Volar Locking Plating of Extra-articular Distal Radius Fracture: A Retrospective Clinical Study Comparing Locking Screws versus Smooth Locking Pegs.

Background Open reduction and internal fixation of distal radius fractures is one of the most common procedures performed in wrist surgery. The use of volar locking plate has gained increasing interest in the past decade. Epiphyseal fixation can be done either with locking screws or smooth locking pegs, with no evidence supporting the use of one rather than the other. Purpose The aim of this study is to compare the stability of distal radius fixation by volar locking plate using locking screws or smooth locking pegs. Methods Adult patients with A2-A3 AO fractures treated with a volar plate with locking screws only or smooth locking pegs only were retrospectively included. Radiographic assessment was performed to evaluate extra-articular parameters in the intraoperative postreduction and fixation period and after bony healing. Forty-seven distal radius fractures were included. Results Twenty-four fractures had fixation with locking screws and 23 had fixation with smooth locking pegs. For both groups, all radiographic parameters measured showed a statistically significant difference between the intraoperative postreduction and fixation period and the remote postoperative period after union of the fracture ( p < 0.05) attesting a slight loss of reduction. Nevertheless, there were no significant differences between the groups in radiographic extra-articular parameters. Conclusion This clinical study shows that there is no difference in stability fixation between locking screws or smooth locking pegs in A2-A3 distal radius fractures. Clinical Relevance The use of smooth locking pegs only for epiphyseal fixation appears to be safe in volar plating of A2-A3 distal radius fractures in adult patients and could be an alternative to locking screws. More clinical data are needed to confirm these results. Level of Evidence Level III; retrospective comparative study.

Understanding the Protective Role of IL-17 During Oropharyngeal Candidiasis.

Oropharyngeal candidiasis is an opportunistic mucosal infection caused predominantly by Candida albicans. While healthy individuals are protected, susceptibility is associated with immunodeficiency. In particular, patients with defects related to T helper-17 (Th17) cells and interleukin (IL)-17 signaling are highly susceptible to mucocutaneous forms of candidiasis. Since mice are naïve to Candida albicans, induction of oropharyngeal candidiasis enables a thorough understanding of IL-17 and its related immune components during acute infection. Here we describe a murine model of oropharyngeal candidiasis. This protocol allows for translatable and reproducible infection with results that can be obtained between 2 and 5 days following infection.

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis.

Fungal infections caused by Candida albicans are a serious problem for immunocompromised individuals, including those undergoing radiotherapy for head and neck cancers. Targeted irradiation causes inflammatory dysregulation and damage to the oral mucosa that can be exacerbated by candidiasis. Post-irradiation the cytokine interleukin-17 (IL-17) protects the oral mucosae by promoting oral epithelial regeneration and balancing the oral immune cell populations, which leads to the eventual healing of the tissue. IL-17 signaling is also critical for the antifungal response during oropharyngeal candidiasis (OPC). Yet, the benefit of IL-17 during other forms of candidiasis, such as vulvovaginal candidiasis, is not straightforward. Therefore, it was important to determine the role of IL-17 during OPC associated with radiation-induced inflammatory damage. To answer this question, we exposed Il17ra-/- and wild-type mice to head-neck irradiation (HNI) and OPC to determine if the IL-17 signaling pathway was still protective against C. albicans. HNI increased susceptibility to OPC, and in Il17ra-/- mice, the mucosal damage and fungal burden were elevated compared to control mice. Intriguingly, neutrophil influx was increased in Il17ra-/- mice, yet these cells had reduced capacity to phagocytose C. albicans and failed to clear OPC compared to immunocompetent mice. These findings suggest that radiotherapy not only causes physical damage to the oral cavity but also skews immune mediators, leading to increased susceptibility to oropharyngeal candidiasis.

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling.

Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra-/- mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra-/- mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

Characterization of Vibrio cholerae isolates from freshwater sources in northwest Ohio.

Vibrio cholerae is a natural inhabitant of aquatic ecosystems worldwide, typically residing in coastal or brackish water. While more than 200 serogroups have been identified, only serogroups O1 and O139 have been associated with epidemic cholera. However, infections other than cholera can be caused by nonepidemic, non-O1/non-O139 V. cholerae strains, including gastroenteritis and extraintestinal infections. While V. cholerae can also survive in freshwater, that is typically only observed in regions of the world where cholera is endemic. We recently isolated V. cholerae from several locations in lakes and rivers in northwest Ohio. These isolates were all found to be non-O1/non-O139 V. cholerae strains, that would not cause cholera. However, these isolates contained a variety of virulence genes, including ctxA, rtxA, rtxC, hlyA, and ompU. Therefore, it is possible that some of these isolates have the potential to cause gastroenteritis or other infections in humans. We also investigated the relative motility of the isolates and their ability to form biofilms as this is important for V. cholerae survival in the environment. We identified one isolate that forms very robust biofilms, up to 4x that of our laboratory strains. Finally, we investigated the susceptibility of these isolates to a panel of antibiotics. We found that many of the isolates showed decreased susceptibility to some of the antibiotics tested, which could be of concern. While we do not know if these isolates are pathogenic to humans, increased surveillance to better understand the public health risk to the local community should be considered.

14-3-3ζ-TRAF5 axis governs interleukin-17A signaling.

IL-17A is a therapeutic target in many autoimmune diseases. Most nonhematopoietic cells express IL-17A receptors and respond to extracellular IL-17A by inducing proinflammatory cytokines. The IL-17A signal transduction triggers two broad, TRAF6- and TRAF5-dependent, intracellular signaling pathways to produce representative cytokines (IL-6) and chemokines (CXCL-1), respectively. Our limited understanding of the cross-talk between these two branches has generated a crucial gap of knowledge, leading to therapeutics indiscriminately blocking IL-17A and global inhibition of its target genes. In previous work, we discovered an elevated expression of 14-3-3 proteins in inflammatory aortic disease, a rare human autoimmune disorder with increased levels of IL-17A. Here we report that 14-3-3ζ is essential for IL-17 signaling by differentially regulating the signal-induced IL-6 and CXCL-1. Using genetically manipulated human and mouse cells, and ex vivo and in vivo rat models, we uncovered a function of 14-3-3ζ. As a part of the molecular mechanism, we show that 14-3-3ζ interacts with several TRAF proteins; in particular, its interaction with TRAF5 and TRAF6 is increased in the presence of IL-17A. In contrast to TRAF6, we found TRAF5 to be an endogenous suppressor of IL-17A-induced IL-6 production, an effect countered by 14-3-3ζ. Furthermore, we observed that 14-3-3ζ interaction with TRAF proteins is required for the IL-17A-induced IL-6 levels. Together, our results show that 14-3-3ζ is an essential component of IL-17A signaling and IL-6 production, an effect that is suppressed by TRAF5. To the best of our knowledge, this report of the 14-3-3ζ-TRAF5 axis, which differentially regulates IL-17A-induced IL-6 and CXCL-1 production, is unique.

A Periplasmic Antimicrobial Peptide-Binding Protein Is Required for Stress Survival in Vibrio cholerae.

Vibrio cholerae must sense and respond appropriately to stresses encountered in the aquatic environment and the human host. One stress encountered in both environments is exposure to antimicrobial peptides (AMPs), produced as a part of the innate immune response by all multicellular organisms. Previous transcriptomic analysis demonstrated that expression of Stress-inducible protein A (SