When Rulers Can’t Understand the Ruled

Johns Hopkins study finds significant gap in demographics, experience and partisanship between Washingtonians and the Americans they govern
Johns Hopkins University political scientists wanted to know if America’s unelected officials have enough in common with the people they govern to understand them.

The answer: Not really.

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Surveying 850 people who either work in government or directly with it, researchers found that the inside-the-Beltway crowd has very little in common with America at large. Washington insiders are more likely to be white. They are more educated. Their salaries are higher, they vote more and have more faith in the fairness of elections. They are probably Democrat and liberal. They more diligently follow the news. And they think the mechanizations of government couldn’t be easier to comprehend. Continue reading “When Rulers Can’t Understand the Ruled”

19th Century Math Tactic Gets a Makeover—and Yields Answers Up to 200 Times Faster


Simulation data showing significantly faster reduction in solution error for the new Scheduled Relaxation Jacobi (SRJ) method as compared to the classical Jacobi and Gauss-Seidel iterative methods.The equation that is being solved here is the two-dimensional Laplace equation on a 128×128 grid.

A relic from long before the age of supercomputers, the 169-year-old math strategy called the Jacobi iterative method is widely dismissed today as too slow to be useful. But thanks to a curious, numbers-savvy Johns Hopkins engineering student and his professor, it may soon get a new lease on life.

With just a few modern-day tweaks, the researchers say they’ve made the rarely used Jacobi method work up to 200 times faster. The result, they say, could speed up the performance of computer simulations used in aerospace design, shipbuilding, weather and climate modeling, biomechanics and other engineering tasks.

Their paper describing this updated math tool was published June 27 in the online edition of the Journal of Computational Physics. Continue reading “19th Century Math Tactic Gets a Makeover—and Yields Answers Up to 200 Times Faster”

Could dog food additive prevent disabling chemotherapy side effect?

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

Johns Hopkins researchers find, in mice, that common preservative may thwart pain and damage of peripheral neuropathy

Working with cells in test tubes and in mice, researchers at Johns Hopkins have discovered that a chemical commonly used as a dog food preservative may prevent the kind of painful nerve damage found in the hands and feet of four out of five cancer patients taking the chemotherapy drug Taxol.

The Food and Drug Administration-approved preservative, an antioxidant called ethoxyquin, was shown in experiments to bind to certain cell proteins in a way that limits their exposure to the damaging effects of Taxol, the researchers say.

The hope, they say, is to build on the protective effect of ethoxyquin’s chemistry and develop a drug that could be given to cancer patients before taking Taxol, in much the same way that anti-nausea medication is given to stave off the nausea that commonly accompanies chemotherapy. While half of Taxol users recover from the pain damage, known as peripheral neuropathy, the other half continue to have often debilitating pain, numbness and tingling for the rest of their lives.

“Millions of people with breast cancer, ovarian cancer and other solid tumors get Taxol to treat their cancer and 80 percent of them will get peripheral neuropathy as a result,” says Ahmet Höke, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and director of the Neuromuscular Division. “They’re living longer thanks to the chemotherapy, but they are often miserable. Our goal is to prevent them from getting neuropathy in the first place.”

A report on Höke’s research is published online in the Annals of Neurology.

Höke and his team knew from previous experiments that adding Taxol to a nerve cell line growing in a petri dish would cause neurodegeneration. In a series of experiments, they set out to hunt for compounds that might interrupt the degenerative process by adding Taxol to nerve cells along with some 2,000 chemicals — one at a time — to see which, if any, could do that.

Ethoxyquin did so, Höke says, apparently by making the cells resistant to the toxic effects of the Taxol.

Once they identified ethoxyquin’s effects, they gave intravenous Taxol to mice, and saw nerves in their paws degenerate in a couple of weeks. But when they gave ethoxyquin to the mice at the same time as the Taxol, it prevented two-thirds of the nerve degeneration, which Höke says would have a big impact on quality of life if the same effects were to occur in humans.

Specifically, Höke and his team discovered that molecules of ethoxyquin were binding to Hsp90, one of the so-called heat shock proteins that cells defensively make more of whenever they are stressed. Hsp90 acts as a cell’s quality control officer, determining whether a protein is properly formed before sending it out where it is needed.  When ethoxyquin binds to Hsp90, two other proteins — ataxin-2 and Sf3b2 — can’t bind to Hsp90. When they can’t bind, the cell senses that these two proteins are flawed, so they are degraded and their levels in the cell diminished.

