Psychotropics Still Commonly Prescribed for Autism.


Children with autism spectrum disorder (ASD) are still commonly prescribed psychotropic medications alone and in combinations despite “minimal evidence” of their effectiveness, new research suggests.

A retrospective study of more than 33,000 children with ASD showed that 64% had been prescribed at least 1 psychotropic. In addition, 35% had been prescribed 2 or more classes of psychotropics concurrently, and 15% had been prescribed 3 or more classes.

“Our results indicate the need to develop standards of care around the prescription of psychotropic medications to children with ASD,” write Donna Spencer, PhD, from OptimumInsight, Life Sciences, in Eden Prairie, Minnesota, and colleagues.

They note that the study participants who had comorbidities such as bipolar disorder or attention-deficit disorders, who were older, or who had visited a psychiatrist were significantly more likely to use psychotropics.

New standards of care should be based on “a coordinated, multidisciplinary approach to improving the health and quality of life of children with ASD and their families,” write the investigators.

The study was published online October 21 in Pediatrics.

Few Treatment Options

As reported at the time by Medscape Medical News, a systematic review of 33 randomized controlled trials, which was published in 2011, showed that only 3 psychotropics (all of which were antipsychotics) “have established evidence” in treating symptoms of ASD.

These included aripiprazole and risperidone for irritability and hyperactivity, aripiprazole for stereotypy, and haloperidol for negative behavioral symptoms. Promising evidence of benefit was shown for methylphenidate, and preliminary evidence was shown for 5 other agents, including naltrexone and atomoxetine.

However, “the humbling or sobering news is that we still have no medicines that treat the core features of autism — social/interaction and language impairments and repetitive behaviors,” said Matthew Siegel, MD, medical director of the developmental disorders program at Spring Harbor Hospital, Maine Medical Center, in Westbrook, at the time.

Yet other studies have shown “increasing rates of psychotropic use and [polypharmacy] among children overall” as well as in children with ASD, note the current investigators.

Because there is a wide variance in use estimates of psychotropic medications and because many reports are based on a period of 1 year or less, are based on parent reports, and include small sample sizes, the researches sought to conduct a study that answered these concerns.

They assessed data from medical and pharmacy claims for 33,565 insured children and adolescents younger than 21 years with ASD (82% boys; 60% between the ages of 6 and 10 years, 22% between the ages of 11 and 17 years, 17% between the ages of 0 and 1 year).

Claims for all participants had been made at least 6 months prior to baseline, and all had at least 6 months of continuous care between January 2001 and December 2009.

For this study, the psychotropic medication classes included antidepressants, both stimulants and nonstimulants for treating attention-deficit disorder (ADD), antipsychotics, anxiolytics, lithium, anticholinergics, and anticonvulsants/antiepileptics.

“Polypharmacy was defined as at least 1 episode of multiclass polypharmacy,” explain the investigators, noting that “an episode of multiclass polypharmacy” denoted prescriptions that overlapped 2 or more classes for at least 30 days.

Increasing Use

Results showed that 63.56% of the participants had any psychotropic use, whereas 34.36% showed evidence of multiclass polypharmacy.

Psychotropic or polypharmacy use increased with the age of the children. A total of 34% of the 0- to 1-year age group had use of any psychotropic, and 10% had polypharmacy use.

These numbers jumped dramatically to 64% and 32%, respectively, for those in the 2- to 10-year age group; to 84% and 57% for those in the 11- to 17-year age group; and to 87% and 62% for those in the 18- to 20-year age group.

Of those in the polypharmacy subgroup, total episodes of multiclass polypharmacy averaged 5.63 per child. The average maximum number of medications per episode was 2.6, and the average maximum number of classes per episode was 3.3.

In addition, 10.4% of the entire study group had 3-class polypharmacy, and 4.5 had polypharmacy with 4 or more classes.

“Common class combinations were antidepressants and ADD medications (38% of subjects), antipsychotics and ADD medications (28%), antipsychotics and antidepressants (20%), and antipsychotic, antidepressant, and ADD medications (18%),” report the investigators.

The average total days of all episodes of polypharmacy was 525. The median was 346 days.

Interestingly, use of either psychotropics or polypharmacy was lower in the participants from the northeast and western regions of the United States and highest in the southern regions.

This raises questions “about the availability of nonpharmacologic, behaviorally based services and treatments in the south, where other health outcomes and health care services have been found to be poorer than in other parts of the country,” note the researchers.

The strongest predictor of psychotropic and polypharmacy use was having a comorbid condition, especially seizures, bipolar disorder, and ADD. Household income was not found be a significant factor.

Overall, the findings emphasize the need for more research of psychotropics in kids with ASD “to assess the value of these medications when weighed against their potential for harm,” conclude the investigators.

Source: Medscape.com

 

 

Study Shows Higher Rate of Unruptured Cerebral Aneurysm.


A large survey of adult residents of China has determined that the prevalence of unruptured cerebral aneurysms (UCAs) is 7%, that UCAs increase with age, and that they seem to be more common in women.

This prevalence rate is higher than in previous research, in some cases more than twice as high, probably at least in part because researchers used high-resolution magnetic resonance angiography (MRA) to detect UCAs, said lead author Ming-Hua Li, MD, PhD, professor and chairman of Neuro-radiology, Shanghai Jiao Tong University, China.

Of these, though, only about 8.7% were judged to be at any imminent risk for rupture, they note.

