News Release

JCI table of contents -- March 22, 2007

Peer-Reviewed Publication

JCI Journals

EDITOR’S PICK: Prenatal exposure to glucocorticoids has long-term deleterious effects on newborns

Researchers at the University of Edinburgh in the United Kingdom have found that, as for rodents and other nonprimates, prenatal exposure of nonhuman primate African vervet monkeys (Chloroceus aethiops) to glucocorticoids has long-lasting deleterious effects on cardiovascular, metabolic, and neuroendocrine function.

Glucocorticoids are still widely used in obstetric practice. So, Jonathan Seckl and colleagues set out to determine the relevance to human pregnancy of rodent and nonprimate data indicating that prenatal exposure to glucocorticoids (through either the administration of dexamethasone or severe maternal stress) has long-lasting deleterious effects. In the study, which appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, they show that although the birth weight of offspring born to nonhuman primate African vervet monkeys treated with dexamethasone from mid-gestation onward did not differ from that of offspring born to untreated animals, the high levels of prenatal dexamethasone impaired postnatal growth, impaired glucose-insulin homeostasis, increased blood pressure 12 months after birth, and increased the production of cortisol in response to mild stress. These data suggest that both repeated glucocorticoid therapy and severe maternal stress late in gestation are likely to have long-term deleterious effects on developing human fetuses.

TITLE: Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function

AUTHOR CONTACT:
Jonathan R. Seckl
University of Edinburgh, Edinburgh, United Kingdom.
Phone: 44-131-242-6777; Fax: 44-131-2426779; E-mail: j.seckl@ed.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30982


EDITOR’S PICK: New protein implicated in autism

Autism is a common neurodevelopmental disorder characterized by severely impaired social, communicative, and behavioral functions. It is thought that genetic make-up predisposes an individual to autism, and several genes have been associated with the development of autism. Although a region of human chromosome 7 has been identified to be associated with susceptibility to autism, none of the genes in this region had been directly implicated in the disorder until researchers from the RIKEN Brain Science Institute in Japan demonstrated that mice lacking the protein CADPS2 exhibited autistic-like characteristics.

In the study, which appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Teiichi Furuichi and colleagues show that mice lacking CADPS2, which is encoded by a gene in the autism susceptibility region of human chromosome 7, had impaired social interactions (when pairs of CADPS2-deficient mice that had never met were placed together they interacted substantially less frequently than pairs of wild-type mice that had never met), hyperactivity, and decreased exploration of a new environment; all of which are characteristics of individuals with autism. Importantly, an abnormal form of CADPS2 mRNA (which is an intermediate in the conversion of the CADPS2 gene to CADPS2 protein) was detected in some individuals with autism and was never detected in their healthy immediate relatives, leading to the suggestion that defects in CADPS2 function might predispose individuals to develop autism.

TITLE: Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients

AUTHOR CONTACT:
Teiichi Furuichi
RIKEN Brain Science Institute, Wako, Saitama, Japan.
Phone: +81-48-467-6079; Fax: +81-48-467-6079; E-mail: tfuruichi@brain.riken.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29031


ONCOLOGY: Leukemic cells find protection in the bone marrow from anticancer drug

As part of their therapeutic regimen, individuals with acute lymphoblastic leukemia (ALL) are treated with asparaginase — a protein that breaks down the amino acid asparagine. ALL cells are sensitive to a lack of asparagine in their environment because they express very low levels of the protein ASNS, which makes asparagine. However, the mechanisms regulating the susceptibility of ALL cells to asparaginase are not completely clear, as ASNS expression levels do not always correlate with clinical effectiveness of the treatment.

In a study that appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Dario Campana and colleagues from St. Jude Children’s Research Hospital, Memphis, show that in vitro, mesenchymal cells (MSCs) from the bone marrow — which is where ALL cells grow in patients — can provide high levels of asparagine to ALL cells, enabling them to overcome the effects of asparaginse. Protection correlated with the level of ASNS expressed by the MSCs; decreased ASNS expression reduced the ability of MSCs to protect ALL cells from asparaginase, whereas enhanced expression increased their protective capacity. This study indicates that MSCs in the bone marrow can provide protective niches for ALL cells and leads to the suggestion that ASNS in MSCs might be a good target for the treatment of individuals with ALL.

