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New bacteria to fight against intestinal inflammation

Nathalie Vergnolle, director of research at Inserm, and her team at the Centre for Physiopathology at Toulouse Purpan (CPTP Inserm / Université Toulouse III – Paul Sabatier /CNRS), with Philippe Langella director of research at INRA and his team at the Institut Micalis[1], in collaboration with the Institut Pasteur, have recently succeeded in producing “beneficial bacteria” capable of protecting the body against intestinal inflammation. This protection is provided by a human protein, Elafin, which is artificially introduced into dairy produce bacteria (Lactococcus lactis and Lactobacillus casei). In time, this discovery could be useful for individuals suffering from chronic inflammatory diseases such as Crohn’s disease or ulcerative colitis.

The results of this research were published in the Science Translational Medicine review on 31 October 2012.

InFrance, nearly 200,000 individuals suffer from chronic inflammatory bowel disease, known as IBD, (specifically Crohn’s disease and ulcerative colitis).  The occurrence rate of this type of disease continues to rise (8,000 new cases diagnosed per year). During inflammatory outbreaks, IBDs are chiefly characterised by abdominal pain, frequent diarrhoea (sometimes with bleeding) or even disorders in the anal area (fissure, abscesses). These symptoms mean that taboos are associated with these diseases.

Different avenues are being explored to explain the origin of IBDs, including the role of genetic or environmental factors. The intestinal flora seems to play an important role in the outbreak of inflammation, although little is known about it. Identifying an effective treatment is also at the heart of the investigations.

Researchers are focussing on a human protein, known for its anti-inflammatory proprieties: Elafin. Although this protein is found naturally in the intestine to protect it against attacks, it disappears in patients suffering from IBDs.

Their hypothesis? Administering Elafin directly into the intestine could protect against inflammatory attacks and restore intestinal equilibrium and its functions.

Using non-pathogenic bacteria found naturally in the intestine and food, scientists from Inserm and Inra have designed modified bacteria to produce Elafin. To this end, the human Elafin gene, isolated in collaboration with a team from the Institut Pasteau, was introduced in Lactococcus lactis and Lactobacillus casei, two food-grade bacteria found in dairy products.

Results in mice…

When administered orally to mice, the human Elafin-producing bacteria are found a few hours later on the surface of the intestine where they deliver the anti-inflammatory protein. In different mice models of chronic or acute intestinal inflammation, oral treatment using these Elafin-producing bacteria provided significant protection of the intestine and decreased inflammatory symptoms.

… and in humans

Elafin expressed by these bacteria also protects cultured human intestinal cell lines from inflammatory outbreaks similar to those observed in chronic inflammatory bowel diseases. Elafin produced in this way restores the equilibrium of intestinal mucus by reducing inflammation and accelerating cell healing processes.

Potential clinical applications

These results may result in a clinical application where Elafin would be administered to patients suffering from IBDs using beneficial bacteria (probiotic), which are already commonly found in food (yoghurt, cheese), thus protecting the patients from inflammatory symptoms. According to the researchers “This kind of secure treatment could even be used over the long-term, to treat inflammatory diseases”.

This research is protected by a patent and an exclusive licence assigned to an industrial partner, managed by Inserm Transfert.   


[1]  Institut MICrobiologie de l’ALImentation au Service dela Santé Humaine (INRA/AgroParisTech) in Jouy-en-Josas

The HOIL1 gene – the cause of a new rare disease

The researcher Capucine Picard, working with the team from Inserm unit 980 “Human genetics and infections diseases”/Université Paris Descartes under the leadership of Jean-Laurent Casanova, along  with researchers from a CNRS/Institut Pasteur laboratory headed by Alain Israël have succeeded in identifying the part played by the HOIL1 gene in cases of paradoxal association of an immune deficiency with a chronic autoinflammatory deficiency and a muscular deficiency in 3 children from 2 different families. This study once more highlights the importance of genetics in the body’s response to infectious agents. These works were published on line in the review Nature Immunology, of 28.10.12.

