Later onset of type 1 diabetes = lower brain connectivity in midlife

People diagnosed with type 1 diabetes in later childhood have weaker brain connectivity in midlife compared to those who were diagnosed at earlier ages, according to a Schools of the Health Sciences study.

The findings were reported in a special issue of Psychosomatic Medicine that is focused on diabetes, obesity and the brain. Sixty-six middle-aged adults (ages 32-58) who were diagnosed with type 1 diabetes as children participated in the study.

Said John Ryan, psychiatry faculty member: “Other studies have shown an association between earlier onset type 1 diabetes and cognitive difficulties, so we expected to find that people with earlier age of onset would have weaker connections between brain regions. But instead, we found that those who were diagnosed later in childhood had the weaker brain connections as they aged.”

All of the study participants had onset of type 1 diabetes before age 18 and were enrolled in the Pittsburgh epidemiology of diabetes complications study, which is an ongoing investigation led by Caterina Rosano, epidemiology faculty member in the Graduate School of Public Health, documenting long-term complications of type 1 diabetes among patients at Children’s Hospital, 1950-80.

The participant group is one of the few in the country in which people with childhood onset type 1 diabetes have been followed throughout their lifespan. “Due to advances in treatments, people with type 1 diabetes are living longer,” said Ryan. “But we don’t yet understand how diabetes and aging interact in the brain.

“The mechanisms underlying these associations are not yet clear,” he added. “However, the relationships between age of diagnosis and connectivity was stronger in older participants, supporting a model of diabetes as accelerated aging.”

Additional public health researchers on this project include Howard J. Aizenstein, Trevor J. Orchard, Christopher M. Ryan, Judith A. Saxton, David F. Fine and Karen A. Nunley.

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Kids may need more vitamin D

Currently recommended daily dietary allowances of vitamin D may be insufficient to prevent deficiency in children, according to researchers at the School of Medicine, the School of Nursing and Children’s Hospital.

In a report published in the Journal of Clinical Endocrinology and Metabolism, they noted that children with suboptimal vitamin D blood levels did not reach optimal levels after taking nearly twice the recommended amount of the nutrient daily for six months.

Vitamin D is important for calcium metabolism and bone health, noted lead investigator Kumaravel Rajakumar, pediatrics faculty member. It is present in a few foods, milk is usually fortified with it and with enough exposure to sunlight the body naturally produces it.

Said Rajakumar: “Vitamin D deficiency is common in the northeastern U.S., especially in black children whose darker skin complexions have higher amounts of melanin, preventing absorption of the ultraviolet light that’s needed to trigger vitamin D synthesis.”

Guidelines differ on adequate blood levels of vitamin D for bone health, highlighting the need for further research. Blood level of 25-hydroxyvitamin D is the best measure of vitamin D status. For example, a blood level of 20 or more nanograms per milliliter (ng/mL) of the vitamin is considered adequate for bone health by the Institute of Medicine, while the Endocrine Society recommends a level of 30 ng/mL for optimal bone health.

Between October and March of 2008-11, the researchers randomly assigned 84 black and 73 white 8- to 14-year-old children from Pittsburgh and Kittanning to take for six months either a daily pill of 1,000 international units (IU) of vitamin D3 or a placebo. They also performed periodic blood tests to assess their 25-hydroxyvitamin D levels and other markers of bone health.

The average vitamin D level at the initial assessment of all children, and particularly black children, was suboptimal (less than 20 ng/mL), and supplementation raised their average level to above 20 ng/mL but not as high as 30 ng/mL. After six months of vitamin D supplementation in children with initial vitamin D levels less than 20 ng/mL, 39 percent remained below 20 ng/mL and only 14 percent rose above 30 ng/mL. Biomarkers of bone turnover remained unchanged.

“Our findings suggest that currently recommended daily dietary allowances of vitamin D of 600 IU may be inadequate for preventing vitamin D deficiency in children,” Rajakumar said. “It may be important to revisit these recommendations, especially since the higher dose of vitamin D used in this study was safe and did not appear to lead to any side effects.”

The team included Pitt faculty Charity G. Moore, Jonathan Yabes, Flora Olabopo, Mary Ann Haralam, Diane Comer, Susan Sereika, Jacqueline Dunbar-Jacob and Susan L. Greenspan, as well as faculty from Boston and Georgia State universities.

The project was funded by the National Institutes of Health (NIH) and Children’s Hospital.

