Volume 15 Issue 10, October 2009

Two years ago, Christopher Murray took the helm of the newly created Institute for Health Metrics and Evaluation. Since 2007, the Institute has been churning out studies that that are shaping the debate on health care reform. Murray spoke with Charlotte Schubert about how having accurate numbers can add up to progress in health care.

Biomedicine would be a breeze if organisms were transparent. With the ability to see through tissues, scientists could spot the development of tumors more easily in study animals. And biologists could study exactly how an animal's organs develop by observing them as they grow. In effect, the secrets of the body would be out there for everyone to see.

The blood-brain barrier constitutes a major obstacle to effective treatment of diseases affecting the central nervous system. A new strategy to target specifically the endothelium of diseased brain may allow the development of more effective gene-based therapies (pages 1215–1218).

Imatinib (trade name Gleevec) preserves fertility in female mice treated with the common chemotherapeutic agent cisplatin. Imatinib seems to block an apoptotic pathway activated by cisplatin in ovarian germ cells (pages 1179–1185). The findings could lead to new ways to protect germ cells from the damaging effects of cancer treatment.

Mouse experiments show how mutation of a gene involved in human epilepsy causes hyperexcitability of the neuronal network (pages 1208–1214). The mutations interfere with the maturation of excitatory synapses during postnatal development.

The number of copies of the gene encoding a ligand for an HIV co-receptor have been found to influence the susceptibility to HIV infection and AIDS progression. New studies dispute this conclusion. The studies are contested by the authors of the original findings, and highlight the inherent difficulties in accurately measuring gene copy numbers (pages 1110–1112, 1112–1115, 1115–1117 and 1117–1120).

Hemorrhages in the brain are responsible for about 15% of strokes and are particularly difficult to treat. Costantino Iadecola assesses a new clinical study that may change the view of why a common form of hemorrhage, subarachnoid hemorrhage, often leads to death. Massive brain lesions often develop days after the initial event, a dangerous complication previously attributed to vasospasm, narrowing of the arteries. The study suggests that these lesions may instead by caused by neuronal depolarization, extending in waves across the brain. Gregory del Zoppo explores the connection between deposition of toxic amyloid-β peptides in the brain and hemorrhage. He discusses studies suggesting that the peptides inactivate proteins in the blood that can stop hemorrhage.

Dying tumor cells release ATP, which activates the NLRP3 inflammasome in dendritic cells, enabling the secretion of interleukin-1β and the subsequent priming of tumor-specific interferon-γ-producing T lymphocytes.

Chemotherapy often leads to premature death of oocytes, and thus infertility, in young individuals with cancer. Here, Stefania Gonfloni and her colleagues show that chemotherapy-induced activation of the kinase c-Abl is responsible for this oocyte failure and that, in vivo, the c-Abl inhibitor imatinib prevents this effect (pages 1124–1125).

Torsten Roepke et al. show that the potassium channel subunit KCNE2—which previously has been most recognized for its role in controlling electrical activity in the heart—is important for normal thyroid function. KCNE2, together with its partner KCNQ1, is expressed in both mouse and human thyroid epithelial cells, and Kcne2 deficiency in mice leads to a constellation of defects resulting from decreased thyroid hormone biosynthesis. These results suggest new genetic links between thyroid and heart function.

Insulin action in the brain is known to inhibit food intake. Now Leona Plum and her colleagues show that in hypothalamic neurons insulin inhibits FoxO1-mediated transcriptional repression of Cpe, a gene that encodes a carboxypeptidase that is required for proper processing of key anorexigenic neuropeptides. The team also found that this pathway is disturbed in states of diet-induced obesity, suggesting that obesity-induced insulin resistance may affect obesity even further.

Lissencephaly is a developmental brain disorder caused by mutations in LIS1 and characterized by impaired neuronal migration. Inhibiting calpain prevents LIS1 degradation in heterozygous mice and rescues the defective neuronal migration in utero.

LGI1, a gene linked to epilepsy in humans, promotes disease by impairing the maturation of glutamatergic circuits in the mouse brain.

Optical frequency domain imaging (OFDI) is a wide-field, three-dimensional intravital imaging technique that provides information on the entire tumor vasculature and surrounding tissue microenvironment, allowing visualization of angiogenesis and lymphangiogenesis during tumor growth and with therapy. Here, Vakoc et al. show that, in contrast to multiphoton microscopy, OFDI can image at greater tissue depths with a wider field of view and without the need for exogenous contrast agents.

In an effort to develop safer therapeutic agents and to limit unintended side effects, Sabah Oney and her colleagues have designed a set of antidote molecules for a series of aptamers exhibiting anticoagulant activities. These so-called universal antidotes are shown to sequester circulating aptamers and reverse their activity, irrespective of the primary sequence and folded structure of the aptamer.