JCI online early table of contents: May 1, 2008

It is thought that intestinal inflammatory conditions such as inflammatory bowel disease are exacerbated by depression. New data, generated by Stephen Collins and colleagues at McMaster University Medical Center, Canada, have characterized a mechanism by which experimental conditions that induced depressive-like behaviors in mice increased susceptibility to intestinal inflammation. Specifically, in two models of depression, increased susceptibility to intestinal inflammation involved decreased signaling along a nerve known as the vagal nerve and required inflammatory cells known as macrophages to be present in the intestine. Further, the tricyclic antidepressant desmethylimipramine restored vagal function and reduced intestinal inflammation, leading the authors to suggest that their data provide good rationale for future studies examining the clinical benefits of tricyclic antidepressants in individuals with inflammatory bowel disease, in particular those who are also depressed.

TITLE: Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression

AUTHOR CONTACT:
Stephen M. Collins
McMaster University Medical Center, Hamilton, Ontario, Canada.
Phone: (905) 525-9140 ext. 22184; Fax: (905) 524-1346; E-mail: scollins@mcmaster.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32849

New data, generated by Fabrizio Barbetti and colleagues in the Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes, have indicated that mutations in the human gene responsible for making insulin are associated with permanent neonatal diabetes mellitus (PNDM) — a rare genetic disorder that causes babies to develop diabetes at approximately 6 months of age — in some patients. Seven mutations in the human gene responsible for making insulin were identified in different individuals with PNDM. Each mutation resulted in a form of insulin that was not secreted from cells and that did not fold properly, causing the cells expressing the misfolded insulin to become stressed and, for some of the mutations, to die by a process known as apoptosis.

TITLE: Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

AUTHOR CONTACT:
Fabrizio Barbetti
University of Tor Vergata, Rome, Italy.
Phone: 39-06-20900672; Fax: 39-06-20900676; E-mail: fabrizio.barbetti@spr-r.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33777

When a subset of immune cells known as invariant NKT (iNKT) cells are activated they rapidly produce a number of soluble factors that influence other immune cells that are nearby. This ability to regulate immune responses has led many researchers to try and develop ways to activate iNKT cells to treat autoimmune diseases and metastatic cancer. New data that have important implications for the development of such therapeutic approaches have now been generated in mice, by Luc Van Kaer and colleagues, at Vanderbilt University School of Medicine, Nashville.

In the study, it was shown that when mice were infected with any one of a several types of bacteria, including Listeria monocytogenes, Staphylococcus aureus, and Eschericia coli, iNKT cells became activated but were then unable to respond normally to subsequent stimulation with a molecule that strongly activated iNKT cells in noninfected mice. Functionally, the ability of bacteria to cause iNKT cells to become unresponsive resulted in reduced liver damage in a model of hepatitis that is dependent on iNKT cell function and eliminated the ability of these cells to mediate therapeutic effects when activated in a mouse model of metastatic cancer. The authors therefore suggest that the utility of iNKT cell–activation therapies might be limited by bacterial infections and vaccinations.

TITLE: Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice

AUTHOR CONTACT:
Luc Van Kaer
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 343-2707; Fax: (615) 343-2972; E-mail: luc.van.kaer@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33071

Paroxysmal exertion-induced dyskinesia (PED) is a disorder whereby individuals suffer involuntary contraction of their muscles (often resulting in painful and abnormal movements and postures) following prolonged (15–60 minutes) exercise. The underlying cause of PED is not well understood, although it is known that some individuals inherit the disease. Holger Lerche and colleagues, at Universität Ulm, Germany, have now provided insight into the underlying cause of PED as they have identified genetic mutations that modify the protein GLUT1 in individuals with PED from 5 families. Importantly, the type of mutation determined the other symptoms suffered by the patients.