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Early HIV treatment improves survival for those with TB

Starting anti-HIV treatment within two weeks of the diagnosis of tuberculosis (TB) improved survival among patients with both infections who had very low immune-cell counts, according to an analysis by researchers at the Graduate School of Public Health. Those with strong immune systems, however, might benefit from waiting until after the end of the six-month TB treatment before initiating anti-HIV therapy, they found.

In a study published in the Annals of Internal Medicine, the team recommended updating physician guidelines to take the findings into account.

Infection with HIV can promote progression and re-infection to active TB after initial exposure to mycobacterium tuberculosis, the organism that causes TB, explained senior author Jean B. Nachega, faculty member in infectious diseases and microbiology as well as epidemiology. Treating HIV and TB simultaneously is challenging for many reasons, including the requirement for patients to take multiple pills several times daily for each infection, drug-drug interactions and overlapping side effects.

Said Nachega: “Current World Health Organization guidelines recommend starting TB treatment first, followed by HIV treatment as soon as possible within two to eight weeks for patients who have moderately to severely compromised immune systems, but there was not conclusive evidence to guide treatment in other levels of immune suppression. We aimed to investigate the optimal timing of HIV initiation in light of recent published randomized clinical trials on this topic.”

The team systematically reviewed data from more than 4,500 people participating in eight randomized clinical trials of early initiation of HIV anti-retroviral therapy (ART) conducted in Asia, Africa and the United States. They found that survival rates were better among patients who started ART within two weeks of the initiation of TB treatment and who also had CD4 T-cell counts of less than 0.050 x 109cells/liter, as measured by a blood test that reflects severe immune system suppression due to HIV infection. Of note is that early initiation also was associated with a two-fold increase in the frequency of a complication called TB-immune reconstitution inflammatory syndrome, which can be fatal in rare occasions. There was no evidence to support or refute a survival benefit for patients with CD4 counts between 0.050 and 0.220 x 109cells/liter.

“Our findings support guidelines recommending early initiation of ART in patients with a high degree of immune system compromise,” Nachega said. “But delaying ART might be possible until the end of TB treatment with patients with CD4 counts greater than 0.220 x 109cells/liter, which could reduce the burden of taking two complex drug regimens at the same time.”

However, Nachega noted that there is other emerging evidence showing the clinical and public health benefits associated with early initiation of HIV treatment, other than survival. Indeed, early treatment may be beneficial by decreasing comorbidities due to ongoing inflammation caused by HIV and decreasing HIV sexual transmission.

“Clinicians will need to weigh these benefits against the burden of co-administration of TB and HIV treatment on a case-by-case basis, but the overarching goal is likely to be a move toward treating all HIV-positive people as early as possible,” said Nachega.

The team included other researchers from Pitt; Johns Hopkins Bloomberg School of Public Health; Warwick Medical School, Liverpool School of Tropical Medicine and University College London, United Kingdom; Stellenbosch University, South Africa; South African Medical Research Council, and University Medical Center Utrecht, The Netherlands.

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New guidelines for thyroid cancer molecular tests

University of Pittsburgh Cancer Institute (UPCI) scientists recently led a panel of experts in revising national guidelines for thyroid cancer testing to reflect newly available tests that better incorporate personalized medicine into diagnosing the condition.

Their clinical explanation for when to use and how to interpret thyroid cancer tests is published in the journal Thyroid. The American Thyroid Association is revising its 2015 Guidelines for Thyroid Nodule and Thyroid Cancer Management to direct doctors to the scientific publication.

Said co-author Robert L. Ferris, chief of the Division of Head and Neck Surgery in the School of Medicine: “Minimally invasive molecular testing for thyroid cancer has improved by leaps and bounds in the last several years. But different tests perform differently and, therefore, need to be interpreted carefully to make the best decisions regarding extent of surgery for patients with thyroid nodules. Our goal with this analysis is to give clinicians a clear understanding of what each type of test can tell them and when to use them to determine the best course of treatment.”

Cancer of the thyroid, which is located just below the “Adam’s apple” area of the neck, is the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.

UPCI, partner with UPMC CancerCenter, has been a national leader in developing personalized genetic tests for thyroid cancer that have spared patients repeat or unnecessary surgeries. A low-cost test called ThyroSeq, developed by a team led by Yuri Nikiforov, director of the Division of Molecular and Genomic Pathology, allows pathologists to simultaneously test for multiple genetic markers of thyroid cancer using just a few cells collected from the nodule. This allows doctors to make a specific cancer diagnosis with a high degree of certainty, without a biopsy to remove a large portion of the thyroid, which would then have to be followed with a second surgery to remove the entire gland, if cancer is detected.

