Behind a Rare Disease: A Gut Sensitive to the Cold and Intolerant of its Own Bacteria

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A mechanism of tolerance towards intestinal flora is thought to be implicated in the onset of a rare familial autoinflammatory disease induced by cold temperatures. This is the finding of researchers from the Center for Infection and Immunity of Lille (Inserm/Université de Lille/CNRS/University Hospital Lille/Institut Pasteur de Lille), the Pathophysiology of Pediatric Genetic Diseases laboratory (Inserm/Sorbonne Université) and the Department of Immunology at the University of Hohenheim. Their research, published in Nature Communications, reveals the implication in its onset of an exacerbated inflammatory response against the gut flora, making for a more effective immune response against certain pathogens. Findings which open up new avenues when it comes to treating patients.

Familial cold autoinflammatory syndrome (or familial cold urticaria) is characterized by episodes of fever triggered by cold temperatures, accompanied by hives and gastrointestinal and joint pain. The patients – with some twenty cases identified to date – carry an NLRP12 gene mutation that is inherited in an autosomal dominant manner (the presence of a single mutated allele is enough to bring on the disease). Until now, the pathophysiological mechanisms behind the disease were unknown.

A team led by Mathias Chamaillard, Inserm researcher at the Center for Infection and Immunity of Lille (Inserm/Université de Lille/CNRS/University Hospital Lille/Institut Pasteur de Lille) along with his coworkers at the Pathophysiology of Pediatric Genetic Diseases laboratory (Inserm/Sorbonne Université) and Department of Immunology at the University of Hohenheim, sought to elucidate the development of this syndrome through human and mouse studies.

The researchers saw that while inactivating the NLRP12 gene in mice triggered inflammation in the gut, it made it resistant to certain pathogenic bacteria, suggesting that NLRP12 could play a key role in immune tolerance towards intestinal flora.

However, they observed that another molecule, NOD2, also played a role in intestinal immunity by promoting the defense against these same bacterial pathogens.

In addition, a NOD2 gene mutation predisposes to Crohn’s disease, which presents disturbing similarities with the syndrome being studied here: intestinal pain and a higher prevalence in cold countries. Finally, the researchers observed the existence of a physical interaction between the proteins NOD2 and NLRP12.

Reduced tolerance of intestinal flora bacteria

In individuals with familial cold autoinflammatory syndrome, the production of protein NLRP12 is reduced. When reproduced in mice, this phenomenon modifies NOD2 activity and reduces tolerance of commensal bacteria with an intensified recruitment of inflammatory cells in the digestive tract. However, the efficacy of pathogen elimination is improved. In other words, under normal conditions, NLRP12 suppresses NOD2 activity and improves tolerance of intestinal bacteria. These findings suggest that an inhibitor of the NOD2 pathway could attenuate these patients’ symptoms.

The reduced tolerance in subjects with familial cold autoinflammatory syndrome generates chronic inflammation which could be the reason behind their intestinal pain. But why does the cold trigger additional symptoms outside the digestive tract? The researchers suspect increased intestinal permeability in the presence of low temperatures, a phenomenon which would be of no consequence in healthy subjects. However, in those with the disease, numerous pro-inflammatory molecules and bacterial debris could pass into the blood en masse, with secondary local inflammation thereby partially explaining the other symptoms, such as fever, headache and joint pain. A new research avenue that Mathias Chamaillard and his colleagues are now exploring, with the help of mice.

Expertise caregivers helps improve patient diagnosis in altered state of consciousness


Hospital teams Pitié-Salpêtrière Hospital AP-HP, Inserm and the Institute of the brain and spinal cord – AP-HP / CNRS / Inserm / University-Sorbonne showed appreciation caregivers (nurses and nursing auxiliaries) for the state of consciousness of patients represented a real added value to medical and electrophysiological exams and conventional brain imaging diagnostics. This work, published in the journal The British Medical Journal Open, apply the principle of “collective intelligence” (or “wisdom of the crowds”).

The waning of severe brain injury, initially a coma patient can progress to altered state of consciousness such as vegetative or minimally conscious state. The determination of the level of consciousness is important both to better assess the patient’s condition, to explain to his family, and also because of the prognostic value of that information.

However it is sometimes difficult to establish and then requires an approach called “multimodal” combining clinical expertise and neuroimaging. The recent international recommendations stress in particular the need to repeat clinical evaluations using a specific scale (the “Coma Recovery Scale – Revised”), and the utility of complement by specialized brain imaging examinations (EEG, evoked potentials cognitive, PET scans and functional MRI).

It is in this context that researchers from Inserm, a medical team of the neurological intensive care hospital Pitié-Salpêtrière AP-HP, led by Dr. Sophie Demeret and a team of the neurophysiology department clinic Pitié-Salpêtrière hospital AP-HP and laboratory “PICNIB lab” at the Institute of the brain and spinal cord led by Prof. Lionel Naccache, professor of physiology at Sorbonne University, wanted to add to this multimodal approach an additional source of information on the principle of “collective intelligence” (or “wisdom of the crowds”): the expertise of the medical staff is constantly in contact with patients throughout their hospital stay.

