Day: 05/02/2017

Clues to Zika Damage Might Lie in Cases of Twins

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While identical twins often share a fate, fraternal twins
typically don’t, a divergence that offers clues to researchers.
But one case is confounding these expectations.

On the bed next to her brother, Ana Vitória da Silva Araújo acted like the 1-year-old she was. She smiled and babbled. She played with a stuffed whale. She plucked the pacifier from her brother’s mouth and the burp cloth from his shoulder.

Her brother, João Lucas, seemed unaware of her, his eyes closed, his mouth making sucking motions. It was typical behavior for a newborn. But João Lucas is the exact same age as Ana Vitória — they are twins.

João Lucas was born with microcephaly and other serious problems, the result of his mother being bitten by a Zika infected mosquito during pregnancy. But the virus that attacked his brain in the womb apparently spared his sister.

The siblings are one of nine sets of twins identified in Brazil’s Zika crisis, and scientists hope they can shed light on how the virus works generally and why it inflicts ruthless damage on some babies and not others.

Twins often yield clues to medical mysteries because their biological similarities allow scientists to identify relevant differences. Determining why one twin became infected in the womb while the other did not may illuminate how Zika crosses the placenta, how it enters the brain, and whether any genetic mutations make a fetus more resistant or susceptible to Zika infection.

Until recently, Brazil’s Zika twins seemed to follow a pattern, said Mayana Zatz, a geneticist and molecular biologist at the University of São Paulo. The cases include two sets of identical twins, and both babies in each pair have microcephaly, she said. There are also six sets of fraternal twins, in which one twin has microcephaly, while the other appears unaffected.

Since identical twins share one placenta while fraternal twins almost always have separate placentas, Dr. Zatz and other experts suggested that the Zika virus may have penetrated one placenta and not the other.

Walking home after their two-hour bus ride to attend medical appointments.Adriana Zehbrauskas for The New York Times

Perhaps the virus entered through a weak spot in one placenta’s membrane, said Dr. Ernesto Marques, an infectious disease expert at the University of Pittsburgh and the Oswaldo Cruz Foundation in Recife, Brazil. Or if one fetus “kicked the placenta,” he said, inflammation from that bruise on the membrane could become a portal.

But one set of twins has broken the pattern. Those twins are fraternal and had separate placentas — but both have microcephaly and other Zika complications. “The boy is more affected than the girl, but both are severe,” Dr. Zatz said.

That case complicates the theory. Dr. Vanessa van der Linden, who helped discover that Zika causes microcephaly and has treated some of the twins, said one explanation might be that in some fraternal cases Zika crossed both placentas, but the twins had genetic differences that influenced why only one became infected or “why the babies reacted differently to the virus.”

Dr. Marques suggested another possibility: that an impaired twin was exposed to Zika before the mother’s body or the placenta developed immune responses against the virus and that the second fetus was infected slightly later.

Ms. Ribeiro took João Lucas for a hearing test. Adriana Zehbrauskas for The New York Times

“It should reach both at an equal time,” he said. “However, if the virus hit one of the babies before the mother actually had developed protective immune responses, you have a problem.”

Dr. Zatz’s lab has drawn blood from affected and unaffected twins, and is growing brain cells from their stem cells. She is testing to see which of those cells are susceptible to Zika infection. That could show whether some twins have genetic predispositions that make Zika infection more likely. Ultimately, Dr. Zatz expects to find an interplay of factors that can vary in each twin pregnancy. “I believe,” she said, “the explanation will be complex.”

For now, why João Lucas is devastated by the virus and his sister is not remains a mystery.

When João Lucas and his twin sister were born in August 2015, their mother, Neide Maria Ferreira da Silva, was unaware he had microcephaly or brain damage, she said. He was born first and was temporarily placed in an oxygen chamber because of breathing problems. And the maternity hospital’s “deformation doctor,” a physician specializing in newborns with deficiencies, recommended he see a geneticist. But Ms. da Silva thought any problems would be mild, she said.

She had already given birth to 10 children, starting when she was 17. It took a month before she brought João Lucas to the geneticist, who said “his brain, it wasn’t like ours,” Ms. da Silva, 42, recalled. “It was going to be always very small.”

