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Showing posts with label Medical Science. Show all posts
Showing posts with label Medical Science. Show all posts

Sunday, 17 November 2019

The glowing iris of a patient reveals a severe form of a rare eye syndrome

The human optical system is a complex arrangement of several anatomical components working in concert, and the pathological disorders of which it can be reached are equally complex in their turn. This is particularly the case of a rare disease, the syndrome of dispersion of pigments, which causes a depigmentation of the iris and its transillumination. In other words, exposed to light, the iris glows in a singular way. Recently, a team of doctors described the case of a particularly severe form of this syndrome.

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According to the doctors' analysis, this strange appearance turned out to be the sign of a rare disorder that caused the disappearance of the pigmentation of the eye. The 44-year-old man went to a clinic after moving to a new area to get an appointment with an ophthalmologist.

He said he has a family history of glaucoma, an eye disease that can damage the optic nerve, the bundle of nerve fibers that connects the back of the eye to the brain. This damage is usually caused by increased eye pressure. Indeed, according to the authors of the article published in The New England Journal of Medicine , the man had already been diagnosed with high eye pressure and was taking medication to reduce it.

Pigment dispersion syndrome: transillumination of the iris

Nevertheless, tests revealed that the pressure in his eye was very slightly higher than normal. In addition, when the doctor performed an eye examination using a microscope and a bright light, the evaluation revealed "transillumination of the iris" in both eyes of the patient. In other words, the light shone through the iris. This occurs when sections of pigment are missing at the iris, allowing the light to pass through.

In pigment dispersion syndrome, pigment agglomerates separate from the iris, allowing light to pass through and be reflected in the background. Credits: OPTH

Doctors have diagnosed in humans a syndrome of dispersion of pigments. According to this eye condition, the pigment is detached from the back of the iris. These pigment clumps can clog the drainage system of the eye, causing an increase in eye pressure, which can lead to glaucoma. Pigment dispersion syndrome is rare, although it is more commonly diagnosed in men aged 20 to 30 and may have a genetic component.

In this case, the man was laser treated to open the drainage channels of the blocked eyes. This therapy helps liquids to flow out of the eye and reduces eye pressure. However, patients often need to continue taking pressure-reducing eye medication after surgery, as was the case for this patient.


Friday, 15 November 2019

Artificial intelligence can predict the risk of death in the short term, and researchers are confused about how it works

Artificial intelligence can predict the risk of an individual's short-term death (during the year) by examining the results of his or her heart tests, which sometimes may seem "normal" to doctors. Scientists currently do not know exactly how this AI works to achieve this.

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Brandon Fornwalt, from health care provider Geisinger in Pennsylvania (US) and colleagues, asked artificial intelligence to examine some 1.77 million ECG results from nearly 400,000 people , in order to predict which would be at higher risk of death in the next year.

As a first step, you should know that an ECG records the electrical activity of the heart: it changes in case of heart disease, including before or after heart attacks, in people with atrial fibrillation (a disorder of rhythm cardiac) or other diseases.

The team created two versions of the AI. A first whose algorithm only received the raw ECG data (which reveals the electrical activity over time). And a second who received the ECG data combined with the age and sex of the patients.

The researchers then measured the performance of the AI ​​using a metric called AUC, which defines to what extent a model distinguishes two groups of people: in this case, the patients who died during the year and those who survived ... The AI ​​consistently scored above 0.85 (the perfect score being 1, and a score of 0.5 would not distinguish between the two groups). " The AUCs for the risk rating models currently used by physicians range from 0.65 to 0.8,  " explains Fornwalt.

For comparison, the researchers also created an algorithm based on ECG features currently measured by physicians, such as certain record regularities. " Anyway, the stress-based model has always been better than any model we can build from features we already measure from an ECG, " says Fornwalt.

AI has accurately predicted the risk of death, even among those considered by cardiologists to have a normal ECG result. The three cardiologists who examined the normal-looking ECGs separately were not able to detect the risk profiles identified by the AI.

This discovery suggests that the AI ​​identifies risks that doctors probably can not see, or at least they ignore and think normal,  " says Fornwalt. " Artificial intelligence can potentially teach us things that we may have misunderstood for decades, " he added.

At present, we still do not know which specific patterns are detected by the AI, which makes some doctors reluctant to use such algorithms. "  This research is based on historical data, and it will be important to demonstrate in clinical studies that such an algorithm improves outcomes for patients,  " says Christopher Haggerty, a Fornwalt collaborator.

Two studies on the performance of this new AI will be presented tomorrow, November 16, 2019, at the American Heart Association's Scientific Sessions.


Tuesday, 12 November 2019

Virologists discover a new strain of HIV

One of the major obstacles in the fight against HIV is the extremely high mutation rate of the virus. This is why virologists are striving to detect and study new strains of the virus in order to better understand it and develop more effective treatments; the ultimate goal being the production of a vaccine. Recently, a team of virologists discovered a new strain of HIV through improved sequencing techniques. Results that should provide a more detailed description of the virus and its mechanisms.

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The researchers identified a new sub-group of the human immunodeficiency virus (HIV) for the first time in nearly two decades. The discovery comes from samples taken in the last 30 years in the Democratic Republic of Congo.

As reported in the Journal of Acquired Immune Deficiency Syndrome , the new strain is the L subtype of the HIV-1 M group . Its existence has long been suspected, since two samples were studied, one taken in 1983 and the other in 1990.

Improved sequencing techniques for identifying new viral strains

To confirm the existence of a new strain, it is necessary to obtain three independent samples. A sample taken in 2001 had promising similarities, but it was difficult to sequence completely. But technological improvements in recent years have allowed researchers to obtain complete genomes faster and from smaller samples. This eventually allowed this team to check whether the 2001 sample was really evidence of a new strain.

The new strain of HIV (red) discovered by virologists will help to better understand the virus and its mechanisms. Credits: Yamaguchi J. et al. 2019

" Identifying new viruses like this is like looking for a needle in a haystack. By advancing our techniques and using next-generation sequencing technology, we 'remove the needle with a magnet'. We are making this new strain available to the research community to assess its impact on diagnostic tests, treatments and potential vaccines, "said Mary Rodgers, head of Abbott's global viral surveillance program.

