JCI table of contents, February 1, 2006

EDITOR'S PICK

Genetic cause of sudden infant death in African Americans

Steve A.N. Goldstein and colleagues from the Pritzker School of Medicine in Chicago have found that a specific mutation, called S1103Y, in a heart protein known as SCN5A is associated with a dramatic, 24-fold increased risk of sudden infant death syndrome (SIDS) in African American infants. The authors show that this mutant protein, when exposed to acidic conditions (which can be caused by low blood oxygen levels when infants are placed in the face-down or "prone" sleeping position), malfunctions in a way that has been previously shown to trigger an irregular heartbeat. The study, which appears in the February issue of the Journal of Clinical Investigation, suggests the existence of a genetic predisposition to SIDS and also demonstrates a relationship between genes and the environment in the development of this fatal syndrome.

In an accompanying commentary, Jonathan Makielski from the University of Wisconsin writes, "These findings provide an excellent illustration of a causal relationship between the interaction of the environment and genetic background in SIDS. For families of SIDS victims, a clear delineation of risk factors, both genetic and environmental, will be instrumental in identifying children who may benefit from therapeutic intervention."

TITLE: A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y

AUTHOR CONTACT:

Steve A.N. Goldstein
Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
Phone: (773) 702-6205; Fax:(773) 702-4523; E-mail: sangoldstein@uchicago.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25618

ACCOMPANYING COMMENTARY:

TITLE: SIDS: genetic and environmental influences may cause arrhythmia in this silent killer

AUTHOR CONTACT:

Jonathan C. Makielski
University of Wisconsin, Madison, Wisconsin, USA
Phone: 608-263-9648; Fax: 608-263-0405; E-mail: jcm@medicine.wisc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27689

ENDOCRINOLOGY

The sugar-coated truth about diabetes-related intestinal disorders

Diabetes is associated with several gastrointestinal problems such as diarrhea, abdominal pain, and constipation, but until now little was known about the causes. In a new study appearing in the February issue of the Journal of Clinical Investigation, Shanthi Srinivasan and colleagues from Emory University in Atlanta show that the high blood sugar (hyperglycemia) associated with diabetes can damage nerves of the gut, impairing the movement of food through the intestines, a process called "gastrointestinal motility". The researchers discovered that nerve cells isolated from normal rat intestines died when grown at hyperglycemic conditions in a laboratory dish. The researchers also found that diabetic mice showed delayed gastric emptying times associated with significantly higher numbers of dead nerves in the intestine. The authors discovered that the cell death in both of these models was associated with reduced activity of a cell survival signaling pathway known as the PI3K/Akt pathway. Using genetically modified mice, the authors found that the nerve cell death and gastrointestinal motility problems caused by diabetes were corrected by production of a nerve survival protein called glial cell line-derived neurotrophic factor (GDNF), which stimulates the PI3K/Akt pathway. These studies demonstrate that hyperglycemia causes direct injury to intestinal nerves, and suggest that GDNF may have a role as a potential therapy for gastrointestinal disorders in diabetes patients.

In an accompanying commentary, Christopher Rayner and Michael Horowitz from the University of Adelaide in Australia note, "these observations allow speculation as to the mechanisms by which high glucose concentrations suppress PI3K activity."

TITLE: GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway AUTHOR CONTACT:

Shanthi Srinivasan
Emory University, Atlanta, Georgia, USA
Phone: (404) 727-5298; Fax: (404) 712-2980; E-mail: ssrini2@emory.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26295

ACCOMPANYING COMMENTARY:

TITLE: Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited?

