusion gene and results in the expression of a chimeric protein regulating many other genes. The inhibition of this protein by antisense strategies has shown its predominant role in the transformed phenotype of Ewing cells. In addition, the junction point at the mRNA level offers a target for short therapeutic nucleic acids that is present only in the cancer cells and not in the normal tissues of a patient. Several teams have, therefore, investigated the activity of antisense oligonucleotides and siRNAs targeted against the junction point in mRNA; thus, inhibiting EWS/FLI1 synthesis. Generally speaking, the molecules induce a cell growth inhibition in culture. Apoptosis has also been reported. One laboratory has reported the in vivo tumour inhibitory effect of phosphorothioate antisense oligonucleotide directed against the EWS part of EWS/FlI1 when injected intratumourally. Independently, a tumour inhibitory effect of oligonucleotides targeting the junction point has been demonstrated provided they are delivered by polymeric nanoparticles through the intratumoural route. Alongside this target, other genes participating to the maintenance of the transformed phenotype of Ewing cells have been downregulated by antisense strategies.

ABSTRACTIn addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-α and nitric oxide derivatives. In the present study, quercetin (3,3′,4′,5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiensedeath by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-α and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.

We have used structured antisense oligonucleotides (AON), which are protected against extra and intracellular degradation by their internal structure. We have shown that if correctly designed this structure does not prevent them from hybridizing to the mRNA target. This concept allows reducing the number of thioate groups in the oligonucleotide and therefore the potential toxicity. Junction oncogenes are found in cancers such as certain leukemias, Ewing sarcoma, and thyroid papillary carcinomas. Ewing sarcoma is a cancer of children and young adults with bone metastasis. It is caused by a chromosomic translocation t(11;22) (q24;q12) creating a fusion gene between the genes EWS and Fli-1 giving rise to a chimeric protein which is an unnatural transcription factor. Immortalized NIH3T3 cells transfected by the EWS-Fli-1 cDNA under the control of the LTR retroviral promoter-which do not undergo apoptosis and which became tumoral-were used for this study. As a model of Ewing sarcoma in nude mice, we have used permanently expressing human EWS-Fli-1 cells grafted to nude mice. The nanospheres or nanocapsules have been used to deliver two different AON: a phosphorothioate, and a structured chimeric AON, both targeted toward the junction area of EWS-Fli-1. Both types of AON-loaded nanoparticles inhibited the growth of the xenografted tumor after intratumoral injections into nude mice, whereas similar nanoparticles with control oligonucleotides had no effect. With AON in nanospheres, we have shown after 24 hours that the mRNA of EWS-Fli-1 was specifically down-regulated, confirming the antisense activity of the targeted AON.

The application of synthetic vectors for gene transfer has potential advantages over virus-based systems. Their use, however, is limited since they generally lack the efficiency of gene transfer achieved with recombinant viral vectors such as adenovirus. Polyamidoamine (PAMAM) and phosphorus-containing dendrimers (P-dendrimers) are specific polymers with a defined spherical structure. They bind to DNA through electrostatic interactions thus forming complexes that efficiently transfect cells in vitro. The influence of anionic oligomers (oligonucleotides, dextran sulfate) on dendrimer-mediated polyfection of cultured cells has been studied. Anionic oligomers have been found to increase significantly the capacity of the PAMAM and P-dendrimers for DNA delivery into cells when they were mixed with plasmid DNA before addition of dendrimers. The efficiency of the DNA/dendrimer penetration depends on the size, structure and charge of anionic oligomers. Our results represent an important step towards the optimisation of gene transfer mediated by two types of dendrimers. The use of anionic oligomers improves the efficiency of gene expression within cells. As a consequence, a very efficient cell polyfection can be achieved with a lower plasmid quantity for the PAMAM dendrimer greatly increasing the gene expression level for P-dendrimers. Copyright © 2002 John Wiley & Sons, Ltd.

