Archive for the ‘UC Davis’ Category

placenta

After most pregnancies, the placenta is thrown out, having done its job of nourishing and supporting the developing baby.

But a new study raises the possibility that analyzing the placenta after birth may provide clues to a child’s risk for developing autism. The study, which analyzed placentas from 217 births, found that in families at high genetic risk for having an autistic child, placentas were significantly more likely to have abnormal folds and creases.

“It’s quite stark,” said Dr. Cheryl K. Walker, an obstetrician-gynecologist at the Mind Institute at the University of California, Davis, and a co-author of the study, published in the journal Biological Psychiatry. “Placentas from babies at risk for autism, clearly there’s something quite different about them.”

Researchers will not know until at least next year how many of the children, who are between 2 and 5, whose placentas were studied will be found to have autism. Experts said, however, that if researchers find that children with autism had more placental folds, called trophoblast inclusions, visible after birth, the condition could become an early indicator or biomarker for babies at high risk for the disorder.

“It would be really exciting to have a real biomarker and especially one that you can get at birth,” said Dr. Tara Wenger, a researcher at the Center for Autism Research at Children’s Hospital of Philadelphia, who was not involved in the study.

The research potentially marks a new frontier, not only for autism, but also for the significance of the placenta, long considered an after-birth afterthought. Now, only 10 percent to 15 percent of placentas are analyzed, usually after pregnancy complications or a newborn’s death.

Dr. Harvey J. Kliman, a research scientist at the Yale School of Medicine and lead author of the study, said the placenta had typically been given such little respect in the medical community that wanting to study it was considered equivalent to someone in the Navy wanting to scrub ships’ toilets with a toothbrush. But he became fascinated with placentas and noticed that inclusions often occurred with births involving problematic outcomes, usually genetic disorders.

He also noticed that “the more trophoblast inclusions you have, the more severe the abnormality.” In 2006, Dr. Kliman and colleagues published research involving 13 children with autism, finding that their placentas were three times as likely to have inclusions. The new study began when Dr. Kliman, looking for more placentas, contacted the Mind Institute, which is conducting an extensive study, called Marbles, examining potential causes of autism.

“This person came out of the woodwork and said, ‘I want to study trophoblastic inclusions,’ ” Dr. Walker recalled. “Now I’m fairly intelligent and have been an obstetrician for years and I had never heard of them.”

Dr. Walker said she concluded that while “this sounds like a very smart person with a very intriguing hypothesis, I don’t know him and I don’t know how much I trust him.” So she sent him Milky Way bar-size sections of 217 placentas and let him think they all came from babies considered at high risk for autism because an older sibling had the disorder. Only after Dr. Kliman had counted each placenta’s inclusions did she tell him that only 117 placentas came from at-risk babies; the other 100 came from babies with low autism risk.

She reasoned that if Dr. Kliman found that “they all show a lot of inclusions, then maybe he’s a bit overzealous” in trying to link inclusions to autism. But the results, she said, were “astonishing.” More than two-thirds of the low-risk placentas had no inclusions, and none had more than two. But 77 high-risk placentas had inclusions, 48 of them had two or more, including 16 with between 5 and 15 inclusions.

Dr. Walker said that typically between 2 percent and 7 percent of at-risk babies develop autism, and 20 percent to 25 percent have either autism or another developmental delay. She said she is seeing some autism and non-autism diagnoses among the 117 at-risk children in the study, but does not yet know how those cases match with placental inclusions.

Dr. Jonathan L. Hecht, associate professor of pathology at Harvard Medical School, said the study was intriguing and “probably true if it finds an association between these trophoblast inclusions and autism.” But he said that inclusions were the placenta’s way of responding to many kinds of stress, so they might turn out not to be specific enough to predict autism.

Dr. Kliman calls inclusions a “check-engine light, a marker of: something’s wrong, but I don’t know what it is.”

That’s how Chris Mann Sullivan sees it, too. Dr. Sullivan, a behavioral analyst in Morrisville, N.C., was not in the study, but sent her placenta to Dr. Kliman after her daughter Dania, now 3, was born. He found five inclusions. Dr. Sullivan began intensive one-on-one therapy with Dania, who has not been given a diagnosis of autism, but has some relatively mild difficulties.

