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Large genetic study uncovers potential new treatments for inflammatory diseases
Researchers from the Research Centre of Applied and Preventive Cardiovascular Medicine at the University of Turku, Finland, have studied over ten million DNA variations and found new links between the human genome and inflammation tracers. The study uncovered new possibilities for treatment of diseases such as multiple sclerosis, Crohn’s disease and coeliac disease.
Cytokines and growth factors, which circulate in the bloodstream, are important proteins for regulating inflammation reactions. Changes in their mode of operation have been linked with many inflammatory diseases, such as Crohn’s disease, multiple sclerosis, atherosclerosis, ulcerative colitis and many types of cancer.
In this latest study, based on population data and coordinated by the University of Turku’s Research Centre of Applied and Preventive Cardiovascular Medicine, an investigation was made of the links between 41 different cytokines and growth factors and 10.7 million DNA variations.
? We wanted to find out the molecular-level processes that lead to an increased risk of developing inflammatory diseases. Understanding these processes will enable more effective treatment of diseases, explains Professor Olli Raitakari, Director of the Research Centre.
Researchers noticed that the medicine daclizumab, previously used for treating organ rejection reactions, could possibly also be used in the treatment of multiple sclerosis and Crohn’s disease. In addition, an increase in the activity of MIP1b-cytokine could also serve as a method of treatment against coeliac disease and Behcet disease. Further clinical studies are required to confirm the observations.
Evidence from human genetics speeds up medical development
Technological development has enabled the practice of genome-wide association studies since the turn of the century.
? In these kinds of studies, millions of DNA variations are examined and their impact is assessed for each property being studied. The studies carried out so far have succeeded in uncovering, for example, over one hundred genomic loci which have an impact on the risk of developing Crohn’s disease or ulcerous colitis.
In studies of connections between genetic variations and disease risks, the precise molecular process causing the increased risk often remains unclear. In order to uncover this molecular process, genome-wide association studies use as response variables molecules that mediate disease-risk through the bloodstream, such as cytokines and growth factors, instead of using the diseases themselves.
Anti-cell death agent a potential treatment for vision loss associated with Multiple Sclerosis
This image shows myelin (blue) in the optic nerve of a normal mouse (top), a mouse with optic neuritis (middle), and an optic neuritis mouse treated with ST266 (bottom) .Ken Shindler, MD, PhD, Perelman School of Medicine, University of Pennsylvania
A new therapeutic agent tested in a mouse model of multiple sclerosis (MS) produced anti-inflammatory activity and prevented loss of cells in the optic nerve, according to a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania, with Pittsburgh-based Noveome Biotherapeutics. The research was conducted in the laboratory of Kenneth Shindler, MD, PhD, an associate professor of Ophthalmology and Neurology, and published in Scientific Reports.
The team demonstrated the therapeutic potential of the agent, called ST266, for treating optic neuritis, inflammation that damages the optic nerve and is a common presenting feature of MS. About half of patients diagnosed with MS experience optic neuritis, which can cause mild to moderate permanent loss of vision, but rarely complete blindness. ST266 is a solution of molecules that stimulate paracrine signaling. This is one way in which cells “talk” to each other: One cell produces a chemical signal that induces changes in nearby cells.
“In this case, the idea is that the many factors in ST266 not only bind to cell receptors and cause changes within the cells they bind to, but those cells then alter their own secretions and provide additional signals to other neighboring cells, thus propagating an effect from a relatively small amount of protein present in the therapy itself,” Shindler said. “To the best of our knowledge, this study demonstrates, for the first time, the ability to treat the optic nerve via the intranasal route of administration.”
When ST266 was given to the MS mice via their nose, it reached the central nervous system within 30 minutes and was detected at higher concentrations in parts of the eye and optic nerve compared to other areas of the brain. These findings demonstrated that this type of delivery can target tissues of the eye, which is easier, less painful, and less invasive than injecting medication directly into the eye.
In mice with optic neuritis, the team showed that early treatment with ST266 prevented damage and dysfunction, marked by significantly reduced loss of optic nerve cells, and suppression of inflammatory cell infiltration into the optic nerve. This in turn was associated with limitation of the degree of demyelination caused by MS- related optic neuritis. However, “it’s not known if these effects are independent effects of the therapy or interdependent effects,” Shindler said.
