JCI table of contents, 1 June 2004

05/24/04

Atherosclerosis Treatment Needs to Go with the Flow

Branch points in the arteries are a common area of atherosclerotic disease, resulting in the occlusion of both branches. These branch points can generally be defined as a main branch and a side branch, and, in treating the disease, the question of what is the optimal course of action, opening the main branch, the side branch, or both, remains uncertain. Studies have shown that using a stent to open a blocked blood vessel is generally more successful that balloon angioplasty, when one is treating a lesion in non-bifurcated area. Current data, however, indicate no such superiority in the use of stents to treat lesions in branching passages. Yoram Richter and colleagues, from Harvard–M.I.T. Division of Health Sciences and Technology, provide a hemodynamic analysis (an analysis of the forces of blood flow) in the region of the bifurcated vasculature to show that stenting of both passages results in a blood flow pattern that is inherently harmful to the main branch, and results in rapid re-occlusion of the main branch. To investigate this system, the authors developed a new dynamic bench top fluid mechanical model system. This system provides a major advance over previous static models by allowing not only the prediction of areas in the blood vessels likely to be damaged, but also by reflecting the true active nature of the arterial system that compensates for and minimizes any disturbance. The authors further tested their in vitro predictions in an animal model, and, in seeing in the animals what was predicted to occur from their bench top model, established the strength of their in vitro modeling system. This study provides an explanation for why stenting in forked blood vessel regions has had a low success rate, and also provides a direction for appropriate treatment of these commonly blocked regions.

An accompanying commentary from R. Wayne Alexander at Emory University, provides a detailed look at the stent methodologies for treating occluded arteries, and describes how the study by Richter and colleagues advances our understanding of how best to treat these occluded branch sites by stenting only the main branch for optimal healing and maintenance of open vasculature.
TITLE: Dynamic flow alterations dictate leukocyte adhesion and response to endovascular interventions

AUTHOR CONTACT:
Yoram Richter
Tel Aviv, Israel
Phone: 972-3-767-9000; Fax: 972-3-647-5351; E-mail: yrichter@biorest.co.il.
View the PDF of this article at: https://www.the-jci.org/press/21007.pdf

ACCOMPANYING COMMENTARY: Getting stents to go with the flow

AUTHOR CONTACT:
R. Wayne Alexander
Emory University School of Medicine
Atlanta, Georgia, USA
Phone: 404-727-1749; Fax: 404-727-3099
E-mail: ralexan@emory.edu.
View the PDF of this commentary at: https://www.the-jci.org/press/22000.pdf

With Fat, Women Have a More Visceral Response

There is a close relationship between abdominal fat and metabolic disease. The theory is that excess visceral fat leads to increased free fatty acids (FFA) being released into the portal vein, thus exposing the liver to higher FFA concentrations. Increased liver exposure to FFAs could effect production of triglycerides, such as VLDL, and have an impact on hepatic insulin resistance. It has been difficult, however, to gain a solid assessment of the effect of visceral fat on hepatic FFA concentration in humans. Now Michael Jensen and colleagues, of the Mayo Clinic, have used isotope dilution/hepatic vein catheterization techniques to directly assess the contribution abdominal fat plays in distribution of FFAs to the liver. The researchers showed that abdominal fat contributed between 10%–50% to the delivery of FFAs to the liver and that this contribution was directly proportional to the amount of abdominal fat. Of greater interest, this study also showed that the correlation was greater in women than in men. These observations are consistent with previous studies that have indicated that there is a much better correlation between abdominal fat amounts and serum triglyceride levels in women than in men, and between abdominal fat amounts and hepatic insulin resistance index. This study, therefore provides the first detailed understanding of how abdominal fat, by increasing FFA concentration in the liver, correlates with the presence of increased risk for metabolic diseases in obese individuals.

An accompanying commentary from Samuel Klein provides an overview concerning the various placement of fat deposition in the body, and details how FFAs are derived from each of these areas. This commentary describes, using the work from this study and previous studies, how each of these areas of fat deposition contribute to systemic arterial circulation and portal circulation FFA levels and how each therefore may have varying impact on an individual's health.