“What would have happened if I did absolutely nothing, I’m not sure,” Dr. Sullivan said. “I think it’s a great way for parents to say, ‘O.K., we have some risk factors; we’re not going to ignore it.’ ”

http://www.nytimes.com/2013/04/25/health/study-ties-autism-risk-to-creases-in-placenta.html?hpw&_r=0

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.

original

When cosmetic surgeon Allan Wu first heard the woman’s complaint, he wondered if she was imagining things or making it up. A resident of Los Angeles in her late sixties, she explained that she could not open her right eye without considerable pain and that every time she forced it open, she heard a strange click—a sharp sound, like a tiny castanet snapping shut. After examining her in person at The Morrow Institute in Rancho Mirage, Calif., Wu could see that something was wrong: Her eyelid drooped stubbornly, and the area around her eye was somewhat swollen. Six and a half hours of surgery later, he and his colleagues had dug out small chunks of bone from the woman’s eyelid and tissue surrounding her eye, which was scratched but largely intact. The clicks she heard were the bone fragments grinding against one another.

About three months earlier the woman had opted for a relatively new kind of cosmetic procedure at a different clinic in Beverly Hills—a face-lift that made use of her own adult stem cells. First, cosmetic surgeons had removed some the woman’s abdominal fat with liposuction and isolated the adult stem cells within—a family of cells that can make many copies of themselves in an immature state and can develop into several different kinds of mature tissue. In this case the doctors extracted mesenchymal stem cells—which can turn into bone, cartilage or fat, among other tissues—and injected those cells back into her face, especially around her eyes. The procedure cost her more than $20,000, Wu recollects. Such face-lifts supposedly rejuvenate the skin because stem cells turn into brand-new tissue and release chemicals that help heal aging cells and stimulate nearby cells to proliferate.

During the face-lift her clinicians had also injected some dermal filler, which plastic surgeons have safely used for more than 20 years to reduce the appearance of wrinkles. The principal component of such fillers is calcium hydroxylapatite, a mineral with which cell biologists encourage mesenchymal stem cells to turn into bone—a fact that escaped the woman’s clinicians. Wu thinks this unanticipated interaction explains her predicament. He successfully removed the pieces of bone from her eyelid in 2009 and says she is doing well today, but some living stem cells may linger in her face. These cells could turn into bone or other out-of-place tissues once again.

Dozens, perhaps hundreds, of clinics across the country offer a variety of similar, untested stem cell treatments for both cosmetic and medical purposes. Costing between $3,000 and $30,000, the treatments promise to alleviate everything from wrinkles to joint pain to autism. The U.S. Food and Drug Administration (FDA) has not approved any of these treatments and, with a limited budget, is struggling to keep track of all the unapproved therapies on the market. At the same time, pills, oils, creams and moisturizers that allegedly contain the right combination of ingredients to mobilize the body’s resident stem cells, or contain chemicals extracted from the stem cells in plants and animals, are popping up in pharmacies and online. There’s Stem Cell 100, for example, MEGA STEM and Apple Stem Cell Cloud Cream. Few of these cosmetics have been properly tested in published experiments, yet the companies that manufacture them say they may heal damaged organs, slow or reverse natural aging, restore youthful energy and revitalize the skin. Whether such cosmetics may also produce unintended and potentially harmful effects remains largely unexamined. The increasing number of untested and unauthorized stem cell treatments threaten both people who buy them and researchers hoping to conduct clinical trials for promising stem cell medicine.

So far, the FDA has only approved one stem cell treatment: a transplant of bone marrow stem cells for people with the blood cancer leukemia. Among the increasing number of unapproved stem cell treatments, some clearly violate the FDA’s regulations whereas others may technically be legal without its approval. In July 2012, for example, the U.S. District Court upheld an injunction brought by the FDA against Colorado-based Regenerative Sciences to regulate just one of the company’s several stem cell treatments for various joint injuries as an “unapproved biological drug product.” The decision hinged on what constitutes “minimal manipulation” of cells in the lab before they are injected into patients. In the treatment that the FDA won the right to regulate, stem cells are grown and modified in the lab for several weeks before they are returned to patients; in Regenerative Sciences’s other treatments, patients’ stem cells are extracted and injected within a day or two. Regenerative Sciences now offers the legally problematic treatment at a Cayman Island facility.