Höke says his team is not certain why too much of those two proteins appears to have a negative effect on nerves, but reducing their levels clearly appears in their studies to make cells more resistant to Taxol toxicity.

Höke and his colleagues are looking into whether this medication could also make nerves more resistant to damage in peripheral neuropathy caused by HIV and diabetes, two other major causes of the pain. A previous study, Höke says, showed that ataxin-2 may cause degeneration in motor neurons in a rare form of ALS, commonly known as Lou Gehrig’s disease, suggesting that ethoxyquin or some version of it might also benefit people with this disorder.

Twenty to 30 million Americans suffer from peripheral neuropathy. Höke says it’s a “huge public health issue” that doesn’t get much attention because it is not fatal.

Höke’s team is hoping to conduct safety studies with ethoxyquin in animals in advance of possible testing in people. He says that while too much ethoxyquin is thought to be potentially harmful to dogs, the needed dose for humans would likely be 20-to-30-fold lower than what is found in dog food. Ethoxyquin was developed in the 1950s as an antioxidant, a compound to prevent pears and other foods from becoming discolored and spoiling.

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Other Johns Hopkins researchers involved in the study include Jing Zhu, Ph.D.; Weiran Chen, M.D.; Ruifa Mi, M.D., Ph.D.; Chunhua Zhou, B.S.; and Nicole Reed, M.S.

The research was supported by the Foundation for Peripheral Neuropathy, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (R01 NS43991) and Johns Hopkins Brain Science Institute.

For more information about Höke, click here.

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.5 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of the Johns Hopkins Hospital and Health System. JHM’s mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness.  JHM operates six academic and community hospitals, four suburban health care and surgery centers, and more than 30 primary health care outpatient sites. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation from 1990 to 2011 by U.S. News & World Report.

Johns Hopkins Medicine Media Relations and Public Affairs Media Contacts:

Stephanie Desmon 410-955-8665; sdesmon1@jhmi.edu

Helen Jones 410-502-9422; hjones49@jhmi.edu

There’s life after radiation for brain cells

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment

Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.

“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”

The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.

In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.

In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.

“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”

His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.

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The research was supported by grants from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (RO1 NS070024), the Maryland Stem Cell Research Fund, the Robert Wood Johnson Foundation, the Howard Hughes Medical Institute, the PROMETEO grant, the Red de Terapia Celular (TerCel) from Instituto de Salud Carlos III, and the Consejo Nacional de Ciencia y Tecnología.

Other Johns Hopkins researchers involved in the study include Vivian Capilla-Gonzalez, Ph.D.; Hugo Guerrero-Cazares, M.D., Ph.D.; Janice Bonsu; Oscar Gonzalez-Perez, M.D.; Pragathi Achanta, Ph.D.; John Wong, Ph.D.; and Jose Manuel Garcia-Verdugo, Ph.D.

For more information: http://tinyurl.com/ofqkea3

JOHNS HOPKINS MEDICINE

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM’s mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, more than 38 primary health care outpatient sites and other businesses that care for national and international patients and activities. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years by U.S. News & World Report.

Johns Hopkins Medicine Media Relations and Public Affairs

Media Contact:

Stephanie Desmon 410-955-8665; sdesmon1@jhmi.edu

Helen Jones 410-502-9422, hjones49@jhmi.edu

Expert questions US public health agency advice on influenza vaccines: “All influenza is “flu,” but only one in six “flus” might be influenza”

Contact: Emma Dickinson edickinson@bmj.com 44-020-738-36529 BMJ-British Medical Journal

Marketing influenza vaccines involves marketing influenza as a threat of great proportions, argues Johns Hopkins fellow

Promotion of influenza vaccines is one of the most visible and aggressive public health policies today, writes Doshi. Today around 135 million doses of influenza vaccine annually enter the US market, with vaccinations administered in drug stores, supermarkets – even some drive-throughs.