The science of genetics of infectious diseases arose from the observation that there is a wide variability of resistance to diseases from one person to another; that the same pathology could be fatal to one person, while benign or asymptomatic in others. The study also demonstrated that the predisposition to an infection is due to genetic particularities that result in variations in the molecular mechanisms of the immune response.

The 3 children, 2 of whom were monitored at the Hôpital Necker sick children’s hospital, suffered simultaneously from 3 pathologies: invasive bacterial infections (pneumococcus or other), an autoinflammatory disease (inherited recurring fevers) and amylopectinosis (a muscular deficiency that can affect the cardiac muscles in particular). The fact that 2 siblings suffered from the same symptoms drew the researchers’ attention to the hereditary genetic cause of this disease.

The team then carried out in-depth genetic studies in an attempt to identify the genetic defect responsible for these 3 observed pathologies: mutations of the HOIL1 gene.

Incomplete expression of this gene causes a dysfunction of the immune system. However, what makes this pathology unique is the fact that the genetic defect does not express in the same way, depending on the type of cells involved in the immune response. On the one had, this mutant gene is responsible for an over-reaction of leucocytes, which explains the autoinflammatory disease. On the other hand and quite to the contrary, this same genetic defect inhibits a response from other cells, which explains the susceptibility of these children to bacterial infections.

The HOIL1 molecule, derived from the gene of the same name, is responsible for an instability of the LUBAC complex that plays an important part in transmitting the signal received by the immune system cells in case of infection. This suggests that the genetic defect on HOIL1 in humans is responsible for a knock-on defect in the LUBAC complex, and that the LUBAC complex controls the immune response differently depending on the cell types involved.

Previously, the LUBAC complex had only been studied in mice. This is the first time that this deficiency has been detected in a human. For the moment, only 3 patients inFranceand inItalyhave been identified with this HOIL-1 deficiency. The discovery of this new genetic defect may allow us to identify new patients in other regions of the world.

New developments reveal a molecule with a promising function in terms of cancer treatment

©Inserm

One of the current challenges in terms of cancer treatment is how it can be best adapted to patients: today the emphasis is on personalised treatment (factoring in genetic and metabolic profiles). In response to this growing need for personalisation, there is an increasing demand for fundamental research to develop adapted future treatments. Researchers from Inserm and CNRS from the Institute for genetics and molecular and cellular biology (IGBMC) and from the Research Institute at the Strasbourg school of biotechnology (Irebs) have focussed their efforts on PARG, currently thought to be a promising new therapeutic target in the treatment of cancer. Their work has revealed the role of this molecule in regulating gene expression. The results were published on 25 October 2012 in the on-line Molecular Cell review.

Cells are subjected to various stresses throughout their life. Some of this stress can damage DNA. Fortunately, cells have several mechanisms used to repair these lesions. Breaking two DNA strands is one of the most serious afflictions a chromosome can suffer. The cell must repair this break if it is to continue dividing. Repair actions are either performed in an optimal manner, and the cell resumes its normal division cycle, or the lesion is not repaired correctly, causing the cell to die or the appearance of an anomaly that may trigger cancer.

One of the repair mechanisms used is poly(ADP-ribosyl)ation. In this mechanism, some molecules (PARPs) detect DNA breaks and cause poly(ADP-riboses) synthesis that binds with proteins, thus initialising the lesion repair system. As such, this system can act as a ‘saviour’ if the repairs are correctly completed, but, it can be equally damaging in the event of incorrect repair.

In the case of cancer, to ensure the cells are destroyed, PARP inhibitors are currently undergoing clinical tests as therapeutic adjuvant used to increase the receptivity of cancer cells to specific chemotherapies.

In terms of fundamental research, researchers know that the poly(ADP-ribosyl)ation mechanism is reversible and is closely regulated by Poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG thus seem to make up a tandem of molecules dedicated to maintaining genome integrity. PARG targeting has proved to potentiate the action of genotoxic agents, making this molecule a promising new therapeutic target in the treatment of some cancers, as is the case for PARP.

