© 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.

Photo by Charles Deluvio ???? on Unsplash

As such, the researchers did not detect any harmful effects of the MON810 and NK603 maize diets on the health and metabolism of the rodents, even after a lengthy exposure period.

Physical contact between HSL and ChREBP in human adipose cells. Each red dot represents an interaction between the two proteins. The cell nucleus is stained in blue. (Credit: I2MC).

Restoring the action of insulin is one of the keys to fighting type 2 diabetes. Researchers from Inserm led by Dominique Langin at the Institute of Cardiovascular and Metabolic Diseases (Inserm/Université de Toulouse) are developing a therapeutic strategy that uses the properties of an enzyme (hormone-sensitive lipase) which, when stimulating fatty-acid synthesis in the fat cells, has a beneficial effect on insulin action. This research has been published in Nature Metabolism.

Diabetes is a disease in which blood sugar levels are high over a prolonged period (hyperglycemia). In the case of type 2 diabetes, this phenomenon which is caused by a disruption of the glucose metabolism develops progressively and insidiously. In France, the prevalence of diabetes is estimated at over 5 % of the 2015 population, with type 2 accounting for 90 % of cases. These figures do not include those who are unaware of their condition, particularly among the overweight or obese.

Hormone-sensitive lipase (HSL) is an enzyme which converts fats into fatty acids and releases them into the bloodstream. In obese patients, these fatty acids trigger the gradual insulin resistance at the origin of type 2 diabetes. Previous research by the Inserm team of Dominique Langin had shown that a decrease in HSL expression in the adipocytes led to a better response to insulin, a sign of good health for these cells.

Surprisingly, the researchers observed that the beneficial effect of a reduction in HSL was not actually due to the reduced release of fatty acid. It was explained by the increased synthesis of oleic acid, the principal fatty acid component of olive oil.

To envisage a therapeutic strategy, it therefore had to be elucidated how reducing HSL exerted this beneficial effect on the action of insulin. The group of Prof. Langin discovered the existence of a physical interaction between HSL and a transcription factor responsible for the synthesis of fatty acids, ChREBP. HSL, when binding to ChREBP, blocks its activity. As such, a decrease in HSL leads to the release of this factor in the nucleus, promoting its activity, oleic acid synthesis and sensitivity to insulin.

Preliminary results indicate that a known inhibitor of HSL blocks the interaction with ChREBP. These data therefore pave the way for the development of molecules which target this interaction. In collaboration with global biopharmaceutical company AstraZeneca, the researchers in Toulouse are currently testing different approaches to block the interaction between HSL and ChREBP. Ultimately this project could lead to the development of new drugs to treat the increasing global epidemic of type 2 diabetes.

©Flore Avram/Inserm

A group of over fifteen scientists, led by Samuel Vergès, an Inserm researcher from the “Hypoxia and Cardiovascular and Respiratory Physiopathologies” group (Inserm/Université Grenoble Alpes), is taking part in a scientific expedition to investigate the effect of low oxygen levels on health. In early 2019 they will spend 6 weeks in the world’s highest settlement, situated in Peru at an altitude of 5,300 m, studying how its inhabitants have adapted physiologically to extreme living conditions and analyzing the specific altitude-related health problems they face. Eventually, the researchers hope to use the data in order to improve the understanding and treatment of diseases related to low oxygen levels.

Understanding how the human body is able to adapt to low oxygen levels, finding out why some individuals are unable to develop these mechanisms, and identifying ways to improve tolerance of low oxygen are key questions for both individuals traveling to or living at high altitude, and for the treatment of many diseases in less extreme environments.

Situated in Peru, on the border with Bolivia and at an altitude of 5,300 m, the town of La Rinconada’s economy is largely based on gold mining. The mine’s employees and their families live in extreme conditions, not only due to the altitude (which is higher than Mont Blanc), but also because it is impossible to connect the settlement to utilities such as electricity and running water.