Ms. da Silva holding Ana Vitória, right, and Ms. Ribeiro with Joao Lucas, left. Ms. Ribeiro is the boy’s guardian. Adriana Zehbrauskas for The New York Times

She was shocked. “I didn’t feel sad or upset,” she said. “I thought about how it was going to be when he grows up” and realized “I will have to take care of him more than the other kids.”

But his symptoms began overwhelming her. “He would fall asleep, and five minutes later he would start screaming,” she said.

Ms. da Silva was especially alarmed by João Lucas’s seizures, which made him “get purple” and look “like his eyes were going to jump out.”

Sometimes he became so agitated, he would scratch himself in the face, Ms. da Silva said. “Blood would come out.”

Ms. Ribeiro giving João Lucas a massage. The boy sometimes became so agitated, he would scratch himself in the face.Adriana Zehbrauskas for The New York Times

Unable to cope with his care, Ms. da Silva started bringing him to a neighbor’s cousin, who began caring for him. The caregiver, Valéria Gomes Ribeiro, 46, brought the baby to his first appointment with a neurologist. The doctor prescribed clonazepam, an anti-anxiety drug, to calm him, but Ms. Ferreira still found that when João Lucas was home, something often went wrong. He developed pneumonia and eating problems, even what she called “an emotional fever” because he seemed to miss Ms. Ribeiro, Ms. da Silva said.

Ms. da Silva’s 11-year-old daughter became pregnant and had an abortion, prompting a child protection agency visit. After Ms. da Silva told the caseworker that a friend was caring for her Zika baby, the agency investigated and initiated proceedings to remove João Lucas from her home. To keep him from being placed in a shelter, both women and the state agreed that João Lucas would live with Ms. Ribeiro, while Ana Vitória stayed with Ms. da Silva. Under court order, João Lucas spends Sundays at his biological mother’s house.

Ms. Ribeiro, who has adorned João Lucas with a bracelet and necklace hung with a good-luck charm called a “figa,” tries to keep up with his many appointments. They include visits with a psychologist who shows João Lucas a panel of black and white squares to stimulate vision and rubs him with a sponge studded with Popsicle sticks to stimulate touch.

On a visit last fall to Ms. Ribeiro’s emerald green house on a dirt street, where the 23rd psalm hangs on a yellow wall, Ana Vitória toddled around, clutching a piece of spongy cake with one hand, thumping a table with the other. Reaching for her brother’s mouth, she touched the green tape that therapists apply around his lips, fingers, back and chin to relax tight muscles. Ms. da Silva waved a rattle before João Lucas, but he did not respond.

So far, his sister — like the other fraternal twins without obvious brain damage — appears unimpaired, but doctors are monitoring her and the others. At Ana Vitória’s one-year exam, she was slightly behind developmentally. Her vocabulary was limited and she was slow to point to her mother when the doctor asked, Ms. da Silva said.

That could be unrelated to Zika, but, she noted, “The doctor never said it’s 100 percent sure that she doesn’t have a problem.”

Source:www.nytimes.com

One Day, a Machine Will Smell Whether You’re Sick

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Blindfolded, would you know the smell of your mom, a lover or a co-worker? Not the smells of their colognes or perfumes, not of the laundry detergents they use — the smells of them?

Each of us has a unique “odorprint” made up of thousands of organic compounds. These molecules offer a whiff of who we are, revealing age, genetics, lifestyle, hometown — even metabolic processes that underlie our health.

Ancient Greek and Chinese medical practitioners used a patient’s scent to make diagnoses. Modern medical research, too, confirms that the smell of someone’s skin, breath and bodily fluids can be suggestive of illness. The breath of diabetics sometimes smells of rotten apples, experts report; the skin of typhoid patients, like baking bread.

But not every physician’s nose is a precision instrument, and dogs, while adept at sniffing out cancer, get distracted. So researchers have been trying for decades to figure out how to build an inexpensive odor sensor for quick, reliable and noninvasive diagnoses.

The field finally seems on the cusp of succeeding.

“You’re seeing a convergence of technology now, so we can actually run large-scale clinical studies to get the data to prove odor analysis has real utility,” said Billy Boyle, co-founder and president of operations at Owlstone, a manufacturer of chemical sensors in Cambridge, England.

