EDITOR'S PICK: Too much sugar is bad, but which sugar is worse: fructose or glucose?
In 2005, the average American consumed 64kg of added sugar, a sizeable proportion of which came through drinking soft drinks. Now, in a 10-week study, Peter Havel and colleagues, at the University of California at Davis, Davis, have provided evidence that human consumption of fructose-sweetened but not glucose-sweetened beverages can adversely affect both sensitivity to the hormone insulin and how the body handles fats, creating medical conditions that increase susceptibility to heart attack and stroke.
In the study, overweight and obese individuals consumed glucose- or fructose-sweetened beverages that provided 25% of their energy requirements for 10 weeks. During this period, individuals in both groups put on about the same amount of weight, but only those consuming fructose-sweetened beverages exhibited an increase in intraabdominal fat. Further, only these individuals became less sensitive to the hormone insulin (which controls glucose levels in the blood) and showed signs of dyslipidemia (increased levels of fat-soluble molecules known as lipids in the blood). As discussed in an accompanying commentary by Susanna Hofmann and Matthias Tschöp, although these are signs of the metabolic syndrome, which increases an individual's risk of heart attack, the long-term affects of fructose over-consumption on susceptibility to heart attack remain unknown.
TITLE: Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans
AUTHOR CONTACT:
Peter J. Havel
University of California at Davis, Davis, California, USA.
Phone: (530) 752-6553; Fax: (530) 752-2474; E-mail: pjhavel@ucdavis.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37385
ACCOMPANYING COMMENTARY
TITLE: Dietary sugars: a fat difference
AUTHOR CONTACT:
Matthias H. Tschöp
University of Cincinnati-College of Medicine, Cincinnati, Ohio, USA.
Phone: (513) 558-8648; Fax: (513) 558-8658; E-mail: tschoemh@ucmail.uc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39332
EDITOR'S PICK: Antibody targeting the protein FGFR3 inhibits cancer cell growth
Several forms of cancer, including bladder cancer and multiple myeloma caused by the t(4;14) genetic abnormality, are associated with either overexpression or perpetual activation of the protein FGFR3. A team of researchers, at Genentech Inc., South San Francisco, has now generated evidence that FGFR3 might be a good therapeutic target for these diseases and developed an FGFR3-targeted antibody that had potent antitumor activity in mice transplanted with either human bladder cancer cells or t(4;14)-positive multiple myeloma cells. Additional in vivo and in vitro analysis indicated that the antibody was active against normal FGFR3 and mutated forms of the protein that are associated with cancer. The authors therefore suggest that antibody targeting of FGFR3 might be a viable therapeutic approach to treating cancers associated with aberrant expression or activation of FGFR3.
In an accompanying commentary, Yaron Hadari and Joseph Schlessinger, highlight the importance of these data and suggest that they might be relevant to other diseases, as similar FGFR3 mutations have been found to cause some skeletal dysplasias, disorders that cause abnormal shape and size of the skeleton.
TITLE: Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice
AUTHOR CONTACT:
Jing Qing
Genentech Inc., South San Francisco, California, USA.
Phone: (650) 467-8266; Fax: (650) 467-8195; E-mail: jqing@gene.com.
Avi Ashkenazi
Genentech Inc., South San Francisco, California, USA.
Phone: (650) 225-1853; Fax: (650) 467-8195; E-mail: aa@gene.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38017
ACCOMPANYING COMMENTARY
TITLE: FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma
AUTHOR CONTACT:
Joseph Schlessinger
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-7395; Fax: (203) 785-3879; Email: joseph.schlessinger@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38948
EDITOR'S PICK: Defining the link between anti-TNF therapies and increased tuberculosis
The life of many individuals with inflammatory diseases such as rheumatoid arthritis has been dramatically improved by treatment with drugs that target the protein TNF, so called anti-TNF therapies. However, anti-TNF therapies can decrease the ability of the immune system to fight infections and have been associated with an increased incidence of tuberculosis. By studying the immune cells of patients before and after treatment with the anti-TNF therapy infliximab Steffen Stenger and colleagues, at the University Hospital of Ulm, Germany, have been able to identify a mechanism by which an anti-TNF therapy impairs host defense against tuberculosis.
In the study, a subset of CD8-expressing effector memory immune T cells characterized by expression of the proteins CD45RA and granulysin (which the authors termed CD45RA+ effector memory CD8+ T cells) were identified as having a major role in targeting the bacterium that causes tuberculosis (Mycobacterium tuberculosis). Furthermore, numbers of CD45RA+ effector memory CD8+ T cells were reduced in patients following treatment with infliximab. As this correlated with a decreased ability of peripheral blood from the patients to kill M. tuberculosis, the authors conclude that the loss of this immune cell subset provides a mechanism to explain the reactivation of latent tuberculosis infection in some individuals being treated with infliximab.
In an accompanying commentary, Elizabeth Miller and Joel Ernst, at New York University School of Medicine, New York, discuss the clinical importance of these data and highlight some of the possibilities that they raise.
