Few situations can be as frustrating as realizing that your mobile phone is not receiving a signal. When this happens, many of us have developed relatively easy strategies to re-establish a solid connection, such as moving closer to a cellular tower or changing cell phone providers.
Unlike getting better phone reception, however, it is not as easy to re-establish lost connections between the brain and organs of the body. This is because damage to the complex network of fibres that transmit and receive signals within the brain is often irreversible. Even if nerve fibres begin to regrow after damage, certain inhibitory signals in the surrounding environment prevent new fibres from re-establishing connections.
A study by Krembil Senior Scientist Dr. Philippe Monnier reveals a new strategy that may help overcome these inhibitory signals to promote the repair of damaged nerve fibres in the eye. Dr. Monnier and his research team focused on the regenerative properties of exosomes, encapsulated particles that are released from one cell type and taken up by another—an important form of cell-to-cell communication.
The team found that when exosomes from fibroblast cells (cells that are responsible for generating scar tissue) are taken up by nerve cells, a nerve fibre repair switch is turned on, promoting nerve fibre growth. This repair happens despite the presence of inhibitory signals in the surrounding environment, and is unique to exosomes from fibroblast cells, but not those of other cell types.
Using major connections between the eye and brain as an experimental model of nerve injury, the researchers demonstrated that treating the area of damage with fibroblast exosomes enhanced repair and prevented cell death.
"Our study is the first to show that fibroblast exosomes trigger a regeneration pathway in nerve cells," explains Dr. Monnier. "It also reinforces the notion that exosomes derived from different cell types have different functions—setting the stage for the development of precise regenerative therapies that can be used to repair the damaged nervous system."
This work was supported by the Krembil Foundation, the Heart and Stroke Foundation of Ontario, the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation.
Tassew NG, Charish J, Shabanzadeh AP, Luga V, Harada H, Farhani N, D’Onofrio P, Choi B, Ellabban A, Nickerson PEB, Wallace VA, Koeberle PD, Wrana JL, Monnier PP. Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS. Cell Rep. 2017 Jul 5. doi: 10.1016/j.celrep.2017.06.009.
“I’ve fallen, and I can’t get up!” is a well-known catchphrase from a 1980s television commercial. The commercial advertised a pendant that could be used by the elderly to alert a dispatch service in the case of a medical emergency, such as a fall.
A limitation of this product is that the wearer of the pendant must be alert enough to report the need for medical attention; however, falls can cause many types of injuries that can leave people unable to communicate. While devices to automatically detect falls exist, many of them frequently trigger false alarms.
To improve the automated detection of falls, researchers have focused on teaching computers to identify falls by using data that is collected from sensors worn on the body; but, falls are a rare event, making it difficult to collect data on real life falls.
A recent study by TRI Scientist Dr. Babak Taati and his postdoctoral fellow Dr. Shehroz Khan aimed to address this issue from a new perspective: instead of using wearable sensor data to teach computers to identify falls, the researchers used the data to teach computers to identify normal behaviours such as standing, jogging/running and jumping—thus defining falls as an abnormal event. The researchers then tested the model with data sets gathered using wearable sensors.
Using computer simulations, their model performed better than traditional methods in differentiating normal from abnormal activities.
The team is now focused on further fine-tuning their computer-based model. “Although our model is still in its early stages, it is a crucial first step towards an accurate automated fall detection device,” says Dr. Taati. “Such a device could be especially useful for the elderly, who are at risk for developing serious medical problems as a result of falling.”
This work was supported by AGE-WELL, the Canadian Consortium on Neurodegeneration in Aging, the Toronto Rehabilitation Institute and the Toronto Rehab Foundation.
Khan SS, Taati B. Detecting unseen falls from wearable devices using channel-wise ensemble of autoencoders. Expert Syst Appl. 2017 Jun 15. doi: 10.1016/j.eswa.2017.06.011.
Your worst nightmares have come true. You have undergone surgery in an attempt to relieve your debilitating back pain. And, at first, things did get better. But now, your symptoms are back—and even worse than before.
Pain in the neck, back or lower back, along with numbness or weakness in the arms or legs, can result from damage caused by compression of the spinal cord, also called degenerative cervical myelopathy (DCM). A number of conditions can cause spine abnormalities that lead to spinal cord compression, including injury, spinal tumor, rheumatoid arthritis or infection.
