Between Bedside and Bench

Type 2 diabetes is often viewed as a disorder of glucose metabolism. But many factors come into play in this condition, with obesity a prime risk factor and cardiovascular disease a major result. In Bedside to Bench, Babak Razani and Clay Semenkovich examine the linkages between diabetes and cardiovascular disease. They call for new research approaches in the wake of clinical trials showing that lowering glucose levels does not decrease cardiovascular events in people with type 2 diabetes. In Bench to Bedside, Steven Shoelson and Allison Goldfine examine how type 2 diabetes and other disorders can stem from obesity—and its effect on inflammation. These authors take a look at two recent studies showing how obesity perturbs inflammatory gene networks.

Inherited neurodegenerative conditions such as Huntington's disease have proximal causes (a defective gene) and downstream causes (pathological events caused by that gene). Albert R. La Spada examines efforts to target bad genes with gene knockdown approaches on the eve of a clinical trial designed to silence the causative gene in familial amyotrophic lateral sclerosis. Masahisa Katsuno, Hiroaki Adachi and Gen Sobue examine the possibility of targeting a potentially damaging downstream event in Huntington's disease—dysregulated cholesterol metabolism in the brain.

Osteoporosis researchers do not suffer from a lack of potential drug targets—so one challenge is to decide which ones to focus on. Yongwon Choi, Matthew C. Walsh and Joseph R. Arron now examine several molecules involved in bone biology and assess their prospects. In a second commentary, Cliff Rosen analyzes findings that serotonin, derived from the gut, regulates bone formation. The findings not only could lead to new drug targets, they also could help explain clinical data that serotonin reuptake inhibitors—widely prescribed as antidepressants—weaken bones.

Numerous drugs have been invented to counteract heart failure, but some have not lived up to their initial promise. As David Kass explains, the development of drugs to increase cardiac contractility has been particularly frustrating—but failure is also leading to new biological insights and new experimental approaches. Mark Anderson and Peter Mohler explore new ways of targeting calcium-mediated signaling in the heart—with a focus on combating heart failure by targeting 'local' forms of signaling in heart muscle.

Toll-like receptors (TLRs), molecules that recognize molecular components of microbes, have taken center stage in immunologists' view of how innate immunity is triggered. A study in people genetically deficient for MyD88, a molecule central to TLR signaling in mice, should now spur a reexamination of simple views of TLR biology, as Rino Rappuoli and his colleagues explain. Delphine J. Lee and Robert L. Modlin examine how TLR9 recognition of self DNA, instead of microbe DNA, may prompt autoimmunity.

Two big challenges of transplantation biology are controlling the reaction of the graft to the host after hematopoietic stem cell transplantation and preventing rejection of donor organs by the host. Raewyn Broady and Megan K. Levings discuss the first challenge, examining studies suggesting that statins might be helpful to control graft-versus-host disease. Kathryn Wood tackles the second challenge in the context of the 'Edmonton protocol', a procedure that can restore the ability to control blood glucose in people with type 1 diabetes—but only in the short term.

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.

The complexity of factors that regulate bleeding and coagulation has long confounded researchers. Andrew Wei and Shaun Jackson help clear the air by examining clinical findings pointing to a mechanistic basis for a common bleeding disorder, immune thrombocytopenic purpura. Mark Kahn tackles two research studies that could lead to improved therapies for a coagulation syndrome that hits people with severe sepsis.

Endocannabinoids are versatile molecules, regulating a variety of functions in the body. Daniele Piomelli explores how recent clinical trials testing rimonabant, an inhibitor of endocannabinoid signaling, for weight loss emerged from studies of individuals with schizophrenia; such trials have spurred basic research into how endocannabinoids affect both energy use and mood. Beat Lutz and Krisztina Monory examine how rimonabant might prove useful for preventing the development of adult epilepsy in response to fever-induced seizures in infants and young children.