Multiple non-catalytic ADAMs are novel integrin α4 ligands.

The ADAM (a disintegrin and metalloprotease) protein family uniquely exhibits both catalytic and adhesive properties. In the well-defined process of ectodomain shedding, ADAMs transform latent, cell-bound substrates into soluble, biologically active derivatives to regulate a spectrum of normal and pathological processes. In contrast, the integrin ligand properties of ADAMs are not fully understood. Emerging models posit that ADAM-integrin interactions regulate shedding activity by localizing or sequestering the ADAM sheddase. Interestingly, 8 of the 21 human ADAMs are predicted to be catalytically inactive. Unlike their catalytically active counterparts, integrin recognition of these "dead" enzymes has not been largely reported. The present study delineates the integrin ligand properties of a group of non-catalytic ADAMs. Here we report that human ADAM11, ADAM23, and ADAM29 selectively support integrin α4-dependent cell adhesion. This is the first demonstration that the disintegrin-like domains of multiple catalytically inactive ADAMs are ligands for a select subset of integrin receptors that also recognize catalytically active ADAMs.

Infective Endocarditis Manifesting as Severe Elevation in Serum Aminotransferases in the Absence of Severe Tricuspid Regurgitation, Heart Failure, or Shock: A Diagnostic Challenge.

Infective endocarditis (IE) is a challenging condition to diagnose, given its protean clinical signs and symptoms, Elevation in serum aminotransferases in IE is associated with valvular regurgitation, acute heart failure, or congestive hepatopathy. Studies show co-existing liver failure portends worsening outcomes in IE and poses a challenge for successful surgical management. Here we report a diagnostic challenge in a 35-year-old man with IE presenting predominantly with gastrointestinal symptoms and severe elevation in serum aminotransferase. The degree of aminotransferase elevation in our patient prompted consideration of alternative causes like acetaminophen toxicity. Severe elevation in aminotransferases as an initial presentation in the absence of significant valvular regurgitation, acute right heart failure, or shock is uncommon. A high degree of suspicion is required to diagnose IE when patients present with atypical signs and symptoms to avoid delay in initiation of antibiotics and improve overall morbidity and mortality.