The study was published in the October 15 issue of the Annals of Internal Medicine.

High Diagnostic Accuracy

This new analysis included 4813 residents aged 35 to 75 years from 2 Shanghai districts: Changning, an economically well-developed urban area, and Zhabei, a less developed suburban area. This age group represents the range that is most clinically significant in terms of screening, said Dr. Li. Those younger than 35 years are less likely to have UCAs and those older than 75 have a shorter life expectancy, he said.

Participants completed a standard questionnaire to provide demographic information, personal and family medical history, and lifestyle risk factors, and they underwent a physical examination.

The researchers used 3-dimensional (3D) time-of-flight MRA with a voxel size of less than 0.7 mm. To evaluate UCAs, they applied 3D volume rendering and single artery highlighting. This imaging modality was proven in a previous study by the same research group to have very high diagnostic accuracy for detecting intracranial aneurysms compared with 3D digital subtraction angiography (DSA), said Dr. Li.

In the current study, 3 radiologists who were blinded to participants’ information determined the location and size of the UCAs.

UCAs were defined as abnormal focal dilatations of a cerebral artery with attenuation of the vessel wall or an infundibulum in patients without a history of subarachnoid hemorrhage (SAH). Aneurysms were categorized as less than 3 mm, 3 mm to less than 5 mm, 5 mm to less than 10 mm, or 10 mm or more.

The survey excluded UCAs with a diameter of less than 2 mm because, as Dr. Li explained, aneurysms with such a small diameter are difficult to diagnose with the spatial resolution of the imaging modality used.

Aneurysm Sites

Aneurysms were morphologically classified as regular (saccular), irregular (lobular), or fusiform. Sites were classified as internal carotid artery (including the posterior communicating artery), anterior cerebral artery (including the anterior communicating artery), middle cerebral artery (including the MI-2 bifurcation), and vertebrobasilar artery.

The researchers found that 130 men and 206 women had UCAs, with excellent interobserver agreement. The prevalence of UCAs was 7.0% (95% confidence interval, 6.3% to 7.7%).

This is a higher prevalence than in other studies, probably because the researchers used 3D high-resolution MRA, which enabled them to detect small UCAs, Dr. Li speculated. “Those small UCAs could possibly be missed on 2D invasive angiography due to overlapping,” he said. “In addition, we excluded volunteers younger than 35, who are less likely to have UCAs. This could potentially lead to higher prevalence in our survey compared to studies with a wider age range.”

The prevalence of unruptured UCAs in North America is still unknown, said Dr. Li.

The prevalence was higher in women (8.6%) than in men (5.5%) (P < .001). “We hypothesized that decreases in estrogen concentration and estrogen-receptor density may contribute to an increased risk of cerebral aneurysm development in women,” said Dr. Li.

The prevalence of UCAs increased with age and peaked at ages 55 to 64 years in both men and women. This, said Dr. Li, is in line with a meta-analysis published in Lancet Neurology in 2011.

The majority (90.2%) of the UCAs were less than 5 mm in diameter. The mean maximum diameter of the aneurysm sac was 3.5 mm, and the diameter was larger in women.

Most aneurysms (81%) were located in the internal carotid artery (ICA), with more than half (53.9%) in the C5–C6 segments of the ICA. A possible explanation for this, said the authors, is that the study excluded ruptured aneurysms, which are most often located in the anterior or posterior communicating arteries. In addition, the MRA technology allowed for visualization of more UCAs in the siphon segment of the internal carotid artery.

The researchers found that 8.7% of the detected lesions were potentially risky in that they were large, lobulated aneurysms or grew during follow-up and so may have been prone to rupture.

The patients with these aneurysms potentially in danger of rupture are being followed closely, said Dr. Li. “We currently follow up those patients annually by 3D MRA if the lesions remain stable — so no growth or daughter-sac formation. If lesion growth is detected at follow-up, we suggest further treatment accordingly.”

The study did not show an association between the prevalence of aneurysms and hypertension or cardiovascular disease. This was a cross-sectional study that mainly focused on the prevalence of UCAs, explained Dr. Li, adding that the association between risk factors such as hypertension and cardiovascular disease and development of UCAs in Chinese adults needs to be explored in other longitudinal studies.

The findings may not apply to the general population or to populations outside of China, said the authors.

No Higher

R. Loch Macdonald, MD, PhD, Keenan Endowed Chair in Surgery and head, Division of Neurosurgery, St. Michael’s Hospital, and professor of surgery, University of Toronto, Ontario, Canada, who has a special research interest in cerebral aneurysms, doesn’t believe that the prevalence of aneurysms is any higher in China than elsewhere in the world.

“I suspect they are not more common compared to other geographic regions and ethnicities or races and that the difference is due to a selected older population and more sensitive screening test,” used in the current study, said Dr. Macdonald when approached by Medscape Medical News for a comment.

He pointed to a previously published meta-analysis that found 3% of the population harbored an aneurysm, adjusted to a population with a mean age of 50 years that was 50% male, and expanded on why the numbers in the current study might be much higher.

“They may have found a higher incidence due to inclusion of only patients aged 35 to 75 years,” he added. “Second, the distribution of aneurysms includes many more very small proximal carotid aneurysms. These may not have been diagnosed as frequently before by other methods, so this new screening study may have detected more due to increased sensitivity of the screening method.”

