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Cedars-Sinai Medical Center Physicians And Scientists Present Findings At Annual Meeting Of The Pediatric Academic Societies

Cedars-Sinai Medical Center

LOS ANGELES (May 2, 1999) -- Researchers at Cedars-Sinai Medical Center are presenting three scientific lectures and several poster-session exhibits at the Pediatric Academic Societies' 1999 Annual Meeting May 1 through 4 in San Francisco.

The first lecture was presented at 9:45 a.m. Sunday, May 2, as part of a program on neuroprotective strategies for hypoxic-ischemic encephalopathy - the effort to reduce or prevent damage to brain cells when blood supply to the brain is reduced or blood to the brain contains insufficient oxygen.

For some time, researchers have thought that the administration of magnesium may have a "protective effect" on brain cells, although the exact mechanism has not been understood. Neonatologist Richard C. Krueger, Jr., M.D., Ph.D., discussed the results of a study that advances this theory, suggesting that the administration of magnesium "could have a dramatic impact on neural development." The study was conducted by researchers at Cedars-Sinai and Chicago Children's Hospital.

The researchers placed brain cells of embryonic chickens into a culture containing only a small amount of magnesium. After five days, they added another measured amount of magnesium, analyzing the cells 24 hours later for overall viability (the ability to live, grow and develop), apoptosis (disintegration), and proliferation (reproduction).

No change was seen in the level of disintegration but both cell viability and proliferation increased. A subsequent test indicated that the cells proliferating during the initial 24-hour period were precursors to glia cells - the supportive structures of the nervous system.

This rapid reproduction of glial precursors is believed to be at least partly due to activation of PI3 Kinase, an enzyme that interacts with other cell proteins and plays an instrumental role in cell growth and other activities. When wortmannin -- a substance that inhibits the activity of PI3 Kinase and is known to cause cell disintegration -- was introduced, the increases in cell viability and proliferation stopped.

Furthermore, the added magnesium appeared to boost wortmannin's ability to cause cell disintegration. This suggests that the addition of extracellular magnesium causes cells to be more dependent on certain "growth factors" that need PI3 Kinase to function. Growth factors are proteins that are involved in cellular responses to growth hormone.

In addition to having at least an indirect role in activating PI3 Kinase, the addition of magnesium activates Akt, an anti-apoptotic kinase that is activated "downstream" from PI3 Kinase.

With this research, increased extracellular magnesium has for the first time been shown to increase cell proliferation in neural cells in culture. This is also the first study to suggest that increased extracellular magnesium may alter the regulation of PI3 Kinase.

The presentation is titled "Increased Extracellular Magnesium Increases Cellular Viability and Cellular Proliferation in Primary Cell Culture of Embryonic Chick Telencephalon: Mechanisms of Magnesium's Action."

The second lecture began at 2:45 p.m. Sunday, May 2. Moshe Arditi, M.D., director of the Division of Pediatric Infectious Diseases, presented a study titled "Bacterial Lipopolysaccharide (LPS) Activates NF-kappa B through Interleukin-1 (IL-1) Signaling Mediators in Cultured Human Endothelial Cells and Mononuclear Phagocytes."

For years, doctors and scientists have sought to understand a complicated mechanism that triggers an over-aggressive immune response in many patients who suffer from severe microbial infections. This immune system overreaction often leads to septic shock, for which no reliable treatments have been found.

Cases of septicemia caused by bacteria that fall into the "Gram-negative" classification have been particularly perplexing. Gram-negative organisms cause about half of all cases of septicemia, a bacterial infection that invades the bloodstream and often leads to septic shock. More than 20,000 people in the United States die each year from septic shock resulting from Gram-negative septicemia.

Gram-negative bacteria contain a toxin, called lipopolysaccharide (LPS) or endotoxin, on their outer membranes. Even tiny amounts of endotoxin shed from the bacteria into the blood are recognized by the immune system, which activates various types of cells, including white blood cells that produce inflammatory molecules called cytokines. Cytokines destroy invading pathogens but if the production of cytokines continues unchecked, they actually become toxic themselves. Patients suffering from septicemia who progress to septic shock actually may die as a result of the excessive immune response rather than from the initial bacterial infection alone.

In this study, headed by Dr. Arditi and involving researchers at Cedars-Sinai and several other institutions, scientists have for the first time identified in actual human cells a "receptor" that may be a key component of this process.

