JCI table of contents, 1 July 2004

06/25/04

This press release contains summaries of newsworthy papers to be published online on 1 July 2004, in the Journal of Clinical Investigation including: A Pregnant Pause for Unexpected Interactions; Half at the Wrong Time Creates Bad Blood; Cancer Patient, Heal Thyself; PAF-way to Bone Loss; Immunology Link May Make You Lose Your Appetite; and PPAR for the Course. Contact information is included for all authors as well as a directory of other articles appearing in the same issue and papers appearing online first.


A Pregnant Pause for Unexpected Interactions

Approximately 1-–3% of all couples experience recurrent pregnancy loss, and about 50–70% of all conceptions fail. The underlying molecular mechanisms causing these heartbreaking conditions, however, remain unknown. Many cases of pregnancy loss are known to due to damage to the fetus through genetic, anatomic, endocrine, or Infectious means. When such causes are ruled out, the other source is thought to be caused by a maternal immune response. Most of the research in this arena has focused on identifying reactions at the maternal-fetal interface in the placenta. Adrian Erlebacher and colleagues, from Harvard School of Public Health, have now, however, identified new means by which maternal immune activation can lead to pregnancy failure. Here, the authors provide a mouse model of early pregnancy loss and present data that unexpectedly links the reproductive hormone secretion system to the immune system. The mouse model shows that when a specific immune cell receptor called CD40 is activated early in pregnancy the resulting inflammatory response caused embryo resorption. The researchers traced the molecular mechanisms underlying this process, and found that the loss of the embryo was not due to fetal damage or activity at the fetal-maternal interface, but rather because the inflammatory response ultimately caused a decrease in progesterone, the hormone responsible for preparing the body for pregnancy and maintaining it until birth. These data make it clear that the immune system, by interfering with the reproductive hormones, may contribute to human infertility, especially in cases of recurrent pregnancy loss. Further the finding that there is a link between the immune system and the reproductive hormone secretion may provide a new means of therapy for women who suffer such repeated and early pregnancy loss by targeting the mediators of such inflammatory responses.

An accompanying commentary, by Jane Salmon at the Hospital for Special Surgery, provides an overview of the immune response system, the reproductive hormone system, and places the data from the paper by Erlebacher and colleagues in context with that and potential clinical treatments.

TITLE: Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
AUTHOR CONTACT:
Adrian Erlebacher
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617-432-0924; Fax: 617-432-0084; Email: aerlebac@hsph.hardvard.edu

View the PDF of this article at: https://www.the-jci.org/press/20645.pdf

ACCOMPANYING COMMENTARY: A noninflammatory pathway for pregnancy loss: innate immune activation?
AUTHOR CONTACT:
Jane E. Salmon
Hospital For Special Surgery, New York, New York, USA.
Phone: 212-606-1422; Fax: 212-717-1192; E-mail: salmonj@hss.edu

View the PDF of this article at: https://www.the-jci.org/press/22258.pdf


Half at the Wrong Time Creates Bad Blood

The identification of a genetic mechanism that underlies one form of thrombocytopenia, may provide new understanding of other completely unrelated diseases. Thrombocytopenias are bleeding disorders that occur world-wide and can become life-threatening situations where a person can bleed uncontrollably from large or small blood vessels. The physical cause is the lack of functioning blood platelets, which promote blood clotting. There are several forms of thrombocytopenia, each with different genetic and molecular mechanisms underlying the lack of functioning platelets; studies in any one of these types of thrombocytopenia, no matter how rare, often provide useful insight into the condition as a whole. Now, work by Remi Favier, William Vainchenker, and colleagues, on a very rare form of thrombocytopenia called Paris-Trousseau/Jacobsen thrombopenia, have now provided not only new understanding of these blood diseases, but have uncovered a genetic mechanism that may underlie other diseases as well. In Paris-Trousseau/Jacobsen thrombopenia, the lack of platelets is caused by a defect in the production of platelets from their progenitor cells called megakaryocytes, large cells found in the bone marrow. A defect in one copy of a gene called FLI1 causes this disease. The researchers, in investigating the expression of this gene, discovered it had an unexpected expression pattern. Most of the time, both copies of FLI1 are expressed in cells, but in the early stages of megakaryocytes development, there is a brief period where only one copy of the gene is expressed. This transient single-copy expression apparently occurs at a critical stage in megakaryocyte differentiation, such that if there is a mutation in one copy of FLI1 during this period, the megokaryocyte will not mature properly, and will therefore ultimately be unable to produce the platelets required for blood clotting. This discovery of transient single-copy expression at an apparently critical time during cellular differentiation explains why this disease occurs even in the presence of one working copy of the gene. This genetic mechanism may also underlie other diseases where the disease state in the presence of a single mutated gene cannot be explained by interference of a biological pathway by a mutant gene product.

An accompanying commentary by Ramesh Shivdasani, from the Dana-Farber Cancer Institute, covers bleeding disorders in general, then focuses on how the specific timing of the single-copy expression of the FLI1 gene effects cellular differentiation and leads to the disease state in Paris-Trousseau/Jacobsen thrombopenia.

