HOUSTON -- (June 30, 2008) -- Eleven years ago, Dr. Mary Estes of Baylor College of Medicine and her colleagues discovered the first viral enterotoxin, rotavirus NSP4, a toxic protein that affects the intestines, causing diarrhea.

The next step was to find the cellular receptor on intestinal cells through which the enterotoxin interacts to cause diarrhea.

"We knew that identifying the receptor might not be straightforward," said the professor of molecular virology and microbiology at BCM. In a report online in the Proceedings of the National Academy of Sciences, Estes and her colleagues describe two receptors for the enterotoxin, both of them integrins.

The two, integrin alpha1 beta1 and integrin alpha2 beta1, are members of a class of molecules that are involved in attaching cells to other cells and to the extracellular matrix (a part of tissue that is not part of any cell). Integrins also are involved in transforming or translating cell signals.

In looking for the receptor, Estes and her colleagues also learned more about the enterotoxin itself.

"It's a new ligand for binding to integrins," she said. "It begins to give us an understanding of how the enterotoxin works in the intestine. Two different domains of the enterotoxin are involved in this interaction. One domain is for binding and the other domain is for signaling through the receptor."

She said she hopes to study the signaling aspect of the enterotoxin more closely because it could hold the clue to the mechanism of induction of diarrheal disease.

"There may be ways to block the interaction between the enterotoxin and the receptor to treat diarrheal disease," said Estes, who is also director of the Texas Medical Center Digestive Diseases Center.

Rotavirus is one of the most common causes of diarrhea, resulting in approximately 3 million cases of diarrhea and 55,000 hospitalizations for diarrhea and dehydration in children under the age of 5 each year in the United States alone. Worldwide, it causes nearly half a million deaths each year. Finding out how rotavirus causes diarrhea and looking for ways to block it is a major aim of Estes' research.

Others who took part in this work include Carl Q.-Y. Zeng, Joseph M. Hyser, Budi Utama and Sue E. Crawford of BCM, Neung-Seon Seo, Kate J. Kim and Magnus Hőők of Texas A&M University Health Science Center at Houston.

Funding for this work came from the National Institutes of Health, including a grant that funds the Texas Medical Center Digestive Diseases Center.

The paper is available at http://www.pnas.org/cgi/reprint/0803934105v1.

HOUSTON -- (June 26, 2008) -- Lack of both the fragile X syndrome gene and one that is related could account for sleep problems associated with the disorder, which is the common cause of inherited mental impairment, said a consortium of researchers led by scientists at Baylor College of Medicine in Houston. Their findings appear in a report in the current issue of the American Journal of Human Genetics.

Mice deficient in the fragile X mental retardation 1 gene (FMR1) and a similar gene called fragile X-related gene 2 (FXR2) have no rhythm to their wake and sleep pattern, said Dr. David Nelson, professor of molecular and human genetics at BCM and co-director of the Interdepartmental Program in Cell and Molecular Biology.

Normal mice have a sleep-wake cycle of just under 12 hours awake and 12 hours asleep. Exposed to light and dark, they are awake in the dark and asleep during the light because they are nocturnal animals. If they are kept in the dark, their cycle reduces by about 10 minutes per sleep-wake period but remains fairly normal. When mice do not have either FMR1 or FXR2, they have a slightly shorter cycle but the difference is not dramatic.

"However, the double-mutants (those without both genes) have no rhythm at all," said Nelson. "This has never been seen in a mouse before." The animals, usually kept in a cage with a wheel on which they run when awake, sleep a little, run a little, sleep a little – but there is no rhythm to it.

The finding is important because parents whose children have autism or fragile X report problems getting their children to go to sleep and stay asleep. Fragile X is the most common known cause of autism. While there are few studies on the topic, said Nelson, "the impression I have is that many fragile X patients have a period of time that's like an extended infancy when they don't settle into a typical sleep–wake period."

Understanding how the gene associated with fragile X affect the circadian clock or the sleep-wake cycle could help explain some of the symptoms experienced by patients, he said.

After ruling out the possibility that the animals without the two genes could not perceive light, Nelson collaborated with a group in The Netherlands to test whether the cell's "central clock" called the suprachiasmatic nucleus in the animals was normal. They concluded that the clock was normal but that somehow the expression of genes that govern it is altered in these mice.