Scientists had previously discovered that a "Toll receptor" found in the cells of fruit flies and even in a number of plants is responsible for triggering the "innate" or primitive immune system to fend off invading organisms. Suspicions and evidence have been mounting over the past several years that similar "Toll-like receptors" exist in humans. In fact, five Toll-like receptors have recently been cloned and several others have been identified.

In this study using human endothelial cells (cells that line the blood vessels) and human monocytes (blood cells that are important in fighting infection), the researchers provided proof that endotoxin uses a Toll-receptor signaling pathway within human cells to induce NF-kappa B (a protein that turns on genes that make cytokines and trigger inflammatory responses). They also were able to show the presence of Toll-like receptors (TLR2 and TLR4) on the surface of the human cells. Identifying the receptors and the signaling pathways may be a crucial step in developing new approaches to stop the deadly cascade of septicemia and septic shock.

John M. Graham, Jr., M.D., Sc.D., director of Clinical Genetics and Dysmorphology at the Cedars-Sinai Medical Genetics Birth Defects Center, will present a lecture titled "Cole-Hughes Macrocephaly-Mental Retardation Syndrome and Associated Autistic Features" beginning at 9:45 a.m. Tuesday, May 4.

Dr. Graham will present the case of a child with Cole-Hughes syndrome, a disorder characterized by an abnormally large head (macrocephaly) and mental retardation. The child exhibits distinctive behavioral patterns and features of autism, and researchers believe this newly recognized behavioral manifestation may also be a part of Cole-Hughes syndrome.

One of several macrocephalic disorders, Cole-Hughes was first differentiated from similar syndromes in 1991 by researchers in the United Kingdom. It is marked by a large head that continues to undergo accelerated growth for the first few years of life, distinctive facial features, mental retardation, and a family history of macrocephaly.

In 1997, another group of researchers noted a link between autism and macrocephaly, suggesting that macrocephaly may be a recognizable feature of a syndrome associated with autism. Dr. Graham and his colleagues are studying several other Cole-Hughes syndrome cases to determine if autistic features are a regular part of this syndrome.

Cedars-Sinai researchers will also be represented at several poster-session exhibits, including:

Tuesday, May 4, 1 p.m., "Effects of Lipopolysaccharide (LPS) and p38 MAP Kinase Pathway in Primary HIV-1 Infection of Normal Donor Peripheral Blood Mononuclear Cells (PBMC)," Moshe Arditi, M.D., director of the Division of Pediatric Infectious Diseases.

This study investigated the effect of lipopolysaccharide (LPS) on HIV-1 replication in mononuclear cells circulating in the blood (peripheral blood mononuclear cells or PBMCs).

Normal mononuclear cells were infected with HIV-1 strain and later treated with LPS and p38 MAP Kinase. P38 MAP Kinase is a human enzyme involved in the signaling pathways within cells. When activated, the p38 MAP Kinase also triggers the production of cytokines that launch an inflammatory immune response.

According to the results, LPS enhances the effect of HIV-1 replication in previously infected PBMCs. This effect can be blocked, however, by inhibiting the p38 MAP Kinase signaling pathway. This indicates that the p38 MAP Kinase pathway of the cell is involved in carrying the LPS signal. The researchers suggest, therefore, that blocking this signaling pathway may have the potential to block HIV-1 replication in infected PBMCs.

"Another implication of this study," said Dr. Arditi, "is that LPS or endotoxin could potentially be used - as interleukin-2 is now used - to stimulate dormant HIV-1 virus in tissues of patients who have undetectable viral load, to 'flush out' the virus."

Tuesday, May 4, 1 p.m., "Bosma Arhinia Microphthalmia Syndrome," John M. Graham, Jr., M.D., Sc.D., director of Clinical Genetics and Dysmorphology at the Cedars-Sinai Medical Genetics Birth Defects Center. Dr. Graham reports new cases of a previously described disorder, Bosma Arhinia Microphthalmia Syndrome. Although these individuals are of normal intelligence, they have a number of physical abnormalities, including abnormally small eyes, lack of a nose, failure of the testicles to descend into the scrotum, and defective function of the gonads.

The presentation describes the gestational stages during which these malformations should develop and suggests certain genes that may be responsible for the disorder. The fact that Bosma syndrome has been previously reported within families lends support to the possibility that this is a genetic disorder. Also, it is important for physicians to recognize infants with this syndrome because its characteristic facial features are similar to those seen in a disorder with a much poorer prognosis (holoprosencephaly malformation sequence).

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