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WHAT IS DEVELOPMENTAL NEUROPATHOLOGY?
“Pathology” is the study of disease. “Neuro-“ refers to the nervous system including the brain, spinal cord, nerves, and muscles. The term “Developmental” is added because the immature (i.e. developing) nervous system (in fetuses, infants, and children) is different than that of adults. Therefore, “Developmental neuropathology” is the study of diseases that affect the brain, spinal cord, and nerves of infants and children.
Dr. Del Bigio a neuropathologist, a medical specialist whose role is to diagnose diseases of the brain and nervous system mainly through microscopic examination of tissue samples. Through careful examination of autopsies, much has been learned much about a wide range of brain diseases. However, much research is still needed to form a deeper understanding that can lead to treatments. In 2001 Dr. Del Bigio established his research laboratory at the Children’s Hospital Research Institute of Manitoba to study neurological diseases of childhood. In 2004 he was awarded the Canada Research Chair in Developmental Neuropathology, and that research chair was renewed in 2010.
Many disease processes can affect the developing nervous system, with serious consequences. Genetic abnormalities can prevent the brain from developing normally or can lead to a defective protein that allows the brain to gradually be destroyed. There are many rare diseases of this type. Abnormalities in the womb or premature birth can damage the brain through effects on the blood supply. Infections can damage the nervous system, particularly if they occur when a baby is growing in the mother’s womb. Chemical exposure can disturb normal brain development (for example drinking alcohol while pregnant can cause fetal alcohol spectrum disorder).
In addition to these projects in his own lab, Dr. Del Bigio collaborates with other scientists to study the biology of brain tumors, brain development, and inflammation in the brain.
The CIHR Team in Children’s Pain started in 2007 with a group of researchers from across Canada who wanted to study and improve practices related to keeping children comfortable when they are ill or having painful procedures. 8 pediatric health centres got involved, including Winnipeg Children’s Hospital.
I became the site investigator in Winnipeg in 2008 and was very fortunate to have a great study nurse, Sandy Taylor on board from the beginning. The project has involved reviewing thousands of patient charts to look at how pain assessment and management are documented. Four units at Children’s Hospital were the initial focus. Two of these units became the “study” units, and in them we formed a “Research Practice Council” of health care professionals from numerous disciplines to look at their own unit and determine what practices they would like to improve on related to pain assessment and management. Sandy worked with these councils and they did amazing work to make things better for the kids on their units.
The next phase of the study, which we are just completing, was to choose one of these two units to do “booster” sessions with, to see if they could keep moving forward in making improvements, without as much help from our team. In June we will have our last booster meeting with them. This large knowledge translation study has given a lot of Children’s Hospital staff an opportunity to be a part of research, but also to learn how to translate research findings into real change that improves the lives of the kids they look after.
The research nurses across the country have put together a book called “Stories From The Floor” which you can access at this link: http://ken.caphc.org/xwiki/bin/view/ChildrensPain/Stories+from+the+Floor
The study will continue until March 2014 with collection of more information to show just how things have improved and to develop tools to help other pediatric units to do the same. I feel like I have just been along for the ride, as Sandy and the staff in the hospital have done most of the hard work, and I have just done my part to keep it moving along. The study team in Toronto works like a well-oiled machine and has been busy communicating and publishing the results all over the world. Thanks to the Children’s Hospital Research Institute of Manitoba for supporting our team in Winnipeg!
I am currently nominated PI on a programmatic grant funded by CIHR and the Heart & Stroke Foundation focusing on tackling health inequities. Our program of research is called PATHS Equity for Children (PAthways To Health and Social Equity) and we’re using the Repository of data at the Manitoba Centre for Health Policy (MCHP) to evaluate a number of interventions aimed at improving children’s health and well-being in Manitoba. For each intervention examined we’re determining not only if the intervention improved children’s outcomes, but also whether the gap in outcomes (inequity) changed as a result of the interventions. Our research program is also enhancing population-based methodologies on equity measurement using administrative databases, exploring synergies across different policies and programs, and qualitatively examining organizational barriers and facilitators to reducing inequities for children. Some of the questions being asked in the evaluations include:
As part of PATHS we have assembled a database that includes 30 years of information on multiple variables (from health, education and social sectors) for Manitoba children, which provides an information-rich resource for conducting longitudinal epidemiologic research on child development. This resources is available for researchers beyond the PATHS program and beyond MCHP. More information about the PATHS program of research, the data resource, and the published findings to date can be found at:
I was also PI on an MCHP deliverable that was released in June 2015 that examined the educational outcomes of children in care in Manitoba.