Many stem cell cosmetics reside in a legal gray area. Unlike drugs and “biologics” made from living cells and tissues, cosmetics do not require premarket approval from the FDA. But stem cell cosmetics often satisfy the FDA’s definitions for both cosmetics and drugs. In September 2012 the FDA posted a letter on its Web site warning Lancôme, a division of L’Oréal, that the way it describes its Genifique skin care products qualify the creams and serums as unapproved drugs: they are supposed to “boost the activity of genes,” for example, and “improve the condition of stem cells.” Other times the difference between needing or not needing FDA approval comes down to linguistic nuance—the difference between claiming that a product does something or appears to do something.

Personal Cell Sciences, in Eatontown, N.J., sells some of the more sophisticated stem cell–based cosmetics: an eye cream, moisturizer and serum infused with chemicals derived from a consumer’s own stem cells. According to its website and marketing materials, these products help “make skin more supple and radiant,” “reduce the appearance of fine lines and wrinkles around the eyes and lips,” “improve cellular renewal” and “stimulate cell turnover for renewed texture and tone.” In exchange for $3,000, Personal Cell Sciences will arrange for a participating physician to vacuum about 60 cubic centimeters (one quarter cup) of a customer’s fat from beneath his or her skin and ship it on ice to American CryoStem Corp. in Red Bank, N.J., where laboratory technicians isolate and grow the customer’s mesenchymal stem cells to around 30 million strong. Half these cells are frozen for storage; from the other half, technicians harvest hundreds of different kinds of exuded growth factors and cytokines—molecules that help heal damaged cells and encourage cells to divide, among other functions. These molecules are mixed with many other ingredients—including green tea extract, caffeine and vitamins—to create the company’s various “U Autologous” skin care products, which are then sold back to the consumer for between $400 and $800. When the customer wants a refill, technicians thaw some of the frozen cells, collect more cytokines and produce new bottles of cream.

In an unpublished safety trial sponsored by Personal Cell Sciences, Frederic Stern of the Stern Center for Aesthetic Surgery in Bellevue, Wash., and his colleagues monitored 19 patients for eight weeks as they used the U Autologous products on the left sides of their faces. A computer program meant to objectively analyze photos of the volunteers’ faces measured an average of 25.6 percent reduction in the volume of wrinkles on the treated side of the face. Analysis of tissue biopsies revealed increased levels of the protein elastin, which helps keep skin taut, and no signs of unusual or cancerous cell growth.

Supposedly, the primary active ingredients in the U Autologous skin care products are the hundreds of different kinds of cytokines they contain. Cytokines are a large and diverse family of proteins that cells release to communicate with and influence one another. Cytokines can stimulate cell division or halt it; they can suppress the immune system or provoke it; they can also change a cell’s shape, modulate its metabolism and force it to migrate from one location to another like a cowboy corralling cattle. Researchers have only named and characterized some of the many cytokines that stem cells secrete. Some of these molecules certainly help repair damaged cells and promote cell survival. Others seem to be involved in the development of tumors. In fact, some recent evidence suggests that the cytokines released by mesenchymal stem cells can trigger tumors by accelerating the growth of dormant cancer cells. Personal Cell Sciences does not pick and choose among the cytokines exuded by its customers’ stem cells—instead, it dumps them all into its skin care products.

Based on the available evidence so far, topical creams containing cytokines from stem cells pose far less risk of cancer than living stem cells injected beneath the skin. But scientists do not yet know enough about stem cell cytokines to reliably predict everything they will do when rubbed into the skin; they could interact with healthy skin cells in a completely unexpected way, just as the unintended interplay between calcium hydroxylapatite and stem cells produced bones in the Los Angeles woman’s eye. Stern acknowledges that unusual tissue growth is a concern for any treatment based on stem cells and the chemicals they release. “Down the line, we want to continue watching that,” he says. Unlike many other clinics, he and his colleagues have been keeping tabs on their patients through regular follow-ups. John Arnone, CEO of American CryoStem and founder of Personal Cell Sciences, says the fact that U Autologous skin care products contain such a diversity of cytokines does not bother him: “I’ve seen worse things out there. I’ve been putting this formulation for almost a year on myself prior to the study. I’m the best guinea pig here.”