TITLE: Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans
AUTHOR CONTACT:
Steffen Stenger
University Hospital of Ulm, Ulm, Germany.
Phone: 49-500-65300; Fax: 49-500-65302; E-mail: steffen.stenger@uniklinik-ulm.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38482
ACCOMPANYING COMMENTARY
TITLE: Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed
AUTHOR CONTACT:
Joel D. Ernst
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-5165; Fax: (212) 263-5165; E-mail: joel.ernst@med.nyu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39143
VIROLOGY: New gene regions linked with susceptibility to HIV-1–associated kidney disease
HIV-1–associated nephropathy (HIVAN) is a kidney disease that occurs commonly in individuals infected with HIV-1. Several studies have linked variants of genes expressed in kidney cells known as podocytes to HIVAN. Using a genetic analysis approach known as expression quantitative trait locus analysis, Ali Gharavi and colleagues, at Columbia University College of Physicians and Surgeons, New York, have now identified new genetic regions associated with kidney disease in a mouse model of HIVAN. As noted by Susan E. Quaggin, at the University of Toronto, Toronto, analysis of corresponding regions of the human genome may well shed new light on genetic susceptibility to HIVAN in humans.
In the study, the initial genetic analysis revealed two new genetic regions associated with kidney disease in the mouse model of HIVAN, HIVAN2 and HIVAN3. Analysis of genes expressed by podocytes indicated that HIVAN2 and HIVAN1 (a genetic region previously associated with HIVAN in mice) markedly affected the levels of expression of Nphs2. Surprisingly, HIVAN1 and HIVAN2 did not contain Nphs2, but regulated the expression of networks of genes expressed by podocytes, thereby impacting expression of Nphs2. As the gene networks modified by these two genetic regions were not completely identical, the authors suggest that the affected genes in HIVAN1 and HIVAN2 impact different points within the network.
TITLE: Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression
AUTHOR CONTACT:
Ali G. Gharavi
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 851-5556; Fax: (212) 305-5520; E-mail: ag2239@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37131
ACCOMPANYING COMMENTARY
TITLE: Genetic susceptibility to HIV-associated nephropathy
AUTHOR CONTACT:
Susan E. Quaggin
The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Phone: (416) 586-4800 ext. 2859; Fax: (416) 586-5130; E-mail: quaggin@lunenfeld.ca.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39254
CARDIOLOGY: From enlarged heart to heart failure: a key role for the protein CaMKII-delta
One of the leading causes of death in the developed world is heart failure, which is usually preceded by cardiac hypertrophy (an increase in the size of the heart muscle cells). Previous studies have suggested the protein CaMKII has a role in cardiac hypertrophy and heart failure. Now, Joan Heller Brown and colleagues, at the University of California at San Diego, La Jolla, have generated mice lacking a specific form of CaMKII (CaMKII-delta) and used them to show that the major role of CaMKII-delta in the heart is in the progression of cardiac hypertrophy to heart failure
In the study, mice lacking CaMKII-delta and normal mice showed the same increase in heart weight and heart muscle cell size after they had been experimentally manipulated to have high blood pressure in the blood vessel leading to the heart (high blood pressure can be a cause of cardiac hypertrophy). This cardiac hypertrophy persisted in the CaMKII-delta–deficient mice but did not progress to heart failure, as it did in the normal mice. Further analysis provided insight into the mechanisms underlying the role of CaMKII-delta in the progression of cardiac hypertrophy to heart failure. The authors and, in an accompanying commentary, Mark Anderson, at University of Iowa Carver College of Medicine, Iowa City, therefore suggest that targeting CaMKII might provide a way to prevent the development of heart failure in individuals with cardiac hypertrophy.
TITLE: Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice
AUTHOR CONTACT:
Joan Heller Brown
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 822-5858; Fax: (858) 822-4011; E-mail: jhbrown@ucsd.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38022
ACCOMPANYING COMMENTARY
TITLE: CaMKII and a failing strategy for growth in heart
AUTHOR CONTACT:
Mark E. Anderson
University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Phone: (319) 353-7107; Fax: (319) 353-6343; E-mail: mark-e-anderson@uiowa.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39262
NEPHROLOGY: Immune cells hurt the kidney
One correlate of the progression of kidney diseases such as glomerulonephritis to kidney failure is the accumulation of immune cells in a region of the kidney known as the tubulointerstitium. Although the identity of these immune cells is known (they include Th cells, CTLs, and DCs), their precise role in disease progression has not been determined. However, Christian Kurts and colleagues, at Friedrich-Wilhelms-Universität, Germany, have now developed a new transgenic mouse model of glomerulonephritis and found that these immune cells cooperate to contribute to disease progression. A particularly important role for DCs was indicated by the fact that when the transgenic mice were depleted of DCs the kidney damage caused jointly by Th cells and CTLs resolved.
