Three-year-old Naomi slaps her forehead a few times, bites her fingers and toddles across the doctor’s office in her white and pink pyjamas before turning her head into a door with a dull thud. Her mother quickly straps on a helmet and adjusts the rainbow chinstrap, then watches as Naomi puts a hand back in her mouth and continues exploring the room.

“She keeps me busy,” acknowledges her mother, Laura Elguea.

Naomi was diagnosed at age 2 with Rett syndrome, a rare, debilitating disease in which patients progressively lose brain function and the ability to walk. While she laughs, smiles and toddles around like most 3-year-olds, Naomi’s repetitive hand behaviours offer clues to her condition.

Relatively little is known about the neuronal causes of Rett syndrome, but UT Southwestern Medical Center scientists have now identified a process in the brains of mice that might explain the repetitive actions – research that could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.

The finding from UT Southwestern’s Peter O’Donnell Jr. Brain Institute could also potentially benefit people with autism spectrum disorder, though more research is needed to evaluate the link to this disease in humans.

“We are exploring the processes that contribute to Rett syndrome in an effort to develop treatments that may prove useful in the disease,” said Dr. Lisa Monteggia, Professor of Neuroscience with the O’Donnell Jr. Brain Institute, who led the research.

The study demonstrated that MeCP2 – the protein that does not work properly in Rett syndrome – is among a group of three proteins that affect the function of a gene previously linked to obsessive compulsive disorder. Researchers were able to induce and then suppress repetitive behaviours in mice by changing the levels of these three proteins at the synapse – the communication junction between nerve cells.

The research is a significant advancement in the understanding of how dysfunction in MeCP2 leads to key symptoms associated with Rett syndrome. Although MeCP2 was identified less than two decades ago as the cause of the postnatal neurological disorder, the link between the protein’s dysfunction and the specific neurological symptoms characteristic of the disease remains elusive.

Rett syndrome affects girls almost exclusively, occurring in 1 of every 10,000 to 15,000 births and usually diagnosed by age 2. It is characterized by developmental regression, autistic traits, slow brain development, lack of speech, repetitive hand movements, seizures, and problems with walking. Many patients live beyond middle age, though not enough data exist to reliably estimate life expectancy beyond age 40.

While current medications and behavioural therapy can sometimes diminish symptoms such as seizures and hand behaviours, no treatment exists to eradicate or reverse the disorder and the repetitive stereotyped behaviours, due in large part to a lack of knowledge about how MeCP2 dysfunction gives rise to these and other symptoms.

UT Southwestern Medical Center www.utsouthwestern.edu/newsroom/news-releases/year-2016/september/rett-syndrome-monteggia.html

Together with AIDS, tuberculosis ranks among those infectious diseases with the highest global mortality rate, claiming the lives of between 1.5 and two million people every year. However, not everyone infected with the bacterium develops tuberculosis. In fact, fewer than ten percent of those infected go on to manifest the disease. An international team of scientists, including researchers from the Max Planck Institute for Infection Biology in Berlin, have now developed a tuberculosis test that can reliably predict whether an individual will develop active tuberculosis. Doctors may be able to use this test in future to predict the progression of the disease and initiate medical care early.
 In future, molecules from blood samples can tell physicians if somebody will develop tuberculosis.

Around 4000 people die of tuberculosis every day and around a third of the world’s population are infected by the causative pathogen, the Mycobacterium tuberculosis bacterium; however, around 90 percent of those infected remain free of symptoms throughout life. In such cases of latent tuberculosis, the bacteria remain dormant in the body without triggering active disease. People with a weak or weakened immune system, for example the very young and very old as well as individuals with other diseases such as HIV or diabetes, are more likely to develop active tuberculosis. A poor diet and poor social conditions are further risk factors.

The blood counts of individuals with latent or active tuberculosis differ from each other. Nevertheless, until now it has not been possible to predict whether an individual with Mycobacterium tuberculosis infection will develop active tuberculosis.

In a recently published study, scientists developed a blood test based on biomarkers that can predict whether active tuberculosis will develop with a reliability of around 75 percent. A biomarker can be a cell, gene or molecule, such as enzymes or hormones, by means of which doctors can detect changes in the body. In order to detect differences between latent and active tuberculosis, scientists of the South African Tuberculosis Vaccine Initiative (SATVI) and the Center for Infectious Disease Research (CIDR) analysed the gene activity in blood samples obtained from more than 10,000 people in South Africa and Gambia, and then observed the subjects for two years.

