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Action on malaria: 16 new mosquito genomes sequenced

The complete genomes of 16 anopheline mosquito species from the five continents have just been sequenced. Ten years of research have enabled an international consortium, coordinated by the University of Michigan and University of Notre Dame (United States) and including researchers from the French Institute for Development Research (IRD) and Inserm, to publish in the 27 November 2014 issue of the journal Science the DNA sequence for these mosquitoes, which are vectors of malaria. These results lead the way to the development of comparative genomic studies, and will make it possible to improve strategies for vector control, which are essential to controlling the disease in the absence of a vaccine.Moustique

© IRD/ M. Dukhan : female mosquito : Anopheles sundaicus

Malaria causes over 600,000 deaths a year, mainly in Sub-Saharan Africa. The parasites, from the genus Plasmodium, are transmitted by mosquitoes of the genus Anopheles. Of the 450 Anopheles species on the planet, only a dozen are responsible for most of the transmission to humans.

In order to improve vector control strategies, researchers have devoted many years to decoding the genome of Anopheles species. That of the African mosquito, Anopheles gambiae, a major vector of malaria, has been available since 2002. Those of its South American (Anopheles darlingi) and Indian (Anopheles stephensi) homologues have been the subject of recent publications, in 2013 and 2014 respectively. Until now, the lack of knowledge on the genetic resources of other Anopheles species has restricted comparisons that would enable the identification the key features determining the ability of some mosquitoes to transmit the parasites.

10 years of North/South partnership

Led by the University of Michigan’s Broad Institute and the University of Notre Dame’s Eck Institute, over a period of 10 years the international consortium enlisted over a hundred researchers from 50 research institutes from the northern (United States, Europe) and southern (Africa, Asia, South America, Oceania, Australia) hemispheres.

The researchers studied Anopheles specimens from many regions in the world: Africa, Asia, Asia Minor, Central America and Oceania. They combined the most recent techniques for sequencing, assembly of genomes and of expressed genes, and chromosome mapping, using innovative methodologies for sequence analysis and genome comparison. Using this multidisciplinary approach, the researchers succeeded in sequencing and annotating the complete genomes of 16 new Anopheles species.

Strong genetic evolution in Anopheles

The sequenced genomes turned out to be very different, both in their composition and their general organisation. Thus their size varies from 135 to 275 million base pairs. Between 10,000 and 16,000 genes were identified per species. The first comparative analyses showed strong genetic peculiarities, including a high rate of molecular evolution compared with other insects (particularly Drosophila), and substantial genomic plasticity, with much gain and loss of genes (or entire groups of genes) in the course of evolution.

Analyses carried out on certain groups of genes involved in key elements of anopheline biology—such as reproduction, immune system, insecticide resistance, composition of the cuticle or saliva, odour perception or hormonal communication—enabled the researchers to identify a certain number of specific genes and traits acquired during evolution, which underpin the emergence of anthropophily[1] and parasite transmission in anophelines.

The knowledge of this genetic material improves the understanding of the mechanisms by which the vectors adapt to humans and their environment. The researchers now have new avenues of research for making their vector control strategies more effective, and controlling the transmission of malaria.

[1] Describes organisms (plant or animal) that live in contact with humans or in places they frequent.

Physical activity and prevention of falls in older people – A collective expert review by Inserm

With advancing age, every individual can be affected by sensory, motor, and cognitive defects, as well as by chronic illnesses. Past the age of 85 years, over three out of four French people state that their activities are limited. Falls, which are frequent events for older people, are part of the risk of losing autonomy and being admitted to an institution, and prove very costly in terms of quality of life and care. In an ageing population, prevention of falls and maintaining independence in daily activities are therefore major challenges for public health.

Inserm was asked by the French Ministry of Community, Youth Affairs and Sports to prepare a collective expert report that would provide a review of the scientific knowledge regarding the contribution of physical activity to the prevention of falls in older people.PhotoCP web© Fotolia

The authors of the collective expert report thus emphasise the beneficial effect of regular physical activity, centred on balance training, for all older subjects at varying risk of falling. To be tailored to the state of health and lifestyle of older people, physical exercise programmes should be better supervised and involve closer cooperation between players from the medical, non-profit and sports sectors.

Extracts:

Accidental falls in older people: current situation and consequences

The elderly population is a very heterogeneous group from a medical and functional point of view. From the age of 65 years, 15-20% of people living at home would be fragile. Moreover, fragility is associated with an increased risk of mortality and insults such as falls.