Source:Medscape.com

Bee-friendly plants put to the test


Honeybee on lavender (c) Science Photo Library

Researchers have used an experimental garden to put pollinator-friendly plants to the test.

The University of Sussex scientists counted the number of insects visiting the plants in their garden.

They say their findings show that insect-friendly plants are just as pretty, cheap and easy to grow as less pollinator-friendly varieties.

Their results are published in the Journal of Functional Ecology.

PhD student Mihail Garbuzov used 32 different varieties of popular garden plants. These included some nectar-rich and highly scented plants he thought would be attractive to insects and some that seemed to be less attractive.

While the small-scale study did not produce an exhaustive list of the best plants for pollinating insects, the team says the data has put a number on just how many more pollinators the right plants can attract.

Mr Garbuzov told the BBC: “Some of the best plants attracted approximately 100 times as many insects as the worst.

“And the plants that are attractive to insects are not more expensive, and they’re just as pretty.”

The researchers wrote in their paper that there was “great scope for making gardens and parks more insect friendly” by selecting the right plants.

Tips for insect-friendly gardening are already available from a variety of sources, but the researchers say they are largely based on “opinion and general experience”.

The aim of this study, said Prof Francis Ratnieks, from the University of Sussex, was to “put that advice on a firmer scientific footing, by gathering information about the actual number of insects visiting the flowers to collect nectar or pollen”.

Counting bees

Honeybee on a flower (c) Ethel M Villalobos
  • Bees have different colour-detection systems from humans, and can see the world in ultraviolet. This helps them to detect the flowers they pollinate and take nectar from.
  • Pollination is essential for agriculture, as well as the reproduction of non-food flowers and plants. According to the UN Food and Agriculture Organization, pollinators including bees, birds and bats are involved in more than a third of the world’s crop production.
  • Honeybees evolved to make honey as a food source for the colony. Selective breeding of European honeybees by humans has produced colonies that make excess honey for us to harvest.

The researchers gathered their data simply by visiting each of the patches of flowers every day over two summers and counting the number of insects on the flowers.

Their results did lead them to make some horticultural recommendations – they found that borage, lavender, marjoram and open-flower dahlias varieties were very good for insects.

The colourfully named bowles mauve everlasting wallflower was also very attractive to pollinators, while the least attractive flowering plant for insects was the very popular geranium.

Marjoram, the researchers say, was probably the best “all-rounder”, attracting honey bees, bumble bees, other bees, hover flies, and butterflies.

Borage was the best for honey bees and lavender and open-flowered dahlias were most attractive to bumblebees.

The team put a number of varieties of lavender to the test and found that highly bred hybrids, including some with novel colours – such as white or pink – that have been carefully bred into the plants proved the most attractive to insects.

Dr Nigel Raine, from Royal Holloway University of London, commented that with bee populations declining across the world, “we can all give bees a helping hand by planting the right flowers to give them the nectar and pollen they need”.

“This study highlights that it’s important for bee-friendly gardeners to choose what you plant with care,” he added.

“Gardeners and town planners should think carefully about the mixture of flowers they plant to ensure food is available for a wide range of bees and other important insect pollinators.

“It’s also important to cater for the needs of the rarer species and provide food at times when there might be fewer wild flowers in bloom.”

In another prior study, a team from the University of California San Diego used this ‘taste test’ to work out if bees are able to detect the scent of a flower. If the bee detects a floral scent, it will stick out its tongue.

Method of recording brain activity could lead to mind-reading devices.


A brain region activated when people are asked to perform mathematical calculations in an experimental setting is similarly activated when they use numbers — or even imprecise quantitative terms, such as “more than”— in everyday conversation, according to a study by Stanford University School of Medicine scientists.

Using a novel method, the researchers collected the first solid evidence that the pattern of brain activity seen in someone performing a mathematical exercise under experimentally controlled conditions is very similar to that observed when the person engages in quantitative thought in the course of daily life. 

“We’re now able to eavesdrop on the brain in real life,” said Josef Parvizi, MD, PhD, associate professor of neurology and neurological sciences and director of Stanford’s Human Intracranial Cognitive Electrophysiology Program. Parvizi is the senior author of the study, published Oct. 15 in Nature Communications. The study’s lead authors are postdoctoral scholar Mohammad Dastjerdi, MD, PhD, and graduate student Muge Ozker.

The finding could lead to “mind-reading” applications that, for example, would allow a patient who is rendered mute by a stroke to communicate via passive thinking. Conceivably, it could also lead to more dystopian outcomes: chip implants that spy on or even control people’s thoughts.

“This is exciting, and a little scary,” said Henry Greely, JD, the Deane F. and Kate Edelman Johnson Professor of Law and steering committee chair of the Stanford Center for Biomedical Ethics, who played no role in the study but is familiar with its contents and described himself as “very impressed” by the findings. “It demonstrates, first, that we can see when someone’s dealing with numbers and, second, that we may conceivably someday be able to manipulate the brain to affect how someone deals with numbers.”

The researchers monitored electrical activity in a region of the brain called the intraparietal sulcus, known to be important in attention and eye and hand motion. Previous studies have hinted that some nerve-cell clusters in this area are also involved in numerosity, the mathematical equivalent of literacy. 

