JCI table of contents: July 3, 2006


Man emerges from 19 years in minimally conscious state as brain repairs itself

Three years ago, 39-year-old Terry Wallis who had persisted in a minimally conscious state (MCS) for 19 years after a traumatic brain injury resulting from a motor-vehicle accident, recovered basic motor function and the power of speech. Using state-of-the-art structural and functional neuroimaging techniques, Henning Voss and colleagues from Cornell University have now examined Terry's brain in order to gain some insight into what caused his "miracle" recovery. In their study, which appears in the July issue of the Journal of Clinical Investigation, they show that neuronal cells in the relatively undamaged areas of Terry's brain have slowly grown new and important connections over a period of years in a process known as axonal re-growth.

Voss et al. compared Terry's post-recovery brain structure and function with that of 20 healthy individuals and another MCS patient that had not shown any recovery after 6 years. The authors suggest that the axonal re-growth may be the result of Terry's brain trying to re-establish connections that would allow for functions like motor control and speech to resume after injury.

In the aftermath of the political, ethical, medical, and legal controversies that surrounded the highly publicized right-to-live versus right-to-die case of Terry Schiavo there has been much debate about the outcome for patients with disorders of consciousness. Unlike patients in a persistent vegetative state like Schiavo, MCS patients will show more than purely reflex or automatic behavior, but they will nevertheless be unable to communicate their thoughts or feelings in more than a limited or intermittent capacity. Our minimal understanding of why some patients recover from these disorders has limited our ability to predict emergence from MCS and optimize the health care options for these individuals.

In an accompanying commentary, Steven Laureys from the University of Liège writes, "Chronically unconscious or minimally conscious patients represent unique problems for diagnosis, prognosis, treatment, and everyday management. They are vulnerable to being denied potentially life-saving therapy….. This case shows that old dogmas need to be oppugned." While the researchers are careful to caution that this process of axonal re-growth may not be occurring in all MCS patients, similar future findings in other MCS patients could effect how these individuals are cared for and evaluated. The results reported here by Voss and coworkers will increase our understanding of severely brain-damaged patients and their "miracle" recovery of consciousness. The study suggests a method by which brain function in these individuals can be monitored and their potential recovery from MCS could be tracked.

TITLE: Possible axonal regrowth in late recovery from the minimally conscious state

Jonathan Weil
Office of Public Affairs, Cornell University, New York, New York, USA.
Phone: (212) 821-0560; Fax: (212) 821-0576; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27021


TITLE: Tracking the recovery of consciousness from coma

Steven Laureys
University of Liège, Liège, Belgium.
Phone: 32-4-366-23-16; Fax: 32-4-366-29-46; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29172


The leak stops here: Platelets deliver healing agent for hemophilia

Hemophilia is a hereditary genetic illness caused by a deficiency in the coagulation factor VIII (FVIII), and results in the body's inability to control bleeding. Gene therapy is an attractive approach for the treatment of hemophilia, as continuous expression of FVIII DNA would ensure clotting factor replacement at constant circulating levels rather than at the peaks and troughs that characterize current protein infusion therapies. In a study in mice appearing in the July issue of the Journal of Clinical Investigation, Robert Montgomery and colleagues from the Blood Research Institute show that targeted expression of FVIII in megakaryocytes (large bone marrow cells that release mature blood platelets), with FVIII storage in the alpha-granules of platelets, has the advantage of delivering clotting factors directly to the site of an injury, where platelets accumulate in large numbers and are activated to release their granule contents.

In an accompanying commentary, Katherine High from The Children's Hospital of Philadelphia discusses whether this encouraging result in mice can be extended to humans with the disease and comments that "an approach that generates 'therapeutic' platelets would be a welcome advance" for this patient population.