However, little research has been conducted into PARG, but in light of its close links with PARP, researchers are now taking a very close look at its functions.

In this new work, the researchers have demonstrated that in addition to its genome repair role, PARG was involved in modulating the cell’s transcriptional activity.

Given the keen current interest on PARP and PARG inhibitors in the treatment of cancer, it is essential to gain accurate knowledge of the functions and action modes of these promising therapeutic targets, as well as the consequences of their invalidation. This study is the first to highlight how PARG action mechanism regulates gene expression.

Psychotropic drugs: consumption and drug dependency

The term ‘psychotropic drug’ is used to define medication that acts on the central nervous system by modifying certain mental processes. Generally speaking, these are medicines used to treat mild or serious mental illness and to alleviate pain.

Due to their psychoactive properties, psychotropic medicines may cause dependency if used chronically or if abused.

Psychotropic medication is sometimes consumed outside any medical context and may be misappropriated or even trafficked in the same way as illegal drugs.

France’s Interministerial Mission to Combat Drugs and Drug Addiction (MILDT) asked Inserm to produce a collective expert opinion on the consumption of psychotropic medication and the misuse and drug dependency associated therewith so that a scientific light can be thrown on these phenomena, with the addition of useful recommendations for improving the regulations and current prevention and care arrangements in France.

To comply this request, Inserm has created a multi-disciplinary group of 11 experts in the fields of epidemiology, drug monitoring, public health, sociology, anthropology, toxicology, psychiatry and neurobiology. The group analysed more than 1100 international scientific publications, making it possible to report on the main findings concerning the French situation.

Principal classes of psychotropic drugs

Class of psychotropic drugsFamily (examples)Molecule (examples)
Anxiolytics or tranquillisersBenzodiazepinesDiazepam, bromazepam
 AntihistaminesHydroxyzine
 CarbamatesMeprobamate
Hypnotics or sleeping pillsBenzodiazepinesFlunitrazepam, nitrazepam
 Benzodiazepine- related

drugs

Zolpidem, zopiclone
Neuroleptics or antipsychoticsTypical neuroleptics typiquesChlorpromazine, haloperidol
 Atypical neurolepticsOlanzapine, risperidone
AntidepressantsInhibitors of serotonin reuptakeFluoxetine
 Inhibitors of noradrenaline reuptakeTrimipramine, mianserine
 Inhibitors of serotonin catabolism (IMAO)Moclobemide
Thymoregulators Lithium carbonate
Psychostimulants SympathomimeticsMethylphenidate
Analgesic opiates Opium alkaloidsMorphine sulfate
Opiate substitutesMorphinomimeticsHigh Dosage Buprenorphine

(HDB), methadone

What is Inserm’s Collective Expert Opinion Centre?

Collective expertise has been an Inserm initiative since 1994. More than seventy collective expert opinions have been produced in numerous healthcare fields.

Inserm’s Collective Expert Opinions throw scientific light on a given healthcare subject based on critical analysis and a summary of the international scientific literature. It is performed at the request of institutions that need recent data produced from research to help them in their decision-making process with respect to public policy. The Expert Opinion should be considered as the initial stage necessary to result in decision-making in the long term.

In response to the issue in question, Inserm brings together a multidisciplinary group of recognised experts consisting of scientists and doctors. These experts meet, analyse scientific publications and summarise them. The salient points are extracted and recommendations are often made.

The conclusions obtained through the collective effort of experts contributes to the debate of healthcare professionals involved and the social debate.

TIM and TAM: 2 paths used by the Dengue virus to penetrate cells

A study carried out by Ali Amara’s team at the combined Inserm/CNRS- Université Paris Diderot “Molecular pathology and virology” unit in the Saint-Louis hospital in Paris, working jointly with the team from the Pasteur Institute in Paris and the team from the Salk Institute in San Diego, has identified two families of receptors that play an important part in the penetration of the Dengue virus into cells. By demonstrating that it is possible to inhibit the viral infection in vitro by blocking the bonding between the virus and these receptors, the researchers have opened the way to a new antiviral strategy. These works were published on line in the review “Cell Host & Microbe” of October 18, 2012.

