Scientists discover new diagnostic markers for Kawasaki disease

Dec. 18, 2012 — Researchers have discovered proteins in human urine that offer new opportunities for the diagnosis, study and maybe even the treatment of Kawasaki disease. Mass spectrometry-based proteomic analysis of the human urine proteome, the entire set of proteins found in human urine, uncovered molecular markers that offer significant improvements for the diagnosis of the disease.

The results are reported in a new study published in EMBO Molecular Medicine.

"There is no diagnostic test for Kawasaki disease. Currently available diagnostic markers lack the specificity and sensitivity needed for reliable detection of the disease which has motivated our decision to use proteomics to identify new, improved biomarkers," said Susan Kim, a rheumatologist at Boston Children's Hospital and an instructor at Harvard Medical School. "Kawasaki disease is often difficult to diagnose and is the most prevalent cause of acquired childhood heart disease in the developed world. Failure to detect it can lead to coronary artery aneurysms and in some cases death, particularly in children who are not diagnosed early enough or when the diagnosis is not considered and acted upon due to the presence of only some of the classic symptoms."

Kawasaki disease can occur at any age but is most commonly found in children under the age of five years. The disease appears to influence the immune system in such a way that it attacks its own tissues. This leads to inflammation that can damage blood vessels, most notably around the heart. If untreated, Kawasaki disease leads to coronary artery aneurysms in up to 25% of cases.

The researchers used highly sensitive mass spectrometry techniques to profile the proteome of urine samples collected from children who had symptoms of Kawasaki disease. Several molecules were discovered that were exclusively present in the urine of patients with the disease. In particular, elevated levels of filamin C and meprin A were detected in both human blood and urine samples and show considerable potential for use as diagnostics.

Filamin C is a protein that helps maintain the structural integrity of heart and skeletal muscle. Meprin A is an enzyme that breaks down proteins and which is known to regulate the activities of other proteins linked to inflammation. Both of these markers could be used to identify patients with Kawasaki disease accurately using tests that are readily amenable for routine medical use.

"The urine proteome consists of thousands of protein molecules. Patients with Kawasaki disease have a unique urinary proteome that is distinct from the proteome observed for children with other causes of fever," remarked Hanno Steen, director of the Proteomics Center at Boston Children's Hospital and associate professor at Harvard Medical School. "In a group of 107 patients, we were able to distinguish children with Kawasaki disease from those with mimicking conditions much more reliably and accurately than currently available testing by measuring their levels of meprin A and filamin C in urine." The researchers note that further validation of the diagnostic markers is needed and this work is in progress.

The researchers suggest that the development of clinical tests using these new markers may improve the accuracy of diagnosis of children with suspected Kawasaki disease and assist in the development of new treatments. For this purpose, the scientists have made the analyzed proteomes openly available at the Peptide Atlas (www.peptideatlas.org).

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The above story is reprinted from materials provided by EMBO - excellence in life sciences, via AlphaGalileo.

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Journal Reference:

Alex Kentsis, Andrew Shulman, Saima Ahmed, Eileen Brennan, Michael C. Monuteaux, Young-Ho Lee, Susan Lipsett, Joao A. Paulo, Fatma Dedeoglu, Robert Fuhlbrigge, Richard Bachur, Gary Bradwin, Moshe Arditi, Robert P. Sundel, Jane W. Newburger, Hanno Steen, Susan Kim. Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease. EMBO Molecular Medicine, 2012; DOI: 10.1002/emmm.201201494

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Extending steroid treatment does not benefit children with hard-to-treat kidney disease, study finds

Dec. 20, 2012 — Extending steroid treatment for the most common form of kidney disease in children provides no benefit for preventing relapses or side effects, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings challenge previous assumptions about optimal treatment strategies for this disease.

Nephrotic syndrome is the most common kidney disease in childhood. Children with the disease are at risk of developing severe infections and other complications because their kidneys leak important proteins from the blood into the urine. Their bodies also retain water, which results in general discomfort and abdominal pain. Steroids such as prednisolone induce remission in 90-95% of patients; however relapses occur in 60-90% of initial responders. Prolonged prednisolone treatment for initial episodes of childhood nephrotic syndrome may reduce the relapse rate (despite potentially causing serious side effects), but whether this results from an increased duration of treatment or from a higher cumulative dose remains unclear.

To investigate, Nynke Teeninga, MD (Erasmus University Medical Centre at Sophia Children's Hospital, in Rotterdam, the Netherlands) and her colleagues conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in the Netherlands. They assigned 150 children (nine months to 17 years old) with nephrotic syndrome to either three months of prednisolone followed by three months of placebo or to six months of prednisolone. Patients were followed for an average of 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m2).