"These genes (FMR1 and FXR2) are new players in the control of circadian (daily) rhythms," said Nelson. Currently, the genes are thought to have a role in translating RNAs (ribonucleic acids) – particularly at the receiving side of the connections between neurons called dendrites. Dendrites are characterized by the fine branches that reach out into tissue. Scientists theorize that FMR1 and FXR2 may be involved in transporting the RNAs to the areas of those branches where the synapse is present.

Others who took part in this work include Jing Zhang and Zhe Fang of BCM, Corinne Jud and Urs Albrecht of the University of Fribourg in Switzerland, Mariska J. Van Steensel and Johanna H. Meijer of Leiden University Medical Center in The Netherlands, Krista Kaasik and Cheng Chi Lee of The University of Texas Health Science Center at Houston and Ben A. Oostra of Erasmus University Medical Center in Rotterdam, The Netherlands.

Funding for this work came from the U.S. National Institute of Child Health and Human Development, the BCM Mental Retardation and Developmental Disability Research Center, the Fragile X Research (FRAXA) Foundation, the Swiss National Science Foundation and EUCLOCK, a project on the circadian clock sponsored by the European Commission.

The article is available at http://www.ajhg.org/.

HOUSTON -- (June 25, 2008) -- Transplanting brain cancer cells directly into similar tissues of immune-deficient mice created a model for the disease that preserved the brain tumor stem cells from which the cancers derived, said researchers at Baylor College of Medicine in Houston in a report that appears in the current issue of the journal Stem Cells.

"We have demonstrated that it looks like the human tumor behaves like and preserves this critical cell population," said Dr. Xiao-Nan Li, assistant professor of pediatrics – hematology and oncology at BCM and Texas Children’s Cancer Center, the pediatric program of The Dan L. Duncan Cancer Center at BCM.

The transfer of tissue takes place within an hour of surgery on the human patients and occurs in an anatomically matched location, he said.

For example, if the tissue is taken from the human cerebellum, it is transplanted into the mouse cerebellum. Li and his associates believe this helps the tumor cells grow better.

Maintaining supplies of the cancer stem cells from the two kinds of tumors – glioma and medulloblastoma – enables researchers to generate enough of the cells to study them, said Li.

He and his colleagues plan to expand the technique to other kinds of cancers, which should allow them to understand how these stem cells keep cancers going. That should help develop ways to block tumor growth.

"It gives us a model system in which to test new compounds and therapeutics," said Li.

Others who took part in this work include Qin Shu, Kwong Kwok Wong, Jack M. Su, Adekunle M. Adesina, Li Tian Yu, Barbara C. Antalffy, Patricia Baxter, Laszlo Perlaky, Jianhua Yang, Robert C. Dauser, Murali Chintagumpala, Susan M. Blaney and Ching C. Lau, all of BCM and the Texas Children's Cancer Center. Yvonne T.M. Tsang and Wong are affiliated with The University of Texas M. D. Anderson Cancer Center.

Funding for this work comes from the Childhood Brain Tumor Foundation, Cancer Fighters of Houston and the National Brain Tumor Foundation.

The report can be found at http://stemcells.alphamedpress.org/cgi/reprint/26/6/1414.pdf.

HOUSTON -- (June 23, 2008) -- For about one-fourth of people with an inherited heart problem called long QT syndrome, the source of their problem was a mystery – until researchers at Baylor College of Medicine, the Texas Heart Institute and Texas Children's Hospital in Houston pinpointed a defect in a structural protein in a report in current edition of the journal Circulation: Arrhythmia and Electrophysiology.

A mutation in a cytoskeletal protein called alpha-1-synotrophin, one of the molecules that helps heart cells maintain their shape, changes the functioning of a tiny pore called a sodium ion channel, resulting in long QT syndrome in at least a portion of these patients, said Dr. Matteo Vatta, assistant professor of pediatrics - cardiology at BCM and associate director of pediatric cardiac research. Vatta is senior author of the report.

Until now, defects in genes for particular ion channels have been blamed for inherited long QT syndrome, said Vatta. However, experts could identify no defects in about 25 percent of people with the problem.

