A new study from researchers at the University of Ottawa Heart Institute (UOHI), sheds light on a mysterious gene that likely influences cardiovascular health. After five years, UOHI researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.
Researchers at the Ruddy Canadian Cardiovascular Genetics Centre had initially identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but its role in multiple health processes made it difficult to tease out how it affects heart disease.
The gene holds instructions for producing a protein called SPG7. This protein resides in mitochondria—the small power plants of cells that produce the energy cells need to function. SPG7’s role is to help break down and recycle other damaged proteins within the mitochondria.
Normally, SPG7 requires a partner protein to activate itself and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can activate itself in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.
‘We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,’ said Dr. Stewart, Principal Investigator in the Ruddy Canadian Cardiovascular Genetics Centre and senior author of the study. ‘Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.’
From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome. Between 13 and 15 per cent of people of European descent possess this variant.
‘The idea of mitochondria contributing to inflammation isn’t new,’ concluded Dr. Stewart. ‘But what is new is that we’ve found one of the switches that regulate this process. We’re excited, because once you know where the switches are, you can start looking for ways to turn them on and off.’ EurekAlert

Dysfunction in dopamine signalling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioural and physiological functions regulated in the prefrontal cortex.

The study was led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signalling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signalling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviours in the mutant mice and that prolonged treatment with a dopamine activator restored regular signalling, pointing to one possible therapeutic approach. University of California, Irvine

New Penn Medicine research shows that neuropsychiatric symptoms such as depression, anxiety and fatigue are more common in newly diagnosed Parkinson’s disease (PD) patients compared to the general population. The study also found that initiation of dopamine replacement therapy, the most common treatment for PD, was associated with increasing frequency of impulse control disorders and excessive daytime sleepiness. The new findings, the first longitudinal study to come out of the Parkinson’s Progression Markers Initiative (PPMI).

The PPMI, a landmark, multicenter observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research, uses a combination of advanced imaging, biologics sampling and behavioural assessments to identify biomarkers of Parkinson’s disease progression. The Penn study, which represents neuropsychiatric and cognitive data from baseline through the first 24 months of follow up, was conducted in collaboration with the Philadelphia VA Medical Center and the University Hospital Donostia in Spain.

The study examined 423 newly diagnosed, untreated Parkinson’s patients and 196 healthy controls at baseline and 281 people with PD at six months. Of these, 261 PD patients and 145 healthy controls were evaluated at 12 months, and 96 PD patients and 83 healthy controls evaluated at 24 months.

PD patients were permitted to begin dopamine therapy at any point after their baseline evaluation.

“We hypothesized that neuropsychiatric symptoms would be common and stable in severity soon after diagnosis and that the initiation of dopamine replacement therapy would modify their natural progression in some way,” says senior author, Daniel Weintraub, MD, associate professor of Psychiatry and Neurology at the Perelman School of Medicine at the University of Pennsylvania and a fellow in Penn’s Institute on Aging.

The Penn team showed that while there was no significant difference between PD patients and healthy controls in the frequency of impulse control disorders, a neuropsychiatric symptom that can lead to compulsive gambling, sexual behavior, eating or spending, 21 percent of newly diagnosed PD patients screened positive for such symptoms at baseline. That percentage did not increase significantly over the 24-month period.

However, six patients who had been on dopamine therapy for more than a year at the 24-month evaluation showed impulse control disorders or related behaviour symptoms while no impulse control incident symptoms were reported in PD patients who had not commenced dopamine therapy. Dopamine therapy did help with fatigue, with 33 percent of patients improving their fatigue test score over 24 months compared with only 11 percent of patients not on dopamine therapy.

The investigators also found evidence that depression may be undertreated in early PD patients: Two-thirds of patients who screened positive for depression at any time point were not taking an antidepressant.

PPMI follows volunteers for five years, so investigators plan to expand upon these results, which Weintraub still considers preliminary. ‘We will more closely look at cognitive changes over time,” he says. “Two years is not a sufficient period of follow up to really look at meaningful cognitive decline.’

