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PUBLIC RELEASE DATE:
2-Jun-2008

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Contact: Karen Honey
press_releases@thje-jci.org
215-573-1850
Journal of Clinical Investigation
@jclinicalinvest

JCI online early table of contents: June 2, 2008

EDITOR'S PICK: Molecular changes in brain fluid give insight into brain-damaging disease

Soon after an individual becomes infected with HIV the virus infects cells in the brain and spinal cord (the central nervous system [CNS]). Although this causes no immediate problems, during the late-stages of disease it can cause dementia and encephalitis (acute inflammation of the brain that can cause death). Monkeys infected with a relative of HIV (SIV) also sometimes develop CNS damage and provide a good model of CNS disease in individuals infected with HIV. Insight into the mechanisms of CNS damage in SIV-infected monkeys has now been provided by a team of researchers at The Scripps Research Institute, La Jolla, who developed an approach to identify molecular changes in the fluid bathing the CNS (the CSF). The researchers, who were led by Howard Fox and Gary Siuzdak, hope that similar approaches could be used to provide new information about other neurodegenerative and neuropsychiatric disorders.

In the study, an approach known as global metabolomics was used to assess the levels of molecules known as metabolites in the CSF before and after SIV-induced encephalitis was manifest. The level of a number of metabolites, including some known as fatty acids and phospholipids, was observed to increase during infection. Consistent with this, a protein known to be important in the generation of fatty acids was found to be increased in the brain of monkeys with SIV-induced encephalitis. Further studies will be required to determine the precise role of the increased level of each metabolite, but it should be noted that many of them are known to induce receptor signaling and thereby might be able to further modulate CNS function.

TITLE: Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

AUTHOR CONTACT:

Howard S. Fox
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-7171; Fax: (858) 784-7296; E-mail: hsfox@scripps.edu or hfox@unmc.edu.

Gary Siuzdak
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-9415; Fax: (858) 784-9496; E-mail: siuzdak@scripps.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34138


METABOLISM: It's not a level playing field, your genes determine your levels of glucose

In individuals with type 2 diabetes, the way the level of glucose (the sugar molecule that is our main source of energy) in the body while not eating (fasting glucose level) is regulated fails and fasting glucose levels increase dramatically. New insight into genetic variations that have an impact on the fasting glucose levels of nondiabetic individuals has now been provided by a team of researchers from the Istituto Nazionale Ricovero E Cura Anziari, Italy, and the University of Southern California. Specifically, an association between one defined genetic variation and increased fasting glucose levels was observed in nondiabetic individuals. This variation was located between two genes known as G6PC2 and ABCB11. As G6PC2 carries the information for making a protein expressed by the cells that become dysfunctional in individuals with type 2 diabetes, the authors suggest that the genetic variation probably affects fasting glucose levels by altering the expression of this gene.

TITLE: Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels

AUTHOR CONTACT:

Angelo Scuteri
Istituto Nazionale Ricovero E Cura Anziari, Rome, Italy.
Phone: 39-3334564136; Fax: 39-06-30362896; E-mail: angeloelefante@interfree.it.

Richard M. Watanabe
Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Phone: (323) 442-2053; Fax: (323) 442-2349; E-mail: rwatanab@usc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34566


DERMATOLOGY: Pinning down a cause of disease in a model of psoriasis

Psoriasis is a chronic skin disease that affects approximately 2-3% of individuals in the Western world. New data, generated by Karin Scharffetter-Kochanek and colleagues, at the University of Ulm, Germany, have indicated that a subset of immune cells known as Tregs (which act to prevent other immune cells from responding inappropriately) are dysfunctional in a mouse model of psoriasis and that this dysfunction contributes substantially to the development of disease.

Mice that express a reduced amount of the protein CD18 (Cd18hypo mice) develop a skin disease that resembles the symptoms of individuals with psoriasis. In the study, Tregs isolated from Cd18hypo mice failed to suppress the proliferation of disease-causing immune cells because they secreted lower levels of the soluble factor TGF-beta than normal Tregs. This was also important for their inability to control disease in vivo, as transplantation of normal Tregs into Cd18hypo mice resulted in a substantial improvement in the psoriasis-like disease, whereas if these cells were transplanted in the presence of antibodies that neutralized TGF-beta there was no improvement in disease. The authors therefore conclude that psoriasis-like disease in Cd18hypo mice is caused mainly by a defect in Treg function and suggest that maintaining CD18 levels is important for ensuring that Tregs function optimally.