Ions are charged chemicals such as sodium or potassium that flow in and out of pores called channels in the cell membranes. The channels open and close in a specific sequence, letting the chemicals in and out of cell in a manner that prompts them to beat in synchrony. When the cells can beat in unison, the heart pumps blood. If the ion channels are defective, it affects the beating of the cells and the heart – often with devastating effects. Untreated long QT syndrome can cause the heart to stop suddenly.

"The mutation in this kind of protein called alpha-1-syntrophin is the first associated with long QT syndrome," said Vatta. Previously, he and colleagues had identified a link between long QT syndrome and a defect in caveolin-3, a scaffolding protein.

"I am interested in the connection between the structural and the electrical part of the heart," said Vatta, whose lab is based in the Feigin Center of Texas Children's. "It could have everything to do with susceptibility to arrhythmias (heart rhythm disruptions) in patients with heart disease. First, we had to prove that the structural part of the heart could be involved in electrical problems."

The caveolin-3 finding led to studies of syntrophin, a protein connected to dystrophin, which when mutated causes Duchenne and Becker muscular dystrophy as well as the X-linked form of cardiomyopathy. As people with Duchenne and Becker muscle-wasting disease age, they develop cardiomyopathy, a weakening of the heart muscle, with heart rhythm disruptions called arrhythmias. This leads to heart failure and an increased risk of sudden cardiac death (sudden heart stoppage) caused by the arrhythmias.

"Syntrophin is the bridge that connects dystrophin to the sodium channel," said Vatta. Dystrophin is critical in the binding of syntrophin to the sodium channel, he said. A mutation in syntrophin disrupts the proper functioning of the sodium channel.

That leads to an electrical problem that disrupts the normal beating of the heart, he said. The finding is proof of the concept that patients with mutations in the structural part of the heart muscle cells also have a problem with how the electrical system of the heart works, leading to dysrhythmias.

"Once you screen all the ion channels and do not find changes that can lead to a pathological effect such as long QT syndrome, then you have to think about all the proteins that interact with the ion channels," Vatta said.

Others who took part in this study include Geru Wu, Tomohiko Ai, Yutao Xi, Shahrzad Abbasi, Kaveh Samani and Jie Cheng, all of the Texas Heart Institute/St. Luke's Episcopal Hospital in Houston; Jeffrey J. Kim, Bhagyalaxmi Mohapatra, Zhaohui Li, Enkhsaikhan Purevjav and Jeffrey A. Towbin, all of BCM and Texas Children's; Michael J. Ackerman of the Mayo Clinic in Rochester, Minnesota, and Ming Qi and Arthur J. Moss of the University of Rochester Medical Center in New York.

Support for this work came from the National Heart, Lung, and Blood Institute and the National Institute of Child and Health Development, the Roderick D. MacDonald General Research Fund, the Cardiovascular Initiative Grant from the St. Luke's Episcopal Hospital/Texas Heart Institute and the Texas Children's Foundation.

The abstract of this report is available at http://circep.ahajournals.org/cgi/content/abstract/CIRCEP.108.769224v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=vatta%2C+m&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1
&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT.

Healthy individuals who gain weight, even to a weight still considered normal, are at risk for developing chronic kidney disease (CKD), as per a research studyappearing in the September 2008 issue of the Journal of the American Society Nephrology (JASN). The study suggests that CKD should be added to the list of conditions that are linked to weight gain, including diabetes and hypertension.

Research has shown that obesity is associated with an increased risk of CKD, but no studies have looked at the effects of weight gain within the "normal" range of an individual's body mass index. To investigate, Drs. Seungho Ryu and Yoosoo Chang of the Kangbuk Samsung Hospital in Seoul, Korea, and their colleagues conducted a prospective study of individuals who were of a healthy weight and had no known risk factors for chronic kidney disease.

In Korea, all workers participate in either annual or biennial health exams, as mandatory by Korea's Industrial Safety and Health Law. As a result, the researchers had access to clinical data from thousands of individuals. For this study, they included 8,792 healthy men who participated in the health exams in 2002.

The scientists discovered a U-shaped association between weight change and development of CKD. Men who lost or gained a lot of weight (more than 0.75 kg per year) had the highest risk of developing CKD. Those whose weight changed minimally (within a range of -0.25 to