Different brain organization identified in autistic children who excel at math

Main Category: Autism
Also Included In: Psychology / Psychiatry
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Different brain organization identified in autistic children who excel at math

Children with autism and average IQs consistently demonstrated superior math skills compared with nonautistic children in the same IQ range, according to a study by researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital.

"There appears to be a unique pattern of brain organization that underlies superior problem-solving abilities in children with autism," said Vinod Menon, PhD, professor of psychiatry and behavioral sciences and a member of the Child Health Research Institute at Packard Children's.

The autistic children's enhanced math abilities were tied to patterns of activation in a particular area of their brains - an area normally associated with recognizing faces and visual objects.

Menon is senior author of the study, published online Aug. 17 in Biological Psychiatry. Postdoctoral scholar Teresa Iuculano, PhD, is the lead author.

Children with autism have difficulty with social interactions, especially interpreting nonverbal cues in face-to-face conversations. They often engage in repetitive behaviors and have a restricted range of interests.

But in addition to such deficits, children with autism sometimes exhibit exceptional skills or talents, known as savant abilities. For example, some can instantly recall the day of the week of any calendar date within a particular range of years - for example, that May 21, 1982, was a Friday. And some display superior mathematical skills.

"Remembering calendar dates is probably not going to help you with academic and professional success," Menon said. "But being able to solve numerical problems and developing good mathematical skills could make a big difference in the life of a child with autism."

The idea that people with autism could employ such skills in jobs, and get satisfaction from doing so, has been gaining ground in recent years.

The participants in the study were 36 children, ages 7 to 12. Half had been diagnosed with autism. The other half was the control group. Each group had 14 boys and four girls. (Autism disproportionately affects boys.) All participants had IQs in the normal range and showed normal verbal and reading skills on standardized tests administered as part of the recruitment process for the study. But on the standardized math tests that were administered, the children with autism outperformed children in the control group.

After the math test, researchers interviewed the children to assess which types of problem-solving strategies each had used: Simply remembering an answer they already knew; counting on their fingers or in their heads; or breaking the problem down into components - a comparatively sophisticated method called decomposition. The children with autism displayed greater use of decomposition strategies, suggesting that more analytic strategies, rather than rote memory, were the source of their enhanced abilities.

Then, the children worked on solving math problems while their brain activity was measured in an MRI scanner, in which they had to lie down and remain still. The brain scans of the autistic children revealed an unusual pattern of activity in the ventral temporal occipital cortex, an area specialized for processing visual objects, including faces.

"Our findings suggest that altered patterns of brain organization in areas typically devoted to face processing may underlie the ability of children with autism to develop specialized skills in numerical problem solving," Iuculano said.

Menon added that previous research "has focused almost exclusively on weaknesses in children with autism. Our study supports the idea that the atypical brain development in autism can lead, not just to deficits, but also to some remarkable cognitive strengths. We think this can be reassuring to parents."

The research team is now gathering data from a larger group of children with autism to learn more about individual differences in their mathematical abilities. Menon emphasized that not all children with autism have superior math abilities, and that understanding the neural basis of variations in problem-solving abilities is an important topic for future research.

"These findings not only empirically confirm that high-functioning children with autism have especially strong number-problem-solving abilities, but show that this cognitive strength in math is based on different patterns of functional brain organization," said Carl Feinstein, MD, director of the Center for Autism and Related Disorders at Packard Children's and professor of psychiatry and behavioral sciences at the School of Medicine. He was not involved in the study.

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Other Stanford co-authors are postdoctoral scholars Miriam Rosenberg-Lee, PhD, and Kaustubh Supekar, PhD; social science research assistants Charles Lynch and Amirah Khouzam; Jennifer Phillips, PhD, clinical associate professor of psychiatry and behavioral sciences and a clinical psychologist at Packard Children's; and Lucina Uddin, PhD, instructor in psychiatry and behavioral sciences.

The study was funded by grants from the Singer Foundation, the Stanford Institute for Neuro-Innovation & Translational Neurosciences, and the National Institutes of Health (grant MH084164).