The discovery of new strains is crucial in the fight against viruses. The new strains give viruses the ability to avoid detection during testing, to be resistant to current treatments, and to be another barrier to the difficult path to vaccine.

" This discovery reminds us that in order to end the HIV pandemic, we must continue to explore this evolving virus in greater depth and use the latest advances in technology and resources to monitor its evolution, " says Carole McArthur. from the University of Missouri, Kansas.


Monday, 11 November 2019

The cerebrospinal fluid flows in waves across the brain and seems to "cleanse" it during sleep

Cerebrospinal fluid (CSF) is a biological fluid contained in the meninges and in which the brain and spinal cord swim. It helps to absorb the physical shocks to which the brain can be subjected, and also to eliminate molecules and other physiological waste. For the first time, neurobiologists have seen how LCS flows in waves through the brain during sleep. Observations that could lead to a better understanding of certain neurological disorders.

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This latest study shows waves of cerebrospinal fluid (CSF), pulsating rhythmically during sleep, while eliminating the toxins accumulated during the day. The team explains that these findings could help in the study of various neurological and psychological disorders, particularly those associated with sleep disorders. The study was published in the journal Science .

" We have known for a long time that there are electrical waves of activity in neurons. But so far, we have not realized that there are really waves in the LCS,  "says neuroscientist Laura Lewis of Boston University.

The pulsatile rhythm of the cerebrospinal fluid

Previous studies have suggested that LCS is important for the elimination of brain toxins, but so far neuroscientists have not known or been able to observe this pulsating action. Combined with slow-wave brain activity (which partly serves to fix our memories) and the decreased blood flow that occurs during sleep, these CSF waves seem to eliminate unnecessary protein.

Graph showing a rise in the frequency of CSF waves during sleep (blue zone) compared to the waking state (pink zone). The data was obtained by fMRI. Credits: Nina E. Fultz et al. 2019

As the slow frequency of brain waves declines as we get older, the new study may help research into normal age-related problems as well as specific disorders. The researchers' work also means that it is now possible to know if a person is sleeping or not, simply by analyzing the LCS patterns on a brain scan.

Better understand the synchronization of physiological processes during sleep

For the purpose of the study, 13 subjects aged 23 to 33 years were followed during their sleep during an MRI. Future research could also focus on older subjects - again to try to detect the deterioration of the process as we get older. The researchers suggest that another improvement in follow-up studies might be finding ways to eliminate MRI: the noise it generates is not very conducive to sleep.

It remains to be seen how the LCS, brain waves and blood flow synchronize so effectively. It may be that when neurons are inhibited for the night, they do not need a lot of blood - and as the blood flows, the pressure in the brain is maintained by the influx of LCS.

Video showing the pulsatile flow of the LCS:


Saturday, 9 November 2019

For the first time in the United States, researchers use genetic editing to treat cancer

The first attempt to use a genetic editing tool (CRISPR) for cancer treatment appears to have been safe in the United States. In total, three patients were treated in this first clinical trial. For the moment, however, it is still too early to conclude on improving the chances of survival of the sick, said the doctors last Wednesday.

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The researchers were able to collect T cells from the immune system (from the blood) of patients and genetically modified them to help them recognize and fight cancer, with minimal and controllable side effects.

The treatment developed has the effect of removing three genes that could suppress the ability of cells to attack the disease, and adds a "fourth feature" to help them do the job.

" It's the most complicated cellular and genetic engineering that has been attempted so far,  " said Dr. Edward Stadtmauer, director of the study, at the University of Pennsylvania in Philadelphia. " This is proof that we can safely edit genes for these cells  ."

After two or three months, one patient's cancer continued to deteriorate and another was stable. The third patient has been treated too recently to find out how she will cope. The plan consists of treating another 15 patients and assessing the safety of the treatment.

" It's very early, but it encourages me a lot, " said an independent expert, Dr. Aaron Gerds, a cancer specialist at Cleveland Clinic. Other cell therapies for some blood cancers "have been a resounding success, taking incurable diseases and healing them," and gene editing could help improve them, he said.

Revive the cells to fight the disease

Gene editing is a way to permanently change DNA to tackle the root causes of a disease. CRISPR is a tool for cutting DNA in a specific place. It has long been used in the laboratory and is currently being tested for other diseases.

This treatment is not intended to directly modify the DNA in the body: instead, it seeks to eliminate, modify and give back to the patient very powerful cells to fight cancer. A form of immunotherapy.

In this January 2019 image, CRISPR-published T-cell containing pouches are prepared for administration to a patient at the Abramson Cancer Center in Philadelphia. The first results, released on Wednesday, November 6, show that doctors have been able to take cells from patients' immune systems and genetically modify them to help them recognize and fight cancer. Credits: Penn Medicine via AP

Chinese scientists have reportedly tried CRISPR on cancer patients, but this is the first study of its kind outside of this country. It's so new that it took more than two years to get approval from US government regulators before it could go to trial.

The first results were published by the American Society of Hematology. Details will be given at its annual conference in December. The study is sponsored by the University of Pennsylvania, the Parker Institute for Cancer Immunotherapy in San Francisco and a biotechnology company, Tmunity Therapeutics.

Multiple myeloma and sarcoma

Two of the patients in the study had multiple myeloma of the blood (a cancer of the blood) and the third a sarcoma, a cancer that forms in connective or soft tissues. All had already done standard treatments that unfortunately failed. Recently, more promising options were offered to them, including this essay.

A unique treatment based on genetically modified T cells

Patients' blood was filtered to remove T cells (real soldiers of the immune system). The latter were then genetically modified in the laboratory and then returned to patients by the intravenous route. This is a unique treatment.

Once administered, the cells multiply in the body and act like a real army. " Until now, the cells have survived and multiplied as expected, " Stadtmauer said.