The tool, called “DoC-feeling” (DoC for Disorders of Consciousness) using a visual analog scale (as used for pain assessment) to collect the subjective perception vis-à-vis the status of carers awareness of the patient quickly and easily. The synthesis of all the measurements taken over a week and provides a “collective” score between 0 and 100.

Forty-nine patients hospitalized for expert evaluation of the level of consciousness in the neurological intensive care unit of the hospital of the Pitié-Salpêtrière AP-HP were included in a year and a half. Nearly 700 evaluations by more than 80 carers were collected. The study, supervised by two referent nurses and supported by health managers, has shown that the median value of individual assessments by caregivers was closely correlated with depth specialized clinical assessments. Another advantage is that this approach allowed to significantly increase the number of patient observations, the state of consciousness may fluctuate over time.

The teams conclude that this approach, in addition to the medical clinic assessment and examinations electrophysiological and brain imaging, should improve the diagnostic accuracy of patients’ state of consciousness. This work puts more and before the interest of the collective intelligence and a collaborative approach to a complex known clinical question.

“This work initiated by two nurses in neurological intensive care hospital Pitié-Salpêtrière AP-HP: Gwen Goudard and Karine Courcoux, which involved more than 80 carers over a period of more than a year, demonstrates extraordinary motivation and the enormous potential of research in allied unity, “ says Dr. Benjamin Rohaut who oversaw the study. He added : “The support of service managers, Louise Richard Gili and Julie Bourmaleau and the help of Dr. Bertrand Hermann, Inserm researcher at the PICNIC-lab for data analysis and writing of the article, were key assets for conducting the study to completion. “

Syndrome Temple and Silver Russell understanding of epigenetic mechanisms regulating fetal growth

© Inserm/Alpha Pict/Caro, Daniel

A team Sorbonne / AP-HP / Inserm, led by Professor Irene Netchine, physiology professor at Sorbonne University and pediatrician at the Hospital Armand Trousseau AP-HP, studied the molecular mechanisms of the clinical similarity between syndrome Temple and Russell Silver syndrome. Their study, published in Science Advances , highlights the importance of gene network concept “imprinted” in the diagnosis and treatment of patients with these rare syndromes.

In the human genome, genetic information is carried by two copies, each inherited from one parent. For most genes, both copies (maternal and paternal) are expressed equivalently. However, some genes are known as ”  subject to parental imprinting  ” when only one of the two copies is expressed; the other copy extinguishing. The expression of these genes corresponds to an epigenetic mechanism, that is to say biochemical modifications of the DNA molecule, which are different on each of the two copies. These imprinted genes are usually involved in growth, metabolism and development .

The genes expressed by the mother copy have a tendency to restrict fetal growth to preserve its own reserves, while the genes expressed by the paternal copy foster meanwhile fetal growth to ensure healthy offspring and pass on its genes to the next generation.

Syndrome Temple and the syndrome Silver Russell are associated with impaired fetal growth is reduced , and are caused by genetic or epigenetic abnormalities in two regions containing imprinted genes, specifically on chromosomes 11 and 14 , respectively.

These patients also have metabolism and food intake disorders, as well as a premature puberty or advanced.

In his study, the team of Prof. Netchine analyzes the molecular mechanisms of the clinical similarity between the two diseases. In Russell Silver syndrome, a decrease in the expression of a gene ( IGF2 ) usually expressed from the paternal chromosome 11, is the origin of stunting. As to Temple syndrome, changes in genes on chromosome 14 (particularly some RNAs normally expressed from the maternal copy of chromosome 14) also impact gene expression IGF2 , while epigenetic marks are unmodified on the chromosome 11.

These discoveries help advance understanding of epigenetic regulation of gene expression, and consider a new approach to the physiology of fetal growth.

Gene therapy durably reverses congenital deafness in mice

Immunofluorescence imaging of the cochlear sensory epithelium in a mouse treated with gene therapy © Institut Pasteur

In collaboration with the universities of Miami, Columbia and San Francisco, scientists from the Institut Pasteur, Inserm, CNRS, Collège de France, Sorbonne University and the University of Clermont Auvergne have managed to restore hearing in an adult mouse model of DFNB9 deafness – a hearing disorder that represents one of the most frequent cases of congenital genetic deafness. Individuals with DFNB9 deafness are profoundly deaf as they are deficient in the gene coding for otoferlin, a protein which is essential for transmitting sound information at the auditory sensory cell synapses. By carrying out an intracochlear injection of this gene in an adult DFNB9 mouse model, the scientists successfully restored auditory synapse function and hearing thresholds to a near-normal level. These findings, published in the journal PNAS, open up new avenues for future gene therapy trials in patients with DFNB9.

Over half of nonsyndromic profound congenital deafness cases have a genetic cause, and most (~80%) of these cases are due to autosomal recessive forms of deafness (DFNB). Cochlear implants are currently the only option for recovering hearing in these patients.