Stanford University Medical Center

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Topical formulation identified for prolonged graft survival in corneal transplants

Main Category: Transplants / Organ Donations
Also Included In: Eye Health / Blindness
Article Date: 20 Aug 2013 - 1:00 PDT Current ratings for:
Topical formulation identified for prolonged graft survival in corneal transplants

Argos Therapeutics Inc., a biopharmaceutical company focused on the development and commercialization of therapies that modulate the immune system to treat cancer, infectious diseases, transplant rejection, autoimmune and inflammatory diseases, has announced the publication of key findings on its soluble recombinant human CD83 protein (sCD83) in cornea transplants. The study, conducted in rodents, demonstrates that CD83 can modulate the immune system and promote graft survival.

The study, which was published in the August 15th print issue of the Journal of Immunology, is a follow on to previous heart and kidney transplant studies using systemic administration of sCD83 in rodents. The current study, however, demonstrated that topical administration in the form of eye drops prolonged graft survival in the high risk corneal transplant mouse model system.

"Our previous studies in rodent model systems of solid organ transplantation involved short-term systemic delivery of sCD83, however, this is the first study demonstrating graft survival benefit after topical application at the graft-host interface," said Charles Nicolette, Ph.D., Chief Scientific Officer and Vice President of Research and Development of Argos Therapeutics. "These results are very encouraging and reinforce our continued efforts to advance sCD83 into human clinical development. In some transplant settings, topical administration represents a relatively non-invasive alternative to systemic administration which may not only promote graft survival, but could possibly minimize long-term side effects such as those associated with chronic immunosuppressive drugs currently used."

More than 40,000 cornea transplants are performed per year in North America, with a one year graft survival rate of 90% and a 15 year survival rate of 55%. If the cornea was previously damaged due to chemical or thermal burns, herpes infections or transplant rejections, then the one-year survival rate of the graft drops to 50%. In past clinical studies, irreversible rejection is the largest cause of corneal graft failure in the majority of cases.

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Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival

The Journal of Immunology, Published online July 12, 2013, doi: 10.4049/?jimmunol.1201531 and in print on August 15, 2013 vol. 191 no. 4 1965-1975

Felix Bock, Susanne Rössner, Jasmine Onderka, Matthias Lechmann, Maria Teresa Pallotta, Francesca Fallarino, Louis Boon, Charles Nicolette, Mark A. DeBenedette, Irina Y. Tcherepanova?, Ursula Grohmann, Alexander Steinkasserer, Claus Cursiefen and Elisabeth Zinser

Argos Therapeutics

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Protein biomarkers identified that predict time to ovarian cancer recurrence

Main Category: Ovarian Cancer
Article Date: 19 Aug 2013 - 0:00 PDT Current ratings for:
Protein biomarkers identified that predict time to ovarian cancer recurrence

Ovarian cancer often remains undetected until it is at an advanced stage. Despite positive responses to initial treatment, many patients are at risk of tumor recurrence. A multitude of genetic markers have been implicated in ovarian cancer prognosis. However, the genetic testing required is not practical or affordable in a clinical setting.

In this issue of the Journal of Clinical Investigation, Roel Verchaak and colleagues at the MD Anderson Cancer Center identify protein biomarkers that are predictive for time of ovarian cancer recurrence and develop a PRotein-driven index of OVARian cancer (PROVAR).

Using PROVAR, the authors were able to discriminate between patients with high and low risk of cancer recurrence, as well as short-term and long-term survival prognosis. In combination with genetic diagnosis, analysis of protein biomarkers may be useful in predicting outcome and determining a treatment plan for ovarian cancer patients.

TITLE: Predicting Time to Ovarian Carcinoma Recurrence Using Protein Markers

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J Clin Invest. doi:10.1172/JCI68509.

Journal of Clinical Investigation

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Subset of type 1 diabetes patients with strong response to therapy identified

Main Category: Diabetes
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Subset of type 1 diabetes patients with strong response to therapy identified

Primary results from a new clinical trial show that patients with type 1 diabetes treated with the monoclonal antibody teplizumab (MacroGenics, Inc.) exhibit greater preservation of C-peptide, a biomarker of islet cell function, compared to controls. Further analyses identified a discrete subset of the treatment group that demonstrated especially robust responses ("responders"), suggesting that these patients could be identified prior to treatment. The trial, entitled "Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes" (AbATE), was conducted by the Immune Tolerance Network (ITN). The results are available online and will be published in the November issue of the journal Diabetes.

The AbATE study, led by Kevan Herold, MD (Yale University), tested teplizumab, which targets the CD3 receptor found on T cells, in patients with new-onset type 1 diabetes. CD3 is required for T-cell activation, which can lead to the destruction of insulin-producing beta cells. A previous ITN study with teplizumab showed that a single course of the drug slowed C-peptide decline in new-onset patients for a year, after which the effects waned. The aim of the AbATE study was to test whether C-peptide preservation could be prolonged by administering two courses of teplizumab, one year apart.

In this open-label, Phase II study, 77 new-onset patients (ages 8 to 30 years old) were randomized to receive either teplizumab or a control. Those in the treatment arm received the scheduled treatment consisting of two 14-day courses of teplizumab, one year apart. Both arms received intensive diabetes care from certified diabetes educators and were followed for two years. The primary endpoint compared C-peptide preservation between the two groups.

After two years, the teplizumab-treated group showed significantly greater preservation of C-peptide (75-percent higher responses compared to the control group).

Further analysis revealed that within the treatment arm two groups of patients could be distinguished based on their C-peptide levels: one group, considered "responders" (22/49), showed very little C-peptide decline over the course of the study (only a 6 percent reduction from baseline), while the "non-responders" (27/49) exhibited a similar rate of C-peptide decline as the control group (less than 40-percent reduction from baseline).

Investigators measured various biomarkers and cell types that might distinguish between these two groups. They found that, at trial entry, "responders" had lower hemoglobin A1c levels (a marker of glucose concentration in the blood) and used less insulin at baseline, compared to "non-responders". Differences in specific T-cell subsets also distinguished between the two groups at baseline, suggesting that immune status might contribute to drug responsiveness. However, further studies will be required to confirm these results.

"This overall approach to identifying characteristics of individuals most likely to respond to therapies shows great promise because the responders in this study experienced a robust and prolonged drug effect," said Dr. Herold. "This type of response has not been seen in other studies of immune therapies."

Type 1 diabetes is a disease marked by immune destruction of insulin-producing beta cells in the pancreas. New-onset patients usually have 20 to 40 percent of their normal beta cell mass remaining, which is still capable of producing insulin. Preserving this remaining mass, even temporarily, could improve long-term clinical outcomes.

Immune modulators, like teplizumab, represent a promising means of inducing tolerance; however, no drug has been shown to prevent or reverse disease, and only a few have temporarily delayed disease progression. The ability to identify a subgroup of patients who may be more responsive to therapy could greatly enhance the clinical use of immune modulators and improve outcomes for those patients. Further analyses with specimens collected from the AbATE study are ongoing to understand the mechanism of response.

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New culprit identified that may make aging brains susceptible to neurodegenerative diseases

Main Category: Neurology / Neuroscience
Also Included In: Seniors / Aging;  Alzheimer's / Dementia;  Parkinson's Disease
Article Date: 15 Aug 2013 - 0:00 PDT Current ratings for:
New culprit identified that may make aging brains susceptible to neurodegenerative diseases

The steady accumulation of a protein in healthy, aging brains may explain seniors' vulnerability to neurodegenerative disorders, a new study by researchers at the Stanford University School of Medicine reports.

The study's unexpected findings could fundamentally change the way scientists think about neurodegenerative disease.

The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer's disease by ridding brains of a substance called amyloid plaque. But the new findings have identified another mechanism, involving an entirely different substance, that may lie at the root not only of Alzheimer's but of many other neurodegenerative disorders - and, perhaps, even the more subtle decline that accompanies normal aging.

The study, published in the Journal of Neuroscience, reveals that with advancing age, a protein called C1q, well-known as a key initiator of immune response, increasingly lodges at contact points connecting nerve cells in the brain to one another. Elevated C1q concentrations at these contact points, or synapses, may render them prone to catastrophic destruction by brain-dwelling immune cells, triggered when a catalytic event such as brain injury, systemic infection or a series of small strokes unleashes a second set of substances on the synapses.

"No other protein has ever been shown to increase nearly so profoundly with normal brain aging," said Ben Barres, MD, PhD, professor and chair of neurobiology and senior author of the study. Examinations of mouse and human brain tissue showed as much as a 300-fold age-related buildup of C1q.