However, the techniques that previous studies have used, such as functional magnetic resonance imaging, are limited in their ability to study brain activity in real-life settings and to pinpoint the precise timing of nerve cells’ firing patterns. These studies have focused on testing just one specific function in one specific brain region, and have tried to eliminate or otherwise account for every possible confounding factor. In addition, the experimental subjects would have to lie more or less motionless inside a dark, tubular chamber whose silence would be punctuated by constant, loud, mechanical, banging noises while images flashed on a computer screen.

“This is not real life,” said Parvizi. “You’re not in your room, having a cup of tea and experiencing life’s events spontaneously.” A profoundly important question, he said, is: “How does a population of nerve cells that has been shown experimentally to be important in a particular function work in real life?” 

His team’s method, called intracranial recording, provided exquisite anatomical and temporal precision and allowed the scientists to monitor brain activity when people were immersed in real-life situations. Parvizi and his associates tapped into the brains of three volunteers who were being evaluated for possible surgical treatment of their recurring, drug-resistant epileptic seizures.

The procedure involves temporarily removing a portion of a patient’s skull and positioning packets of electrodes against the exposed brain surface. For up to a week, patients remain hooked up to the monitoring apparatus while the electrodes pick up electrical activity within the brain. This monitoring continues uninterrupted for patients’ entire hospital stay, capturing their inevitable repeated seizures and enabling neurologists to determine the exact spot in each patient’s brain where the seizures are originating.

During this whole time, patients remain tethered to the monitoring apparatus and mostly confined to their beds. But otherwise, except for the typical intrusions of a hospital setting, they are comfortable, free of pain and free to eat, drink, think, talk to friends and family in person or on the phone, or watch videos.

The electrodes implanted in patients’ heads are like wiretaps, each eavesdropping on a population of several hundred thousand nerve cells and reporting back to a computer.

In the study, participants’ actions were also monitored by video cameras throughout their stay. This allowed the researchers later to correlate patients’ voluntary activities in a real-life setting with nerve-cell behavior in the monitored brain region. 

As part of the study, volunteers answered true/false questions that popped up on a laptop screen, one after another. Some questions required calculation — for instance, is it true or false that 2+4=5? — while others demanded what scientists call episodic memory — true or false: I had coffee at breakfast this morning. In other instances, patients were simply asked to stare at the crosshairs at the center of an otherwise blank screen to capture the brain’s so-called “resting state.”

Consistent with other studies, Parvizi’s team found that electrical activity in a particular group of nerve cells in the intraparietal sulcus spiked when, and only when, volunteers were performing calculations.

Afterward, Parvizi and his colleagues analyzed each volunteer’s daily electrode record, identified many spikes in intraparietal-sulcus activity that occurred outside experimental settings, and turned to the recorded video footage to see exactly what the volunteer had been doing when such spikes occurred.

They found that when a patient mentioned a number — or even a quantitative reference, such as “some more,” “many” or “bigger than the other one” — there was a spike of electrical activity in the same nerve-cell population of the intraparietal sulcus that was activated when the patient was doing calculations under experimental conditions. 

That was an unexpected finding. “We found that this region is activated not only when reading numbers or thinking about them, but also when patients were referring more obliquely to quantities,” said Parvizi.

“These nerve cells are not firing chaotically,” he said. “They’re very specialized, active only when the subject starts thinking about numbers. When the subject is reminiscing, laughing or talking, they’re not activated.” Thus, it was possible to know, simply by consulting the electronic record of participants’ brain activity, whether they were engaged in quantitative thought during nonexperimental conditions.

Any fears of impending mind control are, at a minimum, premature, said Greely. “Practically speaking, it’s not the simplest thing in the world to go around implanting electrodes in people’s brains. It will not be done tomorrow, or easily, or surreptitiously.”

Parvizi agreed. “We’re still in early days with this,” he said. “If this is a baseball game, we’re not even in the first inning. We just got a ticket to enter the stadium.”

– See more at: http://med.stanford.edu/ism/2013/october/parvizi.html#sthash.bBfPaTiH.dpuf

Researchers identify key proteins that help establish cell function


Researchers at the University of California, San Diego School of Medicine have developed a new way to parse and understand how special proteins called “master regulators” read the genome, and consequently turn genes on and off.

Writing in the October 13, 2013 Advance Online Publication of Nature, the scientists say their approach could make it quicker and easier to identify specific gene associated with increased – an essential step toward developing future targeted treatments, preventions and cures for conditions ranging from diabetes to neurodegenerative disease.

“Given the emerging ability to sequence the genomes of individual patients, a major goal is to be able to interpret that DNA sequence with respect to disease risk. What diseases is a person genetically predisposed to?” said principal investigator Christopher Glass, MD, PhD, a professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego.

“Mutations that occur in protein-coding regions of the genome are relatively straight forward, but most mutations associated with disease risk actually occur in regions of the genome that do not code for proteins,” said Glass. “A central challenge has been developing a strategy that assesses the potential functional impact of these non-coding mutations. This paper lays the foundation for doing so by examining how natural genetic variation alters the function of genomic regions controlling gene expression in a cell specific-manner.”

Cells use hundreds of different proteins called transcription factors to “read” the genome, employing those instructions to turn genes on and off. These factors tend to be bound close together on the genome, forming functional units called “enhancers.” Glass and colleagues hypothesized that while each cell has tens of thousands of enhancers consisting of myriad combinations of factors, most enhancers are established by just a handful of special transcription factors called “master regulators.” These master regulators play crucial, even disproportional, roles in defining each cell’s identity and function, such as whether it will be a muscle, skin or heart cell.