Objectives:A representative sample of 1510 preschool children living in the Bandiagra circle (Mopti Region, Mali) was examined between March and April 1997 to determine the level of vitamin A deficiency.Methods:Using a randomized two level cluster sampling, 20 clusters of 75 children aged six months to six years were selected for evaluating xerophthalmia (XN night blindness and/or X1B Bitot spot). Concurrently stature and weight were determined. A semiquantitative seven-day dietary questionnaire was applied to the mothers of 484 infants to assess consumption of vitamin A rich foodstuffs. The prevalence of biochemical deficiency was attested using the Modified Relative Dose Response test (MRDR) on a sub-sample of 192.Results:Of the studied children, 4.3% (95% Confidence interval [CI]: 3.2–5.3) reported night blindness and 2% (95% CI: 1.3–2.7) had Bitot spots. Prevalence of xerophthalmia attested by at least one of these signs was 5.4% (95% CI: 4.2–6.5). The prevalence reached 10.5% at three years of age. The MRDR test proved abnormal in 77.1% of the subjects (95% CI: 70.3–82.7). Serum retinol was lower than 0.35 μmol/L in 43.8% (95.6% CI: 36.9–51.3) and less than 0.70 μmol/L in 92.7% of the children (95% CI: 87.8–95.8). Weekly consumption of vitamin A rich food was rare: 75.8% had not eaten any animal vitamin A rich food, and 22.1% had consumed less than seven times a vitamin A rich food of either vegetable or animal origin.Conclusions:These data define vitamin A deficiency as a severe public health problem in the Bandiagara area of Mali.

Prior to commencing a campaign to eliminate blinding trachoma in Mali, a national disease prevalence survey was conducted from March 1996 to June 1997. The prevalence of trachoma was estimated and potential risk factors were studied.

Objective:To assess the performance of weight related nutritional markers (reported involuntary weight loss greater than 10%, measured weight loss and body mass index-BMI-) in predicting HIV disease progression.Design:Multirisk cohort of HIV-1 infected patients.Method:The three nutritional variables were studied in Cox proportional hazard models as time dependant variables.Results:The sample included 2376 subjects (median follow up: 43.1 months), of those 675 experienced an AIDS defining event. After adjustment for well known prognostic factors, the reported weight loss greater than 10% tripled the risk of progression to clinical AIDS (Hazard ratio [HR] 3.0, 95% confidence interval [CI] 2.5–3.7). For measured weight loss under 5%, between 5% and 10% and greater than 10% of baseline weight compared with no weight loss, hazard ratios were respectively 1.8 (CI 1.5–2.2), 2.6 (CI 2.1–3.2) and 5.1 (CI 4.1–6.4). The relative risks of AIDS were 1.7 (CI 1.3–2.2) for BMI between 17 kg/m2and 18.5 kg/m2, 2.6 (CI 1.7–4.0) for BMI between 16 kg/m2and 17 kg/m2and 4.7 (CI 3.0–7.4) for BMI under 16 kg/m2.Comments:Even a limited weight loss measured at a given time during follow up increases the risk of HIV progression; moreover, a simple cross-sectionnal measure of BMI has a good predictive value for subsequent development of clinical disease.

EWS Fli-1, a fusion gene resulting from a t(11;22) translocation is found in 90% of both Ewing's sarcoma and primitive neuroectodermal tumor (PNET). In the present study, we show that recently developed polyisobutylcyanoacrylate nanocapsules with an aqueous core were able to encapsulate efficiently high amounts of phosphorothioate oligonucleotides (ODN) directed against EWS Fli-1 chimeric RNA. Release of these ODN in serum medium was shown to be biphasic which was explained by the presence of two types of nanocapsules able to release ODN with different kinetics. In addition, nanocapsules were found to provide protection of these oligonucleotides from the degradation in serum. These ODN nanocapsules permitted to obtain inhibition of Ewing sarcoma-related tumor in mice after intratumoral injection of a cumulative dose as low as 14.4 nanomoles. This new type of non viral vector shows great potential for in vivo administration of oligonucleotides.