Adeno-associated viruses (AAVs) are among the most promising vectors for therapeutic gene transfer to treat human diseases. AAV-based gene therapy is a promising therapeutic option for treating deafness but its application is limited by a potentially narrow therapeutic window. In humans, inner ear development is completed in utero and hearing becomes possible at approximately 20 weeks of gestation. In addition, genetic forms of congenital deafness are generally diagnosed during the neonatal period. Gene therapy approaches in animal models must therefore take this into account, and gene therapy efficacy must be demonstrated following a gene injection when the auditory system is already in place. In other words, therapy must reverse existing deafness. The team led by Saaïd Safieddine, a CNRS researcher in the Genetics and Physiology of Hearing Unit (Institut Pasteur/ Inserm) and coordinator of the project, used a mouse model of DFNB9, a form of human deafness that represents 2 to 8% of all cases of congenital genetic deafness.

DFNB9 deafness is caused by mutations in the gene coding for otoferlin, a protein that plays a key role in transmitting sound information at the inner hair cell synapses. Mutant mice deficient in otoferlin are profoundly deaf as these synapses fail to release neurotransmitters in response to sound stimulation, despite the absence of detectable sensory epithelial defects. DFNB9 mice therefore constitute an appropriate model for testing the efficacy of viral gene therapy when it is administered at a late stage. However, as AAVs have limited DNA packaging capacity (approximately 4.7 kilobase (kb)), it is difficult to use this technique for genes whose coding region (cDNA) exceeds 5 kb, such as the gene coding for otoferlin, which has a 6 kb coding region. The scientists have overcome this limitation by adapting an AAV approach known as dual AAV strategy because it uses two different recombinant vectors, one containing the 5’-end and the other the 3’-end of the otoferlin cDNA

A single intracochlear injection of the vector pair in adult mutant mice was used to reconstruct the otoferlin coding region by recombining 5′ and 3′-end DNA segments, leading to long-term restoration of otoferlin expression in the inner hair cells, and then restored hearing.

The scientists have therefore obtained initial proof of the concept of viral transfer of fragmented cDNA in the cochlea using two vectors, showing that this approach can be used to produce otoferlin and durably correct the profound deafness phenotype in mice.

The outcomes achieved by the scientists suggest that the therapeutic window for local gene transfer in patients with DFNB9 congenital deafness could be wider than thought, and offers hope of extending these findings to other forms of deafness. These results are the subject of a patent application filed

In addition to the institutions mentioned in the first paragraph, this research was funded by the French Foundation for Medical Research, the European Union (TREAT RUSH) and the French National Research Agency (EargenCure and Lifesenses LabEx).


Oreille humaine anglais

The left panel is a schematic representation of the human ear. Sound waves are collected by the outer ear made up of the pinna and ear canal. The middle ear, composed of the eardrum and ossicles, transmits sound waves to the inner ear, which features the cochlea – the hearing organ responsible for transmitting auditory messages to the central nervous system. The right panel shows an immunofluorescence image of the auditory sensory epithelium within an injected cochlea. The inner hair cells have been stained for otoferlin in green. Otoferlin is detected in almost all of these cells. The inset is a high magnification area showing an inner hair cell that has not been transduced. © Institut Pasteur

[1] Research published by the Institut Pasteur and Inserm Genetics and Physiology of Hearing Unit (UMRS1120): “Otoferlin, defective in DFNB9 deafness, is essential for synaptic vesicle exocytosis at the auditory ribbon synapse” Cell, October 20, 2006

Successful In Utero Hematopoietic Stem Cell Transplantation in a Fetus with Severe Combined Immunodeficiency

© Inserm/Sarramon, Marie-Françoise

Successful In Utero Hematopoietic Stem Cell Transplantation in a Fetus with Severe Combined Immunodeficiency

Teams from the Biological Therapy Department and Pediatric Immunohematology Unit at Necker-Enfants Malades Hospital AP-HP, the Fetal Medicine Department at Trousseau Hospital AP-HP, Inserm, the Imagine Institute, Université Paris Descartes and Sorbonne Université have achieved the in utero transplantation of hematopoietic stem cells in a fetus with X-linked severe combined immunodeficiency.

This first for the Paris hospital group (AP-HP) was the subject of a publication in the February issue of international journal Blood Advances.

The transplantation was performed in July 2015 in response to a risk of maternofetal transmission of a parasite, Toxoplasma gondii, whose consequences on fetal brain development can be serious and more particularly so here in a fetus with no T-cells.

The graft taken from the patient’s sister, whose immune system was compatible, comprised a mixture of hematopoietic stem cells (able to restore normal immune system development over the long-term) and mature T-cells (able to rapidly defend the fetus from infection with the parasite).

The graft was prepared in the Cell and Gene Therapy Laboratory of the Biological Therapy Department at Necker-Enfants Malades Hospital AP-HP and then infused into the fetus via the umbilical vein under ultrasound guidance in the Fetal Medicine Department at Trousseau Hospital AP-HP.

The transplantation and remainder of the pregnancy were uneventful, with the baby born at full term in the Maternity Unit at Trousseau with a functional immune system. The child is now over three years old and in good health, having needed no hospitalizations or therapeutic interventions since birth.

With such a procedure, the fetus was able to heal during pregnancy without the practical constraints or emotional burden inherent in standard hematopoietic stem cell transplantation, which involves a lengthy hospital stay in a highly protected environment for these very vulnerable young patients.

The indication for in utero transplantation continues to remain very restricted due to its potential risks and the possibility of performing the transplantation very soon after birth.