" This is a brand new therapy, " so it's unclear when anticancer effects will be observed. It will therefore be necessary to follow these patients longer and carry out more clinical trials, he concludes.


Friday, 8 November 2019

The world's first penis and scrotum transplant is fully functional one year after surgery

X-ray performed before the patient's operation. | Redett et al./NEJM

It is more than a year after this particular operation, that the recipient of the very first penis and scrotum transplant in the world, is recovering well. He is a veteran of the US Armed Forces, who lost most of his lower body during an explosion.

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The man in question (who wishes to remain anonymous), was on patrol with his squad in Afghanistan when Taliban fighters ambushed them: while he was going to give the first aid to another soldier, he walked on a explosive device hidden on the road. The explosion took away much of the lower half of his body ... " I remember that everything seemed to have stopped and I was upside down,  " said the man. "  I remember thinking very quickly, 'It's not good,'  " he added.

And indeed, it was not good. During this explosion, the soldier lost almost all of his legs, his genitals and part of his abdomen. The tragedy took place in 2010.

At the time, there was only one total penis transplant, performed in 2006 on a patient in Guangzhou, China. And the results were not really promising ... complications soon appeared and the man's body started to reject the organ, which showed signs of necrosis, probably because of insufficient blood supply. Not to mention psychological issues, including objections from the patient's wife. What remained of the transplant was removed only a fortnight later.

Nevertheless, reconstructive surgery specialists at Johns Hopkins Hospital were convinced that their patient soldier, whom he had met for the first time in 2013, would be a good candidate for transplant surgery: although it took five years of preparation (including extensive experimentation on cadavers) before this can be attempted once a suitable deceased donor organ is finally available.

The patient decided to remain anonymous. Credits: Andrew Mangum / The New York Times

During this long waiting period, three successful penis transplants were performed: two in South Africa (both on patients with penile loss due to circumcision infections) and another involving a man in the United States, who underwent surgery after a partial penectomy following penile cancer.

Yet none of these patients had lost as many elements as this soldier. As a result, his operation was particularly ambitious, involving the transplantation of a single piece of tissue including the penis, scrotum and lower abdominal wall: what the doctors had never tried before!

In total, the entire graft weighed more than two kilograms and was approximately 25 centimeters. Despite the challenges of assembling hundreds of small blood vessels a millimeter or two wide under a powerful microscope, the 14-hour operation, performed by 11 different surgeons, was a success.

The veteran who received a penis transplant also had to undergo physical therapy to regain his strength. Credits: Andrew Mangum / The New York Times

And more importantly, more than a year after this first transplant, the medical team is happy to have been able to announce that the patient was recovering well, and that the organ and its restored nerve connections were functioning as well as they would have done. could have hoped.

" He has almost normal erections and the ability to reach orgasm,  " the researchers write in their case report. "  He has normal sensations in the stem and tip of the transplanted penis and can pinpoint the sensation of touch ... The patient is urinating upright, without effort, without increased frequency or urgency, the urine being discharged in a powerful jet.  They add.

Although the operation required scrotal transplantation, the researchers chose not to transplant the testes from the donor after consulting with bioethicists. " If we had included the testicles, the recipient could have fathered a child with the donor's DNA ," said one of the team members, plastic surgeon and reconstructor. "  This young man has no children, but was happy with the decision. He's not in a relationship, but I'm sure he's considering it now  . "

Another unique decision in this patient's case was a bone marrow infusion from the donor, which reduces the soldier's need for immunosuppression medication (which helps the body to accept the new organ).

Currently, it should only take one tablet a day and the team hopes that with the progress of medicine, it will be able to completely do without the drug "in the next five to ten years". We do not know if this will be possible or not, but what is perfectly clear is that this incredible procedure has greatly improved the life of this young man.

The doctors explained that he is now back in school full time and he lives and walks independently thanks to his leg prostheses. " He announced that he had a better image of him and that he was feeling 'whole again'. He says he is very satisfied with the transplant and its implications for its future, "they explained.

" I do not regret it. It's one of the best decisions I've ever made, "said the young man. This case represents a great victory (and advanced) for doctors, and of course, especially for the patient, who admitted that formerly he even had trouble "to consider himself a man".


Thursday, 7 November 2019

How does the brain react to the loss of a limb?

The brain has a particular structural organization, divided into areas and segments, where each area performs a specific function. Thus, there are brain regions related to language, smell, sight, different limbs, and so on. This organization is called "brain map". However, for example, what happens to the area assigned to a hand if the body is amputated? In a recent study, researchers have shown that in such a case, the brain rearranges this map so that the area in question is reallocated to the remaining hand. These results confirm the exceptional capacity of the brain to adapt to changes.

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Researchers at the University of Missouri have discovered new clues about the functioning of the complex neuronal structure of the human brain. Similar results have already been reported in animal studies, but this is one of the first studies where such a result has been observed in humans. The study was published in the journal NeuroImage.

"When a person touches something with their right hand, a specific" hand-allocated area "in the left side of the brain activates,  " says Scott Frey, a researcher in cognitive neuroscience. " A similar but opposite reaction occurs with the left hand. But when someone loses a hand, we discover that the two areas of the brain's hand - left and right - are dedicated to the remaining hand. This is a striking example of the functional reorganization or plasticity of the human brain ."

Loss of a limb: the brain reorganizes to compensate for amputation

Researchers used the functional brain MRI (brain imaging) MRI to scan the brain of 48 people, 19 of whom had lost a hand. They created a computer-controlled system to deliver a light feel to the hands and face. Functional MRIs are similar to conventional MRIs, but are sensitive to minute changes in blood oxygen levels in the brain that occur when areas of the brain process information.

Complete cerebral scans obtained by fMRI for three patients: (A) Hand-amputated patient, (B) Finger-only amputee patient, and (C) Control patient (unaffected). The colors indicate the intensity of the brain reorganization. Credits: Kenneth F.Valyear et al. 2019

Scientists have observed in scans that when the brain is deprived of information from a lost hand, it reorganizes its neural map and redirects these functions to the remaining hand. This discovery could help neurologists and health professionals better understand the mechanisms underlying plasticity of the brain when body trauma occurs, for example, when returning wounded veterans to the battlefield.

