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Mon 1 Jan 2007 03:32 PM

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Research matters

News from the Harvard Medical School research community

Diabetes

Study shows durability of insulin pump therapy for adolescents

In spite of its many advantages, there are many challenges in using an insulin pump to treat type 1 diabetes. Despite these challenges, however, more and more youngsters are choosing pump therapy, even though important questions remain about the pump's effectiveness for this age group: with all its risks and demands, is it a method of treatment that children and teens can maintain? What causes adolescents to go off of pump therapy and how often does this occur? Is it possible to identify those youth unable to meet the demands of pump therapy and to find interventions that will help them succeed?

Now, in the first long-term investigation conducted among paediatric patients who chose to go on pump therapy (rather than using it as part of a clinical trial), a new study published Diabetes Care by researchers in the paediatric, adolescent, and young adult section at Joslin Diabetes Center, is providing answers. Following a group of 161 children and adolescents, ages 4-21, for an average of four years, the researchers have shown that with proper training and follow-up, for the great majority of patients (more than 80% of the children in this study), insulin pump therapy provides a lasting and effective mode of treatment. They also identified several factors that put patients at risk for failure in adapting to pump use.

"More than 130 patients were able to use the pump effectively," says senior author, Dr Lori Laffel, chief of Joslin's paediatric, adolescent and young adult section, an investigator in the genetics and epidemiology section and associate professor of paediatrics at Harvard Medical School.

"By looking at differences between the patients who remained on pump therapy and those who returned to injected insulin, we were able to identify factors present even at the start of pump therapy that were predictive of failure. For example, patients who resumed injection therapy checked their blood glucose levels less often from the start.

"Healthcare providers can use this information to provide more education, more psychosocial support, and more frequent visits directed at increasing blood glucose monitoring from the start of pump therapy to help kids to succeed."

"The fact that such a high percentage of patients succeeded proves that pump therapy is a viable mode of treatment for children and teens with type 1 diabetes," says the paper's lead author, Dr Jamie Wood, staff physician and research associate at Joslin and instructor of paediatrics at Harvard Medical School. "Our job now is to overcome the barriers to pump therapy, so more patients can benefit from its advantages."

Before beginning pump therapy, patients in the study and their families met with a healthcare team that included a paediatric endocrinologist, a nurse educator and a registered dietitian. The team taught them the mechanics of using and maintaining the pump, how to count carbohydrates, calibrate their insulin requirements and treat risks associated with pump therapy, such as site infections, diabetic ketoacidosis and hypoglycemia. A mental health clinician also met with the children and their families to ensure they were ready to meet any challenges and to help them set up realistic expectations for ongoing diabetes management with the pump.

At three points during the study; the clinical visit just before starting on the pump, one year after initiation, and then at the study's close in January 2005, researchers gathered data on A1C levels (a measurement that indicates the average blood glucose over the past two to three months), rate of daily blood glucose monitoring and growth parameters (height, weight and body-mass index). These data also were monitored at the time of discontinuation for patients who stopped using the pump.

Examining the data associated with success and failure, the researchers observed several significant differences between the two groups of patients, one of which was present at the initiation of pump therapy. "We found that patients who were successful measured their blood glucose levels four or more times a day before they began pump therapy, while those who discontinued pump therapy measured them less," says Dr Wood.

They also discovered that the patients who stayed on the pump had achieved better glycemic control than the patients who discontinued pump therapy. After the first year on pump therapy, the A1C levels of the group that succeeded dropped significantly. Although these levels subsequently rose to near the levels they were at the start of pump therapy, the group still was able to avoid the deterioration of blood glucose control that happens frequently among adolescents. Caused by such factors as increases in growth and puberty hormones, or the declining adherence to good health practices that occurs as they become more independent from their parents, deteriorating glucose control puts youth at greater risk for developing serious complications later in life. The youth in the group that succeeded also experienced decreased rates of hypoglycemia with pump therapy.

The patients who later resumed injection therapy, however, experienced rising blood glucose levels while they were on the pump. Furthermore, while the rate of severe hypoglycemia before beginning pump therapy was similar between the two groups, in the year following the start of pump therapy the patients who discontinued pump therapy experienced a significantly higher rate of severe hypoglycemic episodes.

"Our research suggests several approaches for improving success rates with pump therapy," says Dr Wood. "When you evaluate if a person is ready to begin pump therapy, and you can see he or she is monitoring blood glucose levels only two or three times a day, you can suggest that the patient take some extra time to increase monitoring frequency before starting the pump.

"Or if you have a patient who doesn't show improvement in glycemic control in the first six months of pump therapy, you can try to find out what is interfering with success and help overcome any barriers.

"Our goal is not to determine which patients should be denied pump therapy, but to make it possible for more people to succeed with this remarkable tool."

Cardiology


Cardiac stem cells offer a new paradigm for heart formation

Researchers at Children's Hospital Boston have identified a type of stem cell that is the precursor to at least two main cell types that form the heart. This single cardiac progenitor cell gives rise to both myocardial cells, which form the beating muscle and electrically conductive tissue of the heart, and vascular smooth muscle cells. This cell is responsible for the formation of the left-sided chambers of the heart, the first chambers to form in the embryo.