TITLE: Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitor antibodies

Robert R. Montgomery
Blood Research Institute, Milwaukee, Wisconsin, USA.
Phone: (414) 937-3802; Fax: (414) 937-6811; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=28416


TITLE: The leak stops here: platelets as delivery vehicles for coagulation factors

Katherine A. High
The Children's Hospital of Philadelphia, Pennsylvania, USA.
Phone: (215) 590-4521; Fax: (215) 590-3660; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29193


Headway for hydrocephalus: When cerebrospinal fluid can't go with the flow

Hydrocephalus occurs when there is an abnormal accumulation of cerebrospinal fluid (CSF) in the brain, usually due to a blockage of CSF outflow. In a study appearing in the July issue of the Journal of Clinical Investigation, Sanbing Shen and colleagues from the University of Aberdeen uncover how CSF flow is regulated throughout the brain.

The Sylvian aqueduct is a canal between two cavities of the brain, through which CSF passes. In most vertebrate species, a gland (known as the subcommissural organ or SCO) at the entrance to this canal secretes glycoproteins that form a long, thread-like structure known as Reissner's fiber. This fiber extends through the aqueduct and prevents its closure, thereby ensuring continuous CSF flow. Microscopic hair-like structures known as cilia cover the surface of cells in the aqueduct and also help maintain CSF flow. Shen and colleagues examined mice overexpressing the human PAC1 receptor, which binds the neurotransmitter PACAP, on the surface of SCO cells. These animals developed hydrocephalus-like characteristics and possessed fewer cells in the SCO, which may result in disorganization or absence of Reissner's fiber. In addition, shorter, inefficient cilia were observed on the cells lining the aqueduct. Together, these changes likely result in turbulent CSF flow at the aqueduct entrance and reduced flow within the cerebral aqueduct, promoting hydrocephalus. In an accompanying commentary, David Picketts from the University of Ottawa discusses the novel role for this signaling cascade in the regulation of CSF circulation.

TITLE: Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice

Sanbing Shen
University of Aberdeen, Aberdeen, United Kingdom.
Phone: 44-1224-555730; Fax: 44-1224-555719; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27597


TITLE: Neuropeptide signaling and hydrocephalus: SCO with the flow

David J. Picketts
University of Ottawa, Ontario, Canada.
Phone: (613) 737-8989; Fax: (613) 737-8803; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29148


Cardiac stem cell therapy boosts blood vessel growth and injury repair

Data has suggested that injection or mobilization of bone marrow stem cells into injured heart muscle during or after myocardial infarction would be able to regenerate heart muscle lost due to injury. However, there is a growing consensus that the mechanism of any potential therapeutic benefit is unknown and evidence suggests that any potential improvement in cardiac function observed is largely independent of cardiac muscle regeneration. A study appearing in the July issue of the Journal of Clinical Investigation by Ren-Ke Li and colleagues from Toronto General Hospital now provides evidence that the transplantation of bone marrow–derived c-kit+ cells can lead to improvement in cardiac function in mice after acute myocardial infarction that is independent of the differentiation of these cells into cardiac muscle cells, but rather is associated with the release of molecules known as cytokines that stimulate the growth of new blood vessels to the area of injury, promoting healing.

In an accompanying commentary, Kenneth Chien from Harvard Medical School comments, "On the clinical front, these studies raise the larger question as to whether the mechanistic basis for cardiovascular stem cell therapy following acute myocardial infarction might be more closely related to the biology of wound healing than regenerative medicine."

TITLE: Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines

Alex Radkewycz
Public Affairs, Toronto General Hospital, Toronto, Ontario, Canada.
Phone: (416) 340-3895; Fax: (416) 340-5054; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27019


TITLE: Lost and found: cardiac stem cell therapy revisited

Kenneth R. Chien
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 643-3440; Fax: (617) 643-3451; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29050


Desmoplakin loss causes disaster in a heartbeat

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare form of cardiomyopathy in which the heart muscle of the right ventricle is replaced by fatty or fibrous tissue. The right ventricle is then unable to contract properly and the heart's ability to pump blood is weakened, often resulting in an abnormal heart rhythm, cardiac arrest or death. In a study appearing in the July issue of the Journal of Clinical Investigation, Ali Marian and colleagues from Baylor College of Medicine show that cardiac myocyte–specific loss of a protein called desmoplakin in mice causes the protein plakoglobin to be relocated to the nucleus of these cells, upregulation of the expression of genes involved in fat cell formation and the subsequent accumulation of fat droplets in heart muscle, myocyte apoptosis, and cardiac arrhythmias similar to human ARVC. The study provides a novel molecular mechanism for how this disease develops and an animal model of human ARVC for future study.