The perspective of time is what makes the PPMI such an important initiative, Weintraub points out, since many patients with the disease live for 10 to 20 years following their diagnosis. ‘It’s really a chance to assess the frequency and characteristics of psychiatric and cognitive symptoms in PD, compare it with healthy controls, and then also look at its evolution over time,” he says. “The hope is that we will be able to continue this work so that we can obtain long-term follow up data on these patients,” says Weintraub. Penn Medicine

EKF Diagnostics has acquired Separation Technology, Inc. (STI), the Florida based manufacturer of in vitro diagnostics devices for hematology testing from Thermo Fisher Scientific, Inc. This acquisition complements EKF’s existing offering in the hemoglobin testing market place, which includes Hemo Control (also sold as HemoPoint H2 in USA and Asia). Notably, STI’s primary instrument is the UltraCrit hematocrit measurement device which is FDA-cleared for blood donor screening. STI develops, manufactures and markets specialty IVD devices including ultrasound instruments and tabletop centrifuges for the hematology testing market. STI also has an in-house engineering capability, including product design, production support and new product development. STI’s UltraCrit is the first and only hematocrit/hemoglobin device to use ultrasound technology. The hematocrit reading is displayed automatically in about 30 seconds and provides a hematocrit value that allows for standardization for all collections, including whole blood, apheresis and double red cell collections. UltraCrit uses reagentless cuvettes, a major point of differentiation between different analysers.

EKF Diagnosticswww.ekfdiagnostics.com

An analysis of the genomes and epigenomes of lean and obese mice and humans has turned up a wealth of clues about how genes and the environment conspire to trigger diabetes, Johns Hopkins researchers say. Their findings reveal that obesity-induced changes to the epigenome — reversible chemical “tags” on DNA — are surprisingly similar in mice and humans, and might provide a new route to prevention and treatment of the disease, which affects hundreds of millions worldwide.

“It’s well known that most common diseases like diabetes result from a combination of genetic and environmental risk factors. What we haven’t been able to do is figure out how, exactly, the two are connected,” says Andrew Feinberg, M.D., M.P.H., Gilman Scholar and director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “This study takes a step in that direction.”

Feinberg has long studied the epigenome, which he compares to “software” that runs on DNA’s “hardware.” Epigenetic chemical tags affect whether and how much genes are used without changing the genetic code itself.

Feinberg wondered whether epigenetics might partly explain the skyrocketing worldwide incidence of type 2 diabetes. Obesity is a well-established risk factor for the disease, so Feinberg’s research group teamed with that of a group led by G. William Wong, Ph.D., an associate professor of physiology in the Center for Metabolism and Obesity Research at Johns Hopkins, to study the epigenetics of otherwise identical mice that were fed either normal or high-calorie diets.

Analyzing epigenetic marks at more than 7 million sites in the DNA of the mice’s fat cells, the researchers found clear differences between the normal and obese mice. Some sites that bore chemical tags called methyl groups in the lean mice were missing them in the obese mice, and vice versa. The methyl groups prevent genes from making proteins.

With colleagues at Sweden’s Karolinska Institutet, Feinberg and his team then tested whether the same pattern of differences held in fat cells from lean and obese people, and found, to their surprise, that it did. “Mice and humans are separated by 50 million years of evolution, so it’s interesting that obesity causes similar epigenetic changes to similar genes in both species,” Feinberg says. “It’s likely that when food supplies are highly variable, these epigenetic changes help our bodies adapt to temporary surges in calories. But if the high-calorie diet continues over the long term, the same epigenetic pattern raises the risk for disease.”

The research team also found that some of the epigenetic changes associated with obesity affect genes already known to raise diabetes risk. Others affect genes that had not been conclusively linked to the disease, but that turned out to have roles in how the body breaks down and uses nutrients, a process called metabolism. “This study yielded a list of genes that previously have not been shown to play a role in diabetes,” says Wong. “In further tests, we showed that at least some of these genes indeed regulate insulin action on sugar uptake; they offer insights into new potential targets for treating type 2 diabetes.”

In addition to providing leads for drug development, the results also suggest that an epigenetic test could be developed to identify people much earlier on the path to diabetes, giving more hope for preventing the disease, Feinberg says. John Hopkins Medicine