Surgical decompression—surgery to relieve pressure and pinching of the spinal cord—is the mainstay treatment in patients with DCM, as it can minimize further damage, and improve patients’ physical symptoms and quality of life. However, it has been shown that these improvements may vary significantly depending on a number of factors such as the severity of damage, duration of symptoms and age. Moreover, even after a flawless surgical procedure, patients’ symptoms can worsen within the first 24 hours following surgery.
It is believed that the body’s immune system may be responsible for this worsening of symptoms, due in large part to increased inflammation at the site of surgery. Novel strategies to prevent these “secondary” injury processes may lead to improved outcomes in patients who receive surgical treatment for DCM.
In an effort to uncover the factors that govern whether surgical decompression surgery is successful, Krembil Senior Scientist Dr. Michael Fehlings used an animal model of DCM. The model enabled the research team to compare the effects of surgical decompression surgeries done soon after injury with those done three months after injury.
In the early decompression group, reduced inflammation and improved function in the upper and lower limbs were observed within the first few weeks after surgery. However, when surgical decompression was delayed, there was prolonged activation of immune cells and increased inflammatory markers. Furthermore, delayed surgical decompression led to an increased incidence of complications and function did not return to the same extent in the upper and lower limbs.
Using existing clinical data, the research team confirmed these results in human patients with moderate to severe DCM. Of the 504 patients considered, when surgical decompression was performed within 6 months of symptom onset, patients recovered better than when the surgery was delayed for longer periods of time.
“To our knowledge, this is the first study that demonstrates the relationship between surgical intervention timing and immune system activation after surgery,” said Dr. Fehlings. “Our results suggest that patients who have experienced symptoms for a longer period of time are more likely to achieve suboptimal surgical outcomes—and this is exactly what we see in the clinic.”
This study underlines the importance of early diagnosis and surgery in DCM patients. Furthermore, reducing inflammation post-surgery may represent a novel therapeutic strategy to improve DCM patient recovery after surgical decompression.
This work was supported by the Cervical Spine Research Society, the Canadian Institutes of Health Research, and the Toronto General & Western Hospital Foundation. MG Fehlings is the Halbert Chair in Neural Repair and Regeneration.
Vidal PM, Karadimas SK, Ulndreaj A, Laliberte AM, Tetreault L, Forner S, Wang J, Foltz WD, Fehlings MG. Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy. JCI Insight. 2017 Jun 2. doi: 10.1172/jci.insight.92512.
Anyone who has played the 80s board game Mouse Trap will remember how a chain reaction that starts with a small ball rolling side-to-side down a hill ends with a mouse being trapped under a plastic net.
Just like how different events in the game come together to set the trap, different and sometimes unlikely parts of the body can conspire in the development of disease.
Recent findings from Krembil Scientist Dr. Nigil Haroon have identified a molecule, known as macrophage migration inhibitory factor (MIF), which may link inflammation in the gut and a type of spinal arthritis known as ankylosing spondylitis (AS).
The link between the gut and AS is well known, as over half of those with AS also have bowel inflammation; however, it is still unknown how the gut might contribute to the disease, if at all.
Dr. Haroon’s team focused on MIF, because it is elevated in the blood of patients with AS and other inflammatory diseases, such as psoriasis and inflammatory bowel diseases.
By analyzing clinical data, the researchers revealed that elevated MIF levels could be used to predict the progression of AS. Specifically, they found that MIF can promote inflammation and bone formation in the spine—two hallmarks of AS. Dr. Haroon comments, “We found that MIF can directly mediate bone formation in experimental models involving bone-forming cells known as osteoblasts, and that MIF does this by modulating a cell signalling pathway known as Wnt.”
Another question that the research team explored was: where in the body does MIF originate from?
It was this question that led them to the gut. Initially the researchers looked to circulating immune cells—obvious culprits, as they are involved in inflammation—however, they were unable to find heightened MIF stores in these cells.
Next, they explored whether tissues in the large intestine might be the source. The results revealed, for the first time, that cells of the small intestine known as Paneth cells, as well as ‘resident’ immune cells in the same tissue, known as CD68+ macrophages, produce MIF.