In France, according to the permanent survey on everyday accidents, falls represented 90% of everyday accidents recorded among the over 75s by the emergency services in 2009. 20-33% of people aged 65 years or older report having fallen in the previous year. Of those who had fallen, half would have fallen at least twice that year. Moreover, falls are the main cause of physical trauma among the over 70s.

Physical exercise contributes to reducing the frequency and risk of falling

The most effective exercise programmes are those centred on balance training. Generally, those that include balance exercises lead to a significant reduction in risk of falling in the order of 25%. Nonetheless, muscle strength training and endurance improvement contribute to the maintenance of functional abilities, and have effects that complement balance training in preventing falls. For older people living at home, programmes based on several types of physical activity exercises are effective in both reducing the rate of falls, the risk of falling, and the risk of fractures.

Physical activity: a solution for maintaining autonomy in older people

Older people who devote time to a physical activity have a better perception of their general health, vitality, and mental and physical condition.

RECOMMENDATIONS

Recommended actions by the authors of this collective expert report include three main objectives:

– Develop physical exercise programmes suited to the state of health of the older subject;
– Encourage the implementation of physical activity programmes;
– Educate people about falls, and identify and care for older people at risk.

The authors of the present expert report have also formulated several recommendations for research:

– Carry out studies making it possible to specify optimum programmes in terms of efficacy and acceptability, especially for the oldest, least mobile and most fragile people;
– Perform cost-effectiveness analyses of prevention programmes; analyse the incidence and consequences of falls in France;
– Elucidate the basic mechanisms underlying risk factors for falls; 
– Assess the psychological and behavioural aspects of risk of falling associated with the fear of falling;
– Better define the facilitators and impediments to participation in physical activity by older people.

Anne Dejean-Assémat, is awarded the Inserm Grand Prix for 2014

The annual Inserm awards ceremony for medical research will take place on 3 December 2014 at the Collège de France, in the presence of Marisol Touraine, Minister for Social Affairs and Health, Geneviève Fioraso, Secretary of State for Higher Education and Research, and Yves Lévy, Chairman and Chief Executive Officer of Inserm. Eight prizes will be awarded to eminent scientists who contribute through their work to advances in research and to the excellence of the Institute. The ceremony will conclude an exceptional year, marked by over a hundred events celebrating the 50th anniversary of Inserm.

The event will be streamed live on the Inserm website.

The Inserm Grand Prix is awarded to Anne Dejean-Assémat, director of Inserm/Institut Pasteur Joint Unit 993 “Nuclear Organization and Oncogenesis,” for her entire body of research on the molecular and cellular mechanisms involved in the development of human cancers. PhotoCP webAnne Dejean-Assémat ©Inserm

This researcher established the mutagenic role of hepatitis B virus in liver cancer. She identified one of the main receptors for retinoic acid (RAR), the active form of vitamin A, and subsequently demonstrated its role in some human cancers.

By discovering the systematic alteration of the receptor for this acid in patients with acute promyelocytic leukaemias, and the associated cellular alteration, Anne Dejean-Assémat and her colleagues clarified the molecular and cellular basis for leukaemogenesis, and made it possible to shed light on the mechanisms involved in the effective treatment of this type of leukaemia. These observations are a most illustrative example of targeted cancer therapy.


Since 2004, an Honorary Prize and an International Prize have been awarded, as a tribute to the careers of particularly eminent scientists. The 2014 Honorary Prize will be awarded to William Vainchenker (Inserm/ Institut Gustave-Roussy/University Paris-Sud Unit 1009), and the International Prize will be awarded to Sir Leszek Borysiewicz (University of Cambridge, UK).

Research Awards distinguish researchers, lecturer-researchers and clinician-researchers whose work has marked the area of basic research, clinical and therapeutic research, and public health research. The 2014 laureates are Nadine Cerf-Bensussan (Inserm/ Paris-Descartes University Unit 1163) and Hélène Dollfus (Inserm/University of Strasbourg Unit 1112).

Innovation prizes reward engineers, technicians or administrators for original achievements in the service of supporting research. The 2014 laureates are Frédéric De Bock (Inserm/CNRS/Montpellier Universities 1 and 2 Unit 661) and Mathieu Ducros (Inserm/Paris-Descartes University Unit 1128).