In an accompanying commentary, Andrey Shaw and colleagues, at Washington University School of Medicine, St. Louis, highlight the fact that these data clearly indicate T cells (both Th cells and CTLs) have a causative role in glomerulonephritis and discuss some of the future opportunities that this new model provides for furthering our understanding of the progression of glomerulonephritis to kidney failure.
TITLE: Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury
AUTHOR CONTACT:
Christian Kurts
Friedrich-Wilhelms-Universität, Bonn, Germany.
Phone: 49-228-287-11031; Fax: 49-228-287-11052; E-mail: ckurts@web.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38399
ACCOMPANYING COMMENTARY
TITLE: New roles revealed for T cells and DCs in glomerulonephritis
AUTHOR CONTACT:
Andrey S. Shaw
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-4614; Fax: (314) 362-9108; E-mail: shaw@pathology.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39071
NEUROBIOLOGY: New insights into brain tissue injury following ischemic stroke
The accumulation of cells, particularly blood cells known as platelets and inflammatory cells, at sites of oxygen depletion (ischemia) in the brain can exacerbate the brain damage following ischemic stroke. The protein CD39 on the surface of cells that line blood vessels (endothelial cells) reduces platelet accumulation in the ischemic brain; however, the role of this protein on inflammatory cells and their accumulation in this context has not been determined. In a new study, Matthew Hyman and colleagues, at the University of Michigan Medical Center, Ann Arbor, have revealed that CD39 reduces the accumulation of inflammatory cells and the reactivity of platelets in the ischemic brain, thereby mitigating brain tissue injury following ischemic stroke. Using CD39-deficient mice, the researchers demonstrated that CD39 is vital for the molecular reactions that underlie the regulation of platelet reactivity and the suppression of inflammatory cell trafficking to injury sites. These and other data in the study highlight a link between CD39 on both endothelial cells and inflammatory cells and inflammatory cell trafficking and platelet reactivity that reduces brain tissue injury following ischemic stroke.
TITLE: Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39
AUTHOR CONTACT:
Matthew C. Hyman
University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Phone: (734) 936-7605; Fax: (734) 936-8266; E-mail: mchyman@umich.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36433
PULMONARY: Molecular insight into increased risk of lung infections in those with cystic fibrosis
Chronic bacterial infections of the airways are one of the major causes of death in individuals with cystic fibrosis, an inherited disease caused by disruption to the function of the CFTR protein. Jeffrey Wine and colleagues, at Stanford University, California, have now provided new molecular insight into how disruption of CFTR function in the human lung impairs the secretion of fluids that are required for the action of immune defense mediators in the lung.
The fluids important for immune mediators in the lungs are released from airway glands known as submucosal glands following stimulation by nerves that release a number of factors, including substance P. In the study, fluid secretion mediated by substance P was measured from isolated human submucosal glands and intact lung transplant tissue. Irritants were unable to stimulate substance P–induced production of fluids by glands from individuals with cystic fibrosis. Further, glands from individuals with cystic fibrosis did not respond to substance P, whereas glands from healthy individuals secreted fluids. The authors therefore conclude that CFTR is required for substance P–induced production of fluids by submucosal glands and suggest that a defect in this pathway following exposure to lung irritants contributes to the susceptibility to airway infection seen in individuals with cystic fibrosis.
TITLE: Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process
AUTHOR CONTACT:
Jeffrey J. Wine
Stanford University, Stanford, California, USA.
Phone: (650) 725-2462; Fax: (650) 725-5699; E-mail: wine@stanford.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37284
PULMONARY: A complex web of lung scarring, cell death, and high blood pressure in blood vessels of the lung
Although lung tissue scarring (pulmonary fibrosis) is frequently associated with high blood pressure in the blood vessels that supply the lung (a condition known as pulmonary hypertension), the mechanisms underlying the development of pulmonary hypertension in this setting remain unknown. However, a new study, by Martin Kolb and colleagues, at McMaster University, Hamilton, has revealed a link between the development of pulmonary hypertension in rats with pulmonary fibrosis and a form of cell death known as apoptosis.
In the study, rats treated with the protein TGF-β1, which induced pulmonary fibrosis, exhibited increased apoptosis of the cells that line blood vessels in the lung (endothelial cells), reduced expression of the protein VEGF in the lung, and increased blood pressure in the lung arteries. When rats with pulmonary fibrosis were treated with VEGF, they recovered normal lung artery pressure through reduced apoptosis of endothelial cells in the lung; however, their fibrosis worsened. This link between endothelial cell apoptosis in the setting of pulmonary fibrosis and the development of pulmonary hypertension may be crucial in generating novel therapeutics for treating this combination of conditions.
TITLE: VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats
AUTHOR CONTACT:
Martin Kolb
McMaster University, Hamilton, Ontario, Canada.
Phone: (905) 522-1155 ext. 34973; Fax: (905) 521-6183; E-mail: kolbm@mcmaster.ca.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36136
Journal
Journal of Clinical Investigation