“Our main idea was that the binding of these master regulators is necessary for the co-binding of the other transcription factors that together enable enhancers to regulate the expression of nearby genes,” Glass said.

The scientists tested and validated their hypothesis by looking at the effects of approximately 4 million DNA sequence differences affecting master regulators in macrophage cells in two strains of mice. Macrophages are a type of immune response cell. They found that DNA sequence mutations deciphered by master regulators not only affected how they bound to the genome, but also impacted neighboring needed to make functional .

The findings have practical importance for scientists and doctors investigating the genetic underpinnings of disease, said Glass. “Without actual knowledge of where the master regulator binds, there is relatively little predictive value of the DNA sequence for non-coding variants. Our work shows that by collecting a focused set of data for the master regulators of a particular cell type, one can greatly reduce the ‘search space’ of the in a particular cell type that would be susceptible to the effects of mutations. This allows prioritization of mutations for subsequent analysis, which can lead to new discoveries and real-world benefits.”

Source:  University of California – San Diego

Researchers Identify Liver Cancer Progenitor Cells Before Tumors Become Visible.


Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks).
Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks).
For the first time, researchers at the University of California, San Diego School of Medicine have isolated and characterized the progenitor cells that eventually give rise to malignant hepatocellular carcinoma (HCC) tumors – the most common form of liver cancer. The researchers found ways to identify and isolate the HCC progenitor cells (HcPC) long before actual tumors were apparent.

<p>Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks).</p>

Writing in the October 10, 2013 issue of the journal Cell, principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology, and colleagues report that HcPC take form within dysplastic or abnormal lesions often found in damaged or cirrhotic livers. The liver damage can be due to viral infections like hepatitis or from chronic alcohol abuse.

“It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually pre-malignant lesions that harbor tumor progenitor cells,” said study co-author Debanjan Dhar, PhD, a postdoctoral researcher in Karin’s lab. “Here we show that HcPC are likely derived from dysplastic lesions, can progress to malignant tumors and further demonstrate that the malignant progression of HcPC to full-blown liver cancer depends upon the microenvironment that surrounds them.”

The researchers were able to characterize HcPC based on several biomarkers that distinguish them from normal cells. They also identified cellular signaling pathways activated in HcPC that are critical “to their malignant potential,” said Dhar.

The findings may have profound implications for treating HCC which, while relatively rare in the United States compared to other types of cancer, is difficult to diagnose and treat, with poor prognoses for patients. HCC is usually fatal within three to six months of diagnosis, according to National Institutes of Health data. An estimated 30,000 new cases of liver cancer are diagnosed annually in the U.S., predominantly among men. More than 21,600 Americans die from liver cancer each year, a rate that has been rising slowly for several decades. In other parts of the world, HCC is a major cause of cancer-related deaths.

Most cancers are best detected and treated at the earliest possible stage. HCC is problematic because it develops slowly and frequently displays no symptoms. By the time it is detected, said Dhar, it is usually at an advanced stage with no effective therapy.

“Our findings can be translated into both early detection and therapeutic intervention,” he said. “Better understanding of HcPC cellular networks will provide us with new and effective therapeutic targets.”

For example, the researchers were able to detect “potential” malignant lesions in needle biopsies of a subset of patients infected with the hepatitis C virus, but who hadn’t yet developed HCC. Hepatitis C is a major risk factor for HCC development.

Dhar said identifying premalignant lesions in high-risk patients based on HcPC markers would allow for earlier detection and therapeutic interventions. “Furthermore, in future, therapies can be developed to specifically eliminate the HcPC even before a tumor has developed.”

Co-authors include Guobin He, Joan Font-Burgada, Yuhong Jiang and Shabnam Shalapour, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD; Hayato Nakagawa, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD and Department of Gastroenterology, University of Tokyo; Hisanobu Ogata, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD and Department of Medicine and Clinical Science, Kyushu University, Japan; Ekihiro Seki, Department of Medicine, UCSD; Shawn E. Yost, Bioinformatics Graduate Program and Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD; Kristen Jepsen, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD; Kelly A. Frazer, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD, UC San Diego Moores Cancer Center, Clinical and Translational Research Institute, UCSD and Institute for Genomic Medicine, UCSD; Olivier Harismendy, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD, UC San Diego Moores Cancer Center, Clinical and Translational Research Institute, UCSD; Maria Hatziapostolou and Dimitrios Iliopoulos, Center for Systems Biomedicine, Geffen School of Medicine, UCLA; Atsushi Suetsugu and Robert M. Hoffman, Department of Surgery, UCSD and Anticancer, Inc., San Diego; and Ryosuke Tateishi  and Kazuhiko Koike, Department of Gastroenterology, University of Tokyo.

Funding support for this research came, in part, from the Superfund Basic Research Program, the National Institutes of Health (CA118165 and CA155120), Wellcome Trust, American Diabetes Association, the Center for Translational Science, the National Center for Research Resources IMAT program, postdoctoral research fellowships from the Damon Runyon Cancer Research Foundation, the American Liver Foundation, Daiichi Sankyo Foundation of Life Science, the California Institute for Regenerative Medicine Stem Cell Training Grant II, Kanzawa Medical Research Foundation, the German Research Foundation and a Young Investigator Award from the National Childhood Cancer Foundation “CureSearch.”