This report examined characteristics of children in care in Manitoba and highlighted the educational and social difficulties faced by these children, recommending the need for inter-sectoral solutions to deal with the root causes of the challenges that result in children going into care and in children doing poorly in school. Through the Evidence Network, we have developed two Op-Eds that have received wide circulation within and outside of Manitoba, as well as a podcast focusing on the high numbers of children in care in Manitoba:
If you have seen little sticker-covered children running around the 5th floor of the Children’s Hospital Research Institute of Manitoba or heard Princess Songs and Finding Nemo coming from room 505, chances are you have been witness to some of the clinical visits of the CHILD Study from Dr. Becker’s Allergy Lab.
The Canadian Healthy Infant Longitudinal Development (CHILD) Study is a cohort of 3,300 children recruited before birth, from across Canada. Dr. Becker and his team follow over 1,000 families. The children range from ages 16 months to 5 years from urban and rural Manitoba. The children involved in CHILD are followed over 5 years and data – in the form of questionnaires, measurements, biological and environmental samples – is collected throughout this time.
This large birth cohort offers not just the ability to investigate asthma and allergies, but all chronic diseases.. Asthma and allergies are the primary focus at the moment as they are some of the earliest detectable chronic diseases.
The Manitoba site has an interdisciplinary research team with backgrounds including; engineering, commerce, nursing, biochemistry, microbiology, pharmacy, psychology and, of course, medicine. Our team works together to provide a child-friendly atmosphere to all of our families during the visits. Many of our team members have been able to collaborate with each other and present at local, national and international research conferences across Canada.
We also work with colleagues who are environmental chemistry experts and have begun to study the impact of chemicals commonly found in homes. Perfluorinated compounds (PFCs) are used for stain resistance in fabrics, carpets and to waterproof many other materials (eg microwave popcorn bags). Data was collected by placing an air-sampler in the homes for a few days. These samples were then analyzed by researchers at the University of Winnipeg. We are fortunate to be able to partner with many different
scientists in order to gather data such as these.
There have already been publications from CHILD’s data as well. Dr. Meghan Azad is a collaborator and researcher who has published information looking at the impact of delivery method, breastfeeding, siblings and pets on the diversity of gut microbiota in these children. Many more publications are anticipated as sample collection continues.
We look forward to continue watching these children grow. They truly are the heroes of
this study. Please give them an extra big smile if you see one of our little heroes in the
As a Biostatistician, my research areas are spatial and temporal models, longitudinal data, and survival analysis. I am interested in studying geographical variation and factors associated with the health of children. My other interest is to study how the health of children will be changed over time. How would be changed pattern of survival time of children after diagnosed by a disease? My work in these areas has been focused on the childhood asthma, COPD, and cancer. My goal is to use my expertise to study health of children in other diseases to have a better understating about the diseases and then act for the prevention.
Dr. Cheryl Rockman-Greenberg is currently on administrative leave, having completed 2 terms as Head of the Department of Pediatrics and Child Health. During this administrative leave she is continuing to focus her research on Inborn Errors of Metabolism and on the creation of a Metabolic Disorders Clinical Trial Research Team (MDCTRT) at the Children’s Hospital Research Institute of Manitoba. To date approximately 50 patients are enrolled in various enzyme replacement therapy clinical trials and Patient Registries. She has created a share drive for the MDCTRT and is working with the provincial and national partners to create a framework to expedite licensure and reimbursement protocols for orphan drugs for ultrarare metabolic disorders.
Vital signs – heart rate, respiratory rate, blood pressure, temperature, and sometimes oxygen saturation – are central to the evaluation of sick children. We’ve been measuring vital signs in children for a long time. It would be natural to think that we have vital signs pretty well figured out. But it turns out that there is still a lot that we don’t know about how to interpret vital signs in children.