The Dengue virus circulates in four different forms (four serotypes). It is transmitted to humans by mosquitoes. It is a major public health problem. Two billion people throughout the world are exposed to the risk of infection and 50 million cases of Dengue fever are recorded by the WHO every year. The infection is often asymptomatic, or resembles influenza symptoms, but its most serious forms can lead to fatal haemorrhagic fevers. At present, there is no preventive vaccine or efficient antiviral treatment for these four Dengue serotypes. So it is of vital importance that we develop new therapeutic strategies.

Ali Amara’s team performed genetic screening in order to identify cell receptors used by the virus to penetrate target cells[1]. The researchers have determined the important function played by the TIM receptors (TIM-1, 3, 4) and TAM receptors (AXL and TYRO-3) in the penetration process of the four Dengue serotypes. Mr. Amara’s team has succeeded in demonstrating that the expression of these 2 receptor families makes cells easier to infect. In addition, the researchers observed that interfering RNA or antibodies that target the TIM and TAM molecules considerably reduced the infection of the cells targeted by the Dengue virus. The TIM and TAM molecules belong to two distinct families of transmembrane receptors that interact either directly (TIM) or indirectly (TAM) with phosphatidylserine, an “eat-me” signal that allows the phagocytosis and the elimination of these apoptopic cells. Unexpectedly, the work of the Inserm researchers discovered that phosphatidylserine is abundantly expressed at the surface of virions and that it was essential that the TIM and TAM receptors recognize the phosphatidylserine to allow infection of target cells.

These results have helped to understand the first key stage in the Dengue virus infectious cycle, by discovering a new method of virus entry that works by mimicking the biological functions involved in the elimination of the apoptotic cells. The discovery of these new receptors has also opened the way for new antiviral strategies aimed at blocking bonding of the Dengue virus with the TIM and TAM molecules.

This research has been patent-protected by Inserrm Transfert.


[1] Up till present, only DC-SIGN receptors and L-SIGN receptors were known to play an active role in the penetration of the Dengue virus into target cells

Amazing Science*, a “pulp” and science exhibition

Amazing Science*, a “pulp” and science exhibition

In a nod to the Sci-Fi culture of 1930’s American magazines, the Amazing Science exhibition brought to you by Inserm and CEA takes you on an exploratory journey into uncharted territory, on the frontiers of pulp culture, science fiction and scientific research.

Presented for the first time at the 2012 Nantes Utopiales, this new exhibition invites you to delve into the mysteries of life, matter and the universe. The Amazing Science exhibition has set itself a dual challenge: to promote discovery and understanding through enjoyment and to encourage explanation and learning through transformation.

Reinventing Amazing Stories

With the Amazing Science exhibition, Inserm and CEA continue to follow the adventurous trail blazed by Amazing Stories, the American sci-fi magazine first published in 1926. Back then, Hugo Gernsback’s publication regaled its readers with “scientific romances” complete with shock graphics, bright colours, striking typography and mysterious perspectives.

Opening on 7 November 2012, the Amazing Science exhibition will breathe fresh life into those old magazine covers – 20th Century science fiction reinvented by the 21st Century science. Claude Ecken, science fiction writer, comic script writer, literary critic, broadcaster and public reader†, will join in this revival of “science romances” with a series of short science fiction stories taking visitors on a 26-picture literary journey.

* Science-Fiction

Science and pulp culture

As Maison d’Ailleurs Director Marc Atallah reminds us, “the term ‘pulp’ (or ‘pulp magazine’) refers to the cheap publications printed on poor quality paper in the United States during the first half of the 20th Century.” The exhibition revives the “pulp” look through a blend of scientific research, creative writing and popular culture. From the infinitely small to the infinitely large, the most advanced areas of science are now the realm of unexpected encounters with the real and the imaginary worlds. Each of the exhibition panels features scientific visuals based on a specific research area.