Since 2013, an Opecst-Inserm Award has been jointly awarded by the French Parliamentary Office for the Evaluation of Scientific and Technological Choices and Inserm. It is aimed at rewarding a researcher for his/her involvement in developing the results of research. The 2014 laureate is Mickaël Tanter (Inserm/CNRS/ESPCI de Paris Unit 979).

Further information:

The detailed biography of Anne Dejean-Assémat can be consulted on the French Académie des Sciences website

Photos of the laureates can be downloaded from Serimedis, the Inserm image gallery

Films devoted to the work of the laureates will be available from 4 December on Serimedis

 

 

Stroke (CVA) in young adults: discovery of a susceptibility gene associated with bleeding of the cervical arteries

Researchers from the joint research unit “Public health and molecular epidemiology of aging related diseases” (Inserm/Institut Pasteur Lille/Université Lille 2), in collaboration with Lille Regional University Hospital (CHRU), have discovered a susceptibility gene involved in this major cause of stroke (cerebrovascular accident) in young subjects. This gene, PHACTR1, is also known to be associated with the occurrence of migraine and myocardial infarction. This international study, carried out by the CADISP[1] international consortium and published in the journal Nature Genetics, shows that a form of the gene is associated with a reduced risk of developing a dissection of the cervical arteries responsible for the bleeding that leads to stroke. This work opens up new possibilities for identifying people at risk, and trying to prevent the occurrence of stroke in young adults.
PhotoCP web

Stroke (CVA) ©Inserm/U919

Cervical artery dissection is a major cause of stroke in young subjects. It involves bleeding within the lining of the carotid or vertebral artery walls, which causes longitudinal “splitting” (hence the term dissection) without rupturing the vessel. This bleeding gives rise to a haematoma, which reduces the diameter of the artery and may lead to its closure. Often, the formation of a blood clot inside the artery thus completely stops the flow of blood to the brain, resulting in a cerebrovascular accident, or stroke.

The causes of these dissections are still unknown. The current prevailing hypothesis is of a multifactorial disease, possibly related to a pre-existing abnormality in the elasticity of the blood vessel walls. We observe associated factors in these patients, such as migraine, high blood pressure, infections or recent, sometimes minor, trauma (carrying heavy loads, a fall from a bicycle, neck extension due to acceleration in some roller-coaster rides, blows to the nape of the neck, etc.). In the vast majority of cases, cervical artery dissection occurs in the absence of any family history or underlying hereditary disease. However, several hypotheses favour individual susceptibility to arterial dissection, encoded by the genome. This was the context for launching the CADISP consortium, in order to initiate the largest study ever conducted in the area, and thereby systematically screen our genome and discover the basis for this individual genetic susceptibility.

A total of twelve countries, comprising ten European countries, the United States and Russia, were able to bring together 2,052 patients with dissection, and compare their genomes with those of 17,064 unaffected individuals. The researchers and physicians were able to demonstrate that a particular form of the PHACTR1 gene was associated with a reduced risk of developing a cervical artery dissection. This same form of the PHACTR1 gene has been associated with a reduced risk of migraine and an increased risk of myocardial infarction in other studies. The researchers also identified two other genes that are potentially associated with the risk of dissection: the LRP1 gene, already associated with migraine and abdominal aorta aneurysm, and the LNX1 gene, both of which need further confirmation.

“Given the difficult diagnosis and seriousness of this disease, the characterisation of the genetic susceptibility gene PHACTR1 will help to provide a better understanding of the mechanisms leading to the occurrence of these dissections,” explains Stéphanie Debette, neurologist, first author of the article and coordinator of the CADISP international consortium.

“By pooling research efforts on a worldwide scale, we hope to succeed in more rapidly identifying people at risk, and find solutions in order to prevent the main functional consequences associated with the occurrence of stroke in the young adult,” concludes Philippe Amouyel, epidemiologist, director of the joint research unit involving Inserm, Institut Pasteur Lille and Université Lille 2.

These results have been obtained with the help of all the clinicians and their patients, and the genotyping and analysis facilities of the French National Genotyping Centre of the French Atomic Energy and Alternative Energies Commission (CEA), the Human Polymorphism Study Center (CEPH) and the Institut Pasteur Lille.

