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JCI table of contents: Feb. 21, 2011
Date:2/21/2011

EDITOR'S PICK: Common congenital defect a prickly problem for the kidney

One of the most common congenital defects in humans it is detected in approximately 0.5% of fetuses analyzed by routine antenatal sonography is a kidney abnormality known as hydronephrosis. Hydronephrosis arises because the flow of urine from the kidney to the bladder is impeded. By studying kidney development in mice, Norman Rosenblum and colleagues, at the Hospital for Sick Children, Toronto, have identified a new cellular mechanism underlying hydronephrosis, something that they hope might lead to better therapeutics for the condition and improved diagnosis of its severity.

Rosenblum and colleagues found that the Hedgehog signaling pathway controls the development of two populations of cells required for the initiation and transmission of coordinated contractions of the tract that links the kidney and the bladder (the ureter). Thus, genetic mutations in mice that disrupted the Hedgehog signaling pathway impaired urine flow from the kidney to the bladder, causing hydronephrosis. As noted by both the authors and Doris Herzlinger, in an accompanying commentary, these data have the potential to lead to the development of novel therapeutics for the treatment of hydronephrosis. Further, they suggest that it might be possible to develop genetic tests that discriminate between cases of hydronephrosis that spontaneously resolve (as approximately 70-80% of cases do) and those that do not.

TITLE: GLI3 repressor controls functional development of the mouse ureter

AUTHOR CONTACT:
Norman D. Rosenblum
Hospital for Sick Children, Toronto, Ontario, Canada.
Phone: 416.813.5667; Fax: 416.813.6271; E-mail: norman.rosenblum@sickkids.ca.

View this article at: http://www.jci.org/articles/view/45523?key=09e8c4b6e3da88275a33

ACCOMPANYING COMMENTARY
TITLE: Upper urinary tract pacemaker cells join the GLI club

AUTHOR CONTACT:
Doris Herzlinger
Cornell University Medical College, New York, New York, USA.
Phone: 212.746.6377; Fax: 212.746.8690; E-mail: daherzli@med.cornell.edu.

View this article at: http://www.jci.org/articles/view/46400?key=0a5cc11ee8d53fbb71cb


CARDIOLOGY: Possible new approach to treating two related multi-organ syndromes

LEOPARD syndrome and Noonan syndrome are two genetic conditions caused by mutations that affect the Ras signaling pathway. Individuals with either of these syndromes have a range of symptoms that often includes the potentially fatal heart condition hypertrophic cardiomyopathy. By generating and studying new mouse models of LEOPARD syndrome and Noonan syndrome, two teams of researchers have identified new ways in which the hypertrophic cardiomyopathy associated with these syndromes could perhaps be prevented or reversed with small-molecule inhibitors.

The team led by Benjamin Neel and Toshiyuki Araki, at University Health Network, Toronto, Canada, found that the hypertrophic cardiomyopathy associated with their new mouse model of Noonan syndrome was reversed by treatment with an inhibitor of the Ras signaling pathway component MEK. By contrast, the team led by Maria I. Kontaridis, at Beth Israel Deaconess Medical Center, Boston, and Benjamin Neel found that the hypertrophic cardiomyopathy associated with their new mouse model of LEOPARD syndrome was completely reversed by treatment with rapamycin, an inhibitor of the signaling protein mTOR.

As noted by Bruce Gelb and Marco Tartaglia, in an accompanying commentary, while the data generated by the two teams are exciting, because they suggest realistic therapeutic targets, they are also sobering, as they indicate that distinct therapeutic approaches will be required to treat the hypertrophic cardiomyopathy associated with different genetic mutations that affect the Ras signaling pathway.

TITLE: MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

AUTHOR CONTACT:
Benjamin G. Neel
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Phone: 416.581.7726; Fax: 416.581.7698; E-mail: bneel@uhnresearch.ca.

Toshiyuki Araki
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Phone: 416.581.7726; Fax: 416.581.7698; E-mail: taraki@uhnres.utoronto.ca.