" We could think that the areas of the brain that treat the sensations of our body are organized as a map with separate territories dedicated to specific body regions such as hands, face or feet. We've known for a long time that injuries such as amputation or spinal cord injuries change the way this card is organized, "explains Frey.

" If you lose a hand, for example, the area of ​​the associated hand may be partially supported by the card's neighboring functions involved in the treatment of arm or facial sensations: it is a form of "Cerebral plasticity". This work demonstrates that such plasticity also occurs over large distances between the left and right hemispheres of the brain.

Additional work is underway to determine how, and if, these changes affect the way in which amputees experience sensations, including pain. Neuroscientists hope their discoveries could also help inform efforts to develop prosthetics that provide users with a tactile experience.


Genetics of a Colombian woman offer new clues to fight against Alzheimer's disease

A woman with an Alzheimer-causing mutation and a large accumulation of beta-amyloid (in red) in her brain has maintained good cognitive health for decades. | Aaron Schultz

The search for new treatments to fight the dreaded Alzheimer's disease has gained new momentum in recent years. And sometimes, nature brings its own clues. In 2016, Harvard researchers analyzed the brain and blood of a 73-year-old woman from Medellin, Colombia, who had a genetic mutation that caused many in her family to develop dementia in old age. But for decades, she had naturally avoided the disease. The researchers therefore tried to understand how this was possible. In a new study, they report that another rare mutation (well known as a risk factor for Alzheimer's disease), that of the APOE gene , may also have protected it.

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Although the researchers can not prove that this mutation alone has prevented the disease, their study again draws attention to the possibility of preventing or treating Alzheimer's disease by targeting the APOE protein gene . An idea that, according to some researchers, has already spent too much time in the spotlight.

This is a very special case, " says Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, who did not participate in the research. " It could open up a very promising new avenue in both research and therapy ."

The gene for APOE , the most potent genetic risk factor for Alzheimer's disease, exists in three common forms (alleles). A variant called APOE2 reduces the risk of the disease. The most common variant, APOE3 , does not influence risk. APOE4 (allele 4) increases the risk; about half of people with the disease have at least one copy of this variant.

Researchers have long considered targeting APOE with therapies. To this end, a team from Cornell University will soon begin a clinical trial to "infuse" the APOE2 protective gene into the cerebrospinal fluid of people with two copies of APOE4 .

Protein APOE: genes still too little understood

However, many unanswered questions about  APOE prevented it from becoming a priority drug target. APOE protein binds and transports fats and is abundant in the brain. But "she's doing so much in the brain that's confusing," says Eric Reiman, neuroscientist at Banner Alzheimer's Institute in Phoenix and co-author of the new study, published in Nature Medicine.

APOE4 appears to promote the formation of sticky plaques of beta-amyloid protein, which obstructs the brain in Alzheimer's disease. But the powerful anti-amyloid drugs have largely not benefited patients participating in clinical trials. Some researchers have found no reason to try APOE- targeted therapy , which just seemed like "an anti-amyloid treatment for the poor," says Reiman.

On the left, the two theories explaining Alzheimer's disease: the amyloid hypothesis and that of ApoE (both producing a cognitive decline). Right: Due to stress or injury, the ApoE gene can express itself. This causes overproduction of the ApoE4 protein, which will alter the function of neurons and neuronal mitochondria, leading to learning and memory impairments. Credits: L. Mucke et al. (2012), adapted by T. Lombry

A special case that could change everything about APOE

But the case of the Colombian woman (the research team keeps her name confidential) suggests other ways that APOE can affect the risk of developing Alzheimer's disease. The woman in question participated in a study conducted by researchers from the University of Antioquia in MedellΓ­n, which tracked about 6,000 members of her extended family.

Approximately one-fifth of them had a mutation causing Alzheimer's disease in a gene for a protein called presenilin 1 ; these carriers usually developed dementia in their late forties. However, the woman did not show the first signs of the disease until she was 70, even though she was carrying the mutation. " It's really a special case ," says cell biologist Joseph Arboleda-Velasquez of Harvard Medical School in Boston.

At Harvard, a woman's brain positron emission tomography revealed greater amyloid accumulation than any other member of the scanned family. " It was very striking, " says Yakeel Quiroz, clinical neuropsychologist at Massachusetts General Hospital and Harvard Medical School.

However, the team found no evidence of major neuronal damage and minimal accumulation of another feature of Alzheimer's disease: misfolded tau protein.

Whatever protection the woman had, she did not depend on the fact that the brain was free of amyloid. Her case argues instead for the idea that tau plays a "pivotal role in the clinical manifestations of Alzheimer's disease," says Jennifer Yokoyama, a neurogenetician at the University of California at San Francisco.

A rare mutation in the APOE gene

Sequencing of the genome revealed two copies of a rare mutation in the APOE gene . Discovered for the first time in 1987, the mutation, known as the "Christchurch mutation," occurs in a region distinct from those that determine the APOE2 , 3 , or 4 status of a given person. The Colombian woman wore the neutral variant, APOE3 .

Previous research had revealed that the mutation of Christchurch, as the mutation APOE2 , impairs the ability of APOE to bind and eliminate fat, which sometimes leads to cardiovascular disease.

The researchers also found that this mutation prevented APOE from binding strongly to other molecules called heparan sulfate proteoglycans (HSPGs), which cover neurons and other cells "like a carpet," says Guojun Bu, a neuroscientist at Mayo Clinic of Jacksonville, Florida, who studied the interaction between these molecules and APOE.

APOE2 can also affect the ability of the protein to bind to HSPGs. But the way this mechanism protects against the disease is unclear. A likely clue is the research of neuroscientist Marc Diamond and colleagues at Southwestern Medical Center at the University of Texas at Dallas, suggesting that toxic tau protein relies on HSPGs to promote cell-to-cell propagation. Perhaps the less APOE is related to HSPG, the more difficult it is for tau to spread.