[1] Cervical Artery Dissections and Ischemic Stroke Patients

To find out more :

Cervical artery dissection: what are the signs?
This pathological phenomenon affects young adults, both men and women, around the age of 40 years, with few or no vascular risk factors. It presents as pain at the location of dissection, generally in the neck region, or unusual headaches. In most cases, concurrently or in the following hours, characteristic symptoms of stroke (paralysis, loss of sensation, loss of speech, reduced field of vision, etc.) appear. The frequency of these dissections is approximately 2.5 to 3 per 100,000 inhabitants per year, which makes it a rare disease, and now thought to be underestimated.

Pirate viruses caught in their own trap ?

In order to infect a host cell and proliferate, some viruses, such as the hepatitis C virus, infiltrate the ribosomes, the molecular machines that assemble the proteins present in each of our cells. Viral proteins are thus produced to the detriment of cellular proteins. A group of scientists in Strasbourg has demonstrated that one of the 80 components of each ribosome is essential for infection by certain viruses without being necessary for normal cell functioning. This discovery, which may result in the development of new therapeutic strategies, was made by scientists in the Laboratoire Réponse Immunitaire et Développement chez les Insectes (CNRS) and the Institut de Recherche sur les Maladies Virales et Hépatiques (INSERM/Université de Strasbourg)1, with support from the ANRS, among others. It is the subject of an article published in Cell on 20 November 2014.

A viral infection can be treated by blocking certain viral components. However, these are far less numerous than the host cellular proteins with which they interact. Furthermore, these factors mutate much more easily and can therefore escape treatment. For these reasons, virologists are seeking to develop antiviral agents that can target these cellular proteins (or factors). But there is one downside, and it is considerable: the factors targeted by this strategy often play a crucial role in the cell, causing adverse effects.

In this context, a group of scientists in Strasbourg (France) has identified a promising cell component called RACK1 in the ribosome, the complex cellular machinery where proteins are  assembled. RACK1 could become the target for new types of antiviral therapies as it has been shown to be necessary for the infection of cells by certain viruses — but not essential for normal cell functioning.

The ribosome is an assembly line for proteins, made of amino acids whose alignment is determined by the genetic message the ribosome can read (contained in messenger RNA molecules). The strategy deployed by numerous viruses in order to replicate consists in entering the ribosome of an infected cell, thus forcing the manufacture of their own proteins, to the detriment of cellular proteins. This leads to the production of new viral particles that can infect other cells, and so on. The present study has shown that among the 80 or so sub-units that make up the ribosome, RACK1 is a portal of entry for several viruses, including hepatitis C. More remarkable still is the fact that most cellular mRNA can be translated into proteins in a RACK1-depleted ribosome, while this sub-unit is essential for the RNA translation — and hence the replication— of certain viruses.

The scientists made this discovery by working on the fruit fly (Drosophila melanogaster). RACK1 -depleted adult flies survived normally but could no longer be infected by certain insect viruses. The same observation was made relative to human cells in culture:the absence of RACK1 did not compromise their survival or replication, but prevented infection by the hepatitis C virus. And this may be valid for other viruses that adopt the same cell piracy strategy (such as polio and foot-and-mouth viruses or enteroviruses, etc.).

This discovery thus opens the way towards new therapeutic opportunities based on inhibiting this viral junction point on the cell ribosome. The fact that this mechanism can be used by viruses of markedly different types suggests that it may be possible to develop treatments with a broad spectrum of action that can be used to combat viral infections in insects, animals and humans.

However, if the RACK1 protein is conserved in species as different as the fruit fly and humans, it is probably because it has a function in these organisms. Indeed, although the adults are viable, RACK1- depleted fruit fly larvae and mouse embryos do not survive beyond a certain developmental stage. This means that cellular mRNA deployed in specific situations require RACK1 for their translation. Identifying the conditions under which RACK1 is useful to cells will therefore be crucial before it can be used as a therapeutic target.

At a fundamental level, these findings show that the translation of RNAs into proteins is more complex than previously thought. But they provide opportunities to elucidate the “ribosomal code” (superimposed on the genetic code and on other mechanisms that regulate gene expression); depending on the composition and structure of the ribosome, some RNAs may be selectively translated, and others not. The clues in favor of such a code are accumulating, but it now needs to be deciphered.

This work received support notably from the ANRS (France REcherche Nord&sud Sida – Hiv Hépatites), the FRM (Fondation pour la Recherche Médicale), the Fondation ARC for cancer research and the Institut Hospitalo-Universitaire de Strasbourg Mix-Surg.

1) in collaboration with the Laboratoire Architecture et Réactivité de l’ARN (CNRS) and the Laboratoire Spectrométrie de Masse Biologique et Protéomique (CNRS/ESPCI ParisTech).