The results show that specific genes in immune cells are active in the blood of individuals who later develop active tuberculosis. In future, a blood test for gene activity will be able to identify the activity pattern typical of potential tuberculosis patients. “Such a test could predict the occurrence of the disease more than a year before the disease develops,” says the head of the study, Willem Hanekom of the University of Cape Town. “This long lead period will give doctors enough time to initiate treatment.” The blood test will now be tested in clinical trials to determine whether progression of the predicted disease can be halted with targeted treatment. Max Planck Society

University of Helsinki researchers have previously demonstrated that a point mutation in a gene of serotonin 2B receptor can render the carrier prone to impulsive behaviour, particularly when drunk. Now the research group has established that the same mutation may shield its bearers from obesity and insulin resistance, both of which are associated with type 2 diabetes.

The study focused on the insulin sensitivity, beta cell activity and BMI of 98 Finnish men between the ages of 25 and 30, all of whom had been diagnosed with antisocial personality disorder. The results indicate that carriers of a point mutation in a gene of serotonin 2B receptor had a lower BMI and higher insulin sensitivity than persons without the mutation. Normally, men with low testosterone levels are more susceptible to metabolic disorders, but among carriers of the point mutation, this tendency was reversed – lower levels of testosterone increased insulin sensitivity.

The results also suggest that men in their thirties with antisocial personalities may constitute a risk group for insulin resistance, and consequently type 2 diabetes later in life.

 “It is fascinating to think that this receptor mutation which has been passed through the chain of evolution would impact both the brain as impulsive behaviour and energy metabolism,” says psychiatrist, Dr Roope Tikkanen from the University of Helsinki, who led the study. 

 “We could speculate that the compound effect the mutation and testosterone have on energy metabolism may have been beneficial in the cool, nutrition-poor environment after the Ice Age, particularly for men with a high physiological level of testosterone – they would have survived with a lower calorie intake. Simultaneously, the aggression associated with high levels of testosterone may have helped them compete for food.”

In our modern society with ample food, the carriers of the mutation who have normal or low levels of testosterone may be better protected from metabolic illnesses relating to obesity, such as type 2 diabetes.

 “One would assume that the effect would be particularly pronounced in women, who naturally have lower levels of testosterone than men,” Tikkanen points out.

Over 100,000 Finns and more than 1,000 Finnish infants born every year are carriers of the point mutation in the serotonin 2B receptor. The intention is to study the national health implications of the results from the extensive FINRISKI research material through cooperation between Finnish, Swedish and American researchers.

 “Our results will further highlight the importance of Finnish diabetes research,’ Tikkanen states.

University of Helsinki www.helsinki.fi/en/news/aggressive-drunk-gene-may-protect-carriers-from-obesity

ETH researchers have discovered a molecule in liver cells that controls the release of fat into the bloodstream. This “lock keeper” is present in large quantities in overweight people and leads indirectly to vascular narrowing.

Anyone attending Munich’s famous Oktoberfest will know it can leave physical traces; fatty foods and plenty of alcohol cause the liver to work overtime. This organ stores a portion of any fat consumed (and also converts alcohol to fat), but releases it again once the revelry is over.

However, should the excesses continue – and if they are not offset by exercise and sport – the person becomes overweight and diabetic, leading to a condition known as fatty liver. If corrective action is taken in time, the liver can usually recover completely from its fatty degeneration. In severe cases the organ becomes inflamed – a condition that is almost impossible to treat.

Fatty liver is also associated with elevated blood fat values. When the liver becomes fatty it seeks relief by releasing fat into the bloodstream, including “good” fat in the form of high density lipoprotein (HDL), but also “bad” fat, such as low density lipoprotein (LDL), and its precursor, very low density lipoprotein (VLDL).
If the concentration of LDL and VLDL in the blood is too high, vascular constriction forms through atherosclerotic plaques. Should a plaque detach itself, there is a real risk of a vascular blockage, which results in a heart attack or stroke.

Markus Stoffel, Professor of Molecular Health Sciences at ETH Zurich, has been working with his team in collaboration with other scientists in Switzerland, Germany and the US to gain a closer understanding of the connection between excess weight, fatty liver and vascular constriction. And this has led to a surprising discovery: the scientists succeeded to identify a protein in liver cells known as vigilin, which acts as a kind of “lock keeper”. It regulates the release of fats, including VLDL, from the liver into the bloodstream.

The researchers found vigilin in large quantities in the liver cells of overweight mice – and humans. “The level of vigilin in the liver cells of people with fatty livers bears a strong correlation with the percentage of fat in the liver,” explains Stoffel. “In other words, the more fat liver cells contain, the higher the quantity of vigilin.”