TITLE: FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia
AUTHOR CONTACTS:
Remi Favier
Hematological Laboratory, Armand Trousseau Children's Hospital, Paris, France.
Phone: 33-1-44-73-69-49; Fax: 33-1-44-73-63-33; Email: remi.favier@trs.ap-hop-paris.fr.

William Vainchenker
Institut National de la Sante et de la Recherche Medicale, Villejuif, France.
Phone: 33-1-42-11-42-33; Fax: 33-1-42-11-52-40; E-mail: verpre@igr.fr

View the PDF of this article at: https://www.the-jci.org/press/21197.pdf

ACCOMPANYING COMMENTARY: Lonely in Paris: when one gene copy isn't enough
AUTHOR CONTACT:
Ramesh A. Shivdasani
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: 617-632-5746; Fax: 617-632-4471; Email: ramesh_shivdasani@dfci.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/22353.pdf


Cancer Patient, Heal Thyself

Anti-cancer immune cells are found in cancer patients, but these cells fail to reject tumors; a failure that may be due to a series of different immune cell priming or suppressing mechanisms. Now Viktor Umanksy and colleagues from the German Cancer Research Center, provide a method to enable the specific activation and tumor infiltration of these cells from cancer patients themselves. The authors show that patients' bone marrow is enriched for subsets of anti-tumor–specific T cells. These cells were isolated from bone marrow and stimulated in cell culture to become effective killer cells. Mice that had been previously implanted with tumors were injected with these activated cells. In contrast to cells that were not anti-tumor–specific, the cell-culture activated T cells were now very effective at infiltrating tumor transplants and in reducing tumor size. These results present a potential immunotherapy strategy for cancer treatment with appropriately reactivated anti-tumor–specific T cell subsets that already exist in patients' own body.

TITLE: Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors
AUTHOR CONTACT:
Viktor Umansky
German Cancer Research Center, Heidelberg, Germany.
Phone: 49-621-383-3773; Fax: 49-621-383-2163; Email: v.umansky@dkfzheidelberg.de

View the PDF of this article at: https://www.the-jci.org/press/20278.pdf


PAF-way to Bone Loss

Many women after menopause suffer from the bone disease osteoporosis, where there is an increase in bone re-absorption back into the body; this creates a high risk for bone fracture. A great deal of research has gone into dissecting the molecular underpinnings of this debilitating and painful disease. One gene that has been implicated in bone resorption diseases is platelet-activating factor or PAF. Now, Satoshi Ishii and colleagues, at the University of Tokyo, provide a potential new arena for treating such bone diseases through their characterization of bone loss in mice where the receptor for PAF has been removed, thus effectively inhibiting PAF function. To simulate menopause, these mice had their ovaries removed. The researchers found that in mice without the PAF receptor, ovarectomized mice had greatly improved bone mineral density as well as bone volume compared to ovarectomized mice that still had PAF gene function. Further molecular studies in these mice showed that osteoclasts (the bone cells that responsible for the breakdown of bone material) are responsible for PAF's mechanism of action. In addition, when mice were treated with a molecule that inhibits PAF receptor function, bone resorption was also reduced. These data indicate that inhibition of PAF activity presents a possible strategy for treating osteoporosis and other bone resoprtion diseases.

TITLE: Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy
AUTHOR CONTACT:
Satoshi Ishii
The University of Tokyo, Bunkyo, Tokyo, Japan.
Phone: 81-3-5802-2925; Fax: 81-3-3813-8732; Email: mame@m.u-tokyo.ac.jp

View the PDF of this article at: https://www.the-jci.org/press/20504.pdf


Immunology Link May Make You Lose Your Appetite

A decrease in food ingestion and anorexia are common symptoms during injury, illness, or inflammation. A key to the link between food intake and illness may be a recently identified molecule called ghrelin, which has previously been shown to play a part in maintaining metabolic energy balance. Now Dennis Taub and colleagues from the National Institute on Aging, have added to the ghrelin's role in the body, and show it also has activity in the immune system. They found that ghrelin receptors are expressed in cells in the immune system, and upon exposure to ghrelin, there was an inhibition of the production of molecules involved in the body's inflammatory response. The results here may further our understanding of anorexia and obesity, and support a role for ghrelin as a potential therapeutic target in such disorders.

TITLE: Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells
AUTHOR CONTACT:
Dennis D. Taub
National Institute on Aging, Baltimore, Maryland, USA.
Phone: 410-558-8181; Fax: 410-558-8284; Email: TaubD@prc.nia.nih.gov

View the PDF of this article at: https://www.the-jci.org/press/21134.pdf


PPAR for the Course

Diabetes is often promoted in obesity by higher concentrations of free fatty acids in the blood. Understanding how this process works currently remains very limited. Free fatty acids are generated when glycerol is broken down in the liver or in fat tissue. One gene family thought to be involved in this increasing free fatty acids is the PPAR gene family. Sander Kersten and colleagues, from Wageningen University, now begin to build our understanding of this process with a series of studies on PPAR in mice. The authors utilized array technology and as well as other mechanisms to block PPAR gene family action. In doing so, they were able to dissect specific roles for different members of the PPAR gene family in different tissues. Specifically, their data here show a direct role for PPAR_lpha in the metabolism of glycerol metabolism in the liver, while another member of the PPAR gene family, PPAR_amma_ controls glycerol metabolism in adipose tissue. These data will aid in understanding the complex interactions of genes, small molecules, and proteins that are involved in mechanisms underlying diseases such as diabetes.