However, more studies will be needed to understand if this relationship exists, Diamond warns. The Christchurch mutation could have protective effects unrelated to HSPGs. It is also possible that other genetic mutations (such as Christchurch) have protected the woman.

If the impediments to normal APOE binding had really spared it from Alzheimer's disease, future treatments could be aimed at mimicking this effect. An antibody or small molecule could cling to the APOE protein to interfere with binding; Gene editing could change the structure of APOE to mimic the mutation of Christchurch. Or, a "gene silencing" approach could reduce the production of APOE.

Reiman hopes that the new study will rally researchers to pursue APOE- related treatments . Quiroz, Arboleda-Velasquez and others also published an article (in pre-print) on November 2 showing that people with two copies of APOE2 have a much lower risk of developing Alzheimer's than previously estimated (about 99% of less than people with two copies of APOE4 ).

" When it comes to finding a treatment that could have a profound impact on the disease, APOE may be among the most obvious targets, " concludes Reiman.


Monday, 4 November 2019

Live skin can now be printed in 3D, including blood vessels

In order to treat the severely burned and for the treatment of various diseases affecting the skin, the development of artificial skin grafts has become a field of future research, but so far, the absence of functional vascular system in the grafts is a significant barrier to their integration. To remedy this problem, researchers at the Rensselaer Polytechnic Institute have developed a way to 3D-print "living skin" by incorporating blood vessels.

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" Right now, all that is available as a clinical (transplant) product is more like a sophisticated dressing ," said Pankaj Karande, associate professor of chemical and biological engineering and a member of the Center for Biotechnology and Biotechnology. Interdisciplinary Studies (CBIS), which led this research project at the Rensselaer Polytechnic Institute (USA). " They allow accelerated healing of wounds, but they eventually fall; they never really integrate with host cells  . "

The absence of a functional vascular system in skin grafts constitutes a major obstacle to this integration. Karande has been trying to meet this challenge for several years. He has published previously one of the first articles showing that it was possible, from two types of living human cells, to turn them into "bio-inks" to print skin with more natural biological properties. Since then, he and his team have been working with researchers at the Yale School of Medicine to incorporate blood vessels into artificial grafts.

Their new design, detailed in a document published last week in the journal Tissue Engineering Part A , represents an important step in the creation of artificial grafts with properties close to those of human skin.

Allow cellular communication to interconnect vascular structures

In their article, the researchers show that if they add some key elements, the cells begin to communicate and form a biologically relevant vascular structure within a few weeks. These key elements include: human endothelial cells (keratinocytes) (lining the inside of blood vessels), human pericytes (which surround endothelial cells) as well as animal collagen and other structural cells commonly found in grafts skin.

" As engineers working on the reenactment of biology, we have always appreciated and understood that biology is much more complex than the simple systems we make in the lab,  " said Karande. " We were pleasantly surprised to see that as soon as we tackle this complexity, biology takes over and begins to get closer to what exists in nature  ."

Once the Yale team grafted the new skin onto a special type of mouse, the blood vessels printed by the Rensselaer team began to communicate and connect with the natural vessels of the mouse.

" This is extremely important because we know there is actually a transfer of blood and nutrients to the graft, which keeps it alive,  " said Karande.

Make the graft compatible using the CRISPR genetic editing technique

In order to make artificial skin usable at the clinical level, researchers must be able to edit donor cells using CRISPR technology, so that vessels can integrate and be accepted by the patient's body. " We're not at this point yet, but we're getting closer ," Karande said.

" This significant development (presented in the study) highlights the vast potential of 3D bioimprinting in precision medicine, where solutions can be tailored to specific situations and ultimately to individuals,  " said Deepak Vashishth, director of CBIS. " This is a perfect example of how Rensselaer's engineers solve human health problems  ."

Karande said more studies will be needed to address the challenges associated with burns, including the loss of nerve and vascular endings. But the plugins created by his team will encourage other researchers to help people with more discreet problems, such as diabetes or pressure ulcers.

" For these patients, it would be perfect because ulcers usually appear in separate parts of the body and can be treated with smaller pieces of skin,  " said Karande. " Wound healing usually takes longer in diabetic patients, which could also help speed up this process  ."

In the video below, Karande presents her design:


How are psychiatric disorders in children related to infections during pregnancy?

Infections contracted by a pregnant woman during pregnancy can affect the child's development in different ways. Beyond the purely somatic anatomical and physiological alterations, the alteration of certain precursor neuronal cells can lead to the appearance of psychiatric disorders later in the child, particularly in the schizophrenic and autistic spectrum. This is the conclusion of a new study that highlights the severity of infections and the importance of when they occur.

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Serious infections during pregnancy have been linked to various psychiatric disorders by different studies conducted in humans and animals. Researchers at the University of Copenhagen have shown in mice how infections affect neuronal development and the timing of infection.

Infections, brain development and psychiatric disorders

The health of the mother is very important for the development of the fetal brain during pregnancy. Many factors play a key role in healthy brain development, including nutrition, stress, hormonal balance, and the mother's immune system.

It has been observed in humans and animals that serious infections in pregnant women are a risk factor for developing psychiatric disorders such as schizophrenia and autism spectrum disorders later in the life of the child.

The authors of the study, published in the journal Molecular Psychiatry, showed how infections in the mother can alter the development of stem cells and neuronal precursors of the brain.

Maternal inflammation affects the development of multi-stage interneurons, such as proliferation, migration, differentiation and maturation, resulting in increased vulnerability to mental disorders. Credits: Navneet A. Vasistha et al. 2019

" The connection has already been made in animal studies and clinical observation studies. However, this is the first time we show how infections during pregnancy affect brain development and can lead to cognitive impairment. Although many factors have been assumed or indicated, it is important to show the stages of neuronal development actually affected, "says Konstantin Khodosevich

Infections: the mother's immune response impairs the brain cells of the child

The researchers studied the development of neurons in mice. The mother's immune response to infection has had an effect that extends from stem cells and precursor cells to neuronal cells, causing a profound disruption of their development in the brain. More specifically, the development of cortical GABAergic interneurons - the class of neurons that allows inhibition in the brain - was impaired.