Treatment of later-stage optic neuritis in the MS mice showed similar results, resulting in improved visual function compared to untreated groups. The data suggest that ST266 helps promote optic neuron survival by potentially activating multiple pathways, including those that prevent cell death.
“These results are particularly important as the preservation of retinal cells is a significant factor when treating optic neuritis,” Shindler said. “There is an increased need for combination treatment options that are able to prevent nerve-cell axon loss for patients with optic neuritis.”
Currently, the only acute treatment for MS-related optic neuritis is IV steroids, which only hasten whatever amount of visual recovery will occur even without treatment. Steroids do not prevent nerve damage or permanent vision loss. “ST266’s ability to preserve vision in the preclinical model and reduce neuronal loss would be a huge advance if it translates to human patients,” Shindler said.
The study also has implications beyond MS-related optic problems. “We also showed an effect on cultured neurons, suggesting that effects may translate to other optic nerve diseases, as well as other brain neurodegenerative diseases,” Shindler said.
Overlooked disease: Tens of thousands of people have problems at work
Imagine your head pounding. And when you try to move, a door slams, or curtains are drawn it gets much worse. Ideally, you would like to crawl under your blanket in a dark and quiet room.
This is how it may feel for people suffering from migraine or frequent tension headaches. Untreated, a migraine attack may last for 4-72 hours, and tension headaches may potentially last for a week. In Denmark, it is estimated that approximately 770,000 people suffer from migraine or frequent tension headaches.
Now, for the first time, a new study from the University of Copenhagen shows specifically how migraine or frequent tension headaches affect the ability to work.
“It is especially the ability to remember, make quick decisions and do hard physical work that cause difficulties for people with these headache disorders,” says Project Manager and author of the study Kirsten Nabe-Nielsen.
She hopes that the study will help to focus on the consequences which headaches may have for working life.
“Migraine is the leading cause of functional impairment among people under the age of 50. And headaches have negative effects on sick leave and productivity. So, it would benefit workplaces to open their eyes to the untapped potential that you find here,” says Kirsten Nabe-Nielsen, adding:
“Indeed, we cannot afford not to take it seriously.”
If you ask the Danish working population, 24 per cent of women and 10 per cent of men suffer from migraines or frequent tension headaches.
The possibilities of adapting the work during headache attacks depend on the type of work you have, says Kirsten Nabe-Nielsen, stressing:
“So also in this context, there is a significant inequality in health.”
While people with academic jobs will often be able to go home a little earlier, work from home or choose to postpone the tasks that demand the highest concentration, other people, such as cleaning staff or nursing staff in old people’s homes, do not have the same opportunities to adjust the working hours or postpone the tasks to be solved. Instead, they may have to call in sick.
According to Kirsten Nabe-Nielsen, it takes creativity on the part of the manager and the employees to find out which solutions may be helpful:
“It is about having a good overview of the tasks that need to be solved, and then having a talk as to the best way to arrange a work day. For example, there may be tasks that can be performed later in the day, or that can be solved at a leisurely pace or in a quiet space until the pain has gone.”
“I am going to lay down”
Kirsten Nabe-Nielsen believes that headache disorders such as migraine and frequent headaches are an overlooked epidemic.
“We are stuck with the idea of the character Maude from the Danish TV series Matador saying ‘I am going to lay down’ whenever she is a bit stressed,” she says, explaining:
“Most people have experienced headaches. Therefore, it may be difficult to understand how debilitating migraine and frequent headaches may be for a colleague, friend or family member. People still have the notion that it will be sufficient to swallow a pill.”
Kirsten Nabe-Nielsen believes that there is a lack of knowledge in the general population about the importance of headache disorders. The same applies to the fact that taking too many painkillers to soothe the headache may actually lead to more headaches.
“Some studies show that headaches are the second-most common cause of sick leave – surpassed only by infectious diseases. Therefore, headache disorders carry large personal and socio-economic costs,” says Kirsten Nabe-Nielsen.
Associated with depressive symptoms and muscular pain
The researchers have used self-reported information from more than 5,000 active Danes with different educational backgrounds – from people with long academic educations to unskilled workers.
“It is new that we combine information about migraine and frequent headaches with the participants’ use of painkillers and with their description of the ability to cope with seven different, specific requirements at work,” says Kirsten Nabe-Nielsen.