AUTHOR CONTACT:

Chris Rayner
Royal Adelaide Hospital, Adelaide, Australia
Phone: 61-8-8222-2916; Fax: 61-8-8223-3870; E-mail: chris.rayner@adelaide.edu.au

View the PDF of this article at: https://www.the-jci.org/article.php?id=27758

ENDOCRINOLOGY

Taking the direct approach to controlling liver sugar production

During fasting the liver provides the body with fuel in the form of glucose from two sources: from newly synthesized glucose (gluconeogenesis), or from the breakdown of glycogen (glycogenolysis). Similarly, after a meal the increased blood glucose levels stimulate the production of the pancreatic hormone insulin, which allows cells of the body to internalize this precious sugar, and also tells the liver to stop making it. Insulin inhibits hepatic glucose production (HGP) through both direct (liver-mediated) and indirect (brain-mediated) effects on the liver. However, considerable controversy exists regarding the relative importance of these two effects. In a new study appearing in the February issue of the Journal of Clinical Investigation, Dale Edgerton and colleagues from Vanderbilt University School of Medicine in Tennessee report that infusion of insulin directly into the livers of overnight-fasted dogs inhibits HGP. This inhibition was more potent than insulin infusion into the brain, where an important region known as the hypothalamus regulates metabolism. The study may provide new insights for type 2 diabetes, in which the elevated levels of liver gluconeogenesis result from the failure of this organ to respond to insulin. In fact, hepatic insulin resistance is an important risk factor for the development of type 2 diabetes, suggesting that the "direct" route to controlling HGP could be a potential new focus for understanding this disease.

In an accompanying commentary, Jean Girard from the Université René Descartes Faculté de Médecine in Paris, France notes that, "the relative importance of direct and/or indirect effects of insulin on HGP could have implications for diabetes treatment. This study demonstrates that insulin's direct effect on the liver dominates the control of HGP."

TITLE: Insulin's direct effects on the liver dominate the control of hepatic glucose production

AUTHOR CONTACT:

Dale Edgerton
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Phone: (615) 322-7014; Fax: (615) 322-1462; E-mail: dale.edgerton@vanderbilt.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27073

ACCOMPANYING COMMENTARY:

TITLE: Insulin's effect on the liver: "Direct or indirect?" continues to be the question

AUTHOR CONTACT:

Jean Girard
Université René Descartes Faculté de Médecine, Paris, France
Phone: 33-153-73-27-00; Fax: 33-153-73-27-01; E-mail: girard@cochin.inserm.fr

View the PDF of this article at: https://www.the-jci.org/article.php?id=27743

PULMONARY

The phlegm-de-la-phlegm of airway obstruction

The removal of bacteria and inhaled dust from the lungs is performed by the coordinated actions of two distinct cell types in the airways: cells that produce mucus to trap the dust (goblet cells), and cells with tiny hairs, called cilia, on their surface to sweep the mucus out of the lungs (ciliated cells). However, excess mucus stuck in the airways is a serious cause of breathing difficulty and airway obstruction in chronic lung diseases such as asthma and bronchitis. In a new study appearing in the February issue of the Journal of Clinical Investigation, researcher Michael J. Holtzman and colleagues from Washington University School of Medicine in Missouri show that ciliated cells can transform into goblet cells, leading to increased mucus production in the airways. The authors infected the lungs of mice with a virus to induce inflammation similar to that found in bronchitis, and observed increased activity of a protein called epidermal growth factor receptor (EGFR) specifically on the surface of ciliated cells. These EGFR-activated cells showed prolonged survival, which enabled them to have increased exposure time to a protein called interleukin-13 (IL-13), found in the airways of patients with bronchitis and asthma. IL-13 induced mucus production and loss of cilia in these cells, demonstrating that the combined effects of these two proteins, EGFR and IL-13, can transform ciliated cells into goblet cells. The authors suggest that a patient's genetic predisposition to high EGFR airway activity, combined with increased IL-13 production (which is triggered by allergen exposure) may warrant consideration as an explanation for excessive mucus production, and may be targets of future therapeutic strategies for obstructive lung diseases.

In an accompanying commentary, Lauren Cohn from Yale University School of Medicine in New Haven, Connecticut, points out that these studies raise the important question of whether it is possible to reduce obstruction in chronic lung disease by inhibiting EGFR activation and/or by inhibiting IL-13. She notes that since inhaled steroids have limited effectiveness in chronic bronchitis, therapeutic targeting of IL-13 and EGFR offers a potential way to limit mucus production and improve lung function.