Nevertheless, the success of this transplantation opens up new therapeutic prospects for fetuses with severe immunodeficiency, where a compatible donor exists and where there is a manifest infectious risk during pregnancy. 

Physical activity, prevention and treatment of chronic diseases – A collective expert review by Inserm

© Inserm/F.Koulikoff

Chronic diseases are long-term and sometimes permanent noncommunicable conditions that change over time. According to the World Health Organization (WHO), they are the world’s leading cause of mortality and in Europe “contribute to around 86 % of deaths (…) and represent an increasing burden on healthcare systems, economic development and wellbeing of a large proportion of the population, particularly those aged 50 or above”.

In France, the proportion of those aged 60 or above is expected to increase from one quarter of the total population in 2015 to one third in 2040. Currently, one in four French people has a chronic disease, which increases to three in four beyond the age of 65. With the increase in life expectancy, the number of older adults with chronic diseases is on the up. These are conditions that lead to functional limitations with impacts on quality of life, with the number of dependent individuals expected to rise from 1.2 million in 2012 to 2.3 million in 2060. By improving the prevention and management of chronic diseases, we are therefore taking steps to tackle a major public health emergency.

According to the WHO report of 2010, a large percentage of chronic diseases is responsive to prevention if four primary risk factors are addressed: tobacco use, physical inactivity, alcohol consumption and unhealthy diet. In France, current estimations set the direct (75 %) and indirect (25 %) costs of physical inactivity in the region of €1.3 billion.

Prevention measures can be implemented prior to development of the diseases and at any time during their progression. Given that chronic diseases and their complications contribute very strongly to a state of dependency, preventing their complications and recurrence represents a key challenge for the maintenance of autonomy, notably in older adults.

Inserm was tasked by the French Ministry of Sports with producing a collective expert review in order to take stock of scientific knowledge and to analyze, within the scope of chronic diseases, the impact of physical activity[1] and its place in the care pathway. This review is based on a critical analysis of the international scientific literature made by a multidisciplinary group of thirteen researchers with expertise in various fields relating to chronic diseases, from sports medicine to psychosociology.

The main conditions studied were cardiovascular diseases, cancer, diabetes and chronic respiratory diseases. Obesity, a determinant of chronic diseases and morbid phenomenon in itself, was also included, as were certain mental disorders (depression, schizophrenia), musculoskeletal disorders and multimorbidity.

The research presented in this review comes with three major challenges.

The first is not so much about knowing whether we should recommend regular adapted physical activity for chronic disease sufferers – there is no longer any doubt on the need for this – but rather determining the most efficient program characteristics according to patient physical aptitudes and psychosocial resources, in order to obtain maximum benefit with minimum risk: when should the program begin, what kind of physical activity should it include, at what intensity, how often, in what environment and with what kind of intervention?

The second involves identifying what determines the adoption of behavior that is active, maintained over the long-term and compatible with patient lifestyles. After all, what would be the point of a physical activity program whose efficacy was demonstrated by a clinical trial conducted under ideal conditions, but which turns out to be unsuitable for and ignored by patients?

The third challenge is about understanding the mechanisms through which physical activity acts in general, by improving the physical condition, and also specifically according to the diseases concerned. A large part of the review describes for each disease the benefits/risks of physical activity, and its utility in terms of prevention, treatment and additional care.

The expert group uses these scientific elements as a basis on which to establish recommendations for research as well as recommendations for health authorities in terms of measures to take.

Principal recommendations

  1. Prescribe physical activity for all the chronic diseases studied and include it in the care pathway

While rest has long been the rule in many chronic diseases, we are now seeing a genuine paradigm change with scientific studies showing that, when physical activity recommendations and disease-related complications are taken into account, not only does exercise not worsen the condition but that it is also more beneficial the sooner after diagnosis it is introduced.

Consequently, the expert group considers that physical activity forms an integral part of the treatment of chronic diseases. It recommends its systematic prescription, as early as possible in the care pathways of the diseases studied. It also recommends its prescription prior to any drug treatment in mild to moderate depression, type 2 diabetes, obesity and lower limb peripheral arterial disease.

The expert group has also prepared the following recommendations which, although specific to each disease, do agree on the frequency of adapted physical activity – namely a minimum of three sessions per week.

Here are some examples:

  • obesity: place the emphasis on waist size reduction as a follow-up parameter rather than weight loss and suggest endurance activity programs;
  • type 2 diabetes: opt for muscle strengthening combined with endurance activities of moderate to strong intensity;
  • coronary diseases: perform regular endurance activities which can be optimized by adjusting the intensity of the exercise;
  • lower-limb peripheral arterial disease: the first-line treatment is walking;
  • heart failure: irrespective of disease severity, all patients can benefit from an effort retraining program, thanks to regular and gradual training. Ideally, 30 minutes of moderate activity five times per week in the last phase of the program, which must be life-long;
  • stroke: reduce the impact of neuromuscular sequelae on patient quality of life and prevent relapse by improving cardiorespiratory capacity and muscle strength through regular physical activity that incorporates the practice of daily techniques;
  • chronic obstructive pulmonary disease (COPD): improve quality of life and reduce complication-related functional limitations through varied and long-term regular physical activity (endurance, muscle strengthening, swimming, tai chi…);
  • asthma: reduce the intensity and frequency of attacks by improving VO2max, endurance and exercise capacity through endurance activities;
  • osteoarticular diseases: prevent and/or reduce pain and incapacity through varied and adapted physical activity programs, maintained over the long-term;
  • cancer: improve quality of life and reduce disease and treatment-related side effects (muscular deconditioning, fatigue, treatment intolerance…) and recurrence by offering programs combining endurance and muscle strengthening;
  • depression: prevent recurrence and improve symptoms through programs combining endurance and muscle strengthening.