2) These viruses have evolved in order to circumvent the antiviral strategies of cells. Their mRNAs contain an internal motif (called IRES:internal ribosome entry site),which recruits the ribosomes.
virus DCV drosophila CNRS - Jean luc imler


>Preparation of the DCV (Drosophila C virus) used during the study. © Jean-Luc Imler<


This image is available from the CNRS photo library (rf.srnc@euqehtotohp)

Launch of GrippeNet.fr 2014-2015 season

Public participation in online influenza surveillance


Launched 3 years ago by the Sentinelles Network (Inserm–Pierre and Marie Curie University Joint Research Unit 1136) and the French Institute for Public Health Surveillance (InVS), the GrippeNet.fr website returns for a fourth consecutive year.

GrippeNet.fr complements the traditional surveillance systems for influenza, which are fed information collected in private physician practices and hospitals. These data enable research initiatives (at European as well as national level) aimed at gaining a better understanding of influenza (research on risk factors, the role of age, demand for health care, impact of vaccination, spread of the disease at European level, etc.), and help to monitor changes in the epidemic over time within the population.

The principle of the GrippeNet.fr website is to enable anyone living in metropolitan France, and who wishes to participate in influenza surveillance, whether ill or not, to do so anonymously and voluntarily, regardless of age, nationality or state of health.

GrippeNet version EN

Review of the last season

During the 2013-2014 season, GrippeNet.fr enabled the collection of a large amount of data regarding influenza, over a 5-month period (from 13 November 2013 to 13 April 2014). Although the number of participants remained stable, with 6,000 Internet users, weekly participation increased, with an average of 4,000 questionnaires completed each week (compared with 3,700 during the 2012-2013 season). This season showed an increased retention of participants in the GrippeNet.fr study.

During the 2013-2014 season, 24% of participants reported symptoms consistent with an influenza-like illness (compared with 29% during the 2012-2013 season), which may reflect the short duration of the influenza epidemic. The latter only lasted 5 weeks, and is one of the shortest epidemics recorded by the Sentinelles network. Only 42% of participants with an influenza-like illness consulted a health professional. (More information available at review of 2013-2014 season).

The new season, 2014-2015

Spotlight on pregnant women, a population at risk of developing influenza-related complications

Influenza can have serious consequences for the mother and her infant during pregnancy. Since 2012, influenza vaccination has therefore been recommended in France for all pregnant women. In practice, however, it is difficult to assess whether this recommendation is being closely followed.

As well as the usual monitoring of the general population, specific surveillance of pregnant women has been put in place this year. Project G-GrippeNet is aimed at estimating the frequency of influenza in this particular population, and the number of women vaccinated for influenza during their pregnancy in France. This study is the very first use of the GrippeNet.fr tool to monitor one population in particular.

Once she has created her personal account on www.grippenet.fr, the mother-to-be will complete the first enrolment questionnaire, in which she will reply “yes” to the question “Are you pregnant?” Every week, she will then be invited to complete a questionnaire on symptoms (identical to that on GrippeNet.fr). Another will also be made available to her if she wishes to report the occurrence of a particular event during her pregnancy, or report that she has had her baby. Participants will also receive a monthly newsletter dealing with a pregnancy-related health topic.

In order for GrippeNet.fr estimates to be as reliable as possible, large-scale participation by the population is essential. This makes it possible to study changes in the influenza epidemic over time for different population categories, especially men and young participants, who have been under-represented in past seasons, and now pregnant women. Everyone is invited to participate, regardless of his/her state of health (not susceptible to winter infections, or often sick in winter), age, profession, etc.


Recap of the GrippeNet.fr project

This surveillance system was launched at the end of January 2012 by the Sentinelles network (an Inserm–Pierre and Marie Curie University joint research unit) and the French Institute for Public Health Surveillance (InVS).

The GrippeNet.fr system enables the collection of epidemiological data on influenza directly from members of the public in metropolitan France using the Internet. Data compiled by GrippeNet.fr are not intended to replace information validated by health professionals, but provide complementary information, especially on patients who do not consult health facilities.

Participation in GrippeNet.fr, takes only a few minutes. When registering on the website, only an email address is required. After completing a questionnaire, the participant is invited each week to complete a short questionnaire summarising the symptoms s/he has or has not experienced since last logging in (fever, cough, etc.). These anonymous data are immediately analysed, and contribute in real time to influenza surveillance in France. Participation in this programme is not, of course, a substitute for a visit to one’s GP.