Among the major findings: • Among the 126 children who started taking medication, relapses occurred in 48 (77%) of the 62 patients who received three months of prednisolone and in 51 (80%) of the 64 who received six months of prednisolone. • Frequent relapses occurred with similar frequency between groups as well (45% vs 50%). • There were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% vs 59%), steroid dependence, or side effects.

"In contrast to what was previously assumed but unproven, we found no beneficial effect of prolonged prednisolone treatment on the occurrence of relapses. We believe our work offers an important contribution towards more evidence-based treatment of childhood nephrotic syndrome," said Dr. Teeninga. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration.

Dr. Teeninga added that because many children with nephrotic syndrome face frequent relapses, future research should focus on preventing relapses through new treatment strategies.

Study co-authors include Joana Kist-van Holthe, MD, PhD, Nienske van Rijswijk, MD, Nienke de Mos, MD, Wim Hop, MSc, PhD, Jack Wetzels, MD, PhD, Albert van der Heijden, MD, PhD, Jeroen Nauta, MD, PhD.

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Successful solo rock/pop stars twice as likely to die early as those in a band, study finds

Dec. 19, 2012 — Successful solo rock/pop stars are around twice as likely to die early as those in equally famous bands, indicates research published in the online journal BMJ Open.

And those who died of drug and alcohol problems were more likely to have had a difficult or abusive childhood than those dying of other causes, the findings showed.

The authors included 1489 North American and European rock and pop stars over a 50 year period between 1956 (Elivs Presley) and 2006 (Regina Spektor, The Arctic Monkeys, and Snow Patrol)

Their achievements were determined from international polls and top 40 chart successes, while details of their personal lives/childhoods were drawn from a range of music and official websites, published biographies, and anthologies.

During the 50 year period, 137 (9.2%) famous rock/pop stars died. The average age of death was 45 for North American stars and 39 for those from Europe.

The gap in life expectancy between rock and pop stars and the general population widened consistently until 25 years after fame had been achieved, after which death rates began to approach those of the general population -- but only for European stars.

Solo performers were around twice as likely to die early as those in a band, irrespective of whether they were European (9.8% vs 5.4%) or North American (22.8% vs 10.2%).

A successful solo career may be a proxy for fame, it also raises the question of whether the peer support offered by band-mates may be protective, suggest the authors.

While gender and the age at which fame was reached did not influence life expectancy, ethnicity did, with those from non-white backgrounds more likely to die early. And the chances of survival increased among those achieving fame after 1980.

Nearly half of those who died as a result of drugs, alcohol, or violence had at least one unfavourable factor in their childhoods, compared with one in four of those dying of other causes.

These factors -- referred to as adverse childhood experiences, or ACEs for short -- included physical, sexual, or emotional abuse; living with a chronically depressed, suicidal, mentally or physically ill person; living with a substance abuser; having a close relative in prison; and coming from a broken home or one in which domestic violence featured.

Four out of five dead stars with more than one unfavourable childhood factor died from substance misuse or violence-related causes.

A career as a rock/pop star may be attractive to those escaping an unhappy childhood, but it may also provide the resource to feed a predisposition to unhealthy/risky behaviours, say the authors.

"Pop/rock stars are among the most common role models for children, and surveys suggest that growing numbers aspire to pop stardom," they write. "A proliferation of TV talent shows and new opportunities created by the internet can make this dream appear more achievable than ever."

But they caution: "It is important they [children] recognise that substance use and risk taking may be rooted in childhood adversity rather than seeing them as symbols of success."

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M. A. Bellis, K. Hughes, O. Sharples, T. Hennell, K. A. Hardcastle. Dying to be famous: retrospective cohort study of rock and pop star mortality and its association with adverse childhood experiences. BMJ Open, 2012; 2 (6): e002089 DOI: 10.1136/bmjopen-2012-002089

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Violent crime doesn’t fit in the autism puzzle

Dec. 19, 2012 — As investigators begin to piece together a profile of Connecticut school massacre gunman Adam Lanza, much is being speculated about his possible Asperger's Syndrome diagnosis. But to suggest a tie between autism and violent, sociopathic tendencies is to undermine the large body of research and progress that's been made in understanding the disorder, says autism expert and Executive Director of the Kinney Center for Autism Education and Support at Saint Joseph's University Michelle Rowe, Ph.D.

"We know that children and adults with autism are often misunderstood," she says. "Small talk is not especially easy. Those on the spectrum have trouble understanding sarcasm. They struggle to understand basic social rules -- how to take turns, how to make eye contact.

"We also know that people with autism are not sociopaths. There is no evidence or research that suggests a link between autism and planned violence."

Rowe points to critical differences in the brains of so-called "neuro-typicals" and those on the autism spectrum.