Working in parallel, a separate team at Massachusetts General Hospital discovered a related progenitor cell that, in vitro, gives rise to the right-sided heart chambers, forming myocardial cells, smooth muscle cells, and endothelial cells.

As the cell types were previously thought to have separate ancestors, the studies suggest the range of embryonic stem cells ultimately responsible for the mammalian heart (the earliest organ to develop, and the one most susceptible to congenital defects) may be narrower than previously thought. They also bring researchers a step closer to being able to regenerate tissues to repair congenital heart defects in children and infarct-damaged myocardium in adults. The two laboratories are now trying to determine the relationship between the two types of progenitor cells discovered. Both papers appear in the 15 December issue of the journal Cell.

The Children's team, led by senior investigator Dr Stuart H. Orkin, a Howard Hughes Medical Institute investigator, and Dr Sean Wu, the study's first author, first worked with mouse embryonic stem cells in culture. They allowed the cells to differentiate in a petri dish, then isolated a relatively rare subtype of cell (just 1% of the cells in the dish) that were poised to begin developing along a cardiac pathway. The presence of these cardiac progenitors was indicated by a green fluorescent protein, which lit up when a gene called Nkx2.5 was activated. Orkin and Wu then showed that these cells further differentiated into both myocardial cells and smooth-muscle cells.

Next, using the same fluorescent "tags," Orkin and Wu isolated the same cardiac progenitor cells from live mice early in embryonic development.

"There have been a number of publications about stem-like cells in the heart, but these are the first studies to identify such cells during embryonic development, and to show that they give rise to different cell types," says Orkin, who is the David G. Nathan Professor of Paediatrics at Harvard Medical School and also chairs the department of paediatric oncology at Dana-Farber Cancer Institute. He and Wu are also members of the Harvard Stem Cell Institute.

"Previously, it had been thought that each cell type in the heart had a different origin. Now, it's pretty clear that some have common origins," Orkin adds. "This changes the notion of how the heart develops. Instead of multiple different cell types migrating and coming together to form the heart, the heart comes from stem cells that give rise to multiple cell types in the same local environment; a simpler way of building the organ. And because these cells can make multiple cell types, they could be more useful in repairing the heart than any single kind of cell."

Orkin cautions that there are many steps required before cardiac progenitor cells could be used for cardiovascular tissue regeneration. The current studies took place in mice and in vitro, and it's still unknown what factors make embryonic stem cells differentiate into cardiac progenitors, or what factors make cardiac progenitors differentiate into more specialised cells. But ultimately, cardiac surgeons at Children's hope to be able to use cardiac stem cells to repair congenital heart defects such as defective heart valves, missing or undeveloped arteries, or underdeveloped heart chambers.

"If you understand the process of how things develop from very primitive embryonic stem cells to fully differentiated tissue, you have the potential to duplicate that process in the lab and make a tissue that a patient might need," says Dr John Mayer, a cardiovascular surgeon at Children's who is developing tissue-engineering techniques to create biological replacements for failing heart valves.

Felix Engel, PhD, a cardiology researcher at Children's, recently got cardiac muscle cells to replicate, a feat that normally occurs only during embryonic development and represents another approach to repairing injured cardiovascular muscle. By apparently stimulating tissue regeneration, he was also able improve heart function after a simulated myocardial infarction.

Genetics


Researchers generate human genome map

Researchers have generated the first map of the human genome that looks at copy number variants (CNVs), defined as duplications and deletions of large DNA segments found in healthy individuals, some of which are responsible for individual differences in susceptibility to diseases such as AIDS. These findings appear in the 23 November 2006 issue of Nature and are the product of an international research consortium between Brigham and Women's Hospital (BWH), Harvard Medical School (HMS), The Hospital for Sick Children in Toronto, Canada, The Wellcome Trust Sanger Institute in Cambridge, England, The University of Tokyo and Affymetrix.

"Our CNV map can be combined with preexisting data to provide a much more comprehensive understanding of human genetic variation, which has immediate implications to disease association studies, genetic diagnostic testing and cancer research," said lead author Charles Lee, PhD, a cytogeneticist at Brigham and Women's Hospital's Department of Pathology.

Lee and researchers found approximately 3,000 genes that vary in copy number from their predicted two copies. These variations are thought to result in different protein expression levels and ultimately, point to new explanations for individual differences. During the two-year project, Lee and colleagues employed the latest genome-scanning technologies to examine DNA samples from 270 participants, who were a part of the International HapMap Project, for these CNVs. Previous research only looked at single base pair changes among this study group.

285 of the approximately 3,000 CNVs are already known to be associated with disease, and copy number variations of some of these genes have been or are now being speculated as risk factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and schizophrenia.

One interesting observation that the researchers made during this study was that many of the CNVs have population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an increased risk of prostate cancer in African American men.

As a result of this and other research, the consortium is expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.

"As we study more healthy individuals from different populations, we uncover completely new human DNA sequences, which were absent in the individuals sequenced for the human genome project," said Lee. "These CNVs and the biological implications of these novel DNA sequences can now be fully explored."

“The fact that such a high percentage of patients succeeded proves that pump therapy is a viable mode of treatment for children and teens with type 1 diabetes. Our job now is to overcome the barriers.”
“An interesting observation is that many of the CNVs have population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in certain populations.”

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