EDITOR'S PICK: Why long-term antibiotic use increases infection with a mycobacterium
Azithromycin is an antibiotic that also has antiinflammatory properties. It is these antiinflammatory properties that are thought to account for the improvement in clinical outcome observed when patients with chronic lung diseases such as cystic fibrosis are treated long-term with azithromycin. However, a recent study indicated that azithromycin treatment in patients with cystic fibrosis is associated with increased infection with nontuberculous mycobacteria, a serious complication in such individuals. Now, a team of researchers — led by Andres Floto and David Rubinsztein, at the University of Cambridge, United Kingdom; and Diane Ordway, at Colorado State University, Fort Collins — has confirmed that long-term use of azithromycin by adults with cystic fibrosis is associated with infection with nontuberculous mycobacteria and identified an underlying mechanism. Specifically, the team found that in mice, azithromycin treatment inhibited the intracellular killing of nontuberculous mycobacteria within immune cells known as macrophages by impairing the cellular process autophagy. As azithromycin was not known to block autophagy prior to this work, these data highlight a clinical danger associated with inadvertent pharmacological blockade of this important cellular process.
TITLE: Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection
AUTHOR CONTACT:
R. Andres Floto
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.768801; Fax: 44.1223.768801; E-mail: arf27@cam.ac.uk.
David C. Rubinsztein
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.762608; Fax: 44.1223.768801; E-mail: dcr1000@cam.ac.uk.
Diane Ordway
Colorado State University, Fort Collins, Colorado, USA.
Phone: 970.491.4117; Fax: 970.491.1815; E-mail: D.Ordway-Rodriguez@colostate.edu.
View this article at: http://www.jci.org/articles/view/46095?key=71a577bfa98cacebacdb
CARDIOLOGY: New mechanism underlying Noonan-like syndrome
Noonan syndrome is an inherited disorder characterized by the abnormal development of several parts of the body, including the heart. Genetic mutations that lead to hyperactivation of the RAS/MAPK signaling pathway have been shown to cause the condition in the majority of patients. A team of researchers, led by Christian Thiel, at Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, has now identified the genetic cause of disease in a patient with a Noonan syndrome–like condition. The data, which indicate that mutations in MYST4 are the underlying cause of disease in this patient, define a new mechanism by which the RAS/MAPK signaling pathway can be hyperactivated to cause disease, providing potential new therapeutic targets.
TITLE: Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice
AUTHOR CONTACT:
Christian T. Thiel
Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Phone: 49.9131.85.22319; Fax: 49.9131.852.3232; E-mail: Christian.Thiel@uk-erlangen.de.
View this article at: http://www.jci.org/articles/view/43428?key=1904c58f38235b5a7dc7
METABOLIC DISEASE: Lowering levels of risk factor for heart attack and stroke
High blood levels of the fat-containing molecule Lp(a) are associated with an increased risk of developing coronary artery disease — a disease of the major arterial blood vessels that is one of the major causes of heart attack and stroke. Unfortunately, neither the use of currently available drugs nor the adoption of lifestyle changes have a major impact on Lp(a) levels. More detailed understanding of Lp(a) biology is needed if therapeutics that decrease Lp(a) levels are to be developed. In this context, a team of researchers, led by Gert Kostner, at Medical University of Graz, Austria, has now found that activation of the protein FXR dramatically reduces blood levels of Lp(a) in mice engineered to express the human gene that templates Lp(a). The authors therefore suggest that therapeutics that activate FXR could provide a new approach to treating individuals with high levels of Lp(a) who are at increased risk of developing coronary artery disease.
TITLE: Farnesoid X receptor represses hepatic human APOA gene expression
AUTHOR CONTACT:
Gert M. Kostner
Medical University of Graz, Graz, Austria.
Phone: 43.316.380.4202; Fax:
43.316.380.9615; E-mail: Gerhard.kostner@medunigraz.at.