High altitude represents an extreme environment that tests the human body’s capacity for adaptation, and its limitations. The reduced level of oxygen available at altitude (hypoxia) makes this environment a true open-air laboratory. This is why La Rinconada has attracted the attention of the scientists in Grenoble.

Scientific goals of the expedition

In February 2019, scientists from Inserm unit 1042 with specialist expertise in altitude and hypoxia research will work alongside other international groups to set up a temporary human physiology and biology laboratory in the heart of La Rinconada. With a view to improving treatment of the physiopathological effects of low oxygen levels, and related diseases, they hope to advance knowledge across a number of different areas.

Improving care

When an individual who normally resides at sea level travels to somewhere at altitude, three major conditions with damaging effects on health may occur:

• acute mountain sickness, a syndrome that combines headache, nausea, fatigue, and disturbed sleep, and is experienced by half of all individuals traveling above an altitude of 4,000 m;
• high-altitude pulmonary edema;
• high-altitude cerebral edema.

The last two conditions are much more serious and can be fatal. At present they can only be treated by oxygen therapy supplied in cylinders or reoxygenation in a hyperbaric chamber. In order to combat these conditions, over time the inhabitants of La Rinconada appear to have developed genetic adaptations to living at altitude. However, they also appear to be more frequently affected by another kind of disease: chronic mountain sickness, which affects people who permanently reside at high altitudes.

The researchers’ main objective is to understand the mechanisms of adaptation to high-altitude hypoxia in order to treat both patients suffering from low oxygen levels in La Rinconada and treat diseases that are more common at sea level. These include diseases such as chronic obstructive pulmonary disease, sleep apnea, and sickle cell disease, which are characterized by patient exposure to inadequate oxygenation due to respiratory or hematological abnormalities. Understanding how the human body is able to tolerate hypoxia to a greater or lesser extent could enable the development of personalized care and improved therapeutic management.

Advancing technology

Unit 1042 is developing a number of diagnostic and therapeutic tools especially for low-oxygen conditions, whether at altitude or, for example, in respiratory disease. These include an altitude mask designed to improve oxygen diffusion via the lungs, which was developed by Dr. Vergès’s team during a previous expedition to the Himalayas. This mask is about to become commercially available for individuals living at sea level and traveling to places at altitude.

Reproducing conditions for life in space

Once the terrestrial environment is left behind, it is very difficult to reproduce the exact conditions of oxygen availability found in life on Earth. This means that future space travelers and dwellers will need to be able to live permanently in oxygenation conditions equivalent to those at high altitude, and thus to develop the mechanisms of adaptation to hypoxia that have been mastered over the course of generations by populations living at high altitude on Earth. Understanding these adaptation mechanisms, their benefits, and limitations will therefore make it possible to better imagine human adaptation to life outside Earth’s atmosphere.

Nearly 20 European and Peruvian scientific and medical experts will take part in the expedition.

Phases of the expedition

The research team used an initial 10-day reconnaissance trip to Peru in early October to put in place a number of logistical elements (particularly demanding for this kind of expedition), to establish the necessary relationships with key people on the ground, and to work with Ivan Hancco, a Peruvian doctor in La Rinconada, to study the preliminary data collected over recent months from the town’s inhabitants. These data indicated very high levels of chronic mountain sickness compared to other populations living at altitude. Researchers also observed blood abnormalities reflecting extreme physiological responses to hypoxia.

In February 2019, the researchers will examine 40 of La Rinconada’s inhabitants from head to toe. The volunteer participants will be divided into two groups, one in good health and thus with high tolerance to altitude hypoxia, and the other showing symptoms of intolerance (such as headache, dizziness, palpitations, cyanosis, and varicose veins) and in all likelihood specific underlying diseases that require further investigation. Two further groups of 20 Peruvians living in Lima and, at lower altitude, in Puno (3,800 m) will also undergo the same kind of assessment, enabling comparison of group characteristics.