Beyond the considerable risks to consumers, unapproved stem cell treatments also threaten the progress of basic research and clinical trials needed to establish safe stem cell therapies for serious illnesses. By harvesting stem cells, subsequently nourishing them in the lab and transplanting them back inside the human body, scientists hope to improve treatment for a variety of medical conditions, including heart failure, neurodegenerative disorders like Parkinson’s, and spinal cord injuries—essentially any condition in which the body needs new cells and tissues. Researchers are investigating many stem cell therapies in ongoing, carefully controlled clinical trials. Some of the principal questions entail which of the many kinds of stem cells to use; how to safely deliver stem cells to patients without stimulating tumors or the growth of unwanted tissues; and how to prevent the immune system from attacking stem cells provided by a donor. Securing funding for such research becomes all the more difficult if shortcuts taken by private clinics and cosmetic manufacturers—and the subsequent botched procedures and unanticipated consequences—imprint a stigma on stem cells.

“Many of us are super excited about stem cells, but at same time we have to be really careful,” says Paul Knoepfler, a cell biologist at the University of California, Davis, who regularly blogs about the regulation of stem cell treatments. “These aren’t your typical drugs. You can stop taking a pill and the chemicals go away. But if you get stem cells, most likely you will have some of those cells or their effects for the rest of your life. And we simply don’t know everything they are going to do.”

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https://www.scientificamerican.com/article.cfm?id=stem-cell-cosmetics&WT.mc_id=SA_emailfriend

Thanks to Dr. Nakamura for bringing this to the attention of the It’s Interesting community.

sn-autism

 

A drug used for decades to treat high blood pressure and other conditions has shown promise in a small clinical trial for autism. The drug, bumetanide, reduced the overall severity of behavioral symptoms after 3 months of daily treatment. The researchers say that many parents of children who received the drug reported that their children were more “present” and engaged in social interactions after taking it. The new findings are among several recent signs that treatments to address the social deficits at the core of autism may be on the horizon.

Several lines of evidence suggest that autism interferes with the neurotransmitter GABA, which typically puts a damper on neural activity. Bumetanide may enhance the inhibitory effects of GABA, and the drug has been used safely as a diuretic to treat a wide range of heart, lung, and kidney conditions. In the new study, researchers led by Yehezkel Ben-Ari at the Mediterranean Institute of Neurobiology in Marseille, France, recruited 60 autistic children between the ages of 3 and 11 and randomly assigned them to receive either a daily pill of bumetanide or a placebo. (Neither the children’s parents nor the researchers who assessed the children knew who received the actual drug.)

As a group, those who got bumetanide improved by 5.6 points on a 60-point scale that’s often used to assess behaviors related to autism, the researchers report today in Translational Psychiatry. That was enough to nudge the group average just under the cutoff for severe autism and into the mild to medium category. The study did not look directly at whether the drug improved all symptoms equally or some more than others. “We have some indications that the symptoms particularly ameliorated with bumetanide are the genuine core symptoms of autism, namely communication and social interactions,” Ben-Ari says. More work will be needed to verify that impression. Ben-Ari says his team is now preparing for a larger, multicenter trial in Europe.

The current study already looks interesting to some. “It’s enough to make me think about trying it in a few of my autism patients who haven’t responded to other interventions,” says Randi Hagerman, a pediatrician who studies neurodevelopmental disorders at the University of California, Davis. Social interactions tend to be reinforcing, Hagerman adds, so getting an autistic child to start interacting more can have a positive effect on subsequent brain development.

Other drugs have recently shown promise for autism. In September, Hagerman and colleagues reported that arbaclofen, a drug that stimulates a type of GABA receptor, reduced social avoidance in people with fragile X syndrome, a genetic disorder that shares many features with autism. Many researchers are also hopeful about clinical trials under way with drugs that block certain receptors for glutamate, the main neurotransmitter in the brain that excites neural activity. Results from those trials should come out next year.

All of this work, including the new study, suggests that drugs that reduce neural excitation by blocking glutamate or enhance inhibition by boosting GABA may be helpful for treating autism, says Elizabeth Berry-Kravis, a pediatric neurologist at Rush University in Chicago, Illinois, and a collaborator on the recent arbaclofen study. “There seems to be this imbalance between excitation and inhibition in people with autism.”