  1. Adapt the prescription to patient individual and medical characteristics

The principal barriers to physical activity are generally related to the disease itself (pain, fatigue, side effects of certain treatments…).

The main challenge therefore is to adapt the physical activity to the patient’s health, treatment, physical capacity, medical risks and psychosocial resources.

The expert group recommends:

  • evaluating patient physical activity level through an interview and/or simple tests (e.g. the 6-minute walk test) to evaluate capacity and tolerance for exercise. More complex tests (e.g. cardiopulmonary exercise testing) are required to adapt the prescription in terms of intensity of activity and make it safe for the most vulnerable individuals;
  • monitoring changes in physical condition and exercise tolerance in order to adapt the prescription;
  • individualizing the prescription of physical activity by taking into account its context and type, its conditions (intensity, duration, frequency), and above all patient preferences and expectations that influence their interest and pleasure in performing this type of activity;
  • proposing personalized programs to individually adjust physical activity according to the disease, the patient and their environment in order to promote adherence and compliance, particularly over the long-term.

  1. Structure the patient pathway to encourage physical activity at all stages of the disease

A physical activity project must take the entire patient pathway into account. From the very beginning of treatment, it is important to devise the preparation and identification of the elements enabling the patient to pursue physical activity in or close to their home. It is about enabling the patient to immediately mobilize their capacities and if they wish, to play an active role in their care pathway.

  1. Incorporate an educational approach to promote patient commitment to a physical activity project over the long-term

The main challenge is for the patient to make physical activity part of their daily life, which from the outset involves encouraging their commitment to and the development of their autonomy in an activity that is meaningful for the patient and which they can pursue over the long-term. The correct incorporation of physical activity in the overall treatment and therapeutic education project means regular communication between the adapted physical activity professional and the healthcare team.

The expert group recommends combining the programs of physical activity with programs of therapeutic education and initiating any intervention with a shared educational assessment which invites the patient to identify their life habits, needs, possibilities, desires, obstacles and incentives, and how they would like to be helped… Then an objective should be set and the resources that they will mobilize to achieve that objective identified. Follow-up assessments will make it possible to adjust the objectives and renew the resources throughout the program.

For patients presenting characteristics known to limit or compromise adherence and long-term maintenance of the activity (older age, low socioeconomic level, social precariousness…) and/or with little or no experience of physical activity, the expert group recommends a professionally-supervised educational cycle of adapted physical activity of several months’ duration. The challenge being to enable these patients to experience physical activities appropriate to their possibilities and needs, to feel and get pleasure from the effects and recognize them as being beneficial to their health.

Once the patient has the resources, the expert group then recommends supporting them in building a physical activity project which has meaning for their care pathway and life.

5. Support patient motivation in implementing their project

Suggesting forms of physical activity that are not just effective but also fun and motivating needs to remain an ongoing concern. The commitment of individuals with chronic diseases to regular physical activity is primarily motivated by the pleasure and utility they find in it and also by their beliefs in terms of perceived benefit for their physical health and psychological wellbeing. Inversely, a lack of knowledge of the positive effects of physical activity or negative beliefs according to which it would be useless in managing their condition, may underlie any failure to initiate or maintain this activity.

Patients can also be motivated by the positive self-image generated by physical activity (or the negative view they would have of themselves in its absence). More particularly, having to take oneself in hand in order to face the disease in question is seen by some as a responsibility or a duty.

While intentions and planning are generally an unavoidable stage in establishing physical activity, routines need to be created for it to be adopted over the long-term. To encourage the long-term maintenance of motivation, the expert group recommends using a combination of strategies, which include communicating information on the effects of physical activity and the opportunities for engaging in it, the definition of objectives, the follow-up and anticipation of barriers and obstacles to its pursuit, the social support and sharing of experiences, cognitive reassessment and motivational interviewing.

These strategies have a greater effect on motivation when several of them are used together. They can be used by various stakeholders throughout the care pathway (nursing staff, doctors, psychologists, adapted physical activity specialists…) during individual or group face-to-face sessions. Some strategies may benefit from technological support (accelerometer, social media, websites, telephone calls, text messages, connected health objects, serious games, videoconferences…).

  1. Train doctors in the prescription of physical activity

Training in the theoretical and practical knowledge of the benefits of physical activity and of the physical activity intervention initiatives is required for all healthcare professionals.

As a consequence, the expert group recommends:

  • the widespread implementation of mandatory modules relating to the prescription of physical activity during the training of medical students;
  • the continuing education of doctors with the same objectives as those of the initial training;
  • the participation of experts in health-promoting physical activity as well as experts in adapted physical activity in these multidisciplinary training modules;
  • the development of dialogue and joint deliberation among the various professions involved in favor of the practice of adapted physical activity.

  1. Train physical activity professionals in knowledge of the disease and in incorporating physical activity in the medical intervention

The expert group recommends training adapted physical activity specialists in how to:

  • control the interactions between the physical activity and the chronic disease when devising programs and sessions for patients;
  • implement and interpret specific physical activity tests (in addition to medical tests) in line with individual limitations;
  • implement a shared educational assessment to engage the patient in a project approach and evaluate with them their motivation and obstacles in terms of physical activity, their life habits and conditions and possibilities for activity;
  • devise and plan a physical activity program that develops individual autonomy and that is appropriate to the medical contraindications and indications, to the capacities and limitations of the individual, to their level of physical activity and their objectives;
  • implement intervention programs by adjusting the physical activity to the progression of the individual and to the changes in their state of health on the basis of relevant evaluations;
  • develop an education for health or therapeutic education approach according to the level of qualification and/or the stage of the care pathway at which the intervention takes place;
  • mobilize techniques to support patient motivation and commitment to their personal project;
  • communicate with the patient and the various players implicated in the personalized pathway in respect of the rules of confidentiality;
  • manage, implement and incorporate the principles of patient-caregiver relationship ethics when working with the patient;
  • manage the practice of physical activity in conditions of safety by individuals living with a chronic disease.

  1. Promote research

  • Into the conditions of the intervention and their effects

Few studies evaluate the conditions of maintaining physical activity over the long-term, in a “real-world” environment. Yet a patient with a chronic disease has to face potential side effects or sequelae of the treatments and manage the progression of their disease as they get older. This can take the form of the development of other diseases (comorbidities), anxiety or depression symptoms or neurocognitive dysfunction. Getting patients with chronic diseases to adopt new behaviors requires the precise definition of what is at stake in the psychological adjustment to this type of disease.

The expert group recommends consolidating research concerning the feasibility, benefit-risk balance, adherence over the long term to physical activity and in particular it recommends studying the conditions necessary to maintain it, especially during the transition phases (from the hospital to the follow-up and rehabilitation care center, from the center to community medicine, from community medicine to home) and to study the intervention initiatives.

  • Into the methods of incorporating physical activity in the care pathway and its purposes

It is about pinpointing the meaning that physical activity can have for the patient during their disease, analyzing the impact on its conduct by interactions with healthcare professionals, peers, family members, and by identifying the conditions enabling the patient to establish new parameters for living.

  • Into motivation and compliance over the long-term
  • Into the technological tools

The expert group recommends evaluating the technological tools and testing their efficacy in order to estimate the benefit of their incorporation in the patient pathways.

The innovations and prevention interventions which do not take social health inequalities into account often help make them worse[2]. Consequently, the expert group recommends conducting studies to analyze the cost-effectiveness of these new technologies according to patient culture, age, sociocultural level and expectations.

  • Into the effects of the public health policies in favor of physical activity by individuals with chronic diseases

The French national “Sport, health and well-being” plan has produced new partnerships in the 22 regional territories, helping to develop a physical activity offering with the purpose of preventing chronic diseases. By developing the prescription by treating physicians of adapted physical activity for patients with chronic diseases, article 144 of the French public health law and the tools accompanying it, are targeting the widespread implementation of this type of prescription. This raises the question of the accessibility to this treatment or prevention provision for all sufferers of chronic diseases, irrespective of their age, geographical area of residence or their socioeconomic and cultural resources.

The expert group recommends studying the construction of the medical prescription of physical activity and its impact on social inequalities in health, examining also how covering its cost would affect patient take-up of the programs and their commitment over the long-term.

  • Into the physiological action mechanisms of physical activity, in general and for each disease
  • Into the synergic effects of strategies combining diet and physical activity






[1] Inserm Collective Expert Review. Social inequalities in health linked to diet and physical activity, 2014

[2] WHO defines physical activity as “any bodily movement produced by skeletal muscles that requires energy expenditure”.

Since its creation in 1993, Inserm’s Collective Expert Review has been entrusted with a mission of expert review and knowledge transfer for many institutional bodies and decision-makers (Ministries, Agencies, etc.) in the area of public health.

This mission, performed by the Collective Expert Review Unit attached to the Thematic Institute for Public Health, provides scientific insight to assist decision-making in matters of public policy on health. The Collective Expert Review Unit ensures the scientific framework, bibliographic support, coordination and promotion of collective expert reviews.

Having accumulated widely-renowned experience and know-how, Inserm’s Collective Expert Review currently occupies a unique position in the field of health-related expert review. The expert review procedure relies on the scientific competences of expert researchers and clinicians representing all disciplines useful to public health, gathered into ad hoc working groups by the Collective Expert Review Unit. In a constant drive for scientific excellence, independence and relevance in relation to scientific, economic and social issues raised by the themes addressed, the reviews contribute to the social application of the sciences. Experts are chosen within the French-speaking scientific community for their scientific competences (as evidenced by their publications) and for their independence.

Collective expert reviews, published in book form, address important issues such as health and environment, occupational health, aging, nutrition, addictive behaviors, disabilities, etc. Many of these reports provide a summary and recommendations, available online as soon as the results of the expert review are published. The complete book is available in bookshops and online in the months following publication.