“The Amazing Science exhibition aims to explore scientific research by breaking – through a set of new cultural codes – with science’s occasionally inaccessible image, and by reaching out to the popular imagination,” says Claire Lissalde, project leader and head of the Inserm audiovisual unit.

Inserm to inaugurate an innovative museum on 7 November 2012 

The “Amazing Science” exhibition[1] (‘pulp’ and science), co-produced by Inserm and CEA, gives a nod to Sci-Fi culture and marks the creation of an innovative digital device: an entirely virtual museum.

This virtual museum, located in a space vessel modeled in 3D, will present the entire content of the “Amazing Science” exhibition, taking visitors on a fun, immersive and interactive journey.

Visitors will be able to access the rooms of this special museum from their PCs, touch tablets, or smartphones. They will be able to admire the images, read and listen to texts and multimedia content. References to classic Sci-Fi films will be dotted around the various rooms.

Before the museum opens its doors, discover this virtual world by watching the trailer.

Presented for the first time during the 2012 edition of the Utopiales de Nantes, “Amazing Science” unravels the mysteries of living things, matter and the universe for the general public. This museum means visitors can see the exhibition at any time, with unlimited access!

To make science a truly cultural object, the museum will open new rooms over the next months.

It will be possible to visit the entire virtual museum at the following address as of 7 November 2012: www.musee.inserm.fr


[1]Amazing science: surprising, unprecedented, astounding, unbelievable, stunning, splendid, fascinating science…

Amazing Science, an exhibition designed and produced by the Inserm and CEA communications departments

Project Manager, Claire Lissalde, Head of the Audiovisual Unit at Inserm.

Coordination for CEA, Florence Klotz

Based on an original idea by Eric Dehausse, Inserm iconographer

Proofreading by Maryse Cournut of Inserm

Short stories by Claude Ecken,

Art Direction Alexander Cheyrou

Science Editor Charles Muller

Mission Caladan (Editions Le Pommier 2010) Au réveil il était midi (L’Atalante 2012) Femtopetas (Forthcoming from Bélial)

Pulp illustrations from the Agence Martienne and the Maison d’Ailleurs collections.

Science photos from the Inserm Serimedis *image bank and the CEA Photo Library.

* Serimedis is an Inserm image bank open to the public and accessible online at: www.serimedis.fr. The catalogue contains over 14,000 photographs and 1,500 videos.

Optimizing the care of very preterm infants: A collective European initiative

“Effective Perinatal Intensive Care in Europe: translating knowledge into evidence-based practice”, is the theme that will bring together the 12 institutions taking part in the EPICE project – Effective Perinatal Intensive Care in Europe – a European project funded by the EU 7th Framework Program “Health”, coordinated by Inserm. This meeting organised in Paris from the 25th to the 27th of October, will be the opportunity to mark the end of inclusions for a cohort of over 8000 very preterm infants and to provide feedback on preliminary results of the project, launched in 2011.

Changing practices in obstetric and neonatal units

The EPICE project, set up 18 months ago, collects data from 19 European regions (shown in orange on the map) in order to identify the factors that promote the use of evidence-based medicine in the care of very preterm infants.

 “The need to set up a European research project arose from the observation that mortality and morbidity rates for very preterm infants can vary by a factor greater than two between European regions”, states Jennifer Zeitlin, coordinator of the EPICE project and Researcher at Inserm (Unit 953 “Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health”).

Very preterm infants born before 32 weeks of gestation (the 8th month of pregnancy) represent between 1 and 2% of all births. They have a higher risk of mortality and long term neurological and developmental impairments than full term infants.

The EPICE project thus aims to improve the survival and long-term health of these children by ensuring that medical knowledge is translated into effective care. The project results will provide scientific knowledge on which to base intervention strategies to improve the use of evidence based medicine. It will also build a methodological and conceptual framework for future scientific work on the effectiveness of intervention strategies.