In an accompanying commentary, Ludwig Thierfelder and colleagues from the Max Delbruck Center for Molecular Medicine, Berlin, discuss the signaling pathways involved in this disease and how they manifest their effects on heart cell differentiation and physiology.

TITLE: Suppression of canonical Wnt/b-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy

Ali J. Marian
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-7454; Fax: (713) 790-3147; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27751


TITLE: Arrhythmogenic right ventricular cardiomyopathy: moving toward mechanism

Ludwig Thierfelder
Max Delbruck Center for Molecular Medicine, Berlin, Germany.
Phone: 49-30-9417-2398; Fax: 49-30-9417-2540; Email: [email protected].

Calum A. MacRae
Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone: (617) 726-4343; Fax: (617) 726-5806; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29174


LXR alpha: a new StAR in balancing cholesterols levels in the adrenal gland

Cholesterol is the precursor to all steroid hormones, which control heart rate, blood pressure, and how the body utilizes food. Therefore a constant cholesterol supply must be available to the adrenal gland where such hormones are produced. Liver X receptors (LXRs) are known to limit the accumulation of excess cholesterol by regulating the expression of genes involved in cholesterol storage and passage out of the body. In a study appearing in the July issue of the Journal of Clinical Investigation, David Mangelsdorf and colleagues from the University of Texas Southwestern now show that LXR alpha acts as a safety valve to limit the accumulation of free cholesterol in the adrenal glands of mice, which can be toxic at high levels. LXR alpha achieves this control by coordinately regulating the expression of genes involved in cholesterol efflux (ABCA1), storage (apoE, SREBP-1c), and metabolism to steroids (by the protein known as StAR).

In an accompanying commentary, Colin Jefcoate from University of Wisconsin Medical School discusses the findings of this study in the context of other known pathways of cholesterol transfer, and steroid synthesis in a variety of tissues.

TITLE: Liver X receptors regulate adrenal cholesterol balance

David J. Mangelsdorf
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 645-5957; Fax: (214) 645-5969; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=28400


TITLE: Liver X receptor opens a new gateway to StAR and to steroid hormones

Colin R. Jefcoate
University of Wisconsin Medical School, Madison, Wisconsin, USA.
Phone: (608) 263-3975; Fax: (608) 262-1257; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29160


Adenosine receptors have a split personality

Adenosine, long known to be a regulator of heart function, has recently been identified as an inhibitor of inflammation that acts primarily by activating the A2A adenosine receptor (A2AAR) on lymphoid and myeloid cells. In a study appearing in the July issue of the Journal of Clinical Investigation, Katya Ravid and colleagues from Boston University School of Medicine show that deletion of the gene encoding the A2B adenosine receptor (A2BAR) in mice triggers inflammation. This suggests that activation of A2BARs, particularly those present on macrophages, can have anti-inflammatory effects.

In an accompanying commentary Joel Linden from The University of Virginia explores these results, highlighting that the role of A2BAR remains enigmatic because its activation can either stimulate or inhibit the release of proinflammatory molecules in different cells and tissues.

TITLE: The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Katya Ravid
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: (617) 638-5053; Fax: (617) 638-5054; E-mail: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=27933


TITLE: New insights into the regulation of inflammation by adenosine

Joel Linden
University of Virginia, Charlottesville, Virginia, USA.
Phone: (434) 924-5600; Fax: (434) 924-2828; Email: [email protected].

View the PDF of this article at: https://www.the-jci.org/article.php?id=29125


Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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