Infections during pregnancy impair neuronal development, resulting in a decrease in the number of motor and somatosensory (bley) neurons. Credits: Navneet A. Vasistha et al. 2019

The effect was immediate and had profound consequences through lasting alterations, resulting in multiple "impacts" during the neuronal development process - from the birth of neurons to their maturity.

In addition, the researchers also concluded that newborn mice exhibited symptoms similar to those of human psychiatric disorders, including reduced prepulsion inhibition, impaired social interaction, and cognitive decline.

The importance of the moment of infection during pregnancy

" The study in humans poses big technological and ethical problems, because of the vulnerability of pregnant women. This is why we study the functioning of mechanisms in mice. Psychiatric disorders are very complex and for some, we still do not know how they present themselves. We really want to contribute to the scientific understanding of these diseases, "explains Khodosevich.

Depending on the time of infection during pregnancy, different precursor cells and, consequently, different neurons, were affected. This means that the moment of infection is very important and can lead to variable results depending on the stage of development of the affected brain. This can potentially underlie the complexity of psychiatric disorders.

The researchers are now hoping to deepen their knowledge of the molecular mechanisms and signaling pathways that cause the degradation of interneuron development.


Saturday, 2 November 2019

Researchers develop light-activated insulin-producing cells for diabetes

The researchers caused the beta cells in the artificial pancreas to secrete insulin when exposed to blue light. Insulin is shown here as an atomic model filling the space. Credit: Tufts University

Researchers at Tufts University transplanted beta cells from the modified pancreas into diabetic mice and allowed the cells to produce more than two to three times the typical level of insulin by exposing them to light. Light-switchable cells are designed to compensate for lower insulin production or reduced insulin response in diabetic individuals. The study published in ACS Synthetic Biology shows that glucose levels can be controlled in a mouse model of diabetes without pharmacological intervention.

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Insulin is a hormone that plays a central role in the precise control of circulating glucose levels, the essential fuel used by cells. Diabetes affects more than 30 million Americans according to the Centers for Disease Control and Prevention (CDC). In type II diabetes - the most common form of the disease - the body's cells react ineffectively with insulin and, as a result, the circulating glucose can become dangerously high (hyperglycemia) while the pancreas can not not produce enough insulin to compensate. In type I diabetes, beta cells, which are the only insulin-producing cells in the body, are destroyed by the immune system, resulting in a complete absence of the hormone.

Current treatments include the administration of drugs that enhance insulin production by pancreatic beta cells, or direct injection of insulin to supplement the natural supply. In both cases, the regulation of blood glucose becomes a manual process, the intervention of a drug or insulin being performed after periodic readings of blood glucose, often leading to spikes and troughs that can have adverse effects long-term.

The researchers sought to develop a new way to boost insulin production while maintaining the important real-time link between insulin release and glucose concentration in the blood. They did this by taking advantage of optogenetics, a protein-based approach that modifies their on-demand activity with light. The pancreatic beta cells have been modified with a gene that encodes a photoactivatable adenylate cyclase enzyme (PAC). PAC produces cyclic adenosine monophosphate (cAMP) when exposed to blue light, which increases the production of glucose-stimulated insulin in the beta cell. Insulin production can increase two to three times, but only when the amount of blood glucose is high. When blood glucose is low, insulin production remains low. This avoids the common disadvantages of diabetes treatments, which can overcompensate insulin exposure and leave the patient with a harmful or dangerously low blood sugar level (hypoglycaemia).

The researchers found that transplanting artificial pancreatic beta cells into the skin of diabetic mice improved tolerance and glucose regulation, reduced hyperglycemia, and increased plasma insulin levels during blue light illumination.

"It's a retrograde analogy, but we actually use light to activate and deactivate a biological switch," said Emmanuel Tzanakakis, professor of chemical and biological engineering at the School of Engineering at Tufts University and corresponding author of the 'study. "In this way, we can help, in the diabetic context, to better control and maintain the appropriate glucose levels without pharmacological intervention.The cells naturally perform the work of insulin production and the regulatory circuits within them work from the In the same way, we simply increase the amount of transient cAMP in beta cells to produce more insulin than is needed. "

Blue light simply switches the switch from normal mode to fast mode. Such optogenetic approaches using light-activatable proteins to modulate cell function are being explored in many biological systems and have fueled efforts to develop a new kind of treatment.

"The use of light to control treatment has several advantages," said Fan Zhang, a graduate student at Tzanakakis Lab in Tufts and the first author of the study. "Obviously, the response is immediate, and despite the increased secretion of insulin, the amount of oxygen consumed by the cells does not change significantly, as our study shows." Oxygen deficiency is a common problem in studies involving transplanted pancreatic cells. "


Measles clears some of the immune memory, preventing the body from fighting other infections

Measles is a highly contagious viral infection that usually affects young children. Although the main symptoms may at first seem relatively benign, the virus can spread to the brain or lungs, leading to dangerous life-threatening complications such as encephalitis or pneumonia. In two recent studies, virologists have shown that measles clears some of the body's immune memory, preventing it from fighting infections during or after the disease, even though the patient had already faced to these infections before.

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Once infected, the amnesic immune system no longer recognizes the pathogens it has fought in the past. This means that measles survivors can remain exposed to dangerous diseases - such as influenza and pneumonia - for years, even though they have overcome their initial illness.

" Measles essentially removes their ability to protect themselves effectively, " says Michael Mina, an epidemiologist at Harvard University and co-author of the new study published in the journal Science . The article is associated with another published in the journal Science Immunology .

Using data from a group of unvaccinated children in the Netherlands, both studies revealed what virologists suspected for a long time: the measles virus paralyzes the immune system in a deep and lasting way.

" This work specifies exactly how immunosuppression occurs, and gives us an idea of ​​the magnitude of the immunosuppression in question," says William Schaffner, Professor of Preventive Medicine and Infectious Diseases at Vanderbilt University. The results also point out that this year's record measles outbreaks in the United States will have lingering effects.