TITLE: TGF-beta-dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis

AUTHOR CONTACT:
Karin Scharffetter-Kochanek
University of Ulm, Ulm, Germany.
Phone: 49-731-50057501; Fax: 49-731-50057502; E-mail: karin.scharffetter-kochanek@uniklinik-ulm.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34916


NEUROBIOLOGY: HSN2 mutations lose touch with pain and heat perception

Hereditary sensory and autonomic neuropathy type II, abbreviated to HSANII, is a poorly understood genetic disorder wherein affected patients lose the ability to feel touch, pain, and heat. Although it has been shown to be caused by mutations in a region of DNA known as HSN2, it was not known exactly what this region of DNA was for. In a new study, Guy Roulaeu and colleagues, at the University of Montreal, Canada, have discovered that HSN2 is part of the gene WNK1, but it is only used to generate a protein in the nervous system; in other parts of the body, the gene WNK1 does not use the information in the HSN2 region of DNA to make protein. Further analysis showed that the protein made using information contained in the HSN2 region of DNA (WNK1/HSN2) was found in mouse nerve cells that are vital for relaying sensory inputs such as touch and pain to the brain. Future studies will focus on determining the molecular mechanisms by which WNK1/HSN2 is important for sensing touch, pain, and heat, the very senses lost in individuals with HSANII.

TITLE: Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

AUTHOR CONTACT:
Guy A. Rouleau
University of Montreal, Montreal, Quebec, Canada.
Phone: (514) 890-8000 ext. 24594; Fax: (514) 412-7602; E-mail: guy.rouleau@umontreal.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34088


ONCOLOGY: Linking genes to decreased survival in lung cancer patients

New data, generated by Hongbing Shen and colleagues, at the Cancer Center of Nanjing Medical University, People's Republic of China, has identified a genetic variation that seems to help predict survival in individuals with non-small cell lung cancer (NSCLC).

A systematic screen of the DNA carrying the information for generating regulatory RNA molecules known as a microRNAs identified a specific genetic variant that was associated with decreased survival in individuals with NSCLC. The specific genetic variation resulted in increased levels of expression of the functional miRNA molecule. This was not because more of the miRNA was made but because more of the precursor form of the functional molecule was processed to become functional. The functional miRNA molecule generated by the genetic variation also had different functional properties. The authors hope that further characterization of genetic variations that modify miRNA expression and/or function will uncover other indicators of survival and opportunities for developing new therapeutics.

TITLE: Genetic variants of miRNA sequences and non-small cell lung cancer survival

AUTHOR CONTACT:
Hongbing Shen
Cancer Center of Nanjing Medical University, Nanjing, People's Republic of China.
Phone: 86-25-868-62756; Fax: 86-25-868-62756; E-mail: hbshen@njmu.edu.cn.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34934


VASCULAR BIOLOGY: Blood vessel growth kept under control by the protein LIF

Uncontrolled blood vessel growth is a key feature of many pathological conditions, including the degenerative diabetic eye disease known as diabetic retinopathy. Understanding the factors involved in the process is vital to developing treatments for the disease. In a new study, a team of researchers at Keio University, Japan, has revealed a role for the protein LIF in blood vessel growth in mice.

Specifically, mice lacking LIF were observed to have increased blood vessel growth in many regions of the body, but as this study was focused on the eye, the authors homed in on the increased blood vessel growth in the retina of the eye. Further analysis showed that mice lacking LIF developed more aberrant blood vessels in a model of retinopathy. Mechanistically, LIF was found to inhibit the proliferation of brain cells known as astrocytes as well as inhibit their production of a factor known to promote blood vessel growth, VEGF. It therefore seems that LIF is an important part of the communication between tissues and developing blood vessels, meaning that LIF and the signaling pathway it triggers might serve as a target for new treatment approaches for preventing diabetic retinopathy and other diseases that are associated with uncontrolled blood vessel growth, such as cancer.

TITLE: Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice

AUTHOR CONTACT:

Yoshiaki Kubota
Keio University, Tokyo, Japan.
Tel: 81-3-5363-3475; Fax: 81-3-5363-3475; E-mail: ykubo33@sc.itc.keio.ac.jp.

Toshio Suda
Keio University, Tokyo, Japan.
Tel: 81-3-5363-3475; Fax: 81-3-5363-3475; E-mail: sudato@sc.itc.keio.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34882


ONCOLOGY: Repairing the damage to DNA from chronic inflammation protects against cancer

Individuals who have health conditions associated with chronic inflammation are often at increased risk of developing cancer at the site of the chronic inflammation. For example, individuals with inflammatory bowel disease and those who are chronically infected with the bacterium Helicobacter pylori are at increased risk of colon cancer and stomach cancer, respectively. New insight into the mechanisms by which chronic inflammation can contribute to the development cancer has been generated in mice by Leona Samson and colleagues, at Massachusetts Institute of Technology, Boston.

Using mice lacking the protein Aag, which is involved in the repair of DNA damaged by inflammation-associated molecules known as reactive oxygen and nitrogen species (RONS), it was shown that Aag-mediated DNA repair limits cell damage in a mouse model of episodic inflammatory bowel disease and reduces the severity of the colon cancer that develops in the mice experiencing episodic bowel inflammation. In addition, in a mouse model of Helicobacter pylori infection, Aag-deficient mice were found to exhibit more severe cell damage and the damaged area of the stomach resembled that observed prior to the development of stomach cancer. The authors therefore conclude that repair of DNA damage caused by RONS seems to be important for protection against chronic inflammation-induced cancer.

TITLE: DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

AUTHOR CONTACT:
Leona D. Samson
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Phone: (617) 258-7813; Fax: (617) 253-8099; E-mail: lsamson@mit.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35073

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