Promoting evidence-based medicine

The development of evidence-based clinical-practice guidelines is one of the most promising and cost-effective tools for improving the quality of care The EPICE project researchers are studying a large range of interventions, in order to identify the factors that promote their dissemination in everyday clinical practice.

“The aim is to learn from the experiences of high performing neonatal units in Europe and to use what we learn to improve the care offered to very preterm infants”

explains Jennifer Zeitlin.

19 medical interventions have been selected based on their clinical importance, the solidity of the evidence base and the feasibility of collecting data. These interventions concern such aspects as:

– The use of antenatal corticosteroids to promote lung maturation prior to a very preterm delivery,

– The transfer of pregnant women before delivery to specialised centres with a neonatal intensive care unit (level III units),

– The restriction of post-natal corticosteroid use,

– Promotion of breastfeeding.

Since March 2011, two epidemiological studies have been running in parallel: the first is a cohort study of more than 8000 very preterm infants (between 180 and 1500 depending on the country); the second focuses on the maternity hospitals and neonatal units that care for these infants.

– The cohort study will provide data about the care of very preterm infants and their health from birth to discharge home. These data will be completed with information about health and development at 2 years of age by means of a questionnaire sent to the family.

– Questionnaires given to the medical teams of 261 maternity hospitals and neonatal units collect data on the characteristics of the units, their organization and protocols for use of selected medical interventions and procedures.

The project’s multidisciplinary team has expertise in obstetrics, neonatal medicine, epidemiology and health services research. By grouping and reinforcing national research initiatives, this project enhances cooperation and excellence in Europe.

Why is “evidence-based medecine” necessary?

Evidence-based medecine improves the quality of health care. It is defined by the solidity of the evidence proving the beneficial effects of a practice, its advantages and any risks involved in the treatment. It helps health professionals to select treatments and practices already proven to be effective.

For further information:

EPICE www.epiceproject.eu

“Effective Perinatal Intensive Care in Europe: translating knowledge into evidence-based practice”

The EPICE project is dedicated to the medical care of very preterm infants born before 32 weeks of gestation, in eleven European countries. The aim of the project is to assess practices in order to improve health care for this population of high risk babies.

The EPICE project was launched in 2011 and has been supported by the European Union (FP7) for five years. It is coordinated by Inserm, just like 27 other European “health” projects. The project involves 12 partners and 6 associate partners, based in 11 European countries.

The 12 partners:

Inserm (coordinator), France

SPE, Belgium

Hvidore Hospital, Denmark

Universitas Tartuensis, Estonia

Philipps Universität Marburg, Germany

Bambino Gesu Ospedale Pediatrico, Italy

Laziosanita Agenzia Di Sanita Pubblica, Italy

Radboud University Nijmegen Medical Centre, the Netherlands

Poznan University of Medical Sciences, Poland

U.Porto, Portugal

University of Leicester, United Kingdom

Karolinska Institutet, Sweden

EPICE in France

The EPICE project in France is part of a national study entitled EPIPAGE 2 (an epidemiological study on very preterm babies). It is a cohort study of very preterm infants, launched in 2011 in the 22 regions of mainland France and the French overseas departments. The study will monitor over 6000 premature children up to the age of 11 to 12. Three regions in France: Ile-de-France, Nord-Pas-de-Calais and Bourgogne participate in EPICE project.

The EPIPAGE 2 project is managed by the Inserm unit 953 (“Epidemiological research into perinatal health and the health of women and infants”), in collaboration with team 2, from UMRS 1027, directed by Dr Catherine Arnaud (Perinatal epidemiology, handicap of child and health of adolescents.

For further information on this study: www.epipage2.inserm.fr (Head of studies: Pierre-Yves Ancel, Inserm U953)

Inserm 

Founded in 1964, the French National Health and Medical Research Institute (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of Higher Education and Research and the Ministry of Health.

The mission of its scientists is to study all diseases, from the most common to the most rare, through their work in biological, medical and public health research.