This enormous growth has not been fuelled by popular demand but instead by a public health campaign that delivers a straightforward message: influenza is a serious disease, we are all at risk of complications from influenza, the flu shot is virtually risk free, and vaccination saves lives.

Yet, Doshi argues that the vaccine might be less beneficial and less safe than has been claimed, and the threat of influenza appears overstated.

To support its case, the CDC cites two studies of influenza vaccines, published in high-impact, peer-reviewed journals and carried out by academic and government researchers with non-commercial funding. Both found a large (up to 48%) relative reduction in the risk of death.

“If true, these statistics indicate that influenza vaccines can save more lives than any other single licensed medicine on the planet,” says Doshi. But he argues that these studies are “simply implausible” and likely the product of the ‘healthy-user effect’ (in this case, a propensity for healthier people to be more likely to get vaccinated than less healthy people).

In addition, he says, there is virtually no evidence that influenza vaccines reduce elderly deaths – the very reason the policy was originally created.

He points out that the agency itself acknowledges the evidence may be undermined by bias. Yet, he says “for most people, and possibly most doctors, officials need only claim that vaccines save lives, and it is assumed there must be solid research behind it.”

He also questions the CDC’s recommendation that beyond those for whom the vaccine is contraindicated, influenza vaccine can only do good, pointing to serious reactions to influenza vaccines in Australia (febrile convulsions in young children) and Sweden and Finland (a spike in cases of narcolepsy among adolescents).

Doshi suggests that influenza is yet one more case of “disease mongering” – medicalising ordinary life to expand markets for new products. But, he warns that unlike most stories of selling sickness, “here the salesmen are public health officials, worried little about which brand of vaccine you get so long as they can convince you to take influenza seriously.”

But perhaps the cleverest aspect of the influenza marketing strategy surrounds the claim that “flu” and “influenza” are the same, he concludes. “All influenza is “flu,” but only one in six “flus” might be influenza. It’s no wonder so many people feel that “flu shots” don’t work: for most flus, they can’t.”

Earlier this year, the BMJ launched a ‘Too Much Medicine’ campaign to help tackle the threat to health and the waste of money caused by unnecessary care. The journal will also partner at an international conference Preventing Overdiagnosis to be held in September in the USA

Restless legs syndrome, insomnia and brain chemistry: A tangled mystery solved? (Excessive Glutamate)

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

Johns Hopkins researchers believe they may have discovered an explanation for the sleepless nights associated with restless legs syndrome (RLS), a symptom that persists even when the disruptive, overwhelming nocturnal urge to move the legs is treated successfully with medication.

Neurologists have long believed RLS is related to a dysfunction in the way the brain uses the neurotransmitter dopamine, a chemical used by brain cells to communicate and produce smooth, purposeful muscle activity and movement. Disruption of these neurochemical signals, characteristic of Parkinson’s disease, frequently results in involuntary movements. Drugs that increase dopamine levels are mainstay treatments for RLS, but studies have shown they don’t significantly improve sleep. An estimated 5 percent of the U.S. population has RLS.

The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate — a neurotransmitter involved in arousal — in abnormally high levels in people with RLS. The more glutamate the researchers found in the brains of those with RLS, the worse their sleep.

The findings are published in the May issue of the journal Neurology.

“We may have solved the mystery of why getting rid of patients’ urge to move their legs doesn’t improve their sleep,” Allen says. “We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS.”

For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness. They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.

The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting. In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got. They found no such association in the control group without RLS.

Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness. Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal — day or night.

If confirmed, the  study’s results may change the way RLS is treated,  Allen says, potentially erasing the sleepless nights that are the worst side effect of the condition. Dopamine-related drugs currently used in RLS do work, but many patients eventually lose the drug benefit and require ever higher doses. When the doses get too high, the medication actually can make the symptoms much worse than before treatment. Scientists don’t fully understand why drugs that increase the amount of dopamine in the brain would work to calm the uncontrollable leg movement of RLS.

Allen says there are already drugs on the market, such as the anticonvulsive gabapentin enacarbil, that can reduce glutamate levels in the brain, but they have not been given as a first-line treatment for RLS patients.

RLS wreaks havoc on sleep because lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep. Only getting up and moving around typically relieves the discomfort. The sensations range in severity from uncomfortable to irritating to painful.