The finding was made possible by the diligence and ingenuity of the study's lead author, Alexander Stephan, PhD, a postdoctoral scholar in Barres' lab. Stephan screened upward of 20,000 antibodies before finding one that binds to C1q and nothing else. (Antibodies are proteins, generated by the immune system, that adhere to specific "biochemical shapes," such as surface features of invading pathogens.)

Comparing brain tissue from mice of varying ages, as well as postmortem samples from a 2-month-old infant and an older person, the researchers showed that these C1q deposits weren't randomly distributed along nerve cells but, rather, were heavily concentrated at synapses. Analyses of brain slices from mice across a range of ages showed that as the animals age, the deposits spread throughout the brain.

"The first regions of the brain to show a dramatic increase in C1q are places like the hippocampus and substantia nigra, the precise brain regions most vulnerable to neurodegenerative diseases like Alzheimer's and Parkinson's disease, respectively," said Barres. Another region affected early on, the piriform cortex, is associated with the sense of smell, whose loss often heralds the onset of neurodegenerative disease.

Other scientists have observed moderate, age-associated increases (on the order of three- or four-fold) in brain levels of the messenger-RNA molecule responsible for transmitting the genetic instructions for manufacturing C1q to the protein-making machinery in cells. Testing for messenger-RNA levels - typically considered reasonable proxies for how much of a particular protein is being produced - is fast, easy and cheap compared with analyzing proteins.

But in this study, Barres and his colleagues used biochemical measures of the protein itself. "The 300-fold rise in C1q levels we saw in 2-year-old mice p equivalent to 70- or 80-year-old humans p knocked my socks off," Barres said. "I was not expecting that at all."

C1q is the first batter on a 20-member team of immune-response-triggering proteins, collectively called the complement system. C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system's other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target.

The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q's complement-system "teammates." The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.

Previous work in Barres' lab has shown that the complement cascade plays a critical role in the developing brain. A young brain generates an excess of synapses, creating a huge range of options for the potential formation of new neural circuits. These synapses strengthen or weaken over time, in response to their heavy use or neglect. The presence of feckless connections contributes noise to the system, so the efficiency of the maturing brain's architecture is improved if these underused synapses are pruned away.

In a 2007 paper in Cell, Barres' group reported that the complement system is essential to synaptic pruning in normal, developing brains. Then in 2012, in Neuron, in a collaboration with the lab of Harvard neuroscientist Beth Stevens, PhD, they showed that it is specifically microglia - the brain's in-house immune cells - that attack and ingest complement-coated synapses.

Barres now believes something similar is happening in the normal, aging brain. C1q, but not the other protein components of the complement system, gradually becomes highly prevalent at synapses. By itself, this C1q buildup doesn't trigger wholesale synapse loss, the researchers found - although it does seem to impair their performance. Old mice whose capacity to produce C1q had been eliminated performed subtly better on memory and learning tests than normal older mice did.

Still, this leaves the aging brain's synapses precariously perched on the brink of catastrophe. A subsequent event such as brain trauma, a bad case of pneumonia or perhaps a series of tiny strokes that some older people experience could incite astrocytes - the second tube in the Epoxy kit - to start secreting the other complement-system proteins required for synapse destruction.

Most cells in the body have their own complement-inhibiting agents. This prevents the wholesale loss of healthy tissue during an immune attack on invading pathogens or debris from dead tissue during wound healing. But nerve cells lack their own supply of complement inhibitors. So, when astrocytes get activated, their ensuing release of C1q's teammates may set off a synapse-destroying rampage that spreads "like a fire burning through the brain," Barres said.

"Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease," he said. "Kids don't get Alzheimer's or Parkinson's. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer's disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around."

In 2011, Barres co-founded a company, Annexon, to develop drugs that inhibit the complement cascade to treat Alzheimer's, glaucoma, Parkinson's, stroke, multiple sclerosis and several other neurodegenerative diseases characterized by massive synapse loss. Annexon has licensed multiple associated patent applications from Stanford, which filed them.

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The study was funded by the Ellison Medical Foundation and the National Institute of Drug Addiction (grant DA15403).

Other Stanford co-authors of the study were Daniel Madison, PhD, associate professor of molecular and cellular physiology; Mehrdad Shamloo, PhD, associate professor of comparative medicine; postdoctoral scholars Laurence Coutellier, PhD, and Jose Maria Mateos, PhD; research associate Emilie Lovelett; and graduate student Dominic Berns.