That’s a potentially game-changing insight. Now doctors can only prescribe drugs that treat individual symptoms of autism rather than the underlying cause of the disorder, Berry-Kravis says. Doctors often prescribe antipsychotic drugs to reduce irritability, for example, but those drugs don’t address the social and communication problems at the heart of the disorder. “It’s exciting that now we’re thinking about the underlying mechanisms and treating those.”

http://news.sciencemag.org/sciencenow/2012/12/diuretic-drug-offers-latest-hope.html

 

 

 

 

 

As the number of children with autism has risen dramatically over the past couple of decades, experts have learned that the earlier a child gets diagnosed, the earlier specialized therapy can be initiated, which can significantly improve outcomes.

Now researchers have been able to show that a particular type of behavioral therapy called the Early Start Denver Model (ESDM) not only improves autism symptoms, but actually normalizes brain activity and improves social behavior.

Autism is a neurodevelopmental disorder that starts to become very apparent around age 3. The main signs and symptoms of autism involve communication, social interactions and repetitive behaviors. According to the latest statistics from the U.S. Centers for Disease Control and Prevention, one in 88 children currently is diagnosed with autism, including one in 54 boys.

“Early intervention alters the trajectory of the brain and social development in children with autism,” says Geraldine Dawson, the lead study author who developed the ESDM therapy along with study co-author Sally Rogers.

Dawson was a researcher at the University of Washington when she helped devise ESDM; she’s now the chief science officer for the advocacy and research group Autism Speaks and a professor at the University of North Carolina. Rogers is a professor and researcher at the University of California Davis MIND Institute.

ESDM therapy uses teaching methods from ABA ,or applied behavioral analysis, the traditional one-on-one interaction between a child and the therapist.

But rather than sitting at a desk next to the child — where a teacher or therapist breaks down complex tasks into small components and gives tangible reinforcements — children receiving ESDM are sitting on the floor, playing with their therapist or parents.

It can be done just about anywhere, and Dawson says the play-based method of engaging a child helps him or her develop a social relationship.

The study began with 48 children in Seattle and Sacramento, California, who were between who were between 1 1/2 and 2 1/2 years old. Half of the children received a total of 20 hours of ESDM therapy over five days a week.

But since parents can be taught the methods in just a few hours, they could engage their children using the ESDM method as well. The other half of the toddlers received community-based interventions, which included in some individual therapist sessions and some day care-based sessions. The number of hours spent with therapists was the same in both groups.

Three years ago, Rogers and Dawson published their first findings from this study and found that children receiving ESDM therapy increased their IQ and language skills three times more than children in the community-intervention group.

That in itself was “very significant,” says Dr. Thomas Insel, director of the National Institute of Mental Health, because it proved that early detection and intervention leads to improved outcomes.

In their latest study, published Friday in the Journal of the American Academy of Child & Adolescent Psychiatry, Rogers and Dawson show what parts of a child’s brain are active after two years of therapy, compared to typically developing children, using an EEG (electroencephalogram). In an EEG, electrical activity in different parts of the brain is measured using electrodes that attached to the child’s head.

“If the child wiggles too much, the data is not interpretable,” says Dawson.

In the end, researchers could only get 60% of the children to sit still enough to get usable EEG results, she says, but that was true in both the group of children with autism and those without.

Fifteen children in the EDSM group, 14 in the community intervention group and 17 typically developing children underwent EEGs while looking at pictures of faces (social stimuli) vs. pictures of toys (nonsocial stimuli).

Technicians measuring the brain activity had no idea which children had autism and which did not.

“Children who received ESDM now showed a normal (brain) response, identical to typical 4-year-olds,” Dawson tells CNN. That wasn’t the case with most children who didn’t have ESDM therapy.

Babies are naturally drawn to people and faces, and their brains show greater responses when they look at a face, compared to an object or a toy, Dawson says.

But in young and even older children with autism, the opposite happens. The part of the brain that should be responding to a face or social activity doesn’t light up, but the part of the brain that responds to objects is more active.

Insel says this study shows that the ESDM form of therapy “not only changes behavior, it changes the brain.”

The exact cause, or more precisely causes, of autism are unknown and there is no cure.

Parents and pediatricians are urged to look for early signs of autism including: little or no eye contact, lack of or delay of spoken language, repetitive use of language and behaviors and persistent fixation on parts of objects.

Since 2007, the American Academy of Pediatrics recommends that pediatricians screen 18- and 24-month-old toddlers for signs of autism.