In a study the ETH professor and his co-workers demonstrate that the primary function of vigilin is to regulate proteins that transport fat out of the liver. However, the molecule does not bind directly to these transport proteins, but rather to certain points of the associated messenger RNA.
The messenger RNA is the transcription of a gene. It represents the construction plan for the associated protein and is transported from the cell nucleus to the ribosomes. These molecular machines use the messenger RNA to build the protein.

The assumption is that vigilin supplies the ribosomes with the messenger RNA to which it is bound. But it is not just a transport vehicle, it also accelerates production of the associated protein.

One of these proteins “promoted” by vigilin is apolipoprotein B (ApoB), which is responsible for exporting triglycerides from the liver. Triglycerides also promote vascular calcification when present in concentrated form in overweight people.

In order to establish the causal relationship between vigilin and vascular calcification, the researchers stemmed formation of this protein in the livers of mice using a new process of RNA interference. As a consequence of this intervention, these animals suffered far less from atherosclerosis than animals who processed vigilin normally. By contrast, increased vigilin formation led to substantial deposits in the vessels.

“Vigilin intervenes at the level of gene regulation, which has barely been investigated to date,” says Stoffel. Our knowledge of how genes are regulated at the level of DNA is improving all the time. And the regulatory processes by which DNA templates are transcribed into messenger RNA are increasingly understood. But regulation of the step from messenger RNA to protein is something we know much less about. This makes the knowledge that vigilin has a regulatory function at this level all the more valuable. And researchers are particularly excited by the fact that vigilin is the first RNA-binding protein found in the context of fatty livers and diabetes.

ETH Zurich www.ethz.ch/en/news-and-events/eth-news/news/2016/09/vigilin-the-lock-keeper.html

The babies of obese women who develop gestational diabetes are five times as likely to be excessively large by six months of pregnancy, according to new research led by the University of Cambridge. The study, which shows that excessive foetal growth begins weeks before at-risk women are screened for gestational diabetes, suggests that current screening programmes may take place too late during pregnancy to prevent lasting health impacts on the offspring.

Gestational diabetes is a condition that can affect women during pregnancy, with those who are obese at greater risk. As well as affecting the mother’s health, the condition also causes the unborn child to grow larger, putting the mother at risk during childbirth and increasing the likelihood that her offspring will develop obesity and diabetes during later life. The condition can usually be controlled through a combination of diet and exercise, and medication if these measures fail.

Women are screened for the condition through a blood glucose test at around 8-12 weeks into pregnancy. Current guidelines in the UK and the USA recommend that mothers found to be at greatest risk should then be offered a full test at between 24 and 28 weeks into pregnancy; however, in practice the majority of women are screened at the 28 week mark.

Researchers at the Department of Obstetrics & Gynaecology at the University of Cambridge analysed data from the Pregnancy Outcome Prediction study, which followed more than 4,000 first time mothers using ultrasound scans to assess the growth of their babies in the womb. They measured the abdominal and head circumference of the foetuses and compared the growth in women who developed gestational diabetes with those who did not.

Of the 4,069 women studied, 171 (4.2%) were diagnosed with gestational diabetes at or beyond 28 weeks. The researchers found no association between the size of the child at 20 weeks and the mother subsequently developing gestational diabetes. However, they found that the foetuses of women subsequently diagnosed with gestational diabetes grew excessively prior to diagnosis, between 20 and 28 weeks. Hence, the babies were already large at the time of diagnosis, and their findings suggest that the onset of foetal growth disorder in gestational diabetes predates the usual time of screening.

The researchers also studied women who were obese, as it is well recognised that maternal obesity is a risk factor for childhood obesity. Even in the absence of diabetes, the babies of obese women were also twice as likely to be big at 28 weeks. The combination of obesity and gestational diabetes was associated with an almost 5-fold risk of excessive foetal growth by the 28 week scan.

“Our study suggests that the babies of women subsequently diagnosed with gestational diabetes are already abnormally large by the time their mothers are tested for the disease,” says Dr Ulla Sovio from the Department of Obstetrics and Gynaecology at the University of Cambridge, the study’s first author. “Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women.

“Early screening may be particularly beneficial for obese women, as fetal growth is already abnormal by 20 weeks among these women. Any intervention aimed at reducing the risk of abnormal birthweight in the infants of obese women may need to be implemented even earlier.”

Senior author Professor Gordon Smith, also from the University of Cambridge, adds: “We know that the offspring of women with gestational diabetes are at increased risk of childhood obesity, but so far no clinical trials have successfully demonstrated that screening and intervention in pregnancy reduces this risk. Our study suggests a possible explanation: screening and intervention is taking place when the effects of gestational diabetes are already manifested in the foetus. Cambridge University