Researchers affiliated with the University of Campinas (UNICAMP) in São Paulo State, Brazil, have shown that genetic information can be used to improve early prediction of the response to drugs in patients with mesial temporal lobe epilepsy (MTLE), one of the most severe forms of epilepsy. Patients who do not respond well to treatment with antiepileptic drugs are candidates for surgery.
The research was conducted at the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN) – one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP – and led by Professor Iscia Lopes-Cendes.
"According to estimates, at the world’s best centres, it takes between 15 and 20 years for patients with MTLE refractory to drug treatment to be referred for surgery," Lopes-Cendes said. "Meanwhile, they continue to suffer from uncontrolled seizures. If we can shorten this process, we can improve the lives of many patients, potentially making the difference between going or not going to university, having or not having a job and a normal life."
MTLE, she explained, is caused by alterations in the functioning of neurons located in the deepest structures of the brain, such as the hippocampus and amygdala, which control important functions such as memory, attention, and anxiety, among others. Seizures due to abnormal electric discharges in a large group of neurons may or may not result in convulsions but do impair memory and other brain functions, often putting the patient at risk of accident and death.
Although MTLE is not the most frequent form of epilepsy, accounting for only 30-40% of cases, it is considered the hardest to treat in adults. Up to 40% of patients with MTLE do not respond to any of the available drugs. In these cases, surgical removal of the brain area that originates the seizures is often recommended.
The aim of the study, according to Lopes-Cendes, was to develop a methodology for distinguishing between the two groups by analysing their genetic material. To do this, the researchers selected a set of 11 genes that have been shown to be involved in antiepileptic drug absorption, metabolism, and transport in the scientific literature.
For these 11 genes, they genotyped 119 different single nucleotide polymorphism (SNP) molecular markers to see which alleles were present.
"We deployed a series of statistical procedures to develop the model with the best capacity to predict whether the patient would be responsive to drug treatment," Lopes-Cendes said. "In this model, we included and excluded variables to see which ones contributed most to the power of the predictors. Besides genetic polymorphisms, we also included clinical data such as the presence or absence of hippocampal atrophy, the age at and frequency of seizures at epilepsy onset, patient gender, and so on."
When only the clinical variables were taken into account, the model’s predictions were about 45% accurate, which, according to Lopes-Cendes, is less than would be achieved by tossing a coin.
However, the model’s accuracy increased to 80% when only SNP markers were used and to 82% when both clinical and genetic variables were used.
As Lopes-Cendes explained, in order to be sure that the two groups of patients belonged to the same population from a genetic standpoint and hence were genuinely comparable, the researchers also genotyped 90 other SNPs in different genes located on the same chromosomes as in the previous analysis.
"We call this testing technique ‘genome control’," she said. "Without it, we risk selecting patient and control groups from different populations, which would invalidate the results of the analysis."
In light of the model’s high level of accuracy, Lopes-Cendes revealed that she and her team at BRAINN now plan to begin a multicentre study involving patients from several countries.
"The idea is to genotype these SNPs at the start of treatment and to follow the patients for two years to see what happens. If the results corroborate our findings in this first study, we’ll have sufficient evidence to include the methodology in clinical practice," she said.

EurekAlert
www.eurekalert.org/pub_releases/2017-04/fda-mie040417.php

For years, scientists have been trying to determine what effect a gene linked to the brain chemical serotonin may have on depression in people exposed to stress. But now, analysing information from more than 40,000 people who have been studied over more than a decade, researchers led by a team at Washington University School of Medicine in St. Louis have found no evidence that the gene alters the impact stress has on depression.
New research findings often garner great attention. But when other scientists follow up and fail to replicate the findings? Not so much.
In fact, a recent study published in PLOS One indicates that only about half of scientific discoveries will be replicated and stand the test of time. So perhaps it shouldn’t come as a surprise that new research led by Washington University School of Medicine in St. Louis shows that an influential 2003 study about the interaction of genes, environment and depression may have missed the mark.
Since its publication in Science, that original paper has been cited by other researchers more than 4,000 times, and some 100 other studies have been published about links between a serotonin-related gene, stressful life events and depression risk. It indicated that people with a particular variant of the serotonin transporter gene were not as well-equipped to deal with stressful life events and, when encountering significant stress, were more likely to develop depression.
Such conclusions were widely accepted, mainly because antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) help relieve depression for a significant percentage of clinically depressed individuals, so many researchers thought it logical that differences in a gene affecting serotonin might be linked to depression risk.
But in this new study, the Washington University researchers looked again at data from the many studies that delved into the issue since the original publication in 2003, analysing information from more than 40,000 people, and found that the previously reported connection between the serotonin gene, depression and stress wasn’t evident.
“Our goal was to get everyone who had gathered data about this relationship to come together and take another look, with each research team using the same tools to analyze data the same way,” said the study’s first author, Robert C. Culverhouse, PhD, an assistant professor of medicine and of biostatistics. “We all ran exactly the same statistical analyses, and after combining all the results, we found no evidence that this gene alters the impact stress has on depression.”
Over the years, dozens of research groups had studied DNA and life experiences involving stress and depression in the more than 40,000 people revisited in this study. Some previous research indicated that those with the gene variant were more likely to develop depression when stressed, while others didn’t see a connection. So for almost two decades, scientists have debated the issue, and thousands of hours of research have been conducted. By getting all these groups to work together to reanalyze the data, this study should put the questions to rest, according to the researchers.
“The idea that differences in the serotonin gene could make people more prone to depression when stressed was a very reasonable hypothesis,” said senior investigator Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry at Washington University. “But when all of the groups came together and looked at the data the same way, we came to a consensus. We still know that stress is related to depression, and we know that genetics is related to depression, but we now know that this particular gene is not.”
Culverhouse noted that finally, when it comes to this gene and its connection to stress and depression, the scientific method has done its job.