Mr. Boyle, an electronics engineer, formed the company with two friends in 2004 to develop sensors to detect chemical weapons and explosives for customers, including the United States government. But when Mr. Boyle’s girlfriend and eventual wife, Kate Gross, was diagnosed with colon cancer in 2012, his focus shifted to medical sensors, with an emphasis on cancer detection.

Ms. Gross died at the end of 2014. That she might still be alive if her cancer had been detected earlier, Mr. Boyle said, continues to be a “big motivator.”

Owlstone has raised $23.5 million to put its odor analysis technology into the hands of clinicians. Moreover, Britain’s National Health Service is funding a 3,000-subject clinical trial to test Owlstone’s sensor to diagnose lung cancer.

The sensor is a silicon chip stacked with various metal layers and tiny gold electrodes. While it looks like your mobile phone’s SIM card, it works like a chemical filter.

The molecules in an odor sample are first ionized — given a charge — and then an electric current is used to move only chemicals of diagnostic interest through the channels etched in the chip, where they can be detected.

“You can program what you want to sniff out just by changing the software,” Mr. Boyle said. “We can use the device for our own trials on colorectal cancer, but it can also be used by our partners to look for other things, like irritable bowel disease.”

The company also is conducting a 1,400-subject trial, in collaboration with the University of Warwick, to detect colon cancer from urine samples, and is exploring whether its chips can help determine the best drugs for asthmapatients by sorting through molecules in their breath.

A similar diagnostic technology is being developed by an Israeli chemical engineer, Hossam Haick, who was also touched by cancer.

“My college roommate had leukemia, and it made me want to see whether a sensor could be used for treatment,” said Mr. Haick, a professor at Technion-Israel Institute of Technology in Haifa. “But then I realized early diagnosis could be as important as treatment itself.”

His smelling machine uses an array of sensors composed of gold nanoparticles or carbon nanotubes. They are coated with ligands, molecular receptors that have a high affinity for certain biomarkers of disease found in exhaled breath.

Once these biomarkers latch onto the ligands, the nanoparticles and nanotubes swell or shrink, changing how long it takes for an electrical charge to pass between them. This gain or loss in conductivity is translated into a diagnosis.

“We send all the signals to a computer, and it will translate the odor into a signature that connects it to the disease we exposed to it,” Mr. Haick said.

With artificial intelligence, he said, the machine becomes better at diagnosing with each exposure. Rather than detecting specific molecules that suggest disease, however, Mr. Haick’s machine sniffs out the overall chemical stew that makes up an odor.

It’s analogous to smelling an orange: Your brain doesn’t distinguish among the chemicals that make up that odor. Instead, you smell the totality, and your brain recognizes all of it as an orange.

Mr. Haick and his colleagues published a paper in ACS Nano last December showing that his artificially intelligent nanoarray could distinguish among 17 different diseases with up to 86 percent accuracy.

There were a total of 1,404 participants in the trial, but the sample sizes for each disease were quite small. And the machine was better at distinguishing among some diseases than others.

In the United States, a team of researchers from the Monell Chemical Senses Center and the University of Pennsylvania received an $815,000 grant in February from the Kleburg Foundation to advance work on a prototype odor sensor that detects ovarian cancer in samples of blood plasma.

The team chose plasma because it is somewhat less likely than breath or urine to be corrupted by confounding factors like diet or environmental chemicals, including cleaning products or pollution.

Instead of ligands, their sensors rely on snippets of single-strand DNA to do the work of latching onto odor particles.

“We are trying to make the device work the way we understand mammalian olfaction works,” said Charlie Johnson, director of the Nano/Bio Interface Center at the University of Pennsylvania, who is leading the fabrication effort. “DNA gives unique characteristics for this process.”

In addition to these groups, teams in Austria, Switzerland and Japan also are developing odor sensors to diagnose disease.

“I think the fact that you’re seeing so much activity both in commercial and academic settings shows that we’re getting a lot closer,” said Cristina Davis, a biomedical engineer and professor at the University of California, Davis, who also is helping to develop an odor sensor to diagnose disease.

“My estimate is it’s a three- to five-year time frame” before such tools are available to clinicians, she added.

The researchers may be competing intensely, but all see possibilities for saving lives.

“There’s a lot of good work going on out there,” Mr. Johnson said. “It will be interesting to see who comes out on top.”

Source:https://www.nytimes.com