Publications

Infection of host tissues by Staphylococcus aureus and S. epidermidis requires an unusual family of staphylococcal adhesive proteins that contain long stretches of serine-aspartate dipeptide-repeats (SDR). The prototype member of this family is clumping factor A (ClfA), a key virulence factor that mediates adhesion to host tissues by binding to extracellular matrix proteins such as fibrinogen. However, the biological siginificance of the SDR-domain and its implication for pathogenesis remain poorly understood. Here, we identified two novel bacterial glycosyltransferases, SdgA and SdgB, which modify all SDR-proteins in these two bacterial species. Genetic and biochemical data demonstrated that these two glycosyltransferases directly bind and covalently link N-acetylglucosamine (GlcNAc) moieties to the SDR-domain in a step-wise manner, with SdgB appending the sugar residues proximal to the target Ser-Asp repeats, followed by additional modification by SdgA. GlcNAc-modification of SDR-proteins by SdgB creates an immunodominant epitope for highly opsonic human antibodies, which represent up to 1% of total human IgG. Deletion of these glycosyltransferases renders SDR-proteins vulnerable to proteolysis by human neutrophil-derived cathepsin G. Thus, SdgA and SdgB glycosylate staphylococcal SDR-proteins, which protects them against host proteolytic activity, and yet generates major eptopes for the human anti-staphylococcal antibody response, which may represent an ongoing competition between host and pathogen.

BACKGROUND

Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis.

OBJECTIVE

To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI.

METHODS

Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI) . Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up.

RESULTS

Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P < .01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P < .01) and decreased VT inducibility (9.1% vs 68.4% in control; P < .05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction.

CONCLUSIONS

Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire⁻/⁻ mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.

Magnetic resonance imaging (MRI) and computed tomography (CT) are commonly used to evaluate dogs with thoracolumbar myelopathy; however, relative diagnostic sensitivities for these two modalities have not been previously reported. The purpose of this prospective study was to compare diagnostic sensitivity and observer agreement for MRI and CT in a group of dogs with thoracolumbar myelopathy due to surgically confirmed intervertebral disk herniation (IVDH). All included dogs had magnetic resonance (MR) imaging followed by noncontrast CT using standardized protocols. Three experienced observers interpreted each imaging study independently without knowledge of clinical or surgical findings. The operating surgeon was aware of MR findings but not CT findings at the time surgical findings were recorded. Forty-four dogs met the inclusion criteria. The sensitivity of CT was 88.6% (79.5%-94.2%) and of MR was 98.5% (95% confidence interval, 94.1%-99.7%) for diagnosis of intervertebral disk herniation. Specificity was not calculated, as all dogs had IVDH at surgery. Magnetic resonance imaging was more accurate than CT for identifying the site of intervertebral disk herniation-associated spinal cord compression and differentiating disk extrusion vs. protrusion. Computed tomography was less accurate for lesion localization in per acute cases, as well as for chondrodystrophic, female, older and smaller (<7 kg) dogs. Inter-rater agreement was good for lesion lateralization for both MR and CT (κ = 0.687, 95% CI = 0.552, 0.822, P = 0.002, and κ = 0.692, 95% CI = 0.542, 0.842, P = 0.003). Findings from the current study indicated that MR imaging was more sensitive and accurate than noncontrast CT for diagnosis and characterization of thoracolumbar myelopathy due to IVDH in dogs.

INTRODUCTION

Human immunodeficiency virus (HIV)-infected patients in the current treatment era can achieve normal life expectancies but experience a high degree of medical and psychiatric comorbidity. Impaired physical function and pain, often in the context of mood disorders and substance abuse, are common in HIV-infected patients. The objective of this study was to investigate the relationship of pain, a modifiable condition, to functional impairment in HIV-infected patients, independent of mood disorders and substance abuse.

METHODS

Participants in a prospective cohort of HIV-infected patients at the University of Alabama at Birmingham were included. Patient-reported outcome measures were used to cross-sectionally assess pain and physical function (EuroQOL), mood disorders (PHQ), and substance abuse (ASSIST). Univariate and multivariable models were built with pain as the principal independent variable of interest and three domains of physical function (mobility, self-care, and usual activities) as outcomes. Covariates included mood, substance abuse, age, race, sex, insurance status, HIV transmission risk factor, and CD4+ T-cell count.

RESULTS

Among 1,903 participants, 693 (37%) reported pain; 509 (27%) had a mood disorder; and 157 (8.4%) reported current substance abuse. In multivariable models, pain was independently associated with increased odds of impairment in all three domains of physical function investigated-mobility (aOR 10.5, 95% CI 7.6-14.6), self-care (aOR 4.1, 95% CI 2.2-7.4), and usual activities (aOR 5.4, 95% CI 4.0-7.4).

DISCUSSION

Pain was associated with substantially increased odds of impairment in physical function. Pain should be an important consideration in HIV primary care. Interventions to address pain and impaired physical function should be investigated.

BACKGROUND

Because the association between atrial fibrillation (AF) and race has only been rigorously compared in population-based studies that dichotomized participants as white or black, it is unclear whether white race confers elevated AF risk or black race affords AF protection.

METHODS AND RESULTS

The Healthcare Cost and Utilization Project was used to identify patients receiving hospital-based care in California between January 1, 2005 and December 31, 2009. The association between race and incident AF was examined using Cox proportional hazards models. Interaction analyses were performed to elucidate the mechanism underlying the race-AF association. Among 13 967 949 patients, 375 318 incident AF episodes were observed over a median 3.2 (interquartile range 1.8-4.3) years. In multivariable Cox models adjusting for patient demographics and established AF risk factors, blacks (hazard ratio, 0.84; 95% confidence interval, 0.82-0.85; P<0.001), Hispanics (hazard ratio, 0.78; 95% confidence interval, 0.77-0.79; P<0.001), and Asians (hazard ratio, 0.78; 95% confidence interval, 0.77-0.79; P<0.001) each exhibited a lower AF risk compared with whites. AF risk among whites was disproportionately higher in the absence of acquired cardiovascular risk factors and diminished or reversed in the presence of comorbid diseases. Although Hispanics and Asians also had a lower adjusted risk of incident atrial flutter compared with whites, the risk of flutter was significantly higher among blacks.

CONCLUSIONS

In a large hospital-based cohort, whites have an increased risk of AF whether compared with blacks, Asians, or Hispanics. The heightened AF risk among whites is most pronounced in the absence of cardiovascular comorbidities.