GrippeNet.fr is a project funded by the French National Research Agency (ANR) under the HARMS-flu project (Harmonising Multiple Scales for Approaches to the Modelling of Influenza Spread in France). GrippeNet.fr is part of a European population-based approach for the surveillance of influenza-like illness, Influenzanet. For this new season, 8 other European countries have systems comparable to GrippeNet.fr, and over 40,000 Europeans participated in this surveillance during the 2013-2014 season.



A better understanding of accidents in everyday life

During their lives, every French person will be the victim of one accident in everyday life every 5 years, on average (fall, burn, drowning, etc.). Taken as a whole, these statistics represent 11 million people injured every year. The Accident Prevention and Trauma Treatment team led by Emmanuel Lagarde (Inserm Unit 897 ‘Institute of Public Health, Epidemiology and Development’/University of Bordeaux), in partnership with Calyxis, is today launching the MAVIE study to find out the scale and nature of accidents in everyday life in France. The researchers hope to be able to identify the factors associated with their occurrence and severity, by taking a representative sample of 100,000 French people.



Accidents in everyday life represent all unintentional injuries (excluding road traffic and occupational accidents). In particular they include domestic, sports, leisure and school accidents. Every year these accidents resulted in 11 million injured people, including 5 million requiring emergency treatment. They are also responsible for nearly 20,000 deaths, equivalent to five times more than casualties of road traffic accidents. Among them, the greatest number were victims to falls, suffocation and poisoning.

However, these accidents are still very poorly understood or studied.

Accidents in everyday life: statistics to be updated
The following table presents the annual statistics for accidents in everyday life in France. These data come from studies by Inserm, by the health watchdog of the French National Institute for Accident Prevention and Health Education, as well as studies carried out by the French Institute for Public Health Surveillance, such as the Permanent Survey of Accidents in Everyday Life. However, it is proving essential to update these data.

Sans titre
In France, we have information about the types of these accidents, but little data about the variables explaining them‘, highlights Emmanuel Lagarde, Inserm Research Director.

A cohort study to better understand these ‘invisible’ accidents
The MAVIE study will rely on information collected from a large number of volunteers monitored over several years: in this case, 100,000participants. The methods are therefore based on thorough collection of data reported or observed prior to the accident occurring, such as the domestic environment, habits and lifestyles and, finally, the patient’s health. These data are essential to a better understanding of accidents in everyday life. They would enable priority intervention programmes to be put forward to reduce the number of victims.

The goal is to answer these big questions:
– What are these accidents?
– When, how and where do they occur?
– What factors are associated with their occurrence and severity?
– How can they be prevented?
– What is the outcome for the victims?

How do you volunteer?
100,000 people are needed to take part in the MAVIE study. You can enrol as a household, on the site www.observatoire-mavie.com. The enrolment questionnaire comprises a general description of the household, habits and lifestyles, and secondly a description of each individual member of the household. Quarterly reminders will be used to compile a summary of any accidents occurring in the household.

 To find out more
The press pack and volunteer recruitment campaign displays (posters, flyers, banners) are available and downloadable opposite http://we.tl/jxoAoADQdQ.

For the launch of the MAVIE study, personal accounts may be reported exceptionally from victims of accidents in everyday life at the Accident & Emergency Dept of Bordeaux University Hospital. Don’t hesitate to contact us.


PhotoCP web

© Affiche observatoire MAVIE

Avoiding skin graft rejection: it’s possible!

A research team bringing together José Cohen and Philippe Grimbert (Inserm Unit 955/Université Paris Est Créteil [UPEC] and the Centre for Clinical Investigation – Biotherapies 504 [CIC-BT 504]), and their collaborators at Institut Curie and AP-HP (George Pompidou European Hospital) has succeeded in finding a combination of drugs that reduces the risk of rejection following a skin graft. When tested in mice, this treatment seems effective, since no sign of rejection is observed nearly 30 days after transplantation.
These results are published in the American Journal of Transplantation.


peau

©fotolia


For physicians and researchers, a major challenge of transplantation is avoiding rejection of the transplanted organ or tissue by the recipient’s body. During allogeneic transplantation (i.e. of a graft from donor A into a different recipient, B), the immune system of the recipient recognises the graft as a foreign component. It then makes every effort to destroy it in the same way as it would, for example, destroy an infecting virus. To avoid this phenomenon, physicians administer immunosuppressive drugs to make the recipient’s immune system more tolerant. As with every treatment, there are drawbacks: the recipient’s vulnerability to infections is increased, and the treatment may have toxic effects on other organs (kidney). For the last 30 years, there has been little progress in this area of research. The optimisation of these treatments is therefore central to the current efforts.