TITLE: Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

AUTHOR CONTACT:

Michael J. Holtzman
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: (314) 362-8970; Fax: (314) 362-8987; E-mail: holtzman@im.wustl.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25167

ACCOMPANYING COMMENTARY:

TITLE: Mucus in chronic airway diseases: sorting out the sticky details

AUTHOR CONTACT:

Lauren Cohn
Yale University School of Medicine, New Haven, Connecticut, USA
Phone: (203) 737-1459; Fax: (203) 785-3826; E-mail: lauren.cohn@yale.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27690

CARDIOVASCULAR BIOLOGY

Controlling blood vessel injury with survival factors

Researcher James K. Liao and colleagues at Brigham and Women's Hospital in Massachusetts have identified a new mechanism involved in human arteriosclerosis that may stimulate new treatments for this common cardiovascular disease. The authors, who report their findings in the February issue of the Journal of Clinical Investigation, created mice that express a cell survival protein called Akt specifically in blood vessel–lining cells known as endothelial cells. The authors examined features of arteriosclerotic injuries, known as lesions, that form in the vessel due to blood flow cessation, and found that the Akt mice, in contrast to their wild-type siblings, had lower levels of vessel inflammation, endothelial cell death, and lesion formation. The authors show that the main protective benefit in these Akt mice was due to the increased production of nitric oxide (NO) by an enzyme called eNOS (endothelial nitric oxide synthase), since when they blocked eNOS activity the Akt benefits disappeared. The authors suggest that endothelial expression of Akt can reduce the formation of blood vessel lesions in part by supporting the survival of endothelial cells that would otherwise die during arterial injury, and that agents that stimulate Akt activity may be beneficial in slowing arterial lesion formation and cardiovascular disease.

TITLE: Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

AUTHOR CONTACT:

James K. Liao
Brigham and Women's Hospital, Cambridge, Massachusetts, USA
Phone: (617) 768-8424; Fax: (617) 768-8425; E-mail: jliao@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26223

IMMUNOLOGY

Identifying a genetic cause of eosinophilic esophagitis

Eosinophilic esophagitis (EE), characterized by high numbers of eosinophils (a type of white blood cell) in the esophagus, typically presents with symptoms similar to chronic esophagitis (CE) and gastroesophogeal reflux disease (GERD), with vomiting, heartburn, abdominal pain, and failure to thrive in children. However, EE does not respond to anti-GERD therapy, suggesting that the causes of EE are distinct from those of GERD. EE is linked to allergy, since it responds to anti-inflammatory treatment and allergen removal, and the familial pattern of EE suggests that there may also be a genetic predisposition to this disease. Now, in a study appearing in the February issue of the Journal of Clinical Investigation, researcher Marc Rothenberg and colleagues at Cincinnati Children's Hospital Medical Center in Ohio have identified that an inflammatory protein called eotaxin-3 is the main causative factor in EE. The authors used a laboratory technique called DNA microarray analysis to examine all of the genes expressed in esophageal biopsies of human EE patients and compared them to those of CE patients and to tissue from individuals without disease. The expression levels of eotaxin-3, which stimulates and recruits eosinophils, were dramatically higher in the EE samples. In addition, levels of eotaxin-3 expression correlated directly with the numbers of eosinophils in the esophagus. Next, the authors examined genetically altered mice that did not have the eotaxin receptor (which prevented the eosinophils from responding to eotaxin), and found that these mice were completely protected from experimentally induced EE. The study identifies eotaxin-3 as the primary genetic risk factor for the development of EE and provides novel insights into this human disease.

TITLE: Eotaxin-3 and a uniquely conserved gene expression profile in eosinophilic esophagitis

AUTHOR CONTACT:

Marc Rothenberg
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Phone: (513) 636-7210; Fax: (513) 636-3310; E-mail: Rothenberg@cchmc.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=26679

IMMUNOLOGY

An unlikely mediator links autoimmune disorders and anemia

Autoimmune disorders such as arthritis can result from inappropriate or overzealous activity of cells of the immune system. Special Pac Man–like immune cells called phagocytes are involved in this process, and can cause anemia if they target red blood cells (RBCs) for destruction. However, the autoimmune signals that stimulate phagocytes to continuously destroy RBCs were unknown until now. In a new study appearing in the February issue of the Journal of Clinical Investigation, J. Engelbert Gessner and colleagues from Hannover Medical School in Germany show that autoimmune anemia requires the interaction of two proteins, C5aR and Fc(gamma)R, on liver phagocytes known as Kupffer cells. The authors injected normal mice with RBC antibodies, which led to Kupffer cell–mediated RBC destruction and anemia. However, genetically-altered mice that did not express either Fc(gamma)R or C5aR were resistant to this anemia. The authors show that Fc(gamma)R stimulates production of a small protein, C5a, which activates the C5aR, eventually leading to further activation of Fc(gamma)R. The study reveals a previously unrecognized perpetuating cycle of interaction between two important proteins of the immune system, and the authors suggest that therapeutic strategies to inhibit C5a production may be helpful in treating autoimmune disease.

In an accompanying commentary John P. Atkinson discusses the complexity of enhanced Fc(gamma)R expression and function, which is desirable during infection, but potentially deleterious in autoimmunity. He is hopeful that insights from this study will eventually provide mechanisms to better classify immune reactions.

TITLE: Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice

AUTHOR CONTACT:

Johannes Engelbert Gessner
Hannover Medical School, Hannover, Germany
Phone: 49-511-532-3621; Fax: 49-511-532-5648; E-mail: gessner.johannes@mh-hannover.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=25536

ACCOMPANYING COMMENTARY:

TITLE: C5a and Fc(gamma) receptors: a mutual admiration society

AUTHOR CONTACT: John P. Atkinson
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: (314) 362-8391; Fax: (314) 362-1366; E-mail: jatkinso@im.wustl.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27689

OPHTHALMOLOGY

The importance of timing in turning off blood vessel formation

Choroidal neovascularization (CNV), a main cause of blindness in patients with age-related macular degeneration (AMD), refers to abnormal blood vessel growth in the back of the eye where visual images are processed. A protein called VEGF-A (for vascular endothelial growth factor-A) stimulates blood vessel growth (angiogenesis) in a variety of tissues, and is present in CNV. Now, researcher Jayakrishna Ambati and colleagues from the University of Kentucky report the surprising finding that VEGF-A can be anti-angiogenic and reduce CNV. Using an experimental model, the authors found that CNV lesions in the eyes of mice could be reduced by VEGF-A treatment after injury, and that this reduction occurs due to activation of a protein called VEGFR-1. Importantly, the researchers also found that if VEGF-A was given before the CNV injury, a calcium-binding protein called SPARC (for secreted protein, acidic and rich in cysteine) suppressed VEGFR-1 and thus increased CNV. The study, appearing in the February issue of the Journal of Clinical Investigation, demonstrates that the timing of VEGF-A signaling is critical. The authors suggest that therapeutic treatments to inhibit VEGF-A in CNV disease should include consideration of the level and activity of SPARC.

TITLE: Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A

AUTHOR CONTACT:

Jayakrishna Ambati
University of Kentucky, Lexington, Kentucky, USA
Phone: (859) 323-5867, ext. 259; Fax: (859) 323-1122; E-mail: jamba2@uky.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26316

OPHTHALMOLOGY

Amyloid protein deposits found in the eye during macular degeneration

The presence of insoluble misfolded clumps of protein called " amyloid fibrils" is a characteristic feature of brain diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Now, in a study appearing in the February issue of the Journal of Clinical Investigation, researcher Jeannie Chen and colleagues from the University of Southern California Keck School of Medicine show that deposits in the eye known as "drusen", which cause age-related macular degeneration (AMD), contain similar amyloid deposits to those seen in AD and PD. The authors compared normal eyes and eyes from ndividuals with AMD and found that AMD eyes contained toxic, soluble, pre-fibrillar forms of amyloid known as oligomers, while normal eyes without drusen did not. The authors suggest that amyloid oligomers may be involved in drusen formation during AMD, and that comparable protein misfolding processes occur in AMD and other amyloid diseases.

TITLE: Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers

AUTHOR CONTACT:

Jeannie Chen
Zilkha Neurogenetic Institute, Los Angeles, California, USA
Phone: (323) 442-4479; Fax: (323) 442-4433; E-mail: jeannie@usc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25843

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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