Washington University School of Medicine
medicine.wustl.edu/news/study-reverses-thinking-genetic-links-stress-depression/

Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain.
Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses.
To uncover evidence of these disease types, first author Mady Hornig, MD, director of translational research at CII and associate professor of Epidemiology at Mailman, and colleagues used immunoassays to measure levels of 51 immune biomarkers in cerebrospinal fluid samples taken from 32 cases of classical and 27 cases of atypical ME/CFS. All study participants were diagnosed using the same standard criteria, but atypical cases either had prior histories of viral encephalitis, illness after foreign travel or blood transfusion, or later developed a concurrent malady—seizure disorders, multiple sclerosis-like demyelinating disorders, Gulf War Illness, or a range of cancers—at rates much higher than seen in the general population.
Their analysis revealed lower levels of immune molecules in individuals with atypical ME/CFS than those with a classical presentation and course of illness, including dramatically lower levels of interleukin 7 (IL7), a protein linked to viral infections, and interleukin 17A (IL 17A) and chemokine (C-X-C motif) ligand 9 (CXCL9), inflammatory molecules implicated in a variety of neurological disorders.
“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities,” says Hornig. “Importantly, our results suggest that these early biomarker profiles may be detectable soon after diagnosis of ME/CFS, laying a foundation for better understanding of and treatments for this complex and poorly understood illness.”
“Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes,” says co-author Daniel L. Peterson, MD, principal clinician at Sierra Internal Medicine in Incline Village, NV.
The new study builds on earlier research by Hornig and collaborators that found robust evidence of distinct stages in ME/CFS. A pair of 2015 publications based on analyses of blood and cerebrospinal fluid showed differences in the immune signatures of ME/CFS patients who had the disease for three years or less as compared with those who had been ill for more than three years. The researchers reported that patients were flush with cytokines and chemokines until around the three-year mark—suggesting an over-activated immune response in that phase of the illness; thereafter the immune system showed evidence of “exhaustion,” and levels of immune molecules dropped.
In the new study, both subsets of ME/CFS patients showed signs of an unbalanced or dysregulated immune system within the central nervous system, with immune markers different than those seen in healthy individuals. However, the dampened immune profiles previously observed after the three-year mark were only observed in individuals with the classical form of the disease, not in those with atypical ME/CFS. Among subjects in the atypical group, levels of cytokines and chemokines were more likely to remain steady or increase.
According to Hornig, instead of the immune exhaustion seen in later phases of classical ME/CFS, atypical patients may be experiencing a “smouldering inflammatory process” in which the immune system is still working to recover, although she acknowledges that much work remains to be done to confirm this hypothesis. Alternatively, these findings could suggest a pathway to disease in atypical individuals that involves biomarkers not captured in the 51-molecule assay, potentially even involving non-immune-related processes. Atypical individuals may also have genetic susceptibilities that lead their immune systems to respond differently than in classical cases.

Columbia University Mailman School of Public Health]
www.mailman.columbia.edu/public-health-now/news/scientists-discover-biological-evidence-atypical-chronic-fatigue-syndrome

Research led by scientists at the University of Birmingham has revealed a new cause of high blood pressure which could lead to major changes in managing the disease.
High blood pressure, also known as hypertension, often goes unnoticed but if left untreated can increase the risk of heart attack and stroke.
Studies estimate that one in four adults suffer from hypertension, but most patients have no identifiable cause for the condition.
However, it is known that in up to 10 per cent of hypertensive patients the overproduction of the adrenal hormone aldosterone – a condition known as primary aldosteronism or Conn syndrome – is the cause of disease.
Now the University of Birmingham-led study has, for the first time, made the important discovery that a large number of patients with Conn syndrome do not only overproduce aldosterone but also the stress hormone cortisol.
Professor Wiebke Arlt, Director of the Institute of Metabolism and Systems Research (IMSR) at the University of Birmingham, said: “Our findings show that the adrenal glands of many patients with Conn syndrome also produce too much cortisol, which finally explains puzzling results of previous studies in Conn patients.
“These previous studies had found increased rates of type 2 diabetes, osteoporosis and depression in Conn patients – problems typically caused by overproduction of cortisol, also termed Cushing syndrome, and not by too much aldosterone.”
The authors of the University of Birmingham-led study, conducted in collaboration with a group of scientists from Germany, decided to name this new cause of hypertension – the combined overproduction of aldosterone and cortisol – as Connshing syndrome.
At present, many Conn syndrome patients are treated with drugs that are directed against the adverse effects of aldosterone. However, this leaves the cortisol excess untreated.
Second author of the study, published in JCI Insight, Dr Katharina Lang – an academic clinical lecturer at IMSR – said: “These findings are very likely to change clinical practice.
“Patients will now need to undergo more detailed assessment to clarify whether they suffer from Conn or Connshing syndrome.

University of Birmingham
www.birmingham.ac.uk/news/latest/2017/04/connshing-syndrome.aspx