Stanford University Medical Center

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Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2

Main Category: Cancer / Oncology
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Targeted therapy identified for protein that protects and nourishes cancer - inhibitor found that blocks Skp2

Scientists at The University of Texas MD Anderson who identified a protein's dual role in cancer promotion have discovered a way to shut it down, opening a potential new avenue for cancer treatment.

Reporting this week in the journal Cell, the researchers describe the first compound that directly binds to and blocks Skp2, a protein they previously showed both turns off a cellular defense against cancer and switches on a cancer-feeding metabolic pathway.

"The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work," said co-senior author Hui-Kuan Lin, Ph.D., associate professor of Cellular and Molecular Oncology at MD Anderson.

Lin teamed with co-senior author Shuxing Zhang, Ph.D., assistant professor of Experimental Therapeutics and head of the Integrated Molecular Discovery Laboratory at MD Anderson, to identify and characterize the drug.

"There are many more chemical compounds available than there are estimated stars in the universe," Zhang said. "We have a database with 10 million compounds, but our prescreening analysis narrowed our computerized search to 120,000 and then further to find small-molecule candidates that inhibit Skp2."

Their inhibitor plugs critical binding sites on Skp2, preventing it from connecting to Skp1 to form a complex, which is the first step in its two cancer-promoting functions, Lin said.

Compound hits prostate, lung tumors

"This compound has a high degree of specificity ?" our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells," Lin said. Steps remain to define the drug's potential off-target effects before it can advance to human clinical trials, Lin said.

The researchers also found that the inhibitor suppresses prostate cancer stem cells, which play a role in cancer initiation, progression and resistance to chemotherapy.

Normally, Skp2 E3 ligase binds to and tags other proteins with molecules called ubiquitins, which can serve as activation signals or as targets marking the protein for destruction. Skp2 is overexpressed in numerous cancers and plays a critical role in cell cycle progression leading to cell division, metabolism and dormancy, as well as cancer progression and metastasis.

Lin and colleagues previously showed that Skp2 promotes cancer by:

Marking for destruction a cancer-stifling protein called p27 that renders cells senescent, or incapable of dividing. Firing up a signaling pathway that activates glucose metabolism (glycolysis), which cancer cells primarily rely upon to grow and survive. They also showed that the glycolysis pathway contributes to Herceptin resistance and shorter survival among breast cancer patients whose tumors heavily express the HER2 protein.

By analyzing the connection between Skp2 and Skp1, Zhang's group identified two pocket-like regions on Skp2 where the proteins connect.

Skp2 has been a logical target for cancer therapy, Zhang said, but presented two major obstacles.

Targeting protein-protein interactions is already difficult and Skp2 has a huge area where it interfaces with other proteins, making it hard to find one small molecule to completely block that surface.

"To begin such a search, to rationally design a drug, you must first understand the target's biology and then look at its structure and fully comprehend its complex interactions and how disrupting those will help treat the disease," Zhang said. "Once you understand those, you're ready to screen using computer models."

Virtual screening of the 120,000 compounds with a program developed by Zhang revealed 25 candidates that bind to either or both pockets. Additional analyses showed that Compound #25, also known as SZL-P1-41, effectively disrupted Skp1-Skp2 interactions.

Subsequent experiments showed Compound #25 suppresses Skp2-related tagging and destruction of the cell dormancy protein p27, restoring its expression in prostate cancer cells, and also stifles Skp2 signaling that activates the cancer-feeding glycolysis pathway.

Detailed experiments showed the drug's effect is achieved by binding specifically to one of the pockets on Skp2 to disrupt formation of the Skp2-Skp1 complex.

Initial cell line experiments showed Compound #25 selectively destroyed prostate cancer cells with minimal effects on normal tissue. The drug's effects were confirmed in two lung cancer cell lines and in liver and osteocarcinoma cell lines.

Underlying mechanisms for the drug's effect on prostate cancer cells proved to be cellular senescence initiation and glycolysis suppression.

Recent research indicates that glycolysis is important to cancer stem cell formation and that senescence through telomere shortening restrains cancer stem cell growth.

Since Compound #25 blocks glycolysis and promotes senescence, the team tested its effect on prostate cancer stem cells.

