Volume 14 Issue 10, October 2008

What would a trim 75-year-old grain farmer have to say about drug safety and the payments given to medical researchers by drug companies? Lots, if he happens to be Charles Grassley, who has represented the state of Iowa in the US Senate since 1980. As the senior Republican on the Senate’s finance committee and as a senior member of the judiciary committee, he has carved out a role as a relentless watchdog who acts as a magnet for whistleblowers in government agencies ranging from the US Department of Defense to the Federal Bureau of Investigation (FBI). In the last several years, Grassley has set his investigative sights on issues relating to medicine. A leading critic of the Food and Drug Administration (FDA) since the surprise withdrawal from the market of Merck's painkiller Vioxx in 2004, Grassley is now focusing on university researchers funded by the National Institutes of Health (NIH) who haven't been properly reporting income from drug companies. Meredith Wadman asked the senator what he hopes to achieve through his investigations.

For years, researchers have debated whether the enzyme lipoprotein-associated phospholipase A₂ (Lp-PLA₂), produced by inflammatory cells, is a 'good guy' or 'bad guy' in atherosclerosis. Work in pigs provides strong support for the view that Lp-PLA₂ promotes the formation of atherosclerotic lesions and dangerous, unstable atherosclerotic plaques (pages 1059–1066).

Comparative studies of the immune response to simian immunodeficiency virus in two nonhuman primate species provide insight into a central aspect of HIV infection—the ability of the virus to cause chronic activation of the immune system (pages 1077–1087).

Infections with fimbriated bacteria may trigger autoimmunity and cause a form of severe vasculitis that affects capillaries in the kidney and that can destroy the organ (pages 1088–1096).

Genetic inactivation of the mitochondrial self-destruction mechanism improves cognition in a mouse model of Alzheimer's disease (pages 1097–1105).

Smoke is a solid. Whether from cigarettes, cooking fires or other sources, it is comprised of tiny particles that injure the lung and can lead to lung cancer and chronic obstructive pulmonary disorder, characterized by laborious breathing. Steven D. Shapiro and his colleagues take a look at imaging data in people suggesting that these two conditions have more in common mechanistically than was previously thought. Both diseases seem to stem in part from the ability of inhaled particles to trigger inflammation, a process examined by Robert M. Senior and his colleagues.

Smoke is a solid. Whether from cigarettes, cooking fires or other sources, it is comprised of tiny particles that injure the lung and can lead to lung cancer and chronic obstructive pulmonary disorder, characterized by laborious breathing. Steven D. Shapiro and his colleagues take a look at imaging data in people suggesting that these two conditions have more in common mechanistically than was previously thought. Both diseases seem to stem in part from the ability of inhaled particles to trigger inflammation, a process examined by Robert M. Senior and his colleagues.

Although increased levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with cardiac disease, whether this enzyme has a causal role in the development of atherosclerosis has not been clear. Wilensky et al. now show in a pig model of atherosclerosis that a selective Lp-PLA2 inhibitor reduces progression to complex atherosclerotic lesion formation, an effect that is associated with decreased infiltration of inflammatory cells into the lesions. These results support the use of Lp-PLA2 inhibitors for the treatment of atherosclerotic cardiovascular disease.

The mechanisms that control blood vessel formation are incompletely understood. Sylvain Chemtob and his colleagues now find that blood vessel formation in mouse and rat retinas is controlled by succinate generated during hypoxic and ischemic conditions. Succinate acting through its receptor, GPR91, on retinal ganglion neurons, triggers secretion of canonical proangiogenic factors and the formation of new blood vessels to reinstate adequate tissue supply. This work also identifies GPR91 as a potential therapeutic target for the treatment of ischemic retinopathies.

Unlike HIV-infected humans or SIV-infected rhesus macaques, natural monkey hosts for SIV do not show immune activation or progress to AIDS, even though they have high viral loads after infection. Differences in the innate immune response in these monkeys may provide a clue as to why they remain healthy.

Pauci-immune crescentic glomerulonephritis—an inflammatory disease of the kidneys— may be triggered by bacterial infection. Kain et al. show that almost all individuals with this disease have auto-antibodies to the membrane protein LAMP-2. These antibodies cross-react with the bacterial adhesion FimH, and immunization with FimH causes disease in rats.

Mitochondrial dysfunction has been described in Alzheimer's disease, but how it is induced has remained unclear. Shi Du Yan and her colleagues find that a neurotoxic amyloid protein associated with the disease binds a mitochondrial protein called cyclophilin D and causes neuron death. The authors show that Alzheimer's disease model mice that lack cyclophilin D show improvements in learning and memory.

Some Aβ peptides contain pyroglutamate modifications that affect the aggregation properties of these peptides. The authors find that the enzyme glutaminyl cyclase is responsible for this pyroglutamate modification. When they inhibit the enzyme in Alzheimer's model mice, fewer plaques form in the brain, and some measures of learning and memory are improved.

De-Xue Fu et al. present a novel approach to radiotherapy of herpesvirus-associated tumors by first inducing the expression of viral thymidine kinase by pretreatment with bortezomib and then by administering a radiopharmaceutical that targets the viral enzyme. The authors show that this approach is effective in lymphoid and epithelial malignancies in several xenograft mouse models of human tumors.

Banaszynski et al. combine genetic manipulation with small-molecule regulation to produce rapid, reversible and tunable regulation of protein expression in vivo. The approach builds on earlier work showing that fusion of a destabilizing domain to a gene of interest confers instability to the expressed protein. Degradation of the protein is then prevented by subsequent addition of the cell-permeable stabilizing ligand, Shield-1, which binds specifically to the destabilizing domains. Three in vivo applications of the technology in mice are described.