"The prefrontal cortex (the front part of the brain, just above the eyebrows, that most people know as the frontal lobe) helps "neuro-typicals" make sense of the world," she explains. "We make eye contact and assess facial expressions. This is the brain's way of helping us connect with people. Without that skill -- that ability -- wouldn't we all be misunderstood?"

It's a much different world for people living with autism than it was just 10 years ago, Rowe adds. Awareness is at an all-time high. Services are expanding and those on the autism spectrum are being mainstreamed in schools all across the country.

"We've come too far and we know too much to revert back to the days when people with disabilities were locked up out of fear," says Rowe. "We shouldn't fear autism-- not now-- not when we understand more than we ever have about it."

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People without spouses under-represented in Alzheimer's clinical trials

Dec. 19, 2012 — A new study suggests that people without a spouse are represented less in Alzheimer's disease clinical trials compared to people with spouses. The study is published in the December 19, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Nationwide, half of all unpaid Alzheimer's disease caregivers are under the age of 50 and as many as 68 percent are the children, children-in-law or grandchildren of these patients," said study author Joshua D. Grill, PhD, Assistant Professor of Neurology at the UCLA Mary S. Easton Center for Alzheimer's Disease Research and a member of the American Academy of Neurology. "In contrast, in our analyses, 67 percent of the 2,041 Alzheimer's clinical trial participants had a spouse as their study partner. We found that there were several differences between people with spouse and adult child study partners that could affect the results of the trials and interpretations of those results."

Grill adds that factors such as race and caregiver attitude may also impact recruitment to trials. For example, only five percent of participants across the trials were Hispanic and those with an adult child study partner were twice as likely as those with spouse partners to be Hispanic. In addition, six percent of participants were African-American and those with adult child study partners were nearly three times as likely to be African-American as those with spouse study partners.

For the study, the research team categorized people with Alzheimer's disease based on the type of study partner they had -- either spouse, adult child or other study partners -- from six clinical trials conducted by the Alzheimer's Disease Cooperative Study.

In addition to the differences in enrollment, they found that participants with other study partners were at increased risk to drop out of studies.

After considering other factors, the risk of dropout for the "other" study partner group was 70 percent higher than that for the "spouse" study partner group.

The study was supported by the National Institute on Aging, the Sidell-Kagan Foundation and the Marian S. Ware Alzheimer Program.

To learn more about Alzheimer's disease, visit http://www.aan.com/patients.

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J. D. Grill, R. Raman, K. Ernstrom, P. Aisen, J. Karlawish. Effect of study partner on the conduct of Alzheimer disease clinical trials. Neurology, 2012; DOI: 10.1212/WNL.0b013e31827debfe

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Genetic defect causing fragile X-related disorders more common than thought

Dec. 20, 2012 — A single genetic defect on the X chromosome that can result in a wide array of conditions -- from learning and emotional difficulties to primary ovarian insufficiency in women and tremors in middle-aged men -- occurs at a much greater frequency than previously thought, research led by the UC Davis MIND Institute has found.

The research is based on the first large-scale, multi-center newborn screening effort for the defect in the United States, conducted in a group of more than 14,200 male and female infants at three research university medical centers piloting a new infant screening test developed at UC Davis.

The study, "FMR1 CGG Allele Size and Prevalence Ascertained Through Newborn Screening in the United States," was led by Flora Tassone, professor-in-residence in the Department of Biochemistry and Molecular Medicine, and was conducted using blood spots obtained from infant heel pricks as part of the normal newborn genetic screening process. It is published online Dec. 20 in the journal Genome Medicine.

The investigators examined the prevalence of expanded alleles of the fragile X mental retardation 1 (FMR1) gene. Defects in FMR1 cause conditions as diverse as fragile X syndrome -- the leading cause of intellectual disability and the leading known single-gene cause of autism -- and a Parkinson's disease-like condition called fragile X-associated tremor/ataxia syndrome, or FXTAS. The term "fragile X" is used because of the altered appearance of the X chromosome among sufferers from the conditions.

"This study demonstrates that there is a higher frequency of mutations of the FMR1 gene across racial and ethnic groups than previously believed," said Randi Hagerman, medical director of the UC Davis MIND Institute and one of the world's leading experts on fragile X-related conditions. "It also demonstrates that newborn screening for fragile X mutations is technically feasible in a large-scale setting using the blood spot technique developed by Dr. Tassone."

The degree of disability from defects in FMR1 depends upon the number of repetitions of the sequence of the proteins cytosine-guanine-guanine (CGG) in the promoter region of the gene. The range of repeats in normal individuals is between six and 40. CGG repeats greater than 200 cause what is called the full mutation and fragile X syndrome. Fewer repeats -- in the range of 55 to 200 -- result in a variation called a premutation.