Treatment stymies cancer stem cell formation, shrinks tumors

Treating prostate cancer cells with the compound reduced the population of cancer stem cells in a dose-dependent manner. The drug didn't work at all in cancer cells where Skp2 had been silenced.

Because cancer stem cells are a major cause of chemotherapy resistance, the researchers treated cell lines with Compound #25 and either of the chemotherapies doxorubicin or cyclophosphamide. Combining the new drug tripled the cancer cell growth inhibition of doxorubicin and doubled that of cyclophosphamide.

Finally, evasion of cellular senescence and promotion of glycolysis are hallmarks of cancer progression and drug resistance. The team tested its drug in mice with prostate and lung tumors. In both cases, treated mice had tumors about a quarter of the size of those in mice injected with a control agent.

Lin, Zhang and MD Anderson have filed for patent protection of this work.

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Co-authors and funding

Co-authors include first author Chia-Hsin Chan, Ph.D., Yuan Gao, Guoxiang Jin, Ph.D., Asad Moten, Zhen Cai, Ph.D., Dazhi Xu, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson's Department of Molecular and Cellular Oncology; John Kenneth Morrow of Experimental Therapeutics; Loren Stagg, Ph.D., and John Ladbury, Ph.D., of Biochemistry and Molecular Biology; Christopher Logothetis, M.D., of Genitourinary Medical Oncology; and Chien-Feng Li, M.D., Ph.D., Chi-Mei Foundational Medical Center and the National Institute of Cancer Research, Taiwan.

Gao and Morrow are students in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

This research was funded by the MD Anderson Trust Scholar Award, MD Anderson's Prostate SPORE grant from the National Cancer Institute of the National Institutes of Health (P50 CA140388) and its NCI Cancer Center Support Grant (CA 016672), a grant from the American Cancer Society, an MD Anderson Center for Targeted Therapy-University of Texas at Austin Texas Institute for Drug and Diagnostics Development joint grant; and also a career development award from MD Anderson's NCI Breast Cancer SPORE and a Susan G Komen Foundation Postdoctoral Fellowship Award to Chan.

University of Texas M. D. Anderson Cancer Center

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Five genes identified that play major role in Takayasu arteritis

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

Additional authors: Travis Hughes, Kenan Aksu, Gokhan Keser, Patrick Coit, Sibel Z. Aydin,Fatma Alibaz-Oner, Sevil Kamali, Murat Inanc, Simon Carette, Gary S. Hoffman, Servet Akar, Fatos Onen, Nurullah Akkoc, Nader A. Khalidi, Curry Koening, Omer Karadag, Sedat Kiraz, Carol A. Langford, Carol A. McAlear, Zeynep Ozbalkan, Askin Ates,Yasar Karaaslan, Kathleen Maksimowicz-McKinnon, Paul A. Monach, Hu¨seyin T. Ozer, Emire Seyahi, Izzet Fresko, Ayse Cefle, Philip Seo, Kenneth J. Warrington, Mehmet A. Ozturk, Steven R. Ytterberg, Veli Cobankara, A. Mesut Onat, Joel M. Guthridge, Judith A. James, Ercan Tunc, Nursxen Duzgun, Muge Bicakcigil, Sibel P. Yentu¨r, Peter A. Merkel, Haner Direskeneli.

Disclosures: None

Funding: This work was made possible by funding from the University of Michigan, the Vasculitis Foundation, and the National Institutes of Health.

"Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis," American Journal of Human Genetics, August, 2013, doi:10.1016/j.ajhg.2013.05.026

Güher Saruhan-Direskeneli1, Travis Hughes2, Kenan Aksu3, Gokhan Keser3, Patrick Coit2, Sibel Z. Aydin4, 5, Fatma Alibaz-Oner4, Sevil Kamali6, Murat Inanc6, Simon Carette7, Gary S. Hoffman8, Servet Akar9, Fatos Onen9, Nurullah Akkoc9, Nader A. Khalidi10, Curry Koening11, Omer Karadag12, Sedat Kiraz12, Carol A. Langford8, Carol A. McAlear13, Zeynep Ozbalkan14, Askin Ates14, 15, Yasar Karaaslan14, 16, Kathleen Maksimowicz-McKinnon17, 18, Paul A. Monach19, Hüseyin T. Ozer20, Emire Seyahi21, Izzet Fresko21, Ayse Cefle22, Philip Seo23, Kenneth J. Warrington24, Mehmet A. Ozturk25, Steven R. Ytterberg24, Veli Cobankara26, A. Mesut Onat27, Joel M. Guthridge28, Judith A. James28, Ercan Tunc29, Nursen Duzgun15, Muge Bicakcigil30, Sibel P. Yentür1, Peter A. Merkel13, Haner Direskeneli4 and Amr H. Sawalha2*

Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA Department of Rheumatology, Faculty of Medicine, Ege University, Izmir 35100, Turkey Department of Rheumatology, Faculty of Medicine, Marmara University, Istanbul, 34890, Turkey Unit of Rheumatology, Goztepe Training and Research Hospital, Medeniyet University, Istanbul 34730, Turkey Department of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5L 3L9, Canada Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH 44195, USA Department of Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir 35340, Turkey Division of Rheumatology, St. Joseph’s Healthcare, McMaster University, Hamilton, ON L8N 1Y2, Canada Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey Department of Rheumatology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey Department of Rheumatology, Faculty of Medicine, Hitit University, Çorum 19200, Turkey Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA 15261, USA Division of Rheumatology, Henry Ford Health System, Detroit, MI 48202, USA Section of Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA Department of Rheumatology, Faculty of Medicine, Cukurova University, Adana 01330, Turkey Department of Rheumatology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul 34098, Turkey Department of Rheumatology, Faculty of Medicine, Kocaeli University, Kocaeli 41380, Turkey Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA Department of Rheumatology, Faculty of Medicine, Gazi University, Ankara 06500, Turkey Department of Rheumatology, Faculty of Medicine, Pamukkale University, Denizli 20160, Turkey Department of Rheumatology, Faculty of Medicine, Gaziantep University, Gaziantep 27310, Turkey Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA Department of Rheumatology, Faculty of Medicine, Suleyman Demirel University, Isparta 32260, Turkey Department of Rheumatology, Faculty of Medicine, Yeditepe University, Istanbul 34752, Turkey

Corresponding author*

University of Michigan Health System

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Hope for motion sickness victims: Key neurons identified that sense unexpected movement

Main Category: Neurology / Neuroscience
Also Included In: Public Health
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Hope for motion sickness victims: Key neurons identified that sense unexpected movement

It happens to all of us at least once each winter in Montreal. You're walking on the sidewalk and before you know it you are slipping on a patch of ice hidden under a dusting of snow. Sometimes you fall. Surprisingly often you manage to recover your balance and walk away unscathed. McGill researchers now understand what's going on in the brain when you manage to recover your balance in these situations. And it is not just a matter of good luck.

Prof. Kathleen Cullen and her PhD student Jess Brooks of the Dept of Physiology have been able to identify a distinct and surprisingly small cluster of cells deep within the brain that react within milliseconds to readjust our movements when something unexpected happens, whether it is slipping on ice or hitting a rock when skiing. What is astounding is that each individual neuron in this tiny region that is smaller than a pin's head displays the ability to predict and selectively respond to unexpected motion.

This finding both overturns current theories about how we learn to maintain our balance as we move through the world, and also has significant implications for understanding the neural basis of motion sickness.

Scientists have theorized for some time that we fine-tune our movements and maintain our balance, thanks to a neural library of expected motions that we gain through "sensory conflicts" and errors. "Sensory conflicts" occur when there is a mismatch between what we think will happen as we move through the world and the sometimes contradictory information that our senses provide to us about our movements.

This kind of "sensory conflict" may occur when our bodies detect motion that our eyes cannot see (such as during plane, ocean or car travel), or when our eyes perceive motion that our bodies cannot detect (such as during an IMAX film, when the camera swoops at high speed over the edge of steep cliffs and deep into gorges and valleys while our bodies remain sitting still). These "sensory conflicts" are also responsible for the feelings of vertigo and nausea that are associated with motion sickness.