Measles is an infectious disease transmitted by a morbillivirus of the family Paramyxoviridae . It manifests itself in many symptoms and can lead to serious complications. Credits: CDC / WHO

These children are currently going through a post-measles period more exposed to other infections ." According to the World Health Organization, the number of measles cases has increased by more than 280% since 2018, which means that hundreds of thousands of people who have caught the virus this year could now also be infected. secondary.

Suppression of some of the body's immune memory

Virologists have long believed that the measles virus can cause "immune amnesia," but the underlying mechanism remains unclear. They know that once the virus has infected a person, it reduces the reserves of white blood cells that kill pathogens. The number of immune cells returns to normal levels once the infection is eliminated, but even then the affected person may remain immunocompromised for years.

" But paradoxically, it leaves a solid immunity to measles, " said Duane Wesemann, a professor of medicine at Brigham and Women's Hospital. In other words, while measles survivors struggle to defend themselves against other pathogens, their bodies can prevent a new attack from the measles virus itself.

In fact, before the introduction of the measles vaccine in the 1960s, about 50% of child deaths could have been associated with infections they contracted after surviving a measles crisis, according to a 2015 study released in the journal Science . How, then, does measles cause such damage to the immune system even after the disappearance of the infection?

To find out, the authors of the new articles took blood samples from 82 unvaccinated Dutch children. In a measles outbreak that hit the country in 2013, five of the children managed to avoid infection but most caught the virus. The authors compared blood samples taken from children before and after infection to determine the evolution of their immune system.

Massive loss of B-cells after measles infection

The authors of the Science Immunolog study examined the white blood cells of children, including a type of white blood cell called B cells. When the body detects a new pathogen, B cells produce proteins that target the germ and transmit it. to another protein for destruction. B cells continue to develop these antibodies even after the pathogen disappears, so the body remembers the disease if it should return.

Graphs showing the loss of B and T lymphocytes during infection. B-lymphocytes constitute an acquired immune memory; their loss thus means a disappearance of this immune memory. Credits: Velislava N. Petrova et al. 2019

The researchers found that children infected with the measles virus lose many B-cells trained to recognize common infections.

Forty to fifty days after infection, once the virus is eliminated, the affected children have assembled a new army of B cells to replace those lost during the disease. However, the effectiveness of these in the fight against specific infections is not yet determined - this could be a question for future studies, according to Wesemann.

Antibodies: they partially disappear during infection

Rather than take stock of B cells, the authors of the study published in Science have looked directly at the first line of the immune defense: the antibodies themselves. Trillions of antibodies can be found in every microliter of blood. Many of these antibodies are produced by bone marrow cells called "long-lived plasma cells", which also perish because of the measles virus.

Using a tool called VirScan, researchers determined which antibodies appeared in the blood of children before and after measles. The screening tool allowed researchers to go through the children's medical history and see what pathogens they had encountered in their lifetime. But the measles virus has erased much of this story.

Graph showing the loss of antibodies (in red) during measles infection, compared to control groups (gray and green). Credits: Michael J. Mina et al. 2019

After catching the virus, children lost between 11% and 72% of their total antibody diversity, indicating that measles had partially erased their immune memory. In general, the number of antibodies lost seems to depend on the severity of the measles infection. Vaccinated children, as well as unimmunized individuals who did not contract measles, retained approximately 90% of their antibody repertoire during the same period.

Re-enter pathogens to rebuild immune memory

Measles survivors can recover from immune amnesia, but only by re-familiarizing themselves with all their previous pathogens. In the Science study , some children quickly recovered new antibodies to fight against staphylococcal infections, influenza and adenoviruses, the family of viruses that cause sore throats and pneumonia.

The researchers found that all these children lived together or in the same neighborhoods, which accelerated the spread of pathogens. " What we were actually attending was the re-education of their immune system, " says Mina. Although healthy Dutch children have resisted these secondary infections, malnourished or immunosuppressed children may not be able to cope as well after measles.

Vaccine against measles: the best defense against disease

Wesemann wondered whether antibody replacement therapy, in which people received antibodies from donors, could help maintain children's immune systems after measles infection, while strengthening their defenses. Questions also remain about why some children lose more measles antibodies than others and how the evolution of white blood cell diversity affects survivors.

One thing is clear: the measles vaccine is fantastic. It endows the body with an arsenal of anti-measles antibodies, just like the virus itself. But unlike infection, inoculation does not diminish the body's ability to build antibodies against other pathogens. You get all the benefits and no inconvenience with the vaccine, "Wesemann concludes.

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Friday, 1 November 2019

Two new anti-tumor molecules neutralize protein considered impossible to target so far

During the cancer process, tumor growth is ensured by uncontrolled cell proliferation. A specific protein plays a key role in this mechanism: the KRAS protein. However, the structure of the latter contains no cite allowing the attachment of therapeutic molecules, so much so that for a long time, it was considered impossible to target. But recently, two laboratories have succeeded in developing two new molecules that effectively target this protein. This achievement is an extremely important step in the fight against cancer.

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Oncology researchers are moving towards a goal that has been elusive for more than 30 years: reducing the number of tumors by inhibiting a protein called KRAS, one of which mutates to promote the growth of many types of cancer. A new type of drug targeting KRAS has resulted in the disappearance of tumors in mice and the reduction of tumors in patients with lung cancer.

It is unclear whether the drugs will prolong the life of patients, but the results spark a wave of excitement. And a company, Amgen, reports an unexpected bonus: its drug also appears to stimulate the immune system to attack tumors, suggesting that it could be even more potent if combined with immunotherapy treatments widely available. " It's a great demonstration that a combination of drugs could really work, " says Channing Der, a researcher at the University of North Carolina.

New molecules targeting the KRAS protein

KRAS is one of three genes in the RAS family (for rat sarcoma) that produce proteins that control an on-off switch for cell growth; mutated forms of these genes are found in about 25% of all cancers. But RAS proteins have been considered "non-targetable", in part because their smooth surfaces offer no site to target with a drug.