TITLE: Splanchnic lipolysis in human obesity

AUTHOR CONTACT:
Michael D. Jensen
Mayo Clinic
Rochester, Minnesota, USA
Phone: 507-255-6768; Fax: 507-255-4828
E-mail: jensen.michael@mayo.edu.

View the PDF of this article at: https://www.the-jci.org/press/21047.pdf

ACCOMPANYING COMMENTARY: The case of visceral fat: argument for the defense

AUTHOR CONTACT:
Samuel Klein
Washington University School of Medicine
St. Louis, Missouri, USA
Phone: 314-362-8699; Fax: 314-362-8230
E-mail: sklein@im.wustl.edu
View the PDF of this commentary at: https://www.the-jci.org/press/22028.pdf

The Skinny on Diagnosing Skin Disease

Lichen sclerosus is an autoimmune skin disorder that occurs in more than 1 in 300 people. The disease, which presents with hardened inflamed bumps or patches of skin, most commonly in the genital area, can result in severe scarring, resulting in impaired sexual activity, and can also be complicated by malignancy, most commonly squamous cell carcinomas. There are no biological markers or diagnostic tests to adequately diagnose this common skin disorder, and it is often misdiagnosed as signs of abuse in young children and as lichen planus in adults. Previous work on lichen sclerosus has shown the presence of specific autoantigens to extracellular matrix protein 1 (ECM1), implicating its potential involvement in the disease. ECM1 is a protein present in the epidermis and dermis, and appears to be involved in epidermal differentiation and in protein-protein interactions within the skin. John McGrath and colleagues, from St. Thomas' Hospital in London, have now characterized the portions of EMC1 that are targeted by autoantibodies from the serum of lichen sclerosus patients. They find that patient's serum contains antibodies that detect many different portions of ECM1, but were able to identify a portion of this protein (amino acids 359 to 559) that is detected by autoantibodies in the serum of nearly all disease cases. From this, they developed a novel and highly sensitive ELISA system that provides a diagnostic marker for this disease, and also gives indication of the likely clinical severity. This study provides an essential new diagnostic tool for the detection of this often debilitating skin disease, but it also presents important information on the underlying pathogenicity of the disease, in terms of the development of multiple antibodies to ECM1, a phenomenon called "epitope spreading," which is frequently seen in other autoimmune skin disorders.

TITLE: Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

AUTHOR CONTACT:
John A. McGrath
St. Thomas' Hospital
London, United Kingdom
Phone: 44-20-7928-9292; Fax: 44-20-7922-8175
E-mail: john.mcgrath@klc.ac.uk.
View the PDF of this article at: https://www.the-jci.org/press/20373.pdf

RAGE Against An Immune Response

The receptor for advanced glycation end products (RAGE) is involved in the immune system's response pathways, but its specific role in the innate and adaptive immune response pathways remains unknown. Generation of mice devoid of RAGE and mice with tissue-specific expression of RAGE enabled Peter Nawroth and colleagues, from the University of Heidelberg, to study the function of this cell-surface receptor in these different immune response pathways. Experimental autoimmune encephalomyelitis (EAE) was used to monitor the adaptive immune response. Although RAGE–/– mice responses were similar to those in wild type, RAGE overexpressing mice displayed an amplified reaction, indicating that RAGE is not required for the initiation of the adaptive immune response but is involved in the perpetuation of inflammation. Using the delayed-type hypersensitivity (DTH) model to monitor the responses to inflammation, the researchers found that RAGE–/– mice did not display reduced DTH inflammatory responses. This result is surprising given that previous studies have shown that the application of sRAGE, a soluble truncated form of the receptor that competes for RAGE ligands, did reduce inflammation. RAGE–/– mice were, however, protected from lethal septic shock during multibacterial peritonitis induction by cecal ligation and puncture. This protection was lost in RAGE–/– mice crossed with overexpressing RAGE mice, emphasizing the critical role of RAGE in perpetuating the innate immune response.

