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Month: May 2017

Friday May 12: International Fibromyalgia Awareness Day

Posted on by Priscille Rivière

Centre d'évaluation et de traitement de la douleur de l'hôpital Ambroise Paré

Inserm/ Delapierre, Patrick

Recognized as a rheumatic disease by the WHO in 1992, fibromyalgia is characterized by chronic widespread and persistent pain occurring in multiple areas of the body. This affects functional capacity, which varies over time and from individual to individual.

According to the French National Authority for Health (HAS), between 1.4% and 2.2% of the country’s population are considered to be affected, with 80% of those diagnosed being women.

In addition, sufferers very frequently experience chronic fatigue, cognitive dysfunction, attention and sleep disorders, as well as mood disturbances.

These symptoms that are associated with the chronic pain encountered in fibromyalgia can negatively impact daily living activities. Sufferers may find it difficult to hold down a job, for example, or their family or social lives may be affected, which can in turn lead to depression.

In addition to being difficult to diagnose, many attempts have been made to treat fibromyalgia, involving medication and other types of therapy.

Committed to improving the diagnosis of fibromyalgia and the management of the associated chronic pain, the researchers at Inserm are available to answer your questions.

Read the article (in French) “Fibromyalgie, l’invisible douleur “, published in the latest issue of Science&Santé.

Organic pollutants and obesity are not a good combination

Posted on by Priscille Rivière

Body disease and cancer.Use a magnifying glass concept to add interest.

©Fotolia

A team of researchers from Prof. Robert Barouki’s Inserm unit (Inserm Unit 1124/Université Paris Descartes), led by Prof. Xavier Coumoul, has recently shown that the Seveso dioxin, an organic pollutant found in our food and in the atmosphere, causes liver damage in mice fed a high-fat diet. This effect is related to its action on a signaling pathway also activated by diesel and tobacco particles. The results were published last March in Environment Health and Perspectives.

Several organic pollutants may contribute to the growing onset of chronic liver disease in obese individuals. This is suggested by Xavier Coumoul’s team which worked on one such pollutant: the Seveso dioxin. This substance, named after the 1976 Seveso disaster in Italy, near the town of the same name, originates from industrial activity, such as waste incinerators, metallurgy, etc. It is also known for being one of the substances released with the use of Agent Orange during the Vietnam War. Classified as carcinogenic to humans, the Seveso dioxin (or TCDD) is particularly worrisome as it is very stable over time, persisting in ecosystems and organisms for several years. Mainly stored in adipose tissue and in the liver, it activates the AhR (aryl hydrocarbon receptor) signaling pathway in cells which, to be specific, allows the pollutants to be eliminated.

In 2014, while the team was working on the carcinogenic effects of this substance, researchers noticed that a number of mice exposed to high doses of TCDD (25 µg/kg/week) developed hepatic inflammation (liver fibrosis), the starting point for more serious diseases, such as cirrhosis or liver cancer. Now, nonalcoholic chronic liver disease is usually observed in obese subjects. Researchers thus wished to clarify the possible impact of this dioxin on the liver in the context of obesity. They therefore studied a mouse model over 14 weeks. During this period, two groups of mice were fed different diets.

The combination of TCDD and obesity is essential

The first group of animals were fed a low-fat diet. Over the last 6 weeks of treatment, some of these mice were exposed to TCDD (1 to 10 µg/kg/week), whereas the other mice were not exposed to the substance. No fibrosis was observed, even in the presence of low levels of TCDD (</=5 µg/kg/week). Only a few microlesions were observed at doses above 5 µg/kg/week. This was not a pathological syndrome, and did not give rise to any complications.

At the same time, the second group of animals were fed a high-fat diet, accompanied by exposure to TCDD identical to the first group. All of these mice, having become obese due to their diet, developed liver lesions, characterized by increased fat storage. However, in the presence of TCDD, fat accumulation was increased, and inflammatory cells were recruited locally. Due to the effect of TCDD, liver lesions developed with chronic inflammation, which then progressed to fibrosis.

At the end of this monitoring period, researchers studied gene expression in the hepatic cells. They observed that dioxin-exposed obese mice over-expressed several markers for inflammation and fibrosis.

“The effects of obesity and dioxin are potentiated and cause fibrosis to develop. Both, when combined, lead to excessive fat accumulation in the liver, inhibition of their degradation, an increase in oxidative stress harmful to cells, and the onset of inflammation,” clarifies Xavier Coumoul, Research Manager.

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To be verified in humans based on normal exposure

There is no need to panic just yet, despite these findings. The TCDD dose used in this study was high, equivalent to massive exposure, as observed in the Vietnamese population during the war. This was a deliberate decision so as to observe the effects over a fairly limited period of only a few weeks. The effects in humans have yet to be determined, with a lower dose and long-term exposure in keeping with the general population. Furthermore, from a broader perspective, data on all AhR pathway activators, also including diesel and tobacco, have yet to be confirmed.

This research was funded by the ANR and INCa.