TITLE: Mesenchymal cells regulate the response of acute lymphoblastic cells to asparaginase

AUTHOR CONTACT:
Dario Campana
St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Phone: (901) 495-2528; Fax: (901) 495-5947; E-mail: dario.campana@stjude.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30235


INFLAMMATION: Inflammatory pathway leads to Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and usually results in death by the age of 30. Although mutations in the dystrophin gene cause DMD, they trigger persistent inflammation, which is probably what intensifies disease progression.

In a study that appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Denis Guttridge and colleagues from Ohio State University, Columbus, show that a signaling pathway associated with chronic inflammation (the IKK/NF-kappa-B pathway) is upregulated in both muscle cells and immune cells from individuals with DMD and from mice lacking expression of dystrophin. Impaired IKK/NF-kappa-B signaling in mice lacking expression of dystrophin (achieved by either knocking out one of the genes encoding the p65 NF-kappa-B subunit or treating the mice with an IKK inhibitor) improved their muscle function and muscle regeneration. The authors therefore suggest that the IKK/NF-kappa-B signaling pathway might provide a viable therapeutic target for the treatment of DMD.

TITLE: Interplay of IKK/NF-kappa-B signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy

AUTHOR CONTACT:
Denis C. Guttridge
Ohio State University College of Medicine, Columbus, Ohio, USA.
Phone: (614) 688-3137; Fax: (614) 688-4006; E-mail: denis.guttridge@osumc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30556


HEMATOLOGY: Protein’s role in blood clotting differs in vitro and in vivo

The formation of a blood clot (also known as a thrombus) is a key step in stopping bleeding after tissue injury. The adhesion of platelets to a blood vessel wall and their subsequent aggregation and activation are essential for thrombus formation. Previous in vitro studies have shown that a protein known as vWF is essential for platelet adhesion, aggregation, and activation in thrombus formation. However, researchers from the Beth Israel Deaconess Medical Center, Boston, have now shown that vWF is not required for in vivo platelet activation in mice in which tissue injury was induced with a laser.

In the study, which appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Bruce Furie and colleagues show that in mice lacking vWF, platelet activation (as measured by calcium mobilization) occurred normally following laser-induced injury, although platelet adhesion and aggregation were impaired. Platelet activation following laser-induced injury was shown to occur via the tissue factor–mediated pathway and not the collagen-mediated pathway. Therefore, this study indicates that, surprisingly, vWF is not required for in vivo tissue factor–mediated platelet activation, although other studies have indicated that it might have an in vivo role in collagen-mediated platelet activation.

TITLE: Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model

AUTHOR CONTACT:
Bruce Furie
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 754-1200; Fax: (617) 754-1234; E-mail: bfurie@caregroup.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30537


NEPHROLOGY: Disease-causing genetic mutation reveals its molecular secrets

Pseudohypoaldosteronism type 2 (PHA2), also known as Gordon syndrome, is an inherited disease that causes high blood pressure and high levels of potassium in the blood. Recent studies have identified mutations in two genes (WNK1 and WNK4) as causes of PHA2. Although disease-causing WNK4 mutations are known to increase internalization of a cell surface protein known as ROMK1 (which is involved in regulating potassium uptake) by kidney cells, the molecular details behind this increased internalization have not been clearly defined.

In a study that appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Chou-Long Huang and colleagues from the University of Texas Southwestern Medical Center, Dallas, show that in vitro, rat WNK4 interacts with a protein known as ITSN and that this is important for WNK4-mediated internalization of ROMK1 by kidney cells. Furthermore, interactions between WNK4, ITSN, and ROMK1 were enhanced if WNK4 contained the PHA2-causing mutations, leading to increased ROMK1 internalization. This study therefore describes a molecular mechanism for the observation that disease-causing WNK4 mutations increase ROMK1 internalization by kidney cells.

TITLE: Intersectin links WNK kinases to endocytosis of ROMK1

AUTHOR CONTACT:
Chou-Long Huang
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-8627; Fax: (214) 648-2071; E-mail: chou-long.huang@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30087

###

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.