Volume 15 Issue 5, May 2009

The Second Roche–Nature Medicine Translational Neuroscience Symposium on Autism and other developmental brain disorders was a resounding success.

In 1970, the US government chartered the Institute of Medicine (IOM), a component of the National Academies, to serve as an independent counsel on issues concerning health policy. Harvey Fineberg, former provost of Harvard University, has served at the helm of the IOM as the institute’s president since 2002. He spoke to Prashant Nair about the role of the IOM in biomedical research in the US.

Basic laboratory procedures can present physical challenges for biomedical researchers with disabilities. But a cadre of innovators has come up with technological solutions that make the laboratory bench more accessible to scientists with impaired sight or movement. Stu Hutson reports on how these adaptive research tools help people with disabilities by using everything from computer screen readers to security lasers.

After an increase in dietary salt, the excess sodium is stored under the skin—stimulating lymphatic growth through the activity of macrophages (pages 545–552). The findings should recast thinking about how blood pressure is regulated.

Studies of schizophrenia have been plagued by shortcomings such as weak genetic association with disease, inadequate animal models and limited replication of gene expression findings. Future success may lie not in overcoming any one of these limitations but in a broad approach strengthening the evidence in each area. Using such an approach, neuroscientists have uncovered a new gene behind the disease (pages 509–518).

The chromosomes of human embryos seem to be more unstable than previously thought. An analysis of embryos derived from in vitro fertilization reveals high rates of structural abnormalities (pages 577–583).

Current attempts to block angiogenesis during cancer and other diseases are limited partly by their effects on normal angiogenic processes. Could a more targeted approach emerge from the identification of a factor required for pathological angiogenesis under conditions of hypoxia (pages 553–558)?

The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.

Polymorphisms in a primate-specific isoform of K⁺ channel KCNH2 are associated with schizophrenia. This isoform induces a rapidly deactivating K⁺ current and high-frequency neuronal firing pattern. The disease-associated alleles predict lower intelligence quotient scores, lower speed of cognitive processing and altered memory. This channel isoform represents a potential new drug target for psychotherapypages 488–490.

T cells must enter the brain to induce the autoimmune disease multiple sclerosis. Lydia Sorokin and her colleagues identify a mechanism by which T cells migrate across the endothelial basement membrane, a key step to their passage from the blood into the brain.

Interleukin-7 (IL-7) promotes immune responses and has been touted as a potential tool for improving immune targeting of tumors. Here Pellegrini et al. investigate the mechanisms by which IL-7 increases antitumor responses and the treatment strategies necessary to optimize its effects.

Several tuberculosis drugs are prodrugs that have to be enzymatically activated during metabolism. Ethionamide is such a drug and is activated by the monooxygenase EthA. EthA is itself regulated by the transcriptional repressor EthR. Here Alain Baulard and his colleagues have designed inhibitors of EthR that boost the antimycobacterial efficacy of ethionamide both in vitro and in vivo. Current therapy with ethionamide requires the use of high doses, often eliciting side effects. Its combination with the EthR repressor should allow lower doses to be used.

Salt intake is associated with hypertension, but the mechanisms by which salt affects blood pressure remain unclear. Agnes Machnik et al. now show that mononuclear cells such as macrophages respond to dietary salt intake by producing the growth factor VEGF-C, leading to expansion of the lymphatic capillary network. Interference with this response in rats fed a high-salt diet exacerbates the increase in blood pressure caused by a high-salt dietpages 487–488..

Hypoxia-triggered neovascularization occurs in many types of disease. Endothelial cells must be able to cope with hypoxic stress, which in other cell types can induce a DNA repair response and inhibit replication. Matina Economopoulou et al. now show that hypoxia induces the generation of a hallmark of the DNA repair response, phosphorylated histone H2AX, in proliferating endothelial cells and that H2AX function is required for neovascularization under hypoxic or ischemic conditions in vivopages 491–493..

Primary prostate cancer is genomically highly heterogeneous and is thought to derive from multiple independent clones of cancer cells. Using high-resolution genomic analyses, Bova et al. now show that, in contrast to primary tumors, metastases are monoclonal, originating from a single cancer cell. These findings call into question current views of the origins of primary prostate cancer and suggest that the genomic profile of prostate cancer metastases should inform therapeutic decisions.

Here Fan et al. describe a protein analysis platform for the sensitive, nanoscale diagnosis and investigation of clinical specimens, including monitoring the response to targeted therapeutics. The nanofluidic proteomic immunoassay can be used to quantify total and phosphorylated forms of oncoproteins in small tumor samples and has been validated in vivo in mouse tumors and in clinical specimens from blood, surgical biopsies and fine-needle aspirates.

In this study, Galbán and his colleagues describe a voxel-wise approach for the quantification of tumor microvasculature properties from perfusion magnetic resonance imaging data. When compared to the standard method of using region of interest analysis of changes in relative cerebral blood flow and volume, the parametric response map approach was found to be more predictive of treatment outcomes and overall survival in individuals with high-grade glioma.

Vanneste and her colleagues describe an array-based approach for scoring genome-wide DNA copy number variations and loss of heterozygosity in single cells. They show that chromosome instability patterns, reminiscent of those seen in human cancers, are also common in cleavage-stage in vitro–fertilized embryos. Such findings during early human embryogenesis could provide a basis for the low fecundity and high miscarriage rate in humanspages 490–491..