Background:Although skin disorders associated with long-term sun exposure account for high morbidity, only few data on sun-related preclinical skin changes are available in the general population. Objective:In the present study we determined reference values for markers of photoaging in French adults, and we evaluated the relationship between photoaging, phototype, and both behavioral and environmental factors. Methods:The SU.VI.MAX trial is a multicenter, national intervention trial on 12,735 adults living in France. A transverse analysis was performed on the inclusion data of the sample of volunteers between 45 and 60 years of age who underwent skin evaluation in 1995: 3057 women and 3606 men. Skin was evaluated by means of the Larnier skin photoaging photographic scale and a sun reactive skin type classification derived from those proposed by Fitzpatrick in 1976 and Césarini in 1977. Results:The prevalence of skin photoaging, assessed as a dichotomous variable (from moderate/severe to very severe), was comparable in men and women in same age groups: in women, age group 45-49 years = 22%, 50-54 years = 36%, and 55-60 years = 42%; in men, age group 45-49 years = 17%, 50-54 years = 38%, and 55-60 years = 45%. After adjusting for body mass index, exposure to tobacco, and sunlight exposure, the only variables found to be related to skin photoaging in women were age (55-60 years age group: adjusted odds ratio [AOR] = 6.0, 95% confidence interval [CI] = 4.4-8.2), phototype IIIa, IIIb, and IV (AOR = 0.2, 95% CI = 0.1-0.4; AOR = 0.3, 95% CI = 0.2-0.6; and AOR = 0.4, 95% CI = 0.3-0.8; respectively), menopausal status (AOR = 1.4, 95% CI = 1.1-1.9), and geographic location (Southern France: AOR = 0.7, 95% CI = 0.6-0.9), with a more pronounced effect in lighter phototypes I-II and a protective impact related to southern locations. No relationship was found between the use of oral contraceptives and skin photoaging. The age effect was also found in men (55-60 years age group: AOR = 10.4, 95% CI = 8.3-13.1) and geographic location (Southern France: AOR = 0.8, 95% CI = 0.6-0.9), with a most pronounced effect in darker phototypes (phototypes IV: AOR = 2.8, 95% CI = 1.4-5.6). Conclusion:Our results suggest that the prevalence of skin photoaging in the adult French population is determined by age, sex, geographic location, and phototype. The continuation of this longitudinal study will allow for the investigation of the relationship between skin photoaging and the risk of the development of skin diseases. (J Am Acad Dermatol 2000;42:47-55.)

La pandémie de COVID-19 a révélé le besoin de nouveaux moyens de communication, moins institutionnels et plus accessibles, notamment pour atteindre les jeunes générations. Parmi ces nouveaux moyens, les bandes dessinées de vulgarisation scientifique sont particulièrement intéressantes pour expliquer au grand public des informations scientifiques complexes de manière simple et amusante. Des initiatives dessinées ont ainsi vu le jour à travers le monde entier. Nous présentons ici une initiative française de bande dessinée de vulgarisation scientifique intitulée « Coronaaah, c’est quoi ? ».

En Afrique, bien que le nombre total de décès dus a la COVID-19 semble plus faible quand dans les pays du nord, il existe peu de données sur la gravité de la maladie. Nous rapportons ici le tableau clinique et l’issue chez les malades infectés par le SARS-CoV-2 et suivis dans les centres de traitement COVID-19 (CTC) de deux pays d’Afrique de l’Ouest.

Même en période d’urgence épidémique, les essais cliniques randomisés restent la meilleure approche pour évaluer l’efficacité d’une intervention. Cependant différents défis méthodologiques se posent : pouvoir :

Clinicians and researchers have observed a degree of heterogeneity within the autistic syndrome which suggests different pathophysiological mechanisms. Greater understanding of this heterogeneity was sought by studying more homogeneous subpopulations according to developmental age (DA) within a large population of children with autism. The sample consisted of 145 children with autism (population P), and two subpopulations were determined according to DA criteria: DA < 2 years, population PDA-; DA? 2 years, population PDA+. An original multivariate descriptive statistical method, correspondence analysis, was applied to 13 behavioural data, followed by a classical hierarchical clustering method. In population P, four behaviour profiles were distinguished on the basis of three main functions: auditory perception, imitation and sensorimotility. The study of more homogeneous subpopulations according to DA revealed differences in the factorial structure of both subpopulations. In population PDA+ the main relevant behaviours defining profiles in autism were first abnormal reactivity to auditory stimuli, followed by imitation deficiences. However in population PDA-the main relevant behaviours were first stereotypies, followed by abnormal reactivity to auditory stimuli. Modification of the organization of behaviours in autism according to developmental age is clarified; unlike the auditory perception dimension, imitation and sensorimotor dimensions may be dependent on development. These results thus support the heterogeneity of the autistic syndrome and clarify some aspects of change and continuity in the expression of the disorders contained in this syndrome.