The expert review “Physical activity. Prevention and treatment of chronic diseases”, has taken over 3 years of work and the critical analysis of approximately 1,800 scientific documents.


A nanomedicine which relieves pain without the risk of addiction

©Adobe Stock


A painkiller nanomedicine has just been developed by Patrick Couvreur’s team at Institut Galien Paris-Sud (Université Paris-Sud/CNRS)[i]. This new drug specifically targets the area of painful inflammation without causing the addiction phenomena of current medication.

In pain management, morphine and synthetic opioids are currently effective drugs. Unfortunately, their side effects are serious, in particular respiratory depression, but especially addiction. Opioid addiction is indeed a global healthcare scourge. The United States is particularly affected with 11 million dependent patients and around 175 daily deaths as a result of overdoses.

The use of certain neuropeptides, natural peptides used by neurons to communicate with each other, is undoubtedly an interesting alternative to these drugs. In fact, acting mainly on the neurotransmitter receptors that specifically modulate the pain response function, these natural molecules do not cause these side effects. Unfortunately, after administration these molecules degrade in a few minutes without having time to act.

An effective mode of action without side effects

The “Innovative Nanomedicines for the Treatment of Serious Illnesses” team, led by Patrick Couvreur at the Faculty of Pharmacy at Université Paris-Sud, had the idea of synthesising samples of nanoparticles made up of Leu-enkephalin and coupling them to squalene, a naturally occurring lipid in the body, whose specificity is to be able to provide a protective membrane for the whole compound.

Together with scientists from the Paris Institute of Psychiatry and Neuroscience (Inserm/Université Paris Descartes) and the Neuropharmacology Laboratory (Université Paris-Sud/Inserm), the team demonstrated that these nanomedicines induced a significant and prolonged pain-relief effect in rats, with a higher efficacy than morphine.

The researchers particularly noted that, unlike morphine, the Leu-enkephalin-squalene nanoparticles spared brain tissue and acted solely on peripheral receptors. Furthermore, imaging showed that the nanoparticles were capable of delivering the neuropeptide specifically to the area of painful inflammation, thus avoiding the central effects responsible for addiction phenomena.

Biochemical and histological investigations conducted on the treated animals, have moreover demonstrated that this new painkiller medicine did not cause any toxicity or side effects.

This study, published in the journal Science Advances, on 13 February 2019, represents a breakthrough in pain treatment due to the nanomedicine. Further research is still necessary before being able to move to clinical trials. A start-up could be established in the coming months to raise the funds needed for their financing.

[i]  Together with scientists from the Paris Institute of Psychiatry and Neurosciences (Inserm/Université Paris Descartes) and the Neuropharmacology Laboratory (Université Paris-Sud/Inserm).



Images en cryo-TEM des nanoparticules de Leu-Enképhaline-squalène d’une taille comprise entre 70 et 100 nm.© Institut Galien Paris-Sud, Faculté de Pharmacie  


Effet antidouleur des nanoparticules (courbe bleue) aboli après traitement par l’antagoniste naloxone méthiodide (courbe verte) et l’antagoniste naloxone (courbe rouge). Le traitement par la leu-enképhaline libre ou le vecteur seul est sans effet (courbe noire et grise) © Institut Galien Paris-Sud, Faculté de Pharmacie  

Nanoparticules de Leu-enképhaline-squalène libérant le peptide spécifiquement au niveau du site de la douleur inflammatoire (zone rouge). © Institut Galien Paris-Sud, Faculté de Pharmacie   

Direct-acting antivirals: confirmation of their short-term clinical efficacy in “real life”

©Inserm/Jammart, Baptiste, autophagy vesicle (HCV induced)

A study published in The Lancet on 11 february 2019 shows that direct-acting antivirals have short-term clinical benefits in the treatment of hepatitis C virus infection. These results come from ANRS-funded interdisciplinary research conducted by clinicians,hepatologists, and epidemiologists of the Inserm, Sorbonne University and AP-HP and coordinated by Professors Fabrice Carrat and Stanislas Pol, and Dr Hélène Fontaine,[1] in 9895 patients of the ANRS CO 22 HEPATHER national cohort recruited in 32 centers in France.

The most recent treatments of hepatitis C virus (HCV) infection, the direct-acting antivirals (DAAs), are remarkably effective. Indeed, they eliminate the virus in almost all treated patients (95% in general) in 8 to 12 weeks. DAAs were first prescribed in France in 2014. Initially, priority was given to patients with advanced HCV infection, but from January 2017 DAA therapy was extended to all patients with chronic HCV infection.

The virologic efficacy of DAAs is well established, but until now prospective data on their clinical efficacy (ie, their impact on the progression of liver disease associated with HCV infection in real life) were scarce and related to highly selected patients or to patients from retrospective surveys. An ANRS-funded team of researchers has now compared clinical progression of HCV infection in patients receiving or not receiving DAA therapy. The researchers monitored clinical progression in “real life” in 9895 HCV-infected patients included between 2012 and 2015 in the ANRS CO22 HEPATHER cohort (see box below).