TITLE: Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

AUTHOR CONTACT:
Peter P. Nawroth
Medizinische Klinik I der Universitat Heidelberg
Heidelberg, Germany
Phone 1: 49-6221-568600; Fax 1: 49-6221-565226
E-mail: peter_nawroth@med.uni-heidelberg.de
View the PDF of this article at: https://www.the-jci.org/press/18704.pdf

Benefits of a PKCbeta Blockade

Ischemia/reperfusion (I/R) lung injury induces a slew of cellular pathways that lead to organ dysfunction and damage. Rapid activation of PKCbetaII occurs upon injury and affects several downstream targets. Shi-Fang Yan and colleagues, from Columbia University, explore the impact of PKCbetaII in I/R by subjecting PKCbeta–/– mice and wild-type mice fed a PKCbeta inhibitor to single-lung ischemia followed by reperfusion. PKCbeta inactivation by both gene deletion and pharmacological blockade protected mice from severe lung injury. Downstream effects of PKCbetaII activation that occur after I/R, such as ERK1/2 phosphorylation and Egr-1 expression, were reversed in PKCbeta-blocked mice. Proinflammatory/prothrombotic genes normally upregulated in I/R also showed decreased expression levels in the PKCbeta-blocked mice. Activation of the AP-1 and NF-kB transcriptional pathways were also diminished. These results mark PKCbetaII as a central mediator of I/R pathobiology and a promising therapeutic target for I/R injury.

TITLE: PKCbeta regulates ischemia/reperfusion injury in the lung

AUTHOR CONTACT:
Shi-Fang Yan
Columbia University College of Physicians and Surgeons
New York, New York, USA
Phone: 212-305-6030; Fax: 212-305-5337
E-mail: sy18@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/19225.pdf

Silence of the IL-12Rbeta2

Human primary B cell tumors and transformed human B cell lines lack IL-12Rbeta2 transcript expression, but maintain IL-12Rbeta1 expression. Normal, naive, germinal center B cells and normal memory B cells constitutively express both IL-12R genes. Irma Airoldi and colleagues, from the G. Gasolini Insitute, reasoned, therefore, that IL-12Rbeta2 gene silencing contributes to neoplastic B cell expansion. They researched the role of methylation in silencing this gene and found that gene methylation occurred in transformed B cell lines. Treatment with 5-Aza-2'-deoxycytidine, a selective DNA methylase inhibitor, resulted in de novo expression of the IL-12Rbeta2 transcript in primary neoplastic B cells. Furthermore, these drug-treated cells underwent apoptosis in response to IL-12 treatment. Similarly, apoptosis was induced when IL-12Rb2 was transfected into transformed B cell lines and cells were treated with human recombinant IL-12 (hrIL-12). SCID-NOD mice injected with tumorigenic B cells expressing IL-12Rbeta2 and treated with hrIL-12 had tumors that were significantly smaller and less malignant than those in mice treated with PBS. IL-12Rbeta2 indeed acts as a tumor suppressor and aids IL-12 action as an antitumor agent.

TITLE: The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies

AUTHOR CONTACT:
Irma Airoldi
G. Gaslini Institute
Genoa, Italy
Phone: 39-010-563-6342; Fax: 39-010-563-6524
E-mail: laboncologia@ospedale-gaslini.ge.it
View the PDF of this article at: https://www.the-jci.org/press/20303.pdf

Thyrotropin Receptor Can Be So Insensitive

In Graves autoimmune disease, thyrotropin receptor (TSHR) antibodies bind to and stimulate TSHR, causing hyperthyroidism. Takao Ando and colleagues, from the Mount Sinai School of Medicine, used a hamster antibody (MS-1) with TSHR-stimulating activity to characterize TSHR antibody pathogenesis mechanisms. In an acute study using MS-1 injection in mice, they found a dose-dependent relationship between serum thyroxine and MS-1 antibody levels. In a chronic study, nude mice were injected with MS-1–secreting hybridoma cells, and although serum MS-1 levels were higher than in the acute study, serum thyroid hormone levels were similar to those in pretreatment controls. The authors confirmed that there was no loss of MS-1 bioactivity; thus, chronic stimulation of TSHR seemed to cause desensitization of the receptor. This conclusion was further supported by in vitro studies on TSHR-expressing Chinese hamster ovary cells. A dose-dependent loss of TSHR responsiveness in the presence of high concentrations of MS-1 was due to TSHR downregulation and loss of receptor function. This study provides one explanation for the poor correlation between serum TSHR-antibody concentration and thyroid function seen in Graves disease patients.
TITLE: Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody

AUTHOR CONTACT:
Takao Ando
Mount Sinai School of Medicine
New York, New York, USA
Phone: 212-241-4129; Fax: 212-241-4218
E-mail: takao.ando@mssm.edu
View the PDF of this article at: https://www.the-jci.org/press/21334.pdf

Other Papers in This Issue

Heartbreak at the Uninhibited GSK-3beta Hotel TITLE: Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore

AUTHOR CONTACT:
Steven J. Sollet
National Institute on Aging
Baltimore, Maryland, USA
Phone: 410-558-8657; Fax: 410-558-8150
E-mail: sollotts@grc.nia.nih.gov
View the PDF of this article at: https://www.the-jci.org/press/19906.pdf/

ACCOMPANYING COMMENTARY: Inhibit GSK-3beta or there's heartbreak dead ahead

AUTHOR CONTACT:
Elizabeth Murphy
National Institutes of Health
Bethesda Maryland, USA
Phone: 919-541-3873; Fax: 919-541-3385
E-mail: murphy1@niehs.nih.gov
View the PDF of this commentary at: < href="https://www.the-jci.org/press/21986.pdf">https://www.the-jci.org/press/21986.pdf

Stick a Fork in It -- the Kidney's Differentiated
TITLE: Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1

AUTHOR CONTACT:
Sven Enerback
Goteborg University
Goteborg, Sweden
Phone: 46-31-773-3334; Fax: 46-31-416-108
E-mail: sven.enerback@medgen.gu.se
View the PDF of this article at: https://www.the-jci.org/press/20665.pdf

ACCOMPANYING COMMENTARY: A fork in the road of cell differentiation in the kidney tubule

AUTHOR CONTACT:
Qais Al-Awqati
Columbia University College of Physicians and Surgeons
New York, New York, USA
Phone: 212-305-3512; Fax: 212-305-3475
E-mail: qa1@columbia.edu
View the PDF of this commentary at: https://www.the-jci.org/press/22029.pdf

Inflammatory Response to Fibrin–Integrin Engagement
TITLE: Leukocyte engagement of fibrin(ogen) via the integrin receptor a___a-M-b__a-2/Mac-1 is critical for host inflammatory response in vivo

AUTHOR CONTACT:
Jay L. Degen
Children's Hospital Research Foundation
Cincinnati
Ohio, USA
Phone: 513-636-4679; Fax: 513-636-4317
E-mail: degenjl@cchnc.org
View the PDF of this article at: https://www.the-jci.org/press/20741.pdf

NKT Cells Prefer Producing IL-4

TITLE: The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells

AUTHOR CONTACT:
Sachiko Miyake
National Institute of Neuroscience
Tokyo, Japan
Phone: 81-42-341-2711; Fax: 81-42-346-1753
E-mail: miyake@ncnp.go.jp
View the PDF of this article at: https://www.the-jci.org/press/20862.pdf

T cell Depletion Induces Transplantation Tolerance
TITLE: CD28 ligation induces transplantation tolerance by IFN-_____–dependent depletion of T cells that recognize alloantigens

AUTHOR CONTACT:
Xue-Zhong Yu
Fred Hutchinson Cancer Research Center
Seattle, Washington
Phone: 206-667-5988
Fax: 206-667-5255
E-mail: xyu@fhcrc.org
View the PDF of this article at: https://www.the-jci.org/press/20940.pdf

Diabetes Has a Reversal of Fortune
TITLE: Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

AUTHOR CONTACT:
Kyle W. Sloop
Lily Research Laboratories
Indianapolis, Indiana, USA
Phone: 317-651-2856; Fax: 317-276-9086
E-mail: sloop_kyle_w@lilly.com
View the PDF of this article at: https://www.the-jci.org/press/20911.pdf

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