Entry door for deadly C. difficile toxin suggests new mode of protection

Clostridium difficile
C. difficile (Wikimedia Commons)

Clostridium difficile, also called “C. diff,” tops the CDC’s list of urgent drug-resistant threats. Marked by severe diarrhea and intestinal inflammation, C. diff has become a leading cause of death from gastrointestinal illness, causing half a million infections a year in the U.S. alone.

C. diff flourishes best in hospitals and long-term care facilities where people are on long-term antibiotic treatment. “Antibiotics clear out the normal intestinal bacteria and create a space for C. diff to colonize and grow in the colon,” says Min Dong, PhD, who researches bacterial toxins in the Department of Urology at Boston Children’s Hospital.

In today’s Nature, Dong and postdoctoral fellow Liang Tao, PhD, together with researchers at University of Massachusetts Medical School, reveal how C. diff’s most potent toxin gets into cells. The toxin’s entryway, a receptor called Frizzled, provides an important and interesting clue to fighting the hard-to-eradicate infection.

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Startup uses Uber to get patients to their medical appointments

Uber medical transportation Circulation

Getting to the doctor will soon get easier for some struggling patients. Boston Children’s Hospital has joined forces with the ride-hailing service Uber to pilot a non-emergency medical transportation platform.

The online, HIPAA-compliant tool, called Circulation, connects with health care information systems, enabling hospitals to schedule Uber rides for patients. The pilot will serve Boston Children’s, Mercy Health System in Pennsylvania and Nemours Children’s Health System in Wilmington, Delaware.

A 2005 study estimated that 3.6 million people miss medical appointments because they don’t have access to transportation. While Medicare and Medicaid and other payers provide non-emergency transportation benefits, such as taxi vouchers, patients may be unaware of the programs or have trouble navigating reimbursement rules for the rides. Frequently, the taxi or car service arrives late or doesn’t show up at all.

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Human brain evolution holds clues about autism… and vice versa

human brain evolution autism Human Accelerated Regions
Humans evolved to become more social and cognitively advanced, thanks to genetic changes in regions such as HARs — the child with autism spectrum disorder (ASD) being the exception. While mutations in protein-coding genes continue to be explored in ASD (indicated by the red ribbon of RNA), the scientists at far left are suggesting that mutations in regulatory elements (the histones , in green, and their modifications shown in yellow) may be important in both ASD and human evolution. (Illustration: Kenneth Xavier Probst)

Starting in 2006, comparative genomic studies have identified small regions of the human genome known as Human Accelerated Regions, or HARs, that diverged relatively rapidly from those of chimpanzees — our closest living relatives — during human evolution.

Our genomes contain about 2,700 HAR sequences. And as reported today in Cell, these sequences are often active in the brain and contain a variety of mutations implicated in autism and other neurodevelopmental disorders.

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I feel good! How mood influences time management

time management and mood
(JESHOOTS/Pixabay)

Most theorists boil human behavior down to a pursuit of pleasure. Yet all of us engage in mundane, even unpleasant activities. It’s called being an adult, right? Happy Monday!

But Maxime Taquet, PhD at the Computational Radiology Laboratory at Boston Children’s Hospital (who by day helps conduct advanced brain imaging in children with neurologic conditions) wondered why. If we’re such pleasure-seekers, how do we muster the will to do our taxes or vacuum the house?

Taquet, with Jordi Quoidbach, PhD, of the Department of Economics and Business at the University Pompeu Fabra in Barcelona, and other colleagues developed a smartphone app to track the activities and moods of more than 28,000 French-speaking people for an average of 27 days. At random times during the day, the app asked users to rate their current mood on a scale of 0 to 100 and indicate what they were doing at that moment from a list of options.

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Topical antibiotics for otitis media: A one-squirt cure?

otitis media transtympanic gel
A single-application gel could revolutionize treatment of ear infections, reducing side effects and drug resistance. (Click to play animation.) Credit:Kohane group

Otitis media, or middle-ear infection, affects 95 percent of children and is the number one reason for antibiotic prescriptions in pediatrics. Typically, antibiotic treatment involves 7 to 10 days of oral medication — several times a day — a formidable task for parents of little kids.

“Force-feeding antibiotics to a toddler by mouth is like a full-contact martial art,” says Daniel Kohane, MD, PhD, a pediatrician and director of the Laboratory for Biomaterials and Drug Delivery at Boston Children’s Hospital.

A single-application bioengineered gel could be the answer to parents’ and pediatricians’ prayers. Described in a paper published today in Science Translational Medicine, the gel would provide an entire course of therapy through a single squirt into the ear canal. It was developed by Kohane’s team in collaboration with investigators at Boston Medical Center and Massachusetts Eye and Ear.

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The 21st Century Cures Act: Addressing unmet needs in children with rare disease

21st Century Cures Act and children
Among its other provisions, the Cures Act would advance implementation of the 2013 National Pediatric Research Network Act, boosting therapeutic development for rare childhood diseases.

Medical solutions often require countless hours of investigation, months of testing and monitoring, years of post-trial and market analysis and billions of dollars of investment — with no certainty of success.

Last year, after years of groundwork, the U.S. House of Representatives passed the 21st Century Cures Act. A companion measure is being developed in the Senate, and stakeholders are optimistic that agreement on a package — even a slimmed down bill — could happen this year.

While Congress has addressed research and medical product regulatory needs before, the Cures Act has been unique in its comprehensive approach, looking at all elements of the research spectrum — from basic discovery science to translational research to regulatory review. It would upgrade the National Institutes of Health’s research capabilities and update the Food and Drug Administration’s approval policies to get new drugs and devices to the clinic sooner.

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Keeping up with HIV mutations: Building a nimble vaccine test system

AIDS vaccine
A new technology speeds up natural antibody “evolution” to create a nimble HIV vaccine test system. (Images: Wikimedia/Pixabay)

An AIDS vaccine able to fight any HIV strain has thus far eluded science. HIV frequently mutates its coat protein, dodging vaccine makers’ efforts to elicit sufficiently broadly neutralizing antibodies.

Yet sometimes HIV-infected people can produce such antibodies on their own. This usually requires years of exposure to the virus, allowing the immune system to modify its antibodies over time to keep up with HIV mutations. But the goal is generally achieved too late in the game to prevent them from being infected.

“Only a small fraction of patients are able to develop broadly neutralizing antibodies, and by the time they do, the virus has already integrated into the genomes of their T-cells,” says Ming Tian, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM).

Tian is part of a group led by PCCM director Frederick Alt, PhD, that developed a technology to greatly speed up HIV development. Described today in Cell, the group’s method generates mouse models with built-in human immune systems. The model recapitulates what the human immune system does, only much more rapidly, enabling researchers to continuously test and tweak potential HIV vaccines.

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BCL11A-based gene therapy for sickle cell disease passes key preclinical test

sickle cell gene therapy coming
(unsplash/Pixabay)

Research going back to the 1980s has shown that sickle cell disease is milder in people whose red blood cells carry a fetal form of hemoglobin. The healthy fetal hemoglobin compensates for the mutated “adult” hemoglobin that makes red blood cells stiffen and assume the classic “sickle” shape.

Normally, fetal hemoglobin production tails off after birth, shut down by a gene called BCL11A. In 2008, researchers Stuart Orkin, MD, and Vijay Sankaran, MD, PhD, at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center showed that suppressing BCL11A could restart fetal hemoglobin production; in 2011, using this approach, they corrected sickle cell disease in mice.

Now, the decades-old discovery is finally nearly ready for human testing — in the form of gene therapy. Today in the Journal of Clinical Investigation, Dana-Farber/Boston Children’s researchers report that a precision-engineered gene therapy vector suppressing BCL11A production overcame a key technical hurdle.

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Could targeting specific neurons in the hypothalamus relieve anxiety?

anxiety hypothalamus
(Ichiban Yada/Sketchport.com)

Anxiety disorders are the most common mental illness in the U.S., but lack an ideal treatment. The current drugs, SSRIs and benzodiazepines, have many side effects. More recently developed treatments seek to block corticotropin-releasing hormone (CRH), the classic stress hormone that activates our “fight or flight” response; in people with anxiety, CRH gets activated at the wrong time or too intensely.

But in clinical trials, results have been disappointing: of the eight completed phase II and III trials of CRH antagonists for depression or anxiety, six have been published, with largely negative findings, says Joseph Majzoub, MD, of the Division of Endocrinology at Boston Children’s Hospital.

Rong Zhang, PhD, who works in Majzoub’s research lab, had a hunch that blocking CRH throughout the brain, as was done in these trials, isn’t the best approach. “Blocking CRH receptors all over the brain doesn’t work,” she says. “We think the effects work against each other somehow. It may be that CRH has different effects depending on where in the brain it is produced.”

Today in Molecular Psychiatry, Zhang, Majzoub and colleagues demonstrate that certain neurons in the hypothalamus play a central, previously unknown role in triggering anxiety. When they used genetic tricks to selectively remove the CRH gene from about 1,000 of these neurons in mice, the effect was startling — they erased the animals’ natural fears.

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Treating relapsed child leukemia by matching therapy to the mutations

next generation sequencing cancer drugs child leukemia
(Bainscou / National Cancer Institute / Wikimedia Commons)

Although current treatments can cure 80 to 90 percent of cases, acute lymphoblastic leukemia (ALL) remains the second leading cause of cancer deaths in children. Patients with a resistant form of the disease, who relapse following successful treatment or who have other high risk features have few treatment options. Acute myeloid leukemia (AML) is also difficult to treat in children.

In a first-of-its-kind study, investigators at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center are testing precision cancer medicine in children and young adults with relapsed or high-risk leukemias. The goal is to determine whether powerful next-generation DNA sequencing can spot mutations or genetic changes in leukemia cells that can be targeted by cancer drugs.

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