“It’s exciting to see something totally new in the field — something that really makes sense for the biology of arousal and sleep,” Allen says.

As more is understood about this neurobiology, the findings may not only apply to RLS, he says, but also to some forms of insomnia.

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The study was funded in part by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (R01 NS075184 and NS044862), the National Institute on Aging (P10-AG21190) and the National Center for Research Resources (M01RR02719).

Allen has received honoraria serving on advisory boards from impax, Pfizer and UCB and honoraria for scientific lectures, consultancy and research support from UCB, GSK, Pfizer and Pharmacosmos.

Other Johns Hopkins researchers involved in the study include Peter B. Barker, D.Phil.; Alena Horska, Ph.D.; and Christopher J. Earley, M.D., Ph.D.

For more information:

http://www.hopkinsmedicine.org/neurology_neurosurgery/specialty_areas/restless-legs-syndrome/

Media Contact: Stephanie Desmon 410-955-8665; sdesmon1@jhmi.edu

Helen Jones; 410-502-9422; hjones49@jhmi.edu

Estrogen fuels autoimmune liver damage

Contact: Ekaterina Peshva epeshev1@jhmi.edu 410-502-9433 Johns Hopkins Medicine

Johns Hopkins research in mice unravels mystery behind sex disparities in drug-induced hepatitis

A life-threatening condition that often requires transplantation and accounts for half of all acute liver failures, autoimmune hepatitis is often precipitated by certain anesthetics and antibiotics. Researchers say these drugs contain tiny molecules called haptens that ever so slightly change normal liver proteins, causing the body to mistake its own liver cells for foreign invaders and to attack them. The phenomenon disproportionately occurs in women, even when they take the same drugs at the same doses as men.

Results of the new study, described in the April issue of the journal PLoS One, reveal that estrogen and a signaling molecule called interleukin-6 collude to form a powerful duo that leads to immune cell misconduct and fuels autoimmune liver damage.

The findings, the research team says, also suggest therapeutic strategies to curb damage in people who develop drug-induced liver inflammation.

“Our study shows that estrogen is not alone in its mischief but working with an accomplice to set off a cascade of events that leads to immune cell dysregulation and culminates in liver damage,” says Dolores Njoku, M.D., a pediatric anesthesiologist and critical care expert at Johns Hopkins Children’s Center.

In the study, led by Njoku, researchers induced liver inflammation in mice by injecting them with drug-derived haptens. Female mice developed worse liver damage than male mice, and castrated male mice fared worse than their intact brethren, likely due to loss of testosterone and altered estrogen-to-testosterone ratio, the researchers say. Female mice with missing ovaries — the chief estrogen-secreting organs — suffered milder forms of hepatitis than mice with intact ovaries.

Female mice produced more liver-damaging antibodies and more inflammation-triggering chemicals, specifically the inflammatory molecule interleukin-6, known to fuel autoimmunity. Liver damage was notably milder in female mice whose interleukin-6 receptors were blocked or missing compared with normal female mice. On the other hand, male mice and female mice with missing ovaries had nearly undetectable levels of interleukin-6, while castrated male mice showed simultaneous upticks in both estrogen and interleukin-6.

The research team further zeroed in on a class of cells known as regulatory T cells, whose main function is keeping tabs on other immune cells to ensure they don’t turn against the body’s own tissues. When researchers compared the number of regulatory T cells present in the spleens of male and female mice, they noticed far fewer regulatory T cells in the spleens of female mice. The spleen, the researchers explain, is the primary residence of mature immune cells.

“Deficiency of regulatory T cells effectively takes the reins off other immune cells, leading to overactive immunity,” Njoku says.

In a final, dot-connecting move, the researchers immersed spleen-derived immune cells in estrogen. What they observed proved beyond doubt that estrogen, interleukin and regulatory T cells form a powerful triangle. Estrogen induced the immune cells of female mice to express more interleukin-6, which in turn diminished the expression of inflammation-taming regulatory T cells.

When the researchers injected sick female mice with a booster dose of regulatory T cells, their liver inflammation subsided to levels seen in male mice.

This powerful response, the researchers say, suggests that therapy with regulatory T cells may reduce estrogen-related liver damage in patients with autoimmune hepatitis. Such treatment, however, remains years away from human application.

One reason, the researchers say, is that regulatory T cells maintain the fine equilibrium between overactive and underactive immunity. Because an overactive immune system can lead to autoimmune diseases and an underactive one can promote tumor growth, any therapy with regulatory T cells must be precisely calibrated to avoid tipping this precarious balance.

“We first must figure out where the golden mean lies,” Njoku says.

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Co-investigators on the study included Joonhee Cho, Lina Kim, Zhaoxia Li, Noel Rose and Monica Vladut Talor, all from Johns Hopkins.

The research was funded in part by the William R. Rienhoff Scholars Foundation, by the American Autoimmune Related Diseases Association, by the National Institute of Diabetes and Digestive and Kidney Diseases (grant number NIHR21DK075828) and by the Scoby Family Foundation.

Founded in 1912 as the children’s hospital of the Johns Hopkins Medical Institutions, the Johns Hopkins Children’s Center offers one of the most comprehensive pediatric medical programs in the country, with more than 92,000 patient visits and nearly 9,000 admissions each year. Hopkins Children’s is consistently ranked among the top children’s hospitals in the nation. Hopkins Children’s is Maryland’s largest children’s hospital and the only state-designated Trauma Service and Burn Unit for pediatric patients. It has recognized Centers of Excellence in dozens of pediatric subspecialties, including allergy, cardiology, cystic fibrosis, gastroenterology, nephrology, neurology, neurosurgery, oncology, pulmonary, and transplant. For more information, visit http://www.hopkinschildrens.org.

Johns Hopkins Medicine Media Relations and Public Affairs Media Contacts: Ekaterina Pesheva, epeshev1@jhmi.edu, 410-502-9433, 410-926-6780 cell Helen Jones, hjones49@jhmi.edu, 410-502-9422

Johns Hopkins study: Risk of pancreatitis doubles for those taking new class of diabetes drugs

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

People who take the newest class of diabetes drugs to control blood sugar are twice as likely as those on other forms of sugar-control medication to be hospitalized with pancreatitis, Johns Hopkins researchers report.

In an article published online in JAMA Internal Medicine, the scientists say the new drugs — glucagon-like peptide-1-based therapies (GLP-1) — are associated with an increased risk of hospitalization for acute pancreatitis. The agents sitagliptin and exenatide — generic names for the drugs sold under the brand names Januvia and Byetta — appear to contribute to the formation of lesions in the pancreas and the proliferation of ducts in the organ, resulting in wellsprings of inflammation.

Physicians and regulators have been aware that pancreatitis could be a side effect of GLP-1 therapies, a risk that emerged in animal studies and reports to the U.S. Food and Drug Administration. But the Johns Hopkins investigators say their study is the first to accurately measure the strength of this risk in analyses that accounted for other pancreatitis risk factors, such as gallstones, obesity and heavy alcohol use.

“These agents are used by millions of Americans with diabetes. These new diabetes drugs are very effective in lowering blood glucose. However, important safety findings may not have been fully explored and some side effects such as acute pancreatitis don’t appear until widespread use after approval,” says study leader Sonal Singh, M.D., M.P.H., an assistant professor in the Division of General Internal Medicine at the Johns Hopkins University School of Medicine.

Patients should be alert to symptoms of pancreatitis — nausea, vomiting that won’t stop, abdominal pain — and seek treatment immediately if any symptoms noted on the drug label occur.

Pancreatitis is marked by inflammation of the pancreas, the organ that releases such hormones as insulin and glucagon, as well as enzymes that help digest food. A painful condition, pancreatitis can be dangerous if left untreated.

Singh and his colleagues based their findings on analysis of data from seven BlueCross BlueShield health insurance plans. They first identified 1,269 beneficiaries with type 2 diabetes who filled at least one prescription for any drug to treat the disease between 2005 and 2008. After matching them with 1,269 type 2 diabetics who had not, and controlling for the other known pancreatitis risk factors, the researchers found that people who took one of the GLP-1 therapies were twice as likely to be hospitalized with pancreatitis within 60 days of first taking the drugs as those who had taken a different medication.

In a healthy person, the pancreas releases insulin to help the body store and use sugar from food. Diabetes occurs when the pancreas does not produce the right amount of insulin or the body does not respond appropriately to the hormone. When there isn’t enough insulin, or the insulin is not used as it should be, glucose (sugar) can’t get into the body’s cells and builds up in the bloodstream instead. Because of the role of the pancreas in diabetes, people with diabetes are already at an increased risk for pancreatitis.

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This research was supported by the Johns Hopkins Clinical Research Scholars Program, the National Institutes of Health’s National Center for Research Resources (1KL2RR025006-03) and the NIH Roadmap for Medical Research.

Other Johns Hopkins researchers involved in the study include Hsien-Yen Chang, Ph.D.; Thomas M. Richards, M.S.; Jonathan P. Weiner, Dr.Ph.; Jeanne M. Clark, M.D., M.P.H.; and Jodi B. Segal, M.D., M.P.H.

For more information: http://www.hopkinsmedicine.org/gim/faculty/Singh.html

ADHD symptoms persist for most young children despite treatment

Contact: Ekaterina Pesheva epeshv1@jhmi.edu 410-502-9433 Johns Hopkins Medicine

Nine out of 10 young children with moderate to severe attention-deficit hyperactivity disorder (ADHD) continue to experience serious, often severe symptoms and impairment long after their original diagnoses and, in many cases, despite treatment, according to a federally funded multi-center study led by investigators at Johns Hopkins Children’s Center.

The study, published online Feb. 11 in the Journal of the American Academy of Child & Adolescent Psychiatry, is the largest long-term analysis to date of preschoolers with ADHD, the investigators say, and sheds much-needed light on the natural course of a condition that is being diagnosed at an increasingly earlier age.

“ADHD is becoming a more common diagnosis in early childhood, so understanding how the disorder progresses in this age group is critical,” says lead investigator Mark Riddle, M.D., a pediatric psychiatrist at Johns Hopkins Children’s Center. “We found that ADHD in preschoolers is a chronic and rather persistent condition, one that requires better long-term behavioral and pharmacological treatments than we currently have.”

The study shows that nearly 90 percent of the 186 youngsters followed continued to struggle with ADHD symptoms six years after diagnosis. Children taking ADHD medication had just as severe symptoms as those who were medication-free, the study found.

Children with ADHD, ages 3 to 5, were enrolled in the study, treated for several months, after which they were referred to community pediatricians for ongoing care. Over the next six years, the researchers used detailed reports from parents and teachers to track the children’s behavior, school performance and the frequency and severity of three of ADHD’s hallmark symptoms—inattention, hyperactivity and impulsivity. The children also had full diagnostic workups by the study’s clinicians at the beginning, halfway through and at the end of the research.

Symptom severity scores did not differ significantly between the more than two-thirds of children on medication and those off medication, the study showed. Specifically, 62 percent of children taking anti-ADHD drugs had clinically significant hyperactivity and impulsivity, compared with 58 percent of those not taking medicines. And 65 percent of children on medication had clinically significant inattention, compared with 62 percent of their medication-free counterparts. The investigators caution that it remains unclear whether the lack of medication effectiveness was due to suboptimal drug choice or dosage, poor adherence, medication ineffectiveness per se or some other reason.

“Our study was not designed to answer these questions, but whatever the reason may be, it is worrisome that children with ADHD, even when treated with medication, continue to experience symptoms, and what we need to find out is why that is and how we can do better,” Riddle says.

Children who had oppositional defiant disorder or conduct disorder in addition to ADHD were 30 percent more likely to experience persistent ADHD symptoms six years after diagnosis, compared with children whose sole diagnosis was ADHD.

ADHD is considered a neurobehavioral condition and is marked by inability to concentrate, restlessness, hyperactivity and impulsive behavior. It can have profound and long-lasting effects on a child’s intellectual and emotional development, Riddle says. It can impair learning, academic performance, peer and family relationships and even physical safety. Past research has found that children with ADHD are at higher risk for injuries and hospitalizations.

More than 7 percent of U.S. children are currently treated for ADHD, the investigators say. The annual economic burden of the condition is estimated to be between $36 billion and $52 billion, according to researchers.

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Other Johns Hopkins investigators on the research included Elizabeth Kastelic, M.D., and Gayane Yenokyan, Ph.D.

The other institutions involved in the research were Columbia University Medical Center, Duke University, the Nathan Kline Institute, University of California—Irvine and University of California—Los Angeles.

The research was funded by the National Institute of Mental Health under grant numbers: U01 MH60642 (Johns Hopkins), U01MH60848 (Duke University Medical Center), U01MH60943 (New York University Child Study Center), U01MH60903 (Columbia University), U01 MH60833 (University of California–Irvine) and U01H60900 (University of California—Los Angeles).

Related

Journal of the American Academy of Child & Adolescent Psychiatry http://www.jaacap.com/article/S0890-8567%2812%2900993-8/abstract

Popular ADHD Drug Safe and Effective for Preschoolers http://www.hopkinschildrens.org/Popular-ADHD-Drug-Safe-and-Effective-for-Pre-Schoolers.aspx

Increasing Prevalence of Parent-Reported Attention-Deficit/Hyperactivity Disorder Among Children — United States, 2003 and 2007 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5944a3.htm?s_cid=mm5944a3_w

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Popular HIV drug commonly prescribed anti-retroviral drug efavirenz attacks brain cells

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medicine

Popular HIV drug may cause memory declines

Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells

The way the body metabolizes a commonly prescribed anti-retroviral drug that is used long term by patients infected with HIV may contribute to cognitive impairment by damaging nerve cells, a new Johns Hopkins research suggests.

Nearly 50 percent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities. It has long been assumed that the disease was causing the damage, but Hopkins researchers say the drug efavirenz may play a key role.

People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades. Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain. Doctors have long believed that it might be possible to alleviate cognitive impairment associated with HIV by getting more drugs into the brain, but researchers say more caution is needed because there may be long-term effects of these drugs on the brain.

“People with HIV infections can’t stop taking anti-retroviral drugs. We know what happens then and it’s not good,” says Norman J. Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine. “But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV.”

For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics, researchers obtained samples of blood and cerebrospinal fluid from HIV-infected subjects enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz. Researchers looked for levels of the drug and its various metabolites, which are substances created when efavirenz is broken down by the liver. Performing experiments on neurons cultured in the lab, the investigators examined the effects of 8-hydroxyefavirenz and other metabolites  and found major structural changes when using low levels of 8-hydroxyefavirenz, including the loss of the important spines of the cells.

Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons. The dendritic spine is the information processing point of a neuron, where synapses — the structures that allow communication among brain cells — are located.

In the case of efavirenz, a minor modification in the drug’s structure may be able block its toxic effects but not alter its ability to suppress the virus. Namandje N. Bumpus, Ph.D., one of the study’s other authors, has found a way to modify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to suppress the HIV virus.

“Finding and stating a problem is one thing, but it’s another to be able to say we have found this problem and here is an easy fix,” Haughey says.

Haughey says studies like his serve as a reminder that while people infected with HIV are living longer than they were 20 years ago, there are significant problems associated with the drugs used to treat the infection.

“Some people do seem to have this attitude that HIV is no longer a death sentence,” he says. “But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It’s nothing you should treat lightly.”

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The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental Health (MH077543, MH075673 and MH71150), the National Institute on Aging (AG034849) and the National Institute of Neurological Disorders and Stroke (NS049465).

Other Hopkins researchers involved in the study include Luis B. Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin McArthur, M.B.B.S., M.P.H.

For more information:http://www.hopkinsmedicine.org/neurology_neurosurgery/research/jhu_nimh/researchers

Having a tonsillectomy can cause Obesity

Contact: David March
dmarch1@jhmi.edu
410-955-1534
Johns Hopkins Medicine

Age, not underlying diagnosis, key factor in weight gain in children after tonsillectomy

Potentially worrisome weight gains following tonsillectomy occur mostly in children under the age of 6, not in older children, a study by Johns Hopkins experts in otolaryngology- head and neck surgery shows.

Sudden increases in body mass index, or BMI, have been routinely observed for months after some of the more than half-million surgeries performed annually in the United States to remove the sore and swollen tissues at the back of the throat.

The Johns Hopkins study, in 115 children in the Baltimore region, is believed to be the first to dispel long-held beliefs that such weight gains occurred mostly in children whose tonsils were removed as primary treatment for diagnosed sleep apnea, when the swollen, paired tissues partially obstruct breathing and disrupt sleep. It is also believed to be the largest study to analyze weight gain specific to every child’s age group, from 1 through 17.