In these 9895 patients, who were followed up for a median period of 33 months(2), statistical analysis showed in the 7344 patients who received DAAs before the end of the study that this treatment was associated with reductions in mortality and in the occurrence of hepatocellular carcinoma (liver cancer). After adjustment for individual factors (age, disease staging, presence of other diseases, etc.), the patients treated with DAAs showed a 52% reduction in mortality risk and a 33% decrease in the risk of liver cancer compared with patients at a similar disease stage but not treated with DAAs.

“We could have expected these results. It seems logical that the elimination of the virus causing the damage is linked to clinical improvement,” said Prof Fabrice Carrat. “Our results show that these benefits are obtained soon after virologic control and the patients are no longer highly selected as in early trials. Our analysis reflects real-world efficacy for all patients.”    

The prolonged collection of data from these patients cured of an HCV infection will allow definition of the long-term benefit of DAA therapy and of the modalities needed for medical follow-up (How frequent should liver cancer screening be? How long after the cure? At what cost?). One of the difficulties sometimes encountered in this sort of study arises when patients who are cured are lost to follow-up. The “linking” of medical data from the patients of ANRS CO22 HEPATHER cohort to the national health data system (SNDS), which was validated by the French Data Protection Authority (CNIL) on 19 July 2018, should help researchers obtain exhaustive information on healthcare consumption by these patients over the long term.

This study was conducted in collaboration with the AFEF (French Hepatology Society) and supported by the ANR (French National Research Agency) in the framework of investments for the future and from industrial partners: Gilead, Abbvie, MSD, Janssen BMS, and Roche.

The ANRS CO22 HEPATHER cohort initiated in 2012 in collaboration with the French Association for the Study of the Liver now includes more than 21 000 patients (6500 infected by HBV, 14 600 by HCV, and 95 by both). The main purpose of this cohort, which is coordinated by Professors Fabrice Carrat and Stanislas Pol, and Dr Hélène Fontaine, is to measure the benefits and risks associated with different therapeutic modalities in the management of hepatitis B and hepatitis C and to identify their individual, virologic, environmental, and social determinants.

(1) Fabrice Carrat (Institut Pierre Louis d’Epidémiologie et de Santé Publique, Sorbonne université, Inserm UMS-20 – unité de santé publique – hôpital Saint-Antoine, AP-HP), Stanislas Pol (Département d’Hépatologie, Hôpital Cochin AP-HP; Université Paris-Descartes; Inserm, Institut Pasteur), Hélène Fontaine (Département d’Hépatologie, Hôpital Cochin, AP-HP).

(2) Median: the value that separates the higher half from the lower half of a data sample.

Early Environmental Exposures and Child Respiratory Health: the Exposome Reveals its Preliminary Results

©Photo by Kelly Sikkema on Unsplash

A team of researchers from Inserm, CNRS, Université Grenoble Alpes and Barcelona Institute for Global Health has shown that prenatal and postnatal exposure to various chemical pollutants is linked to decreased respiratory function in children. These results, based on the concept of the exposome (defined as the totality of an individual’s environmental exposures from conception until old age), were obtained as part of the European HELIX project and have been published in The Lancet Planetary Health.

With the changes in our lifestyles and the development of synthetic chemistry, exposure to environmental contaminants has become multiple and complex. Pregnancy and the early years of life are recognized as being periods of high sensitivity to environmental factors, with potential lifetime health consequences for the child. Researchers from Inserm, CNRS, Université Grenoble Alpes and Barcelona Institute for Global Health have measured a large number of environmental factors to which children are exposed – including through maternal exposure during pregnancy –, and which are defined as the “early life exposome”.

The objective of this approach is to link these exposures to the health of children between 6 and 12 years of age, particularly respiratory function.

The researchers collected data from prenatal and postnatal exposures related to the external environment (pollution of the air with fine particles, noise…), chemical contaminants (endocrine disruptors, metals, persistent organic pollutants…), and lifestyle (diet…) in over 1,000 pregnant women and their children in six European countries. Through 85 prenatal exposures and 125 postnatal exposures, a snapshot of the early-life environment was established for each child. The pregnant women and the children had generally been exposed to dozens of chemical substances at variable levels. Over two-thirds of the chemical exposure biomarkers had levels detectable in at least 9 women or 9 children out of 10.

The analysis suggests that prenatal exposure to perfluorinated compounds (used for their hydrophobic properties in various industrial and consumer products, such as some non-stick kitchen utensils or stain-resistant coatings) and postnatal exposure to ethylparaben (a paraben used as a preservative in cosmetics) and metabolites of phthalates (diethylhexyl phthalate (DEHP), a known endocrine disruptor, and diisononyl phthalate (DINP), used as a plasticizer) could be linked to decreased respiratory function in children.

This study, one of the very first large-scale implementations of the exposome approach, suggests links between pre- and postnatal exposure to chemical substances and deteriorated respiratory function in children. Valérie Siroux, Inserm researcher and joint-coordinator of the study specifies: “Identifying the risk factors of decreased early-life respiratory function is important because lung development is a determinant factor not just of a child’s lifetime respiratory health, but also their general health”.

This exposome approach must be seen as an initial selection step making it possible to identify questionable exposures for which more specific research is needed.