With a budget of 905 million euros in 2011, Inserm supports more than 300 laboratories across France. In total, the teams include nearly 13,000 researchers, engineers, technicians and administrative staff, etc.

Inserm is a member of the National Alliance for Life and Health Sciences, founded in April 2009 with CNRS, Inserm, the CEA, INRA, INRIA, the IRD, the Pasteur Institute, the Conference of University Presidents – Conférence des Présidents d’Université (CPU) and the Conference of Chairmen of The Regional and University Hospital Centres – Conférence des directeurs généraux de centres hospitaliers régionaux et universitaires. This alliance forms part of the policy to reform the research system by better coordinating the parts played by those involved and by strengthening the position of French research in this field through a concerted plan.

Inserm is Europe’s leading European project instigator, with 28 projects coordinated by the Institute as part of the FP7 scheme.

Infertility: how can the ovulation function be restored?

It is well known that breast feeding increases the secretion of the prolactin hormone and inhibits ovulation in women. This prevents the onset of a new pregnancy too soon, and so breast feeding was used in the past as a method of contraception. In addition to this physiological condition, there are many other pathological conditions in which the production of prolactin is increased. One of the most frequent is the existence of tumours that induce an over-secretion of this hormone. These women present with chronic infertility due to anovulation. Thanks to the work of the Inserm researchers from unit 693 “Steroid receptors: endocrinian and metabolic physiopathology”, the intimate mechanism of the hyperprolactinaemia alterations affecting reproduction in mice has been discovered.

This work has been published in the journal JCI.

Hyperprolactinaemia is a major cause of anovulation and is responsible for menstruation disorders and infertility.  However, not much was know in detail of the mechanisms that cause this pathology.

All that was known was that an increase in prolactin in women disturbed one of the most important hormones affecting reproduction and fertility: GnRH[1].

Up until now, we had been unable to understand this inhibition of prolactin in the GnRH neurons, because most of these neurons did not express the prolactin receptor.

So the researchers put forward another hypothesis: what if it was due to the indirect action of other molecules?

The team led by Jacques Young and Nadine Binart from Inserm unit 693 “Steroid receptors: endocrinian and metabolic physiopathology” at the Bicêtre hospital, discovered that prolactin had an indirect effect on GnRH. Using mice as models, they demonstrated that prolactin effectively inhibits the secretion of neurons situated upstream the GnRH neurons and that are essential to their functioning. They secrete a neurohormone known as kisspeptin.

Kisspeptin: the key to infertility?

In mice, hyperprolactinaemia directly inhibits the secretion of kisspeptin and by preventing the secretion of GnRH, effectively blocks ovarian cyclicity. By administering kisspeptin, we can restore the release of GnRH and restart ovarian cyclic functioning and ovulation despite hyperprolactinaemia.

Retentissement de l’hyperprolactinémie sur le cycle ovulatoire

The effect of hyperprolactinaemia on the ovulation cycle (credit: J Young/Inserm)

This is both a physiopathological discovery that for the first time explains the link between infertility and hyperprolactinaemia, and a new approach opening the way to an original therapy. On-going studies are aiming to validate the concept in women, so that we can provide a therapeutic alternative when the subject is resistant to the available medication.


[1] GnRH  is a hypothalamic hormone released in a pulsatile manner. It regulates what is known as the pituitary gonadotropins LH and FSH that control ovarian cyclicity

(French)Un test automatisé pour évaluer la migration cellulaire et l’efficacité de nouvelles molécules anticancéreuses

Development of two tests for rapid diagnosis of resistance to antibiotics

Two new tests capable of rapidly diagnosing resistance to wide-spectrum antibiotics have just been developed by Inserm Unit 914 “Emerging resistances to antibiotics” (Bicêtre Hospital, Le Kremlin-Bicêtre) under the direction of Professor Patrice Nordmann. Thanks to these tests, it now takes only 2 hours to identify certain bacteria that are resistant to the most used and the most important antibiotics in hospitals. The main targeted bacteria are enterobacteriacae (such as E. Coli), that are responsible for infections. With their excellent sensitivity and specificity, the use of these extremely efficient tests on a world-wide scale would allow us to adapt antibiotic treatments to the individual’s needs and to be more successful in controlling antibiotic resistance, particularly in hospitals.