<p>Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks).</p>
Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks).
For the first time, researchers at the University of California, San Diego School of Medicine have isolated and characterized the progenitor cells that eventually give rise to malignant hepatocellular carcinoma (HCC) tumors – the most common form of liver cancer. The researchers found ways to identify and isolate the HCC progenitor cells (HcPC) long before actual tumors were apparent.

Writing in the October 10, 2013 issue of the journal Cell, principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology, and colleagues report that HcPC take form within dysplastic or abnormal lesions often found in damaged or cirrhotic livers. The liver damage can be due to viral infections like hepatitis or from chronic alcohol abuse.

“It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually pre-malignant lesions that harbor tumor progenitor cells,” said study co-author Debanjan Dhar, PhD, a postdoctoral researcher in Karin’s lab. “Here we show that HcPC are likely derived from dysplastic lesions, can progress to malignant tumors and further demonstrate that the malignant progression of HcPC to full-blown liver cancer depends upon the microenvironment that surrounds them.”

The researchers were able to characterize HcPC based on several biomarkers that distinguish them from normal cells. They also identified cellular signaling pathways activated in HcPC that are critical “to their malignant potential,” said Dhar.

The findings may have profound implications for treating HCC which, while relatively rare in the United States compared to other types of cancer, is difficult to diagnose and treat, with poor prognoses for patients. HCC is usually fatal within three to six months of diagnosis, according to National Institutes of Health data. An estimated 30,000 new cases of liver cancer are diagnosed annually in the U.S., predominantly among men. More than 21,600 Americans die from liver cancer each year, a rate that has been rising slowly for several decades. In other parts of the world, HCC is a major cause of cancer-related deaths.

Most cancers are best detected and treated at the earliest possible stage. HCC is problematic because it develops slowly and frequently displays no symptoms. By the time it is detected, said Dhar, it is usually at an advanced stage with no effective therapy.

“Our findings can be translated into both early detection and therapeutic intervention,” he said. “Better understanding of HcPC cellular networks will provide us with new and effective therapeutic targets.”

For example, the researchers were able to detect “potential” malignant lesions in needle biopsies of a subset of patients infected with the hepatitis C virus, but who hadn’t yet developed HCC. Hepatitis C is a major risk factor for HCC development.

Dhar said identifying premalignant lesions in high-risk patients based on HcPC markers would allow for earlier detection and therapeutic interventions. “Furthermore, in future, therapies can be developed to specifically eliminate the HcPC even before a tumor has developed.”

Co-authors include Guobin He, Joan Font-Burgada, Yuhong Jiang and Shabnam Shalapour, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD; Hayato Nakagawa, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD and Department of Gastroenterology, University of Tokyo; Hisanobu Ogata, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, UCSD and Department of Medicine and Clinical Science, Kyushu University, Japan; Ekihiro Seki, Department of Medicine, UCSD; Shawn E. Yost, Bioinformatics Graduate Program and Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD; Kristen Jepsen, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD; Kelly A. Frazer, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD, UC San Diego Moores Cancer Center, Clinical and Translational Research Institute, UCSD and Institute for Genomic Medicine, UCSD; Olivier Harismendy, Rady Children’s Hospital-San Diego and Department of Pediatrics, UCSD, UC San Diego Moores Cancer Center, Clinical and Translational Research Institute, UCSD; Maria Hatziapostolou and Dimitrios Iliopoulos, Center for Systems Biomedicine, Geffen School of Medicine, UCLA; Atsushi Suetsugu and Robert M. Hoffman, Department of Surgery, UCSD and Anticancer, Inc., San Diego; and Ryosuke Tateishi  and Kazuhiko Koike, Department of Gastroenterology, University of Tokyo.

Funding support for this research came, in part, from the Superfund Basic Research Program, the National Institutes of Health (CA118165 and CA155120), Wellcome Trust, American Diabetes Association, the Center for Translational Science, the National Center for Research Resources IMAT program, postdoctoral research fellowships from the Damon Runyon Cancer Research Foundation, the American Liver Foundation, Daiichi Sankyo Foundation of Life Science, the California Institute for Regenerative Medicine Stem Cell Training Grant II, Kanzawa Medical Research Foundation, the German Research Foundation and a Young Investigator Award from the National Childhood Cancer Foundation “CureSearch.”

‘Bottled mucus’ may help gut disease.


Bottled mucus may one day play a role in some gut diseases, according to US researchers.

A study of the slimy lining of the bowels, published in the journal Science, showed mucus had a role in calming the immune system.

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The team at Mount Sinai Hospital, in New York, believe it may be useful in diseases in which inflammation runs rampant in the intestines.

The human body naturally produces around a litre of mucus every day.

Researchers at the hospital and Mount Sinai School of Medicine were investigating why the lining of the bowel does not react to the trillions of bacteria which call the human intestines home. Elsewhere in the body, the immune system would launch a brutal attack against such invaders.

The team investigated the interaction between the mucus produced by the intestines and the immune system.

They showed that a mucus was not only acting as barrier between bacteria and immune system, but a component of the mucus was also calming the immune response. Sugars, or glycans, stuck to the a mucus protein called MUC2 were having the effect.

Lead researcher Dr Andrea Cerutti told the BBC: “We were able to show its ability to dampen the immune reaction in a specific type of immune cell, a dendritic cell, which orchestrates the immune response.