View this article at: http://www.jci.org/articles/view/44929?key=8b3664dc592d4ec23214

ACCOMPANYING ARTICLE
TITLE: Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndromeassociated PTPN11 mutation

AUTHOR CONTACT:
Maria I. Kontaridis
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617.735.4248; Fax: 617.735.4255; E-mail: mkontari@bidmc.harvard.edu.

Benjamin G. Neel
Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Phone: 416.581.7710; Fax: 416.581.7698; E-mail: bneel@uhnresearch.ca.

View this article at: http://www.jci.org/articles/view/44972?key=d41da5d8008437f07737

ACCOMPANYING COMMENTARY
TITLE: RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it

AUTHOR CONTACT:
Bruce D. Gelb
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.241.3302; Fax: 212.241.3310; E-mail: bruce.gelb@mssm.edu.

View this article at: http://www.jci.org/articles/view/46399?key=b94279a9b368432e4ab3


VIROLOGY: The genetic variant that increases the severity of hepatitis A virusinduced disease is

Infection with hepatitis A virus usually results in asymptomatic infection or mild disease. However, in a small subset of patients it can lead to severe disease and even liver failure. A team of researchers, led by Dale Umetsu, at Children's Hospital, Harvard Medical School, Boston, and Sergio Rosenzweig, at Hospital Nacional de Pediatra J. P. Garrahan, Argentina, have now identified a form of the TIM1 gene (which generates the protein to which hepatitis A virus binds as it enters cells) that is associated with severe hepatitis A virusinduced liver disease. Surprisingly, this form of the gene has previously been associated with protection against asthma and allergic diseases. The authors therefore suggest that infection with hepatitis A virus has driven the natural selection of forms of the TIM-1 protein that bind hepatitis A virus less efficiently, thereby protecting against severe hepatitis A virusinduced disease, but which may predispose toward inflammation associated with asthma and allergy.

In an accompanying commentary, Lucienne Chatenoud and Jean-Franois Bach, at Hpital Necker Enfants Malades, France, discuss the importance of this paper and highlight the novel concepts it introduces.

TITLE: A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

AUTHOR CONTACT:
Dale T. Umetsu
Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.919.2439; Fax: 617.730.0384; E-mail: dale.umetsu@childrens.harvard.edu.

Sergio D. Rosenzweig
NIAID, NIH, Bethesda, Maryland, USA.
Phone: 301.451.8971; Fax: 301.451.7901; E-mail: srosenzweig@niaid.nih.gov.

View this article at: http://www.jci.org/articles/view/44182?key=6b81894e21816f2823dd

ACCOMPANYING COMMENTARY
TITLE: Genetic control of hepatitis A severity and susceptibility to allergy

AUTHOR CONTACT:
Jean-Franois Bach
INSERM U1013, Hpital Necker Enfants Malades, Paris, France.
Phone: 33.1444953.73; Fax: 33.1430623.88; E-mail: jean-francois.bach@academie-sciences.fr.

View this article at: http://www.jci.org/articles/view/46418?key=78670636caec9be10289


VIROLOGY: HIV-1 takes control of its own destiny

Both animal and human studies suggest that the immune molecule IFN-alpha has a role in the progression of disease in individuals infected with HIV-1. A team of researchers, led by Nina Bhardwaj, at New York University School of Medicine, New York, has now determined that HIV-1 itself is able to skew immune cells known as pDCs toward a state in which they persistently secrete IFN-alpha and uncovered the mechanism by which it does this. The team suggests that by skewing pDCs to a persistently IFN-asecreting state, HIV-1 may promote its own survival and thereby disease progression. The team also suggests that even greater understanding of the pDC/HIV-1 interaction could elucidate new therapies for HIV-1 disease.

TITLE: Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-alphaproducing and partially matured phenotype

AUTHOR CONTACT:
Nina Bhardwaj
New York University School of Medicine, New York, New York, USA.
Phone: 212.263.5814; Fax: 212.263.6729; E-mail: Nina.Bhardwaj@nyumc.org.