View this article at: http://www.jci.org/articles/view/45277?key=ffb0f326b043f1c1b600
AUTOIMMUNITY: How one genetic variant can't keep immune cells in check
Autoimmune diseases, which occur when an individual's immune system attacks a particular cell or tissue in their body, affect about 5% of the population of the US. Specific variants of the PTPN22 gene, in particular one that templates a protein known as the PTPN22 R620W variant, are associated with the development of autoimmune disease. New insight into how the PTPN22 R620W variant can contribute to the development of autoimmune disease has now been provided by work with human cells by a team of researchers, led by Eric Meffre, at Yale University School of Medicine, New Haven. The team found that the PTPN22 R620W variant interferes with the body's immune system checkpoint that removes immune cells known as B cells during their development if they are able to react to proteins and/or tissues of the body. These data indicate that specific genetic variants can impair the body's ability to remove B cells that could one day turn on the body and that this occurs before the onset of autoimmune disease.
TITLE: The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans
AUTHOR CONTACT:
Eric Meffre
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.737.4535; Fax: 203.785.7903; E-mail: Eric.meffre@yale.edu.
View this article at: http://www.jci.org/articles/view/45790?key=901737baa89f1f214d35
AUTOIMMUNITY: New negative regulator of autoimmune arthritis
Rheumatoid arthritis is an autoimmune inflammatory disease of the joints that arises when the body's immune system mistakenly attacks the joints and surrounding tissues. A team of researchers, led by William Robinson, at Stanford University School of Medicine, Stanford, has now identified a role for the protein CPB (carboxypeptidase B) as a negative regulator of one branch of the inflammatory response underlying disease in a mouse model of rheumatoid arthritis. Consistent with the mouse data, the team also determined that a form of CPB that persisted in the human body longer than other forms of CPB was associated with a less severe form of rheumatoid arthritis. These data therefore indicate that CPB plays a protective role in autoimmune arthritis.
TITLE: Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis
AUTHOR CONTACT:
William H. Robinson
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.849.1207; Fax: 650.849.1208; E-mail: wrobins@stanford.edu.
View this article at: http://www.jci.org/articles/view/46387?key=fab65cc245ff9cfe2fc7
VASCULAR DISEASE: Say NO to blood vessel diseases
Nitric oxide (NO) produced by cells that line blood vessels (endothelial cells) regulates blood pressure by inducing muscle cells in the blood vessel wall to relax. Aberrant regulation of the protein that controls NO production by endothelial cells (eNOS) is linked to numerous diseases involving blood vessels (vascular diseases). A team of researchers — led by William Sessa, at Yale University School of Medicine, New Haven; and Pascal Bernatchez, at the University of British Columbia, Vancouver — has now identified a peptide called Cavnoxin that can increase NO release by endothelial cells and reduce blood pressure in mice. The effects of Cavnoxin were extremely specific, leading the authors to suggest that the mechanism that they uncovered as underlying the effects of Cavnoxin could be manipulated for the treatment of individuals with vascular diseases characterized by decreased production of NO.
TITLE: A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice
AUTHOR CONTACT:
William C. Sessa
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.737.2291; Fax: 203.737.2290; E-mail: william.sessa@yale.edu.
Pascal Bernatchez
University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Phone: 604.682.2344, ext. 66060; Fax: 604.806.9274; E-mail: pbernatc@interchange.ubc.ca.
View this article at: http://www.jci.org/articles/view/44778?key=fbeaede472883073b309
BONE BIOLOGY: Molecular control of bone formation unraveled
Osteoporosis is one of the most common diseases of aging; an estimated 50% of women experience fractured bone as a result of the condition during their lifetime. New treatments that promote bone formation are greatly needed. As a result, much research effort is being focused on understanding how we can enhance the generation and function of bone-forming cells (osteoblasts). In this context, a team of researchers — led by Henry Kronenberg and Joy Wu, at Massachusetts General Hospital, Boston — has now determined that the signaling protein Gs-alpha regulates bone formation in mice by at least two distinct mechanisms: it facilitates the generation of osteoblast-lineage cells and it prevents the differentiation of osteoblasts into osteocytes, which are not efficient bone-forming cells. The team suggests that the data provide hope that a specific targeted intervention to increase bone mass, quality, and strength can be developed.
TITLE: Gs-alpha enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice
AUTHOR CONTACT:
Henry M. Kronenberg
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: 617.726.3966; Fax: 617.726.7543; E-mail: hkronenberg@partners.org.
Joy Y. Wu
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: 617.726.3966; Fax: 617.726.7543; E-mail: jywu@partners.org.
View this article at: http://www.jci.org/articles/view/46406?key=5dd09bceb98c1f868461
Journal
Journal of Clinical Investigation