As Nikiforov’s group added more genetic sequences to the ThyroSeq test to create a larger and more sensitive version of the test, it now also is performing as a test that can tell doctors with a high degree of certainty that a patient does not have cancer.

Other available tests use different technology to serve as accurate “rule-out” tools, but do not have the high sensitivity needed to also reliably “rule-in” cancer. And, in some cases, the accuracy of the “rule-out” tests depends on the prevalence of cancer in the patients seen by each individual cancer institute. This is critical because clinicians must know this rate at their institution to correctly calculate the accuracy of “rule-out” test results for each patient.

In addition to Ferris and co-author Sally E. Carty, chief of the Division of Endocrine Surgery and co-director of the UPMC/UPCI Multidisciplinary Thyroid Center, the panel reviewing the tests was a multidisciplinary group from a dozen institutions in the U.S. and Canada.

Ferris noted that “these tests give us the ability to not only better diagnose and treat thyroid cancer, but also significantly reduce surgeries for people who don’t have cancer.”

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Cholesterol metabolism in immune cells linked to HIV progression

Enhanced cholesterol metabolism in certain immune cells may help some people infected with HIV naturally control disease progression, according to research from the Graduate School of Public Health.

The findings, funded by the National Institute of Allergy and Infectious Diseases and presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Vancouver, provides a basis for potential development of new approaches to control HIV infection by regulating cellular cholesterol metabolism.

Said lead author Giovanna Rappocciolo, faculty member in the Department of Infectious Diseases and Microbiology: “We’ve known for two decades that some people don’t have the dramatic loss in their T cells and progression to AIDS that you’d expect without drug therapy. Instead, the disease progresses more slowly, and we believe altered cholesterol metabolism in certain immune cells may be a reason.”

Immune cells known as antigen-presenting cells (APCs) can deliver HIV to its primary target — T cells — through a process known as trans infection. HIV then uses T cells as its main site of replication. It is through this mechanism that levels of HIV increase and overwhelm the immune system, leading to AIDs.

However, some HIV-infected people do not progress to AIDS for many years, even without antiretroviral therapy, because their APCs do not effectively trans infect T cells. These people are known as “nonprogressors.” A closer look revealed that this defect in trans infection is likely due to altered cholesterol metabolism within the APCs, which appears to be an inherited trait.

This discovery was made possible by using 30 years of data and biologic specimens collected through the NIH-funded Multicenter AIDS Cohort Study (MACS), a confidential research study of the natural history of untreated and treated HIV/AIDS in men who have sex with men. The Pittsburgh arm of the study is the Pitt Men’s Study.

Rappocciolo and her colleagues searched for patterns in gene expression, or the degree to which specific genes are turned on or off, in APCs from eight HIV nonprogressors and eight progressors enrolled in MACS.

“Compared to APCs from progressors, cells from nonprogressors expressed higher levels of several cholesterol-related genes associated with defective trans infection,” Rappocciolo said.

“These results improve understanding of how nonprogressors control HIV without drug therapy and potentially may contribute to new approaches to manage HIV infection.”

Other contributors to this research were public health’s Jeremy Martinson, Diana Campbell and Maureen McGowan.

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$20 million establishes center for transfusion medicine

The Vascular Medicine Institute (VMI) has received a new commitment of $15 million over the next 10 years from the Institute for Transfusion Medicine’s (ITxM) Blood Science Foundation, as well as an additional $5 million to establish the Institute for Transfusion Medicine Research Endowment. Funding from ITxM’s Blood Science Foundation and Hemophilia Center of Western Pennsylvania now totals $50 million since 2008.

“This is an extraordinary gift,” said Chancellor Patrick Gallagher, “that will be a springboard to draw in other funding from the National Institutes of Health and other national organizations.”

Current funding has allowed the recruitment and support of investigators who are experts in vascular biology, red cell and platelet biology, and hemostasis and thrombosis research, all focused on understanding human vascular and blood diseases and developing new targeted therapies, noted Mark Gladwin, VMI director and distinguished professor, who also is the Dr. Jack D. Myers Professor of Internal Medicine and chair of the Department of Medicine in the School of Medicine.

Said Gladwin: “We anticipate that the study of vascular biology will enable the development of new therapies and interventions for a multitude of vascular conditions, such as sickle cell disease, diabetes, coronary artery disease and hemophilia.”

—Compiled by Marty Levine

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The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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