The participants also answered questions about their health, depressive symptoms and pain in muscles and joints.
Here, the researchers found that depressive symptoms and pain in muscles and joints play an important role for the context between headache disorders and the ability to work.
“Our results indicate that the handling of depressive symptoms and pain in the musculoskeletal system may be an important factor in improving the ability to work among people with headache disorders,” says Kirsten Nabe-Nielsen.
Previous studies support the finding that headaches, muscle and joint pain coincide with depressive symptoms. Among other things, you may see mood changes, and neck pain may be a warning sign of a migraine attack, just as frequent headache attacks may affect the mood negatively.
Under- and overmedication
The researchers find the lowest ability to work in the group of headache sufferers who do not use painkillers at all and the group who use painkillers on a daily basis.
“This raises the question whether these two groups are undertreated and overtreated, respectively,” says Kirsten Nabe-Nielsen.
According to Kirsten Nabe-Nielsen, it seems to indicate that the group taking painkillers on a daily basis may not receive a treatment that works as intended – and they might even suffer from medication overuse headaches.
“On the other hand, when you look at the group who does not take medication at all, it seems to indicate that they are undermedicated. And maybe it has to do with the fact that they do not consider their illness to be severe enough to seek medical attention – but that is just our guess,” says Kirsten Nabe-Nielsen.
Facts: What are migraines and frequent headaches?
The two most common forms of headaches are migraine and tension headache.
Migraine is characterised by bouts of moderate or severe pulsating headache accompanied by nausea, vomiting and sensitivity to light and sound. Chronic migraine occurs more than 14 days a month.
Tension headache is characterised by mild to severe pain on both sides of the head. Nausea and vomiting are usually absent. Chronic headache occurs more than 14 days a month.
Neural signature for fibromyalgia may aid diagnosis and treatment
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An MRI image showing the multivariate brain pattern that predicts fibromyalgia status on the basis of brain activation during multisensory stimulation Image: Cognitive and Affective Control Laboratory / University of Colorado Boulder.
University of Colorado Boulder researchers have discovered a brain signature that identifies fibromyalgia sufferers with 93 percent accuracy, a potential breakthrough for future clinical diagnosis and treatment of the highly prevalent condition.
Fibromyalgia is commonly defined as chronic widespread musculoskeletal pain accompanied by symptoms such as fatigue, anxiety and mood disorders. The Centers for Disease Control and Prevention (CDC) estimates that fibromyalgia affects more than five million adults annually in the U.S., with significantly higher occurrence rates in women than in men.
Historically, fibromyalgia has been difficult to diagnose and treat due to a lack of a well-categorized tissue pathology and symptoms that overlap with other common chronic illnesses.
CU Boulder researchers used functional MRI scans (fMRI) to study brain activity in a group of 37 fibromyalgia patients and 35 control patients as they were exposed to a variety of non-painful visual, auditory and tactile cues as well as painful pressure.
The multisensory testing allowed the researchers to identify a series of three sub-markers, or neurological patterns, that correlated with the hypersensitivity to pain that characterizes fibromyalgia.
“The novelty of this study is that it provides potential neuroimaging-based tools that can be used with new patients to inform about the degree of certain neural pathology underlying their pain symptoms,” said Marina López-Solà, a post-doctoral researcher in CU Boulder’s Cognitive and Affective Control Laboratory and lead author of the new study. “The set of tools may be helpful to identify patient subtypes, which may be important for adjusting treatment selection on an individualized basis.”
The findings were recently published in the journal PAIN, published by the International Association for the Study of Pain.
“Though many pain specialists have established clinical procedures for diagnosing fibromyalgia, the clinical label does not explain what is happening neurologically and it does not reflect the full individuality of patients’ suffering,” said Tor Wager, director of the Cognitive and Affective Control Laboratory. “The potential for brain measures like the ones we developed here is that they can tell us something about the particular brain abnormalities that drive an individual’s suffering. That can help us both recognize fibromyalgia for what it is – a disorder of the central nervous system – and treat it more effectively.”
If replicated and expanded upon in future studies, the results could eventually provide a neurological road map to brain activity that would inform diagnosis and therapeutic interventions for fibromyalgia.
“This is a helpful first step that builds off of other important previous work and is a natural step in the evolution of our understanding of fibromyalgia as a brain disorder” said López-Solà.