Diabetes mellitus is considered an indicator of poor prognosis for acute ankle fractures, but this risk may be specific to an identifiable subpopulation. We retrospectively reviewed 42 patients with both diabetes mellitus and an acute, closed, rotational ankle fracture. Patients were individually matched to controls by age, gender, fracture type, and surgical vs non-surgical treatment. Outcomes were major complications during the first six months of treatment. We contrasted secondarily 21 diabetic patients with and 21 without diabetic comorbidities. Diabetic patients and controls did not differ significantly in total complication rates. More diabetic patients required long-term bracing. Diabetic patients without comorbidities had complication rates equal to their controls. Diabetic patients with comorbidities had complications at a higher rate (ten patients; 47%) than matched controls (three patients; 14%, p = 0.034). A history of Charcot neuroarthropathy led to the highest rates of complication. An increased risk of complications in diabetic patients with closed rotational fractures of the ankle are specific to a subpopulation with identifiable related comorbidities.

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The family of zinc-and calcium-dependent matrix metalloproteases (MMPs) play an important role in remodeling of the airways in disease. Transcriptional regulation by proinflammatory cytokines increases lymphocyte-derived MMP9 levels in the airway lumen of asthmatics. Moreover, the levels of the MMP9 inhibitor, tissue inhibitor of metalloprotease (TIMP1), are decreased leading to increased protease activity. The mechanism by which MMP9 activity leads to asthma pathogenesis and remodeling remains unclear. Using a model of well-differentiated human airway epithelia, we found that apical MMP9 significantly increases transepithelial conductance. Moreover, apical MMP9 treatment decreased immunostaining of tight junction proteins suggesting disruption of barrier function. Consistent with this, viruses gained access to the epithelial basolateral surface after MMP9 treatment, which increased infection efficiency. All of these effects were blocked by TIMP1. In addition, loss of epithelial integrity correlated with increased epithelial cell death. Thus we hypothesized that MMP9 exerts its effects on the epithelium by cleaving one or more components of cell-cell junctions and triggering anoikis. Taken together, these data suggest that a component of airway remodeling associated with asthma may be directly regulated by MMP9.protease; adhesion; cell death THE AIRWAY EPITHELIUM SITS at the interface between the external environment and the body proper. With each inhaled breath, viruses, bacteria, pollutants, and allergens are introduced into the system, each with the potential to adversely affect the host. In the airways, mechanisms to reduce these hazards have evolved including mucociliary clearance, mucus secretion, as well as sneeze and cough. In addition, the polarized nature of the epithelium itself poses a structural barrier to inhaled challenges. At the apical pole of cell-cell interfaces, the tight junction, a large complex of proteins that functions as a fence, separates the apical and basolateral epithelial compartments and restricts flow through the paracellular space.Two transmembrane components of tight junctions are occludin and the claudins. Both are tetraspanning proteins that extend their extracellular loops across neighboring cells. Claudins comprise a large family of 24 known members that form homo-and heterotypic associations with one another. In addition, claudins have recently been characterized as forming anion-/cation-selective pores within the paracellular space; selectivity is regulated by the specific claudins that associate across the membrane (4,23,25). Thus the claudin expression profile, as well as how claudins interact with one another, largely regulates the epithelial selectivity for cation/anion transport. In addition, together with occludin, the tight junction forms a seal, demarcating the apical and basolateral membranes. Electron microscopic analysis of the tight junction shows that this protein complex forms a continuous, anastomosing array of fibrils that circumscribes each epithelial cel...

Paraoxonases (PONs) are a family of lactonases with promiscuous enzyme activity that has been implicated in multiple diseases. PON2 is intracellularly located, is the most ubiquitously expressed PON, and has the highest lactonase activity of the PON family members. Whereas some single-nucleotide polymorphisms (SNPs) in PON1 have resulted in altered enzymatic activity in serum, to date the functional consequences of SNPs on PON2 function remain unknown. We hypothesized that a common PON2 SNP would result in impaired lactonase activity. Substitution of cysteine for serine at codon 311 in recombinant PON2 resulted in normal protein production and localization but altered glycosylation and decreased lactonase activity. Moreover, we screened 200 human lung samples for the PON2 Cys311 variant and found that in vivo this mutation impaired lactonase activity. These data suggest that impaired lactonase activity may play a role in innate immunity, atherosclerosis, and other diseases associated with the PON2 311 SNP.

Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.A ctivated T-cell trafficking across the vascular endothelium is essential for ongoing immune surveillance of tissues and for effective immune responses to conditions such as infection and cancer. Conversely, in situations of immune dysregulation, inhibition of self-reactive T-cell trafficking represents a promising target for therapeutic immunomodulation. Disruption of these pathways, such as by antibody blockade of α4 integrins, is a highly effective approach to immunomodulation (1, 2). However, the molecular mechanisms by which chemokine receptor and adhesion molecule signaling induce the T-cell cytoskeletal machinery to promote extravasation are not yet fully elucidated.Transendothelial migration (TEM), the process by which T cells extravasate from the blood into tissues, is characterized by four distinct steps: rolling along the vascular wall, arrest or adhesion, intravascular crawling, and diapedesis across the endothelial barrier (3). Surface adhesion molecules play well-characterized roles in each step of the process. For example, the initial rolling step of TEM is facilitated by interactions between T-cell and endothelial selectins, whereas the adhesion, intravascular crawling, and diapedesis steps of TEM are mainly regulated by chemokineand shear force-stimulated modulation of lymphocyte functionassociated antigen 1 (LFA-1, αLβ2 integrin, CD11a/CD18) and very late antigen 4 (VLA-4, α4β1 integrin, CD49d/CD29) interactions with intracellular adhesion molecule 1 ...