Over a 30-day period, the researchers will study the genetic profile of participants, their sleep quality, and capacity for physical exertion, and gather data on their blood, cardiovascular, and brain characteristics.

In concrete terms, this will involve setting up a scientific and medical laboratory for a period of 6 weeks, requiring several hundred kilos of specialist equipment to be transported by plane and ATV to the 3 study sites in Peru (Lima, Puno, and La Rinconada). The research group will see 6 to 8 volunteers a day, with each subject spending two days with the team in order to undergo all the assessments. Participants will also be studied during their sleep and will have to wear sensors for a 24-hour period. Some of the blood samples taken will undergo on-site laboratory testing (such as blood viscosity, for example), while others will be frozen and sent to France for specific analyses (including genetic and epigenetic testing).

The results obtained should enable the team to identify the mechanisms developed by the human body for living at lower oxygen levels: mechanisms developed over the course of generations by Peruvians living at altitude, including genetic adaptations, and mechanisms that might be manipulated to help individuals suffering from a lack of oxygen to maintain an adequate health status. The group’s preliminary results will be published from September 2019 onward.

Proven expertise

This scientific expedition follows other studies previously undertaken by the same research group:

• in 2011, a fully working laboratory was set up in the Mont Blanc mountain range at an altitude of 4,300 m in order to study brain changes caused by exposure to high altitude in subjects living at sea level;
• in 2015, the team led an international scientific expedition to the Himalayas, which brought together participants from 7 different countries to study cardiorespiratory and metabolic adaptations in 50 volunteer subjects trekking to an altitude above 5,000 m.

These two scientific studies resulted in the publication of numerous international scientific articles, as well as the development of a number of technologies and patents. These include two articles published in Neurology in 2013 and Frontiers in Physiology in 2016, which presented the first MRI evidence of the brain changes associated with a 1-week stay at an altitude over 4,000 m.

A patent for the mask mentioned above has been filed and developed in the laboratory and has already been tested in the previous two expeditions. Use of the mask increases saturation (the level of oxygen in the blood) by 8 to 9% at high altitude, which equates to providing the body with the oxygenation conditions of an altitude 1,000 to 1,500 m lower than the one at which the user is currently at.

A wide array of communication methods

Mindful of the unique nature of this scientific and humanitarian mission, the researchers will share their daily news on site thanks to support from communication specialists, some of whom will be based in Peru during the expedition. A website, Facebook page, and an Instagram account have been created for this purpose. It will also be possible to follow the expedition on Inserm’s social media accounts (Twitter and Facebook). A documentary video will be filmed on site by a professional videographer.

The teams of hepato-gastroenterology department of adult Bicetre Hospital, AP-HP, in collaboration with the department of neurology adult, Inserm and the Université Paris-Sud, show that a derivative of somatostatin may be effective to treat chronic diarrhea suffered by patients with family amyloid neuropathy (NAF). This side effect concerns a quarter of patients after 5 years of follow-impairing their quality of life.

The results of this study, which highlight once again the expertise of the AP-HP in the treatment of rare diseases, are published in the journal Plos One .

Professor Franck Carbonnel and Dr. Michael Collins, Inserm researcher of Hepato-Gastroenterology department of adult Bicetre Hospital, AP-HP conducted a retrospective study of four patients with familial amyloid neuropathy (NAF). This is a rare progressive genetic disorder that causes multiple organ dysfunction and loss of autonomy.

The teams analyzed particularly gastrointestinal side effects such as diarrhea, nausea, vomiting, abdominal pain and incontinence. A quarter of patients after 5 years of follow suffer from chronic diarrhea. Diarrhea is a symptom very debilitating for patients.

The researchers show that similar to somatostatin, octreotide and lanreotide, appear effective for treating chronic diarrhea. Nine of the fourteen patients who received this treatment had a remission of chronic diarrhea after 6 months follow-up. These molecules are already available for other medical indications, including the treatment of neuroendocrine tumors, hemorrhagic complications of portal hypertension and some endocrine disorders. They are also used off-label in the treatment of severe dumping syndrome.