View this article at: http://www.jci.org/articles/view/44960?key=eea0f21f81ff48e26de2


VIROLOGY: Secrets about virus-induced immune cell cancers revealed

Kaposi sarcoma herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (a cancer that develops from the cells that line lymph or blood vessels). It has also been linked to primary effusion lymphoma and multicentric Castleman disease, which are poorly understood and largely incurable cancers that arise from immune cells known as B cells. Two independent research groups (one led by Don Ganem, at the University of California, San Fransisco, and the other led by Ethel Ceserman, at Weill Cornell Medical College, New York) have now generated new insight into how KSHV infection of B cells is regulated and how this affects B cell function and causes disease.

In an accompanying commentary, Chris Boshoff, at University College London, United Kingdom, discusses further the importance of these two papers for understanding KSHV-induced B cell cancers.

TITLE: Active lytic infection of human primary tonsillar B cells by KSHV and its noncytolytic control by activated CD4+ T cells

AUTHOR CONTACT:
Don Ganem
University of California at San Fransisco, San Francisco, California, USA.
Phone: 415.476.2826; Fax: 415.476.0939; Email: don.ganem@ucsf.edu.

View this article at: http://www.jci.org/articles/view/43755?key=6edefffd09cce851fd27

ACCOMPANYING ARTICLE
TITLE: Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice

AUTHOR CONTACT:
Ethel Cesarman
Weill Cornell Medical College, New York, New York, USA.
Phone: 212.746.6948; Fax: 212.746.8816; E-mail: ecesarm@med.cornell.edu.

Gianna Ballon
Weill Cornell Medical College, New York, New York, USA.
Phone: 212.746.6948; Fax: 212.746.8816; E-mail: gib2004@med.cornell.edu.

View this article at: http://www.jci.org/articles/view/44417?key=6d0f6b00e8af4d639963

ACCOMPANYING COMMENTARY
TITLE: Unraveling virus-induced lymphomagenesis

AUTHOR CONTACT:
Chris Boshoff
University College London, London, United Kingdom.
Phone: 44.20.7679.6850; Fax: 44.20.7679.6817; E-mail: c.boshoff@ucl.ac.uk.

View this article at: http://www.jci.org/articles/view/46499?key=debb8601ce5a2dfb8163


INFLAMMATION: Bacteria with attachment issues linked to Crohn disease

Crohn disease is a form of inflammatory bowel disease that most commonly affects the lower part of the small intestine. Some data indicate that bacteria have a role in the onset and perpetuation of Crohn disease. Adherent-invasive E. coli (AIEC) are one population of bacteria found in the small intestine of patients with chronic Crohn disease, but whether they cause or are a result of the condition has not been determined. A team of researchers, led by Arlette Darfeuille-Michaud, at Clermont Universit, France, has now generated data in mice that suggest that AIEC can contribute to the induction of the early stages of Crohn disease and that they do so via their adherence factor LPF. However, in an accompanying commentary, Warren Strober, at the National Institutes of Health, Bethesda, concludes that further work is needed to prove that AIEC are necessary for the initiation or persistence of Crohn disease.

TITLE: Crohn diseaseassociated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae

AUTHOR CONTACT:
Arlette Darfeuille-Michaud
Clermont Universit, Clermont-Ferrand, Auvergne, France.
Phone: 33.4.73.17.79.97; Fax: 33.4.73.17.83.71; E-mail: arlette.darfeuille-michaud@u-clermont1.fr.

View this article at: http://www.jci.org/articles/view/44632?key=7de02b901f294f280590

ACCOMPANYING COMMENTARY
TITLE: Adherent-invasive E. coli in Crohn disease: bacterial "agent provocateur"

AUTHOR CONTACT:
Warren Strober
National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
Phone: 301.496.6810; Fax: 301.402.2240; E-mail: Wstrober@niaid.nih.gov.

View this article at: http://www.jci.org/articles/view/46333?key=6ad5cc80bfde0d210df8


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Contact: Ushma Neill
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Journal of Clinical Investigation
Source:Eurekalert

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