Targeting post-transplant diabetes
Between 10 percent and 30 percent of patients undergoing a stem cell transplant develop new-onset diabetes. Immunosuppressive white blood cells, called Tregs, are implicated in the prevention of autoimmune diseases (like type I diabetes) as well as the inhibition of alloimmune responses, like “graft-vs.-host disease” (GVHD), a common adverse effect of stem cell transplant.
Brian Engelhardt, M.D., James E. Crowe, Jr., M.D., Madan Jagasia, M.D., and colleagues assessed the role of Tregs in post-transplantation diabetes mellitus (PTDM) in patients who received stem cells from a related or unrelated donor.
They report, in the March 8 issue of Blood, that the balance of Treg subtypes in these patients was disturbed: transplant patients with new-onset diabetes showed a decrease in skin-homing Tregs, but an increase in gut-homing Tregs. Predictably, PTDM was also associated with skin GVHD but not gut GVHD.
The results suggest that targeting PTDM and related metabolic disruptions could modulate abnormal immune responses like GVHD and improve clinical outcomes after stem cell transplant.
The research was supported by grants from the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, the American Cancer Society, and the Sartain-Lanier Family Foundation.
— Melissa Marino
Wilms’ tumors differ in developing nationsDiseases that are treatable in developed nations are often lethal in developing countries. For Wilms’ tumor, the most common childhood kidney cancer, survival rates in developed countries exceed 90 percent – but in developing nations, survival can be as low as 35 percent.
Lack of adequate health care resources is largely responsible for this survival disparity, but co-investigators Andrew J. Murphy, M.D., Jason Axt, M.D., and colleagues suspected that biological factors may also contribute. The researchers assessed various cellular and molecular features in tumor samples from 15 Kenyan children and compared the results to those from North American Wilms’ tumor samples.
They report in the International Journal of Cancer that Kenyan Wilms’ tumors exhibit a predominance of immature cells (a feature of aggressiveness), cellular features of treatment resistance, and a molecular signature distinct from that of North American tumors.
The results suggest that these biological features may contribute to the poor outcomes in developing countries and that such tumors may require different treatment approaches than those of developed nations.
The research was funded by grants from the National Center for Research Resources and the National Cancer Institute of the National Institutes of Health, and the Department of Defense.
— Melissa Marino
Pathways to delirium in the ICU
Delirium – incoherence of thought and inattention – in intensive care unit (ICU) patients is associated with increased length of hospital stay, mortality and long-term cognitive impairment. Despite its high prevalence, the pathophysiology is unclear.
Pratik Pandharipande, M.D., Jessica Adams Wilson, M.D., and colleagues previously demonstrated that plasma tryptophan levels were associated with delirium in ICU patients. Tryptophan – a precursor for the neurotransmitter serotonin – can be metabolized through an alternate kynurenine pathway, and an imbalance in beneficial and neurotoxic kynurenine metabolites was hypothesized to be associated with delirium.
The investigators studied plasma kynurenine and tryptophan levels in 84 ICU patients. They report in the March issue of Critical Care Medicine that elevated plasma kynurenine and kynurenine/tryptophan ratios were both associated with fewer days free of delirium/coma, after adjusting for sedative exposure, age and severity of illness.
The findings demonstrate that increased kynurenine pathway activation is associated with longer duration of acute brain dysfunction. The kynurenine pathway could be a therapeutic target for reducing delirium/coma in ICU patients.
This research was supported by the National Institute on Aging of the National Institutes of Health, by the Veterans Affairs Clinical Science Research and Development Service, and by the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center.
— Leigh MacMillan
Clues to cholesterol-defect disorder
Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder caused by mutations in the gene encoding the last enzyme in the cholesterol biosynthetic pathway. The mutations result in reduced levels of cholesterol and accumulation of the precursor 7-DHC, which can be oxidized in free radical-mediated reactions to oxysterols such as DHCEO.
Zeljka Korade, Ph.D., Ned Porter, Ph.D., and colleagues explored the consequences of 7-DHC and DHCEO accumulation in the brain tissue of a mouse model for SLOS. They found that cholesterol, 7-DHC and DHCEO have region-specific distributions in the brain, suggesting that the midbrain and cortex are the primary sites of vulnerability. They also showed that an oxysterol mixture is toxic to neurons and that DHCEO alone accelerates differentiation and changes the growth pattern of cortical neurons.
The findings, reported in the March issue of Neurobiology of Disease, suggest that 7-DHC oxidative metabolites contribute to altered neural development in SLOS. The results imply that using antioxidants to reduce oxidative stress may be a beneficial treatment for SLOS.
This research was supported by grants from the National Institute of Mental Health, the National Institute of Environmental Health Sciences, and the National Institute of Child Health and Human Development of the National Institutes of Health.
— Leigh MacMillan
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