The current study found the estimated prevalence of the premutation to be 1 in 200 females, a finding somewhat greater than earlier estimates. However, it estimates the prevalence among males to be 1 in 400 -- double what had previously been reported. The researchers said that the sample size in the current study was not great enough to estimate the true prevalence of the full fragile X mutation, currently estimated at between 1 in 2,500 and 1 in 8,000 females and 1 in 5,000 males.

While most people with the premutation appear normal, some individuals can have mild difficulties in childhood, such as such as learning problems or emotional difficulties including social anxiety and attention deficit hyperactivity disorder (ADHD), said Hagerman, a professor in the Department of Pediatrics. Individuals with the premutation also can suffer from FXTAS, which causes debilitating tremors, balance problems and dementia primarily in older men, and premature ovarian insufficiency in women.

Tassone, a researcher affiliated with the MIND Institute, is one of the world's leading experts on screening and identification of the FMR1 mutation. Her polymerase chain reaction (PCR)-based test used in the current study was described in January 2008 in the Journal of Molecular Diagnostics.

"This study shows that newborn screening for the FMR1 mutation is technically possible on a large scale," Tassone said. "However, the screening will identify far more carrier and gray-zone infants than those with a full fragile X mutation. As we now know that there may be clinical involvement with these individuals, such as FXTAS, we need to better understand the impact of identifying these mutations on families before widespread newborn screening can be instituted."

Hagerman said that the study is important because early intervention can be helpful for children with these mutations who experience developmental problems. In addition, a baby who is positive for the mutation will have other family members who also carry mutations. Genetic counseling is essential for the family members, in addition to treatment for the medical or psychiatric problems associated with the premutation or full mutation, she said.

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Genomic 'hotspots' offer clues to causes of autism, other disorders

Dec. 20, 2012 — An international team, led by researchers from the University of California, San Diego School of Medicine, has discovered that "random" mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate.

Clusters of mutations or "hotspots" are not unique to the autism genome but instead are an intrinsic characteristic of the human genome, according to principal investigator Jonathan Sebat, PhD, professor of psychiatry and cellular and molecule medicine, and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego.

"Our findings provide some insights into the underlying basis of autism -- that, surprisingly, the genome is not shy about tinkering with its important genes" said Sebat. "To the contrary, disease-causing genes tend to be hypermutable."

Sebat and collaborators from Rady Children's Hospital-San Diego and BGI genome center in China sequenced the complete genomes of identical twins with autism spectrum disorder and their parents. When they compared the genomes of the twins to the genomes of their parents, the scientists identified many "germline" mutations (genetic variants that were present in both twins but not present in their mother or father).

Nearly 600 germline mutations -- out of a total of 6 billion base pairs -- were detected in the 10 pairs of identical twins sequenced in the study. An average of 60 mutations was detected in each child.

"The total number of mutations that we found was not surprising," said Sebat, "it's exactly what we would expect based on the normal human mutation rate." What the authors did find surprising was that mutations tended to cluster in certain regions of the genome. When the scientists looked carefully at the sites of mutation, they were able to determine the reasons why some genomic regions are "hot" while other regions are cold.

"Mutability could be explained by intrinsic properties of the genome," said UC San Diego postdoctoral researcher Jacob Michaelson, lead author of the study. "We could accurately predict the mutation rate of a gene based on the local DNA sequence and its chromatin structure, meaning the way that the DNA is packaged."

The researchers also observed some remarkable examples of mutation clustering in an individual child, where a shower of mutations occurred all at once. "When multiple mutations occur in the same place, such an event has a greater chance of disrupting a gene," said Michaelson.

The researchers surmised that hypermutable genes could be relevant to disease. When they predicted the mutation rates for genes, the authors found that genes that have been linked to autism were more mutable than the average gene, suggesting that some of the genetic culprits that contribute to autism are mutation hotspots.

The authors observed a similar trend for other disease genes. Genes associated with dominant disorders tended to be highly mutable, while mutation rates were lower for genes associated with complex traits.

"We plan to focus on these mutation hotspots in our future studies," said Sebat. "Sequencing these regions in larger numbers of patients could enable us to identify more of the genetic risk factors for autism."

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Journal Reference:

Jacob J. Michaelson, Yujian Shi, Madhusudan Gujral, Hancheng Zheng, Dheeraj Malhotra, Xin Jin, Minghan Jian, Guangming Liu, Douglas Greer, Abhishek Bhandari, Wenting Wu, Roser Corominas, Áine Peoples, Amnon Koren, Athurva Gore, Shuli Kang, Guan Ning Lin, Jasper Estabillo, Therese Gadomski, Balvindar Singh, Kun Zhang, Natacha Akshoomoff, Christina Corsello, Steven McCarroll, Lilia M. Iakoucheva, Yingrui Li, Jun Wang, Jonathan Sebat. Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation. Cell, 2012; 151 (7): 1431 DOI: 10.1016/j.cell.2012.11.019

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