When something is wrong in the brain — not just in autism, but also in diseases like Alzheimer’s and Parkinson’s — what’s causing the disease is occurring much earlier than when symptoms appear, Insel explains.

Based on the new findings, perhaps using EEGs to measure this type of brain activity could be a biomarker for autism, he says. A biomarker is a distinct characteristic that indicates a particular condition.

Measuring a baby’s brain activity as early as 3 and 6 months could identify changes in the brain before changes in behavior are noticed, he says, and therapy could begin even earlier.

The ESDM model could be applied as early as 12 months, say Dawson and Rogers.

More research will probably have to be done to confirm the biomarker. So until there is a definitive test for diagnosing autism, Dawson says this it’s even more important that pediatricians screen children for autism as early as possible.

“The average age of diagnosis is still 4 and 5 and even older in minority groups,” she says. “We really need to close the gap.”

Autism Speaks has many tools on its website to help parents see what a child with autism looks like compared to a typically developing child. There are also many tool kits to help families of children with autism.

http://www.cnn.com/2012/10/31/health/autism-therapy-brain/index.html?hpt=hp_t3

Scientists say they’ve found the gene that sets the common tabby pattern – stripes or blotches.

It’s one of several genes that collaborate to create the distinctive design of a cat’s coat, and it’s the first of the pattern genes to be identified.

Cats with narrow stripes, the so-called “mackerel” pattern, have a working copy of the gene. But if a mutation turns the gene off, the cat ends up with the blotchy “classic” pattern, researchers reported online last week in the journal Science.

It’s called “classic” because “cat lovers really like the blotched pattern,” said one of the authors, Greg Barsh. He works at both Stanford University and the HudsonAlpha Institute of Biotechnology in Huntsville, Ala.

The research team, which included scientists from the National Cancer Institute, examined DNA from wild cats in California to identify the gene.

They also found that a mutation in the same gene produces the blotches and stripes of the rare “king” cheetah, rather than the spots most cheetahs have.

Leslie Lyons, a cat geneticist who studies coat color traits at the University of California, Davis, but didn’t participate in the new work, agreed that the research has identified the tabby’s stripes-versus-blotches gene. She noted that mysteries remain, such as just what genetic machinery gives a tabby spots.

 

When western scrub jays encounter a dead bird, they call out to one another and stop foraging.

The jays then often fly down to the dead body and gather around it, scientists have discovered.

The behaviour may have evolved to warn other birds of nearby danger, report researchers in California, who have published the findings in the journal Animal Behaviour.

The revelation comes from a study by Teresa Iglesias and colleagues at the University of California, Davis, US.

They conducted experiments, placing a series of objects into residential back yards and observing how western scrub jays in the area reacted.

The objects included different coloured pieces of wood, dead jays, as well as mounted, stuffed jays and great horned owls, simulating the presence of live jays and predators.

The jays reacted indifferently to the wooden objects.

But when they spied a dead bird, they started making alarm calls, warning others long distances away.

The jays then gathered around the dead body, forming large cacophonous aggregations. The calls they made, known as “zeeps”, “scolds” and “zeep-scolds”, encouraged new jays to attend to the dead.

The jays also stopped foraging for food, a change in behaviour that lasted for over a day.

When the birds were fooled into thinking a predator had arrived, by being exposed to a mounted owl, they also gathered together and made a series of alarm calls.

They also swooped down at the supposed predator, to scare it off. But the jays never swooped at the body of a dead bird.

The birds also occasionally mobbed the stuffed jays; a behaviour they are known to do in the wild when they attack competitors or sick birds.

The fact that the jays didn’t react to the wooden objects shows that it is not the novelty of a dead bird appearing that triggers the reaction.

The results show that “without witnessing the struggle and manner of death”, the researchers write, the jays see the presence of a dead bird as information to be publicly shared, just as they do the presence of a predator.

Spreading the message that a dead bird is in the area helps safeguard other birds, alerting them to danger, and lowering their risk from whatever killed the original bird in the first place, the researchers say.

Other animals are known to take notice of their dead.

Giraffes and elephants, for example, have been recorded loitering around the body of a recently deceased close relative, raising the idea that animals have a mental concept of death, and may even mourn those that have passed.

http://www.bbc.co.uk/nature/19421217