In 2013, however, the laboratory of molecular biologist Kevan Shokat of the University of California identified a small molecule that could target a KRAS mutant called G12C (for glycine mutated to cysteine ​​at position 12).

The mutant is present in about 13% of the most common lung tumors, 3% of colorectal cancers and 2% of other solid tumors. A company called Wellspring Biosciences later showed that when mice with human tumors carrying KRAS (G12C) were given an improved version of the Shokat molecule reduced their growth.

Computer graphics explaining the role played by KRAS protein in cell growth. When it malfunctions, cell proliferation becomes anarchic. Credits: Amgen

Amgen's drug, AMG510, targets a second groove in the same KRAS protein. This seems to make it more powerful and specific than Wellspring's compound, the company reports in the journal Nature . After administering sufficient doses of the drug to mice with several types of tumors with KRAS (G12C), most tumors have decreased or even disappeared

Inhibition of KRAS: a significant reduction in the number of tumors in humans

Amgen also describes the preliminary results of the first human trial of a KRAS inhibitor, revealing that his drug partially reduced the tumor in two of four patients with advanced lung cancer after six weeks of treatment. At meetings this year, the company also showed that tumors were declining in about half of a larger group of 13 lung cancer patients.

Early results for colon cancer are not as encouraging; only one in 12 patients responded. But " it was planned, " says Jude Canon, Director of Research at Amgen, because colon cancer is more biologically complex and may require combinations of drugs.

Another company, Mirati, also announced promising human results this week at a meeting and in an article published in the journal Cancer Discovery . Its KRAS inhibitor (G12C) reduced tumors in three of six patients with lung cancer, as well as in one of four colon cancer patients.

Eliminate tumors while stimulating the immune system

In addition to blocking the protein KRAS (G12C), Amgen's drug stimulates immune cells called T cells to attack the tumor. When AMG510 was combined with a drug called PD-1 inhibitor, which removes T-cell blockade, tumors disappeared permanently in 9 of 10 mice. PD-1 inhibitors alone can eliminate some cancers, but most patients do not respond.

KRAS-G12C protein is represented in gray; the yellow zone indicates the binding site of the AMG 510 molecule developed by the Amgen laboratory. Credits: Amgen

The results suggest that treatments may be possible if PD-1 drugs are combined with Amgen's KRAS. Amgen has already started testing this drug combination in cancer patients. Although it is not the first targeted cancer drug that stimulates the tumor microenvironment to attract T cells, " it's nice to see it in action as well, " says David Tuveson, a biologist at the Cold Spring Harbor Laboratory.

The new findings are an "encouraging" step toward "a clinically effective KRAS inhibitor," says Harold Varmus of Weill Cornell Medicine, who launched the RAS initiative, an effort to target these proteins, in 2013. Der, who is consulting for Mirati warns that since the tumors are likely to develop resistance to these KRAS inhibitors, patients will probably need drug combinations.


Excessive regulation of genetically modified rice crops would cost the lives of many children around the world

According to scientific writer Ed Regis, golden rice would cause millions of unnecessary deaths as well as many cases of blindness among poor children. Indeed, he describes in detail the tragic situation of the golden rice in his last book.

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What is golden rice? It is a genetically modified variety of rice (Oryza sativa). It was created at the ETH Zurich (Swiss Federal Institute of Technology Zurich). Golden rice has been genetically modified to include beta-carotene, a chemical that our body can use to produce vitamin A. Namely, vitamin deficiency is a major cause of preventable childhood blindness in the world. In fact, nearly 500,000 children become blind each year.

Lack of vitamin A can also increase the risk of death from childhood diseases and infections. According to the World Health Organization (WHO), this problem is widespread in more than half of the world's countries, especially in Africa and South-East Asia. Although supplements can help fill this gap, WHO notes that fortification is a more direct way to tackle the problem, but in the long run. And it is exactly for this purpose that the golden rice was developed at first.

Although yellow rice has existed since the beginning of the century, it has not yet found its way to the populations that need it most in Asia ... In the new book by Ed Regis, titled Golden Rice: The Imperiled Birth of a Superfood GMO (Golden Rice: The Dangerous Birth of a GMO Superfood ), the author claims that the authorities are mainly to blame.

It should be noted that Greenpeace has strongly expressed its opposition to the introduction of golden rice and genetically modified crops in general. The organization claimed that the promotion of golden rice was motivated by commercial interests, that it had not been proven that it actually increased vitamin A levels (although clinical trials seem to indicate otherwise) and that it was diverting attention from other attempts to end child poverty.

Although many controversies over gold rice research continue to fuel debate among scientists, the main problem, according to Regis, is the Cartagena Protocol on Biosafety. This international treaty, concluded in 2003, makes it very difficult to introduce GM crops around the world, assuming that these foods are dangerous until their safety is proven, not the other way around.

Such regulations exist because of the irrational fears of GMOs, ignorance of the science involved and over-observance of the precautionary principle ," said Regis.

Although we can all agree that health should always be a priority, Regis says that the potentially life-saving effects of golden rice (we are talking about 670,000 lives a year!), Would "  mitigate a little the approach "Prevention is better than cure ".

" In Bangladesh, China, India and elsewhere in Asia, many children survive only through a few bowls of rice a day, and almost nothing else,  " says Regis in his book. "  For them, a daily supply of golden rice could help preserve the gift of life that is sight,  " he continues.

This is a debate that has raged for many years: in 2016, more than 100 Nobel laureates signed a petition condemning the blockage of genetically modified products such as golden rice, noting that no negative results for health had been registered for humans or animals.

In 2018, a review of more than 6,000 studies concluded that GMOs lead to increased yields and important health benefits: this is convincing evidence that foods like golden rice are worthy of mention. to be grown to potentially improve diets in the poorest regions of the world.

Hope for golden rice?

It should be noted that it is currently approved only in four countries: Australia, New Zealand, the United States and Canada. But some scientists hope that it will also get the green light in Bangladesh and the Philippines by the end of the year, where it is sorely lacking.