But while the areas of the brain involved in estimating spatial orientation have been identified for some time, until now, no one has been able to either show that distinct neurons signaling "sensory conflicts" existed, nor demonstrate exactly how they work. "We've known for some time that the cerebellum is the part of the brain that takes in sensory information and then causes us to move or react in appropriate ways," says Prof. Cullen. "But what's really exciting is that for the first time we show very clearly how the cerebellum selectively encodes unexpected motion, to then send our body messages that help us maintain our balance. That it is such a very exact neural calculation is exciting and unexpected."

By demonstrating that these "sensory conflict" neurons both exist and function by making choices "on the fly" about which sensory information to respond to, Cullen and her team have made a significant advance in our understanding of how the brain works to keep our bodies in balance as we move about.

The research was done by recording brain activity in macaque monkeys who were engaged in performing specific tasks while at the same time being unexpectedly moved around by flight-simulator style equipment.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our neurology / neuroscience section for the latest news on this subject.

To read the full paper in Current Biology click here.

The research was funded by the Fonds de Recherche du Québec Nature et Technologies and Canadian Institutes of Health Research as well as through a National Institutes of Health grant.

McGill University

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'Hope for motion sickness victims: Key neurons identified that sense unexpected movement'

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Novel mechanism identified in host-pathogen gastroenteritis interactions

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: GastroIntestinal / Gastroenterology
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Novel mechanism identified in host-pathogen gastroenteritis interactions

A seafood contaminant that thrives in brackish water during the summer works like a spy to infiltrate cells and quickly open communication channels to sicken the host, researchers at UT Southwestern Medical Center report.

Vibrio parahaemolyticus bacteria, which cause gastroenteritis, inject proteins called effectors into host cells. One of those effectors, VopQ, almost immediately starts to disrupt the important process of autophagy via a novel channel-forming mechanism, the scientists report in the investigation available online at the Proceedings of the National Academy of Sciences. Autophagy is the cellular housekeeping mechanism used to recycle nutrients in cells as well as to fight off pathogens. The term autophagy comes from the Greek words for self and eating. During the process, nutrients are recycled by the lysosome, an internal organelle, to produce metabolites that can be used by the cell.

"Our study identifies a bacterial effector that creates gated ion channels and reveals a novel mechanism that may regulate autophagy," said Dr. Kim Orth, professor of molecular biology and biochemistry. She is a corresponding author on the published study. The first author is Anju Sreelatha, a graduate student in Dr. Orth's laboratory.

"Disruptions of autophagic pathways are implicated in many human diseases, including neurodegenerative disease, liver disease, some cancers, and cardiomyopathy (heart muscle disease)," Ms. Sreelatha said.

She explained that ion channels are pores in the membranes of cells or of organelles within cells that allow regulated passage of small molecules or ions across membranes. Gated channels have a mechanism that opens and closes them, making these proteins potential targets for drug development.

"The identification of a channel that opens and closes and thereby affects autophagy may give us a handle by which to modulate this important process," she said, adding that the researchers found that VopQ's channel activity turned off autophagy.

"During infection, VopQ is injected into the host cell where the protein binds to a lysosomal membrane protein and forms small pores, all within minutes of infection. The resulting complex of proteins causes ions to leak and the lysosomes to de-acidify. Lacking acidification, lysosomes cannot degrade the unneeded cellular components and autophagy is disrupted," Ms. Sreelatha said.

Dr. Orth said "Bacterial pathogens have evolved a number of ways to target and manipulate host cell signaling; the ability of VopQ to form a gated ion channel and to inhibit autophagy represents a novel mechanism."

Further characterization of the mechanism by which VopQ sabotages cells to disrupt autophagy may lead to a better understanding of host-pathogen interactions as well as advance our understanding of the pathway, eventually leading to new treatments for diseases in which autophagy has gone awry, they noted.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our infectious diseases / bacteria / viruses section for the latest news on this subject.

Other UT Southwestern scientists involved were Dr. Hui Zheng, a postdoctoral researcher of cell biology, and Dr. Qiu-Xing Jiang, assistant professor of cell biology. Also participating were Terry Bennett and Dr. Vincent Starai of the University of Georgia.

Funding was provided by the National Institute of Allergy and Infectious Diseases; the Burroughs Wellcome Foundation; the Welch Foundation; the National Institute of General Medical Sciences; the Cancer Prevention and Research Institute of Texas; and by University of Georgia Startup Funds.

UT Southwestern Medical Center

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'Novel mechanism identified in host-pathogen gastroenteritis interactions'

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