These works were published in September in two international reviews: Emerging Infectious diseases and The Journal of Clinical Microbiology.

These diagnostic tests will allow rapid identification of certain bacteria that are resistant to antibiotics and hence:

  • Allow us to better adapt the treatment to the infected patients
  • Avoid the inappropriate use of certain antibiotics, thus avoiding the over-use of certain wide-spectrum antibiotics
  • Isolate patients infected with these resistant bacteria and thus avoid the development of epidemics in hospitals

There is an ever-increasing number of emerging bacteria that cause cross-border epidemics. Researchers all agree on the fact that it is not the number of bacteria that is the problem, but their increasing resistance to antibiotics. The situation is particularly dramatic for certain species of bacteria, Gram-negative bacilli such as enterobacteriacae[1].

 

A worrying situation both for banal infections and for major treatments.

Whereas certain antibiotics such as wide-spectrum cephalosporins used to be reserved for the most serious cases, now there are cases where they are totally inactive against certain bacterial germs and consequently there is no effective antibiotic treatment for these. And so we are now faced with situations where the treatment of banal infection such as urinary or intra-abdominal infections has no effect. And this puts the life of the patients at risk. Every year, an estimated 25,000 deaths in Europe are due to multi-resistance to antibiotics.

Furthermore, the development of resistance to antibiotics affects an entire aspect of modern medicine that needs efficient antibiotics (grafts, transplants, major surgery, reanimation, etc.).

Undetected importation of multiresistant strains from foreign countries can also considerably accelerate the diffusion of this multiresistance phenomenon.

Two ultra-rapid tests: from Red to Yellow

In an attempt to slow down these increasing resistances, the Inserm researchers have developed a system that can rapidly detect the two enzymes responsible for causing resistance to the bacteria of two classes of common antibiotics: wide-spectrum cephalosprins and carpabenems. In these tests, the presence of an enzyme indicates the presence of a resistant bacteria.

These tests (Corba NP test and ESBL NDP test) are based on the acidification properties generated by the activity of the enzymes (ß-lactamases and carbapenemases) when they are in the presence of an antibiotic. If any one of these enzymes is present, the medium becomes acid and the acidity indicator (pH) turns from red to yellow (Figure, Corba NP test).

(Figure, le Carba NP test)

At present, these tests can be performed using bacteria isolated from urine samples taken during a detected infection, or from bacteria present in stools. The result is obtained in less than 2 hours (compared to 24 to 72 hours using current techniques). These tests are highly sensitive and highly reliable (100%). They are totally inoffensive since they are carried out on bacteria isolated from patients or on biological products such as urine, etc.

Patrice Nordmann, Inserm Research Director and main author of this work, points out that

“These tests are currently being assessed in order to ascertain their sensitivity directly from infected sites such as blood or urine”.

The invention of these tests is an important breakthrough in the fight against the resistance to antibiotics. These tests will provide a simple, inexpensive  means of very rapidly detecting the most serious cases of resistance to antibiotics in human medicine and will contribute to limiting international diffusion.

As Patrice Normann states “We can hope, in particular in many Western countries where the situation has not yet reached endemic proportions multi-resistances (France, in particular), to be able to preserve to a certain extent the efficiency of wide-spectrum cephalosporins and carbapenems, antibiotics used as a “last resource”.

Used straight at the patient’s bedside, these tests will help us to optimise the use of antibiotic treatment, in particular in the developing countries where the levels of resistance are extremely high.

Two international patent applications have been filed with Insert Transfert.


[1] Enterobaceriacae, including E. coli, usualy infest the human intestine. Given their proximity to the urinary and digestive tracts, urinary and digestive infections due to these germs are the most frequent.

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