Normal ranges for vital signs can be found in textbooks, study aids, scoring tools used to help identify sick children, and many other sources. These normal ranges are generally based on the opinion of experts who’ve taken care of many sick children and know a lot about pediatrics. But these experts don’t agree with each other regarding what normal vital signs are, particularly for heart rate and respiratory rate.
For example, look at the range for normal heart rate in a 7 month-old baby in two well-respected sources. The Harriet Lane Handbook is a widely used reference for inpatient pediatrics. Nelson’s Pediatrics is a widely used textbook. The normal range for heart rate in a 7 month-old in Harriet Lane is 110-170. The normal range in Nelson’s is 80-120. The ranges are so different that they barely overlap. This is one of the more dramatic examples, but there are substantial differences between heart rate ranges from a wide variety of sources at all ages before adolescence. The same is true for respiratory rate.
Along with several collaborators, I am working on several projects to help expand the evidence base regarding heart rate and respiratory rate in children. Some of the projects focus on identifying typical values for vital signs by age in hospitalized children and children in the emergency department. Lately I have been able to start some projects that compare vital signs in children with and without serious illness in order to help define which vital signs indicate increased risk of illness. I hope that my research will help clinicians identify children who are at increased risk of having a dangerous illness and need more evaluation or treatment.
Across North America the emergence of 2nd generation type 2 diabetes mellitus (T2DM) is troubling. Children born to a woman with T2DM or gestational diabetes mellitus (GDM), have a substantially higher risk for the early development of T2DM. It is not known why in utero exposure to GDM accelerates the onset of T2DM in the offspring. Thus, in collaboration with Drs. Vernon Dolinsky and Ruey Su we examined the immune responses from rat pups born to dams with GDM compared to pups from healthy dams. GDM was induced by feeding dams a high fat/sucrose (HFS) diet. Upon weaning pups were either fed a HFS or low fat (LF) diet.
We examined the immune responsiveness of spleen cells to toll like receptor (TLR)4 and 2 activators that potentiate immune mediated damage in diabetes. Spleen cells were harvested from adolescent/young adult pups (~16 wk old) and cultured with lippolysaccharide (LPS, TLR4 agonist), pam3CSK4 (TLR4 agonist) and palmitate. TLR4 and 2 are activated in bacterial infections upon the binding of bacterial carbohydrates such as LPS, and by certain dietary carbohydrates such as palmitate. The findings indicated that in utero exposure to HFS diet resulted in an up regulation of spleen cell IL-1β production in response to TLR4 and TLR2 simulation independent of subsequent pup diet. IL-1β is considered a “gatekeeper” molecule to metabolic disease. In addition, IL-10 was also enhanced in the HFS diet possibly as a physiological attempt to inhibit IL-1β production. In contrast there was no difference in IL-6 or TNFα production. This was supported by RNA analysis of whole spleen ex vivo. No cytokine RNA differences were noted in the corresponding liver samples.
The potential of resveratrol to rescue the HFS phenotype in pups was also examined. When HFS fed dams were given resveratrol, neonatal spleen cell IL-1β production was attenuated, concomitant with an increase in IL-10 synthesis. This profile was maintained for older pups (16 wks). Resveratrol did not alter the cytokine production of pups exposed to a LF diet in utero.
In conclusion, exposure to HFS diet in utero can result in enhanced spleen cell IL-1β production into 16 wks of pup life relative to pups exposed to LF diets (independent of pup diet). The effect of HFS diet can be attenuated by resveratrol administration to dams with HFS diets.
As a human population and disease geneticist, my research is focused on understanding the genetic etiology of Mendelian and complex traits, how human population history and cultural practices influence patterns of genetic variation, and the ways in which these patterns can be harnessed to advance the discovery of genes that underlie human disease. My work in these areas is currently focused on understanding how homozygosity-by-descent patterns in human populations can be leveraged to identify recessive disease-associated mutations, the genetic architecture and adaptive origins of metabolic and anthropometric characteristics in Central African Pygmies, and the identification of a modifier gene for polycystic kidney disease. My efforts will hopefully provide a foundation for the development of diagnostic and therapeutic strategies that will help reduce the disease-burden of diverse populations.