“But these are just initial studies; we know very, very little about mucus.”

Mucus treatments?

One area the team think mucus could help in is some bowel problems.

Crohn‘s disease, inflammatory bowel disease and ulcerative colitis are all poorly understood diseases, but do have inflammation, a part of the immune response, as a common feature.

Dr Cerutti said mucus was often disrupted in these patients and suggested that it may be possible to use mucus as a treatment.

One vision is to artificially synthesise mucus, although this is not currently possible, or a drug which can stimulate the same effect in the lining of the gut.

Whether such approaches to boost the mucus layer of the guts would help patients with bowel disorders is still unknown.

Mucus is not unique to the digestive system. It lines the lungs and streams out of the nose during a cold.

There is speculation that it could be producing similar immune-calming effects in the respiratory system and may be playing a role in allergies and asthma.

Dr Cerutti said even cancer may be affected by mucus: “Several aggressive tumours, such as colon, ovarian, and breast cancers produce mucus, including MUC2.

“Mucus produced by malignant cells may prevent protective immune responses against the malignant cells.”

Prof Jon Rhodes, from the department of gastroenterology at the University of Liverpool, said: “There’s a massive amount of work in this intriguing paper and it’s fascinating to read.

“To extrapolate this to just swallowing mucus would be hopelessly naive, but what might actually be interesting to speculate is that when the nature of the glycans are better understood it could lead to a very exciting and new type of therapeutic”

Source: BBC

Jacob Barnett, 14-Year-Old With Asperger’s Syndrome, May Be Smarter Than Einstein.


When Jacob Barnett was 2 years old, he was diagnosed with moderate to severe autism. Doctors told his parents that the boy would likely never talk or read and would probably be forever unable to independently manage basic daily activities like tying his shoe laces.

But they were sorely, extraordinarily mistaken.

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Today, Barnett — now 14 — is a Master’s student, on his way to earning a PhD in quantum physics. According to the BBC, the teen, who boasts an IQ of 170, has already been tipped to one day win the Nobel Prize.

Since enrolling at Indiana University-Purdue University Indianapolis (IUPUI) at the age of 10, Barnett has flourished — astounding his professors, peers and family with his spectacular intelligence.

The teen tutors other college students in subjects like calculus and is a published scientific researcher, with an IQ that is believed to be higher than that of Albert Einstein. In fact, according to a 2011 TIME report, Barnett, who frequently tops his college classes, has asserted that he may one day disprove Einstein’s Theory of Relativity. (Watch him explain his genius to 60 minutes’ Morley Safer in a 2012 interview in the video above.)

Outside of his rigorous university commitments, Barnett, who has Asperger’s Syndrome, is also an entrepreneur and aspiring author

The teen, who, with his family, runs a charity called Jacob’s Place for kids on the spectrum, has used his story to raise awareness and dispel myths about autism.

“I’m not supposed to be here at all,” he said last year during a TEDx Teen speech about “forgetting what you know” in New York City. “You know, I was told that I wouldn’t talk. There’s probably a therapist watching who is freaking out right now.”

 

Though he makes it all look so easy,his mother, Kristine Barnett, says that he has to work hard on a daily basis to handle his autism.

“He overcomes it every day. There are things he knows about himself that he regulates everyday,” his mother told the Indianapolis Star last month.

In April, Kristine Barnett’s memoir about her family’s experience with autism, “The Spark: A Mother’s Story of Nurturing Genius,” was released. A movie deal is said to be in the works.

“I hope it really inspires children to actually be doing something,” Barnett told the Star of his mom’s book and potential film. “[I hope it] encourages them to do what they like doing. I just hope it is inspirational.”

For more on Jacob Barnett, watch this March 2013 YouTube video of him working through what is described as “a simple quantum mechanics problem“:

 

CT nanoparticle contrast: Good as gold?


CT nanoparticle-based contrast agents are all investigational — and at this point all preclinical — but they’re out there. In a few years, the tiny contrast agent delivery vehicles, which work well in animals, could greatly affect the diagnosis and treatment of disease in humans.

That’s according to David Cormode, PhD, assistant professor of radiology at the University of Pennsylvania. He spoke on nanoparticle CT contrast media at last month’s International Society for Computed Tomography (ISCT) annual meeting in San Francisco.

The integration of nanoparticle CT contrast into the clinical mainstream will take a while, Cormode said, but the process might be speeded up if elements are developed that are cheaper than gold, which is currently used to make the nanoparticles.

Nanoparticles for CT imaging aren’t so different in design and structure from those built for other imaging modalities such as MRI, except that they contain CT contrast agents in their lipid-based cores. Inside every nanoparticle agent is an inner core surrounded by various layered and scattered components including liposomes, micelles, emulsions, and nanocrystals with biocompatible coatings, Cormode said.

CT contrast agents have bigger cores than, for example MR agents, because they need them. Due to CT’s relative insensitivity to contrast compared to other imaging modalities, high-contrast payloads are required for better sensitivity, Cormode said. Nevertheless, they are still quite small, typically less than 4 nm in diameter.

“If you compare the Earth to the size of a soccer ball, it’s about 58 millionth of the size,” he said. “Going from [the soccer ball] to a nanoparticle, it’s about the same factor of difference in sizes.”

In recent years, interest in imaging nanoparticles has soared, with about 80 peer-reviewed studies being published a year, compared with fewer than 10 as recently as 2006, Cormode said. The reason is, quite simply, their vast potential in diagnosing and treating disease.