Communication between neurons implicated in autism spectrum disorders and intellectual disabilities

Posted on by Priscille Rivière

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© Fotolia

An international collaborative study coordinated by Frédéric Laumonnier (Unit 930 “Imaging and Brain” Inserm/University of Tours) and Yann Hérault of the Institute of Genetics and Molecular and Cellular Biology (Inserm/ CNRS/ University of Strasbourg) provides new and original findings on the pathophysiological role of the contact areas between neurons in certain brain disorders. The study reveals that mutation of one of the genes involved in intellectual disability and autism spectrum disorder leads to dysfunction of the synapses, which are essential for neuronal communication. The research was published on April 18, 2017, in Molecular Psychiatry.

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders that generally emerge when a child’s brain is developing and often persist into adulthood. Behavioral disorders and inabilities to communicate and establish social interactions are observed in people with ASD. In addition, those with ID present difficulties with comprehension, memory, and learning. While the origins of these disorders remain poorly understood, we now know that a significant proportion are associated with genetic mutations.

During the brain development process, synapse formation is essential for brain functions such as memory and learning. Synapses are the points of contact between neurons which enable neurons to connect with each other and propagate information.  Some synapses are inhibitory and others excitatory, to enable the establishment of functional neuronal networks. However, mutations of the so-called PTCHD1 (Patched Domain containing 1) gene, which is located on the X chromosome and enables the expression of a protein potentially involved in synaptic functioning, have recently been identified in boys with the aforementioned disorders. These mutations stop the gene from expressing itself.

In order to validate the involvement of PTCHD1 gene mutations in ASD and ID, Hérault and his co-workers created a mouse model that was deficient for the PTCHD1 gene. In these animals, they observed major memory deficits and significant symptoms of hyperactivity, thus confirming the gene’s involvement in ASD and ID. Parallel studies by Laumonnier’s team showed a presence of the PTCHD1 protein in the excitatory synapses and also detected changes in the same mice’s synapses.

These changes to synaptic structure and activity in the excitatory neuronal networks were found to be particularly significant in a central brain region known as the hippocampus. This region plays a major role in cognitive processes, particularly those involving memory and the formation of new memories.

Genetic abnormalities impacting the structure or functioning of these synapses constitute a pathophysiological target in ASD and ID. In this context, this research defines a new “synaptic disease” caused by a PTCHD1 gene mutation. This dysfunction emerges during the development of the central nervous system and is associated with ID and ASD. Understanding of the pathophysiological mechanisms that underlie these neurodevelopmental disorders, particularly through the study of model organisms, is essential to improve therapeutic strategies.

Two blood tests for predicting the efficacy of a lung cancer treatment

Posted on by Priscille Rivière

Cancer prevention screening check-up disease ill illness healthy health nurse doctor

Fotolia

ALK gene rearrangement is observed in 4% of non-small-cell lung cancer (NSCLC) patients. Researchers from Gustave Roussy, Inserm and Université Paris-Sud, have shown that two blood samples can now predict the efficacy of treatment (crizotinib). These blood samples (taken before treatment initiation and 2 months afterwards) are able to measure the changes in the number of circulating tumor cells[1] (CTC) with a specific genetic abnormality (abnormal number of ALK gene copies). A reduction in this cell count is predictive of longer relapse-free survival in these patients. This research was published in the Cancer Research journal on May 1st. It illustrates the potential of CTC as a liquid biopsy.

“The extent and duration of the response to crizotinib is impossible to predict, and the onset of resistance varies considerably between patients, from a few months to several years. There is currently no way to distinguish between patients who will show a sustainable response and those who will display early resistance. Identifying a biomarker is a major challenge for them as other treatments targeting crizotinib resistance have been developed,” explains Françoise Farace, Rare Circulating Cell Platform Director at Gustave Roussy.

Available since 2011, crizotinib is the standard treatment for ALK-rearranged NSCLC patients. These patients are generally young and non-smokers.

All 39 patients included in this study gave a blood sample before starting crizotinib. A second blood sample was taken two months later from 29 patients (the blood samples from 10 patients followed up at other sites could not be analyzed). Researchers isolated CTC from the two blood samples, and used them to analyze ALK gene rearrangement, together with the presence of an abnormal number of gene copies.

Progression-free survival is significantly longer for those patients showing a decrease in the number of CTC with an abnormal number of ALK gene copies in the first two months of treatment. Median progression-free survival associated with the disease was 14 months for these 13 patients, and 6 months for the 16 patients in whom this cell count increased or remained stable.

“These results should be confirmed by other studies in order to be applied to routine clinical practice. In this case, two blood samples will be sufficient to predict the efficacy of crizotinib in these patients. This cannot be achieved either by tumor biopsy, an invasive procedure which is not always possible to perform particularly during treatment, or by circulating DNA, or a single analysis of CTC prior to treatment,” concludes Françoise Farace.

[1] Circulating tumor cells or CTC, found in small quantities in blood, may be isolated from other blood components and analyzed. Their analysis is more complex than circulating DNA sequencing, but provides more comprehensive information.

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