Although researchers have yet to pinpoint the underlying cause of the weight-gain phenomena, they did find that it happened at the same rate in the 85 children who had the surgery for obstructive sleep apnea as in the 30 who had it due to recurrent episodes of tonsil inflammation.

Senior study investigator, otolaryngologist and sleep medicine expert Stacey Ishman, M.D., M.P.H., says her team’s study findings, scheduled to be presented Sept. 12 at the annual meeting of the American Academy of Otolaryngology—Head and Neck Surgeons in Washington, D.C., should help alleviate rising concerns among many parents whose adolescent children are already overweight that tonsillectomy may aggravate the problem; or start one in normal weight kids. Recent surveys have shown that record numbers of American children, as many as one-third, are overweight or obese.

“Our study results show that parents’ current concerns about weight gain are serious, but only underweight or normal weight children between the ages of 2 and 6 are most likely to gain even more weight, not older children,” says Ishman, an assistant professor at the Johns Hopkins University School of Medicine.

“Parents with overweight adolescent children need not fear tonsillectomy, and those with younger, normal weight and overweight children just really need to closely watch their child’s diet following surgery, and make caloric adjustments,” says Ishman, who has performed hundreds of the roughly 30-minute procedures that typically require a general anesthetic.

In the study, researchers analyzed the medical records of children between the ages of 6 months and 18 years who had had their tonsils removed at the Johns Hopkins Outpatient Center between 2008 and 2011. Researchers looked only at those medical records for children who had been routinely examined for at least six months after their procedure, with detailed measurements of any possible weight gain, which were averaged and compared based on a formula involving age, gender and height. All also had a history of recurrent tonsillitis or obstructive sleep apnea, as strictly determined by an individual sleep study analysis.

Results showed an averaged post-surgical weight gain of 2 to 5 pounds – or a 1.0- to 1.2-point increase in averaged BMI scores—but the gains were not dependent on whether the underlying condition was inflammation or sleep apnea. Only age mattered, researchers say, after discounting gender and height.

Ishman says that while such weight gains might appear small, in these children’s small bodies, whose initial weight was between 22 and 60 pounds (or between 10 to 30 kilos), “a 10 percent weight gain can be quite worrisome.”

Results showed a normal weight, 5-year-old boy, weighing 40 pounds (or 18 kilos) and measuring 42 inches tall, who gained 3 pounds after tonsillectomy, would move from the 68th percentile to the 89th percentile in their age-weight group, and become overweight. For an underweight 5-year-old boy of similar height, originally weighing 34 pounds (15 kilos), the same 3-pound weight gain would shift them from the 24th percentile group to the 28th percentile, moving them closer to a normal weight.

However, she says, in an overweight 10-year-old boy, already weighing 90 pounds (41 kilos) and 55 inches tall, there was no weight gain post tonsillectomy, and he remained in the 92nd percentile group, meaning his poor condition did not worsen.

Ishman says her team’s next steps are to gain a better understanding of why and how children’s age affects weight gain post-tonsillectomy. She already has plans to monitor children immediately after surgery to find out what factors or interventions may help underweight children gain pounds, while helping those who are overweight to not get any bigger.

Since 2002 tonsillectomy has been recommended by the American Academy of Pediatrics as the primary treatment for obstructive sleep apnea, as sleeping aids and drug therapies are not as effective. Studies have shown that if left untreated, sleep apnea can lead to long-term health problems, including increased heart and lung diseases, even death.

 

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Funding support for this study was provided by The Johns Hopkins Hospital.

In addition to Ishman, other Johns Hopkins researchers involved in this study were David Smith, M.D., Ph.D., and Emily Boss, M.D., M.P.H. Other study co-investigators included Ami Vikani, B.S., at the George Washington University School of Medicine, in Washington, D.C.; and Fernando Aguirre-Amezquita, M.D., at Escuela de Medicina Ignacio A. Santos de Monterrey, in Mexico.

For more information, go to:
http://www.hopkinsmedicine.org/otolaryngology/our_team/faculty/ishman.html
http://www.entannualmeeting.org/12/