Inserm researchers under the leadership of José Cohen became interested in a drug with special properties, namely the cytokine interleukin 2 (IL-2). This drug is already used in some treatments for cancer and type 1 diabetes. In cancer, administration of IL-2 in high doses increases antitumour activity by boosting the immune system. Interestingly, Eliane Piaggio, a co-author of this study, had shown that when administered at very low doses in type 1 diabetes, it has the opposite effect. IL-2 thus impedes the action of the immune system, which reacts too strongly against self in this disease.

Given that, in transplantation, the immune response is too strong, the researchers hypothesised that administration of IL-2 might impede the action of the immune system (by analogy with its action in type 1 diabetes), and might therefore reduce graft rejection.

“Our initial experiments proved negative: IL-2 used alone did not give the expected results,” explains José Cohen. “We had to redirect our efforts and our attention to the specific functioning of 2 types of cells from the immune system, namely the regulatory T lymphocytes controlled by IL-2, and the “classical” T lymphocytes.”

The immune system is composed of several categories of cells, each with a specific role in maintaining its balance: it must not be too aggressive or too tolerant. Generally, regulatory T lymphocytes, as their name indicates, act on the other populations of classical T lymphocytes to prevent them from over-reacting. Hence the initial idea of boosting their activity via IL-2. However, this strategy turned out to be inadequate.

The researchers therefore used IL-2 in combination with rapamycin, which has the ability to inhibit the division of classical T lymphocytes. Using this combination, the researchers managed to doubly control the classical T lymphocytes: directly using rapamycin and indirectly using IL-2 (via the regulatory T lymphocytes). Graft rejection was thereby avoided.

“Skin grafting in mice is the most difficult experimental model to control. In our experiment, mice show no sign of rejection 30 days following a skin graft. This is very encouraging when we know that this rejection usually occurs in 10 days: the tissue becomes irreversibly necrotic.”

These results are a first step before clinical evaluation. An advantage of these two drugs is that they have marketing authorisation for use in humans. If the next steps are successful, especially in the liver transplant model, their use in the area of transplantation (any kind of transplantation) might soon begin.

MSF and Inserm join their forces against Ebola : first trials

In the absence of specific treatments for Ebola, international medical humanitarian organisation Médecins Sans Frontières/Doctors Without Borders (MSF) announced today that it will host clinical trials in three Ebola treatment centres in West Africa. The separate trials, which are aimed at quickly finding an effective therapy that can be used against the disease which has so far taken around 5,000 lives in the current outbreak in the region, will be led by three different research partners.

See the press conference

The French National Institute of Health and Medical Research (INSERM) will lead a trial using antiviral drug favipiravir in Guéckédou, Guinea; the Antwerp Institute of Tropical Medicine (ITM) will lead a trial of convalescent whole blood and plasma therapy at the Donka Ebola centre in Conakry, Guinea; and The University of Oxford will lead, on behalf of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), a Wellcome Trust-funded trial of the antiviral drug brincidofovir at a site yet to be determined. The World Health Organization (WHO) and health authorities of the affected countries are also taking part in this collaborative effort.

“This is an unprecedented international partnership which represents hope for patients to finally get a real treatment against a disease that today kills between 50 and 80% of those infected,” said Dr Annick Antierens, who coordinates the investigational partnerships for MSF. “As one of the principal providers of medical care to Ebola patients in West Africa, MSF is taking part in these accelerated clinical trials to give people affected by the current outbreak a better chance of survival.”

The trials’ protocols are in the final stages of development and are designed with a simple target of 14-day survival and with broad inclusion criteria. The protocols will ensure that disruption to patient care will be minimal, that internationally-accepted medical and research ethical standards are respected, and that sound scientific data will be produced and shared for public good. The main principles and designs have been shared with the respective countries’ ethical authorities, with the goal of starting the first trials during December 2014. Initial results could be available in February 2015.

The two drugs, brincidofovir and favipiravir, were selected from WHO’s shortlist of potential Ebola treatments after careful review of safety and efficacy profiles, product availability, and ease of administration to patients.