TITLE: PPARalpha governs glycerol metabolism
AUTHOR CONTACT:
Sander Kersten Wageningen University, Wageningen, The Netherlands.
Phone: 31-317-48-57-87; Fax: 31-317-48-33-42; Email: sander.kersten@wur.nl

View the PDF of this article at: https://www.the-jci.org/press/20468.pdf


OTHER PAPERS IN THIS ISSUE:

Keeping Airways Open

TITLE: Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness

AUTHOR CONTACT:
Scott S. Wagers
Vermont Lung Center, Burlington, Vermont, USA.
Phone: 802-656-8917; Fax: 802-656-8926; Email: Scott.Wagers@uvm.edu

View the PDF of this article at: https://www.the-jci.org/press/19569.pdf

ACCOMPANYING COMMENTARY: Coagulation-dependent mechanisms and asthma

AUTHOR CONTACT:
Michael A. Mathay
University of California, San Francisco, California, USA.
Phone: 415-353-1206; Fax: 415-353-1990; E-mail: mmatt@itsa.ucsf.edu

View the PDF of this article at: https://www.the-jci.org/press/22288.pdf

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The Tau of Alzheimer Disease

TITLE: Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

AUTHOR CONTACT:
Carl W. Cotman
University of California, Irvine, Irvine, California, USA.
Phone: 949-824-5847; Fax: 949-824-2071; Email: cwcotman@uci.edu

View the PDF of this article at: https://www.the-jci.org/press/20640.pdf

ACCOMPANYING COMMENTARY: Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect?

AUTHOR CONTACT:
Dennis W. Dickson
Mayo Clinic, Jacksonville, Florida, USA
Phone: 904-953-7137; Fax: 904-953-7117; Email: dickson.dennis@mayo.edu

View the PDF of this article at: https://www.the-jci.org/press/22317.pdf

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Stroke Mediation

TITLE: Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury

AUTHOR CONTACT:
Robert O. Messing
Ernest Gallo Clinic and Research Center and University of California San Francisco, Emeryville, California, USA.
Phone: 510-985-3950; Fax: 510-985-3101; Email: romes@itsa.ucsf.edu

View the PDF of this article at: https://www.the-jci.org/press/21655.pdf

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AngII in Blood Pressure

TITLE: Involvement of chymase-mediated angiotensin II generation in blood pressure regulation

AUTHOR CONTACT:
Ahsan Husain University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: 205-996-2738; Fax: 205-996-2586; Email: ahusain@physiology.uab.edu

View the PDF of this article at: https://www.the-jci.org/press/20805.pdf

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Deep Breaths for Tolerance

TITLE: Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-beta and FOXP3

AUTHOR CONTACT:
Anuradha Ray University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: 412-802-3191; Fax: 412-692-2260; Email: raya@pitt.edu

View the PDF of this article at: https://www.the-jci.org/press/20509.pdf

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Eye Disease Gets A Complex

TITLE: Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

AUTHOR CONTACT:
Ching-Hwa Sung Weil Medical College of Cornell, New York, New York, USA.
Phone: 212-746-2291; Fax: 212-746-6670; Email: chsung@mail.med.cornell.edu

View the PDF of this article at: https://www.the-jci.org/press/21136.pdf


ONLINE FIRST PAPERS

Resistin Insulin All Over the Place

Insulin acts on three primary target tissues, skeletal muscle, liver, and fat, in its regulation of glucose metabolism. Recent evidence suggests that there is cross-talk between these tissues coordinating overall response to insulin within the organism. The fat cells release several hormones and cytokines, which appear to play a role in controlling this response. One of these fat cell-derived proteins, resistin, is thought to play a role in this by effecting overall insulin response. Two groups with papers that are appearing online first different methodologies -- one by increasing, the other by decreasing, resistin levels -- to increase our understanding these mechanisms. The work by the groups of Luciano Rosetti and colleagues and Jerrold Olefsky and colleagues substantiates the important physiological role resistin plays in the development of insulin resistance and its potential involvement in diseases such as type 2 diabetes mellitus and syndrome X.

TITLE: Role of resistin in diet-induced hepatic insulin resistance
AUTHOR CONTACT:
Luciano Rossetti
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718-430-4118; Fax: 718-430-8557; Email: rossetti@aecom.yu.edu

View the PDF of this article at: https://www.the-jci.org/press/21270.pdf

TITLE: Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats
AUTHOR CONTACT:
Jerrold M. Olefsky
University of California, San Diego, La Jolla, California, USA.
Phone: 858-534-6651; Fax: 858-534-6653; Email: jolefsky@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/press/20785.pdf


Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.

 

 

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