“These results led us to propose a new hypothesis: inflamed cells of the gut secrete MIF, perhaps as a response to altered gut microbes, which then travels to the spine where it contributes to the inflammation and irregular bone formation in the joints of the back, ultimately leading to the debilitating pain and stiffness experienced by individuals with ankylosing spondylitis,” says Dr. Haroon.
Future studies will be focused on advancing the use of MIF to predict AS progression, as well as the development of future therapeutics that target MIF to slow or stop progression of the disease.
This work was supported by the Arthritis Society, the Krembil Foundation, the Canadian Institutes of Health Research, and the Toronto General & Western Hospital Foundation.
Macrophage Migration Inhibitory Factor induces inflammation and predicts spinal progression in Ankylosing Spondylitis. Ranganathan V, Ciccia F, Zeng F, Sari I, Guggino G, Muralitharan J, Gracey E, Haroon N. Arthritis Rheumatol. 2017 Jun 8.
Dr. Sharon Walmsley, TGHRI Senior Scientist and Assistant Director of UHN's Immunodeficiency Clinic, was among 99 new appointments to the Order of Canada made by Governor General David Johnston.
She will receive her insignia at a ceremony in Ottawa later this year.
Dr. Walmsley, who was made a Member of the Order of Canada, was cited "for her advancement of HIV/AIDS research that has led to a broader understanding of the disease's effects on women as well as to improved treatment options."
Dr. Walmsley has made a profound difference in the care of people living with HIV. She has been part of more than 200 HIV clinical trials. She has spearheaded the evaluation and introduction of new antiretroviral therapies for people living with HIV, helped shape national and international treatment guidelines for the earlier initiation of HIV antiretroviral therapy, and led in establishing treatment standards and protocols for women living with HIV.
Her current work focuses on co-infection between HIV and other viral infections including hepatitis C, hepatitis B and herpes simplex virus.
The Order of Canada recognizes outstanding achievement, dedication to the community and service to the nation; 2017 marks the 50th anniversary of the Order. Close to 7,000 people from all sectors of society have been invested into the Order since its creation in 1967.
A full list of the 99 new appointments can be viewed here.
Despite being hampered by painful injuries, many athletes continue to compete and win. For example, Toronto Maple Leafs Defenseman Bobby Baun played several playoff games with a broken ankle and helped his team win the Stanley Cup in 1964.
Why is it that some individuals can perform a task—and do it well—while experiencing pain?
Krembil Senior Scientist Dr. Karen Davis has shown that individuals can be classified as one of two types depending on how pain affects their performance. In P-type individuals, pain interferes with performing a task; whereas, in A-type individuals, such as Bobby Baun, pain enhances their performance.
To gain a better understanding of this divergent behaviour during pain and the factors that contribute to it, Dr. Davis and her PhD student Joshua Cheng led a study examining brain function in these two groups.
The study included 51 healthy participants who were asked to perform a challenging mental task (ie, counting the number of digits within three boxes on screen and reporting which box has the largest number of digits) as quickly and accurately as possible. All participants performed the task 96 times, half of which with the application of a painful electrical sensation on their skin and the other half without. They also underwent a functional Magnetic Resonance Imaging (fMRI) scan to record their spontaneous brain activity at rest (ie, when not performing the task).
The researchers found that pain reduced the speed and consistency of task performance in P-type individuals; whereas it enhanced the speed and consistency of performance in A-type individuals. By examining the fMRI scans, they also found that task performance was linked to participants’ brain activity at rest. Specifically, activity between two major brain networks, the executive control network and the salience network, as well as within the salience network, was less sporadic (ie, less flexible) in P-type individuals. On the other hand, activity between/within these brain networks was more sporadic (ie, more flexible) in A-type individuals.
These findings suggest that increased flexibility in communication within the brain is important for prioritizing task performance over pain. Future research will examine how treatments for chronic pain—medications, meditation and cognitive-behavioural therapy—affect flexibility in communication within the brain, which may contribute to more personalized treatments for chronic pain.
This work was supported by the Canadian Institutes of Health Research, the Ontario government, the University of Toronto and the Toronto General & Western Hospital Foundation.
Cheng JC, Bosma RL, Hemington KS, Kucyi A, Lindquist MA, Davis KD. Slow-5 dynamic functional connectivity reflects the capacity to sustain cognitive performance during pain. Neuroimage. 2017 Jun 3. doi: 10.1016/j.neuroimage.2017.06.005.