Professor Peter Horby, the Chief Investigator of the ISARIC-led trial, said, “Conducting clinical trials of investigational drugs in the midst of a humanitarian crisis is a new experience for all of us, but we are determined not to fail the people of West Africa. It has been a privilege to witness the extraordinary willingness of all the partners in this initiative to step outside their comfort zones in order to fast track these critically important trials.”

“These three trials are part of the first phase of a research aimed at finding the best treatment to cure patients with Ebola,” said Professor Denis Malvy, who will lead the INSERM trial in Guinea. “The three trial boards will therefore be coordinated in a very reactive way, so that any new fact can be discussed rapidly and our research plans can be adapted accordingly. Strengthening the link between our teams is all the more important as there is the possibility that, should our trials give positive results, the next phase could consist of combining interventions.”

Trial of convalescent whole blood and plasma therapy will consist of administering blood or plasma, containing antibodies from survivors, to infected patients. This approach is also endorsed by WHO.

“Convalescent plasma from recovered patients, containing antibodies against pathogens, has been safely used for other infectious diseases,” said ITM’s Johan van Griensven, coordinating investigator of the trial. “We want to find out whether it works for Ebola, whether it is safe and whether it can be scaled-up to reduce the number of deaths in the current outbreak. Close communication with people who recovered from Ebola, and the community at large, will be vital for a successful trial. We hope that recovered patients donating blood and plasma to help sick people could reduce fear of the disease and reduce stigmatisation of those who survived.”

When other experimental or off-label products with promising efficacy and safety data become available, they will be assessed with the view of proposing further trials in other MSF Ebola management centres in the region.

All three trials will prioritise community engagement and informed consent from patients or their representative. Each patient who consents to be part of a trial will have the potential risks of being subjected to a new therapy clearly explained. “We need to keep in mind that there is no guarantee that these therapies will be the miracle cure,” added MSF’s Dr Antierens. “But we need to do all we can to try the products available today to increase the chances of finding an effective treatment against Ebola.”

While clinical trials are underway, MSF is urging the drugs’ developers to scale up production supply now, to ensure there is no gap between the end of the trials and the large-scale introduction of products found to be safe and effective. MSF is also urging drug manufacturers to ensure that end products are affordable and available in the quantities needed to tackle the outbreak at its epicentre in West Africa. Distribution of end products should be driven by needs, irrespective of where people live or the capacity of a country to pay.

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For general interviews and questions regarding the sites, please contact MSF:

Yasmin Rabiyan gro.fsm.aveneg@nayibar.nimsay +41 79 441 8996

Sandra Smiley gro.fsm.nodnol@yelims.ardnas +32 471 71 58 69

For general interviews and questions specific to the individual trials, please contact:

At INSERM: Priscille Riviere rf.mresni@ereivir.ellicsirp +33 68 932 8774

At the University of Oxford: the News Office ku.ca.xo.nimda@eciffo.swen +44 1865 280530

At ITM: Roeland Scholtabers eb.gti@sreblatlohcsr +32 47 706 8384

November 14th 2014: World Diabetes Day

Diabetes type 1 or type 2 is a chronic disease caused by an insufficient mass of pancreatic beta cells, which produce insulin, or by poor use of this hormone by the body. This results in an elevated level of glucose in the bloodstream (hyperglycaemia), and may lead to serious complications (infarct, impaired vision, blindness, stroke, etc.).

Diabetes affects 347 million people worldwide. In 2012, it was the immediate cause of 1.5 million deaths.

Initiated in 1991 by the International Diabetes Federation and World Health Organization, World Diabetes Day is aimed at making the general public aware and informed about prevention and management.

Throughout the year, Inserm researchers work hard to try to better understand the mechanisms involved in order to prevent and treat the disease effectively.

The work of Raphael Scharfmann, Inserm Unit 1016, “Cochin Institute,” focuses on the mechanisms (development, growth, stability, destruction) that control the functional mass of human pancreatic beta cells.

“The development of functional human beta cell lines makes it possible to study specific forms of neonatal diabetes, and to understand the maintenance of the differentiated status of a human beta cell throughout life, as well as the mechanisms that bring about its destruction,” explains Raphael Scharfmann

These approaches could allow the characterisation of new drugs enabling these cells to function adequately for life.

 1 Insulin is a hormone that regulates the concentration of sugar in the bloodstream

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