Nanoparticles are designed to be long-lasting contrast agents that do not need to be readministered in the case of multiple exams being acquired over several hours or potentially even days, Cormode said.

“Compared to agents we are currently using, nanoparticles have long circulation half-lives,” he said. “They can be targeted to allow molecular imaging or specific cells or specific processes. They can be used with spectral CT, and they can also be multifunctional, providing contrast for more than one imaging technique.”

Although no nanoparticle agents are approved for CT, a couple have been cleared for use with MRI, including Doxil, a liposomal formulation of doxorubicin approved for head and neck cancers in the mid-1990s, and Feridex, an iron-oxide nanoparticle contrast agent.

The tiny structures have become more complex in recent years, featuring multiple layers of different coatings, and an antibody or protein used to direct the agent to a biological target. For example, a 2009 in vitro and rat study by Pan and colleagues examined an iodine-loaded agent targeted to fibrin for thrombus imaging, he said.

Representing a new class of nanoparticles designed for CT, the colloidal, radio-opaque and metal-encapsulated polymeric (cROMP) particle offered severalfold enhancement both in vivo and in a rat model, its authors reported, with sensitivity reaching to the low nanomolar particulate .

Key CT nanoparticle studies

In 2006, Mukundan and colleagues tested a blood-pool contrast nanoparticle encapsulating a high concentration of iodine. They injected the agent into five mice and scanned them with micro-CT. The researchers measured high initial enhancement of about 900 HU in the aorta, which plateaued at about 800 HU when measured again two hours later, and there was excellent contrast discrimination between the myocardium and cardiac blood pool .”I imagine if they had continued the study for a longer time, you would have seen the same amount of contrast,” Cormode said.

In a 2010 study of a gold high-density lipoprotein nanoparticle targeted at atherosclerosis, Cormode and colleagues showed that nanoparticles can distinguish several different components in a single scan. The group performed spectral imaging on a preclinical CT scanner developed by Philips Healthcare to differentiate gold (Au-HDL), iodine-based contrast, and calcium phosphate in phantoms. The gold nanoparticles were injected in mice and followed 24 hours later by an iodine-based contrast agent.

The gold particles were detected in the aortas of the mice, while the iodine-based contrast agent was highlighted in the blood and the calcium-rich tissue of the skeleton during a single CT scan. Microscopy showed that the gold was primarily localized in macrophages in the aorta, thereby showing that spectral CT also provided information about the macrophage burden 

“You can use nanoparticles … to extract several different parameters at the same time,” Cormode said of the study.

Also in 2010, Cormode collaborated with van Schooneveld et al to examine an all-in-one contrast agent for MRI, CT, and fluorescence imaging. The researchers created a gold/silica nanoparticle agent to enhance macrophage cells in vitro using MRI, CT, and fluoroscopy and mice livers in vivo using MRI and CT. The agent is useful in many applications, including cell tracking and target-specific molecular imaging, and is “a step in the direction of truly multimodal imaging,” the authors wrote.

Diagnostic and therapeutic

Gold nanoparticle-based contrast was also the agent of choice in a study by von Maltzahn et al, who used a gold nanorod agent to visualize and then ablate tumors in mice. The nanomaterials improved the specificity of cancer ablation by homing into tumors and acting as antennas for externally applied radiofrequency ablation, the authors .

The polyethylene glycol (PEG)-protected gold nanorods “actually absorb laser radiation very strongly, and when they do they heat up the surrounding material,” Cormode said of the study. “This can be used as a kind of hyperthermia technique” to completely eradicate the tumors, he noted.

In summary, CT nanoparticle contrast agents “are out there, but gold is sort of expensive and we need to create cheaper agents,” Cormode said. In addition, “extensive clearance and toxicity testing” will be needed before the agents are ready for routine clinical use.

Calcium, vitamin D failed to halt BMD loss in breast cancer.


Calcium plus vitamin D supplements are often suggested for patients at risk for osteoporosis and in women undergoing breast cancer treatment, but a recent analysis published in Critical Reviews in Oncology/Hematologyhighlights the insignificant data behind this methodology.

“We evaluated clinical trial evidence for calcium and vitamin D supplementation in maintaining skeletal health of women with breast cancer,” Gary G. Schwartz, PhD, a cancer epidemiologist at Wake Forest Baptist Medical Center in Winston-Salem, N.C., said in a press release. “At the doses recommended, the data show that these supplements are inadequate to prevent loss of [bone mineral density].”

Of 16 trials, researchers found that none of them evaluated calcium plus vitamin D supplements vs. no supplements in preventing BMD loss in women with breast cancer. Additionally, researchers reported inadequacies in the prevention of BMD loss when doses of 500 mg to 1,500 mg calcium and 200 IU to 1,000 IU vitamin D per day were administered among pre- and postmenopausal women with breast cancer.

However, exercise or pharmacologic interventions could prevent BMD loss in this patient population when such supplementation is not effective, researchers wrote. The researchers added that controversial literature exists regarding the risk for cardiovascular disease with the use ofcalcium supplements.

“The take-home message is that this very common practice of supplementation doesn’t really seem to be working,” Schwartz said. “Future trials are needed to evaluate the safety and efficacy of calcium and vitamin D supplementation in women undergoing breast cancer therapy.”

Source: Endocrine Today.