Their use in the refractory diarrhea had already been studied in the context of HIV, chemotherapy-induced diarrhea or diarrhea secondary to digestive suffering from scleroderma.

Induced diarrhea amylose is a multifactorial diarrhea, but involves disorders of the secretion of digestive hormones (including somatostatin) and of intestinal motility disorders.

Often humps transit aggravate constipation in these patients, associated with dysmotility. Sandostatin acts on intestinal secretion and intestinal motility in complex ways. Treatment with octreotide should be monitored and patients with amyloidosis warned of the risk of hypoglycemia.

This work was conducted in collaboration with the teams of Adult Neurology Service – reference center for family amyloid neuropathy and other neuropathies few devices – Professor Adams that showed the effectiveness of the drug candidate Patisiran, Interferent RNA, promising to treat and improve familial amyloid neuropathy transthyretin in July 2018.

To date, in France there are between 40,000 and 50,000 people with neuromuscular disease (NM).

The conditions under national chain of neuro muscular diseases FILNEMUS include muscle diseases (myopathy), diseases of the neuromuscular junction, rare diseases of the peripheral nerve and spinal muscular atrophy infantile.

Crédits: AdobeStock

While we already knew that the Zika virus is sexually transmitted and that it remains in the semen for several months after infection, what we did not know was why it persists and why there is a decrease in the number of spermatozoa in infected men. A team of Inserm researchers led by Nathalie Dejucq-Rainsford (Unit 1085 “Research Institute for Environmental and Occupational Health”, Irset), has shown that the virus infects several types of testicular cells –including the germ cells responsible for spermatozoa– which could alter the process of sex cell production. In addition, the low levels of immune defense of the testicle against Zika could be detrimental to eliminating the virus in the organ and as such contribute to its persistence in semen. This research was published in Journal of Clinical Investigation.

The mosquito-borne Zika virus leads to birth defects and can also be sexually transmitted from men to women. The virus can persist in semen for several months and be transmitted more than 40 days after symptoms disappear, which suggests infection of the male reproductive system. Animal models suggest that sexual transmission could facilitate infection of the fetus in pregnant women. Decreases in the number of spermatozoa and increases in abnormal spermatozoa have also been observed in the semen of infected men. However, the organ responsible for the persistence of the virus in semen remained to be elucidated, in addition to the origin of the modifications of the semen.

Using a novel human testicular culture model, the team of Dr. Dejucq-Rainsford at Inserm (Inserm Unit 1085 “Research Institute for Environmental and Occupational Health”, Irset) has shown that the Zika virus infects a number of testicular cell categories, including the germ cells responsible for spermatozoa. They did this by exposing to the virus testicular fragments from uninfected men and maintaining them in culture for 9 days to track the development of the infection. These findings were confirmed in Zika patients with the demonstration of infected testicular germ cells and spermatozoa in semen.

Following further analysis, the researchers suggest that the testicle could constitute a reservoir for the virus, which would explain why it is found in semen long after having disappeared from the rest of the body. Indeed, this organ has low levels of defense against the infection because it does not produce the proteins essential for an antiviral response (interferons) and that it produces only very small quantities of the molecules tasked with signaling the presence of pathogens to the immune system (pro-inflammatory cytokines).

In addition, and unlike other organs, the infected testicular cells do not die – they persist in the testicle. These various elements could enable the virus to be produced in the testicle for long periods without it being eliminated by the immune system.

Finally, infection of the germ cells themselves as well as of other testicular cells involved in the spermatozoa production process (Sertoli cells, Leydig cells) and in their expulsion from the testicle (peritubular contractile cells) could affect semen production. A hypothesis supported by the observation of modifications of semen recorded in infected men up to two months after contact with the Zika virus.

This study provides essential information on the manner in which the Zika virus can persist in semen and modify its parameters, as well as a valuable tool for testing the efficacy of antiviral agents on testicular infection ex vivo.