The authors studied 3 generations of individuals with PED and other symptoms, including hemolytic anemia with deformed red blood cells (hemolytic anemia with echinocytosis), from a single family and identified a genetic mutation that deleted part of the protein GLUT1. The deletion was shown to have two effects on the function of GLUT1: it was unable to transport as much glucose as normal GLUT1 and it allowed sodium, potassium, and calcium to leak from cells. Different genetic mutations that only affected the ability of GLUT1 to transport glucose were identified in individuals who had PED but not hemolytic anemia with echinocytosis from 4 other families. When combined with brain imaging studies, these data led to the suggestion that PED can be caused by impaired GLUT1 transport of glucose in the brain, whereas hemolytic anemia with echinocytosis can be caused by sodium, potassium, and calcium leak from red blood cells through GLUT1.

TITLE: GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak

AUTHOR CONTACT:
Holger Lerche
Universität Ulm, Ulm, Germany.
Phone: 49-731-500-63117 or 49-731-177-5203; Fax: 49-731-177-1202; E-mail: holger.lerche@uni-ulm.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34438

Individuals with long QT syndrome (LQT) are at increased risk of potentially fatal changes in their heart rate, usually with exercise or sudden excitement. In a subset of these individuals, disease is caused by mutations in their SCN5A gene and they are said to have type 3 LQT (LQT3). Mutations in the SCN5A gene also cause another heart defect known as Brugada syndrome, whereby individuals have an increased risk of sudden death, and some individuals suffer symptoms of both syndromes. New data, generated by Naomasa Makita and colleagues, at Hokkaido University Graduate School of Medicine, Japan, has now provided insight into the basis for this observed overlap in symptoms in some, but not all, individuals with LQT3 — mutations in the SCN5A gene associated with both LQT3 and Brugada syndrome were found to alter the function of sodium channels in the heart, whereas a mutation that causes only LQT3 did not have this effect. The authors note that these data have important implications for treatment as they suggest that a class of drugs known as class IC drugs, which block sodium channels in the heart, should not be used to treat individuals with both LQT3 and Brugada syndrome but can be used to safely treat those with just LQT3.

TITLE: The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

AUTHOR CONTACT:
Naomasa Makita
Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Phone: 81-11-706-6973; Fax: 81-11-706-7874; E-mail: makitan03@ybb.ne.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34057

One of the characteristic features of the disease type 2 diabetes is the inability of cells of the body to respond to the hormone insulin, something known as insulin resistance. To determine whether resistance to the effects of insulin on cells in the brain or on cells outside the brain is important for disease, Jens Brüning and colleagues at the University of Cologne, Germany, engineered mice such that when they were given a drug the receptor for insulin was eliminated in either all the cells of the body or only the cells outside the brain.

It was observed that one of the effects of insulin resistance, high levels of glucose circulating in the blood, was more pronounced in the mice in which the receptor for insulin was eliminated in all cells of the body than in the mice in which the receptor for insulin was only eliminated in the cells outside the brain. The mice lacking the receptor for insulin in all their cells also had less of the white type of fat tissue. Consistent with this, injection of insulin into the brain of normal mice increased the mass of white fat tissue and the size of white fat cells. These data indicate that the cells of the brain mediate some effects in response to insulin that are not mediated by cells outside the brain when they detect the same hormone.

TITLE: Central insulin action regulates peripheral glucose and fat metabolism in mice

AUTHOR CONTACT:
Jens C. Brüning
University of Cologne, Cologne, Germany.
Phone: 49-221-470-2467; Fax: 49-221-470-5185; E-mail: jens.bruening@uni-koeln.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31073

John Oates and colleagues, at Vanderbilt University Medical Center, Nashville, have provided new insight into the function of the protein cPLA2-alpha in humans.

The protein cPLA2-alpha is involved in the generation of molecules known as eicosanoids, which are important signaling molecules that regulate many functions throughout the body. The authors studied a patient thought to have a deficiency in the generation of eicosanoids. Platelets in the blood of the patient were found to produce lower levels of several eicosanoids than were platelets in the blood of healthy individuals and were found to be dysfunctional. Further analysis indicated that the gene responsible for making cPLA2-alpha contained mutations, leading to the suggestion that cPLA2-alpha is important for platelet function and for maintaining the integrity of the small intestine, as the patient had multiple recurrent ulcers in the small intestine.

TITLE: Inherited human cPLA2-alpha deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction

AUTHOR CONTACT:
John A. Oates
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: (615) 343-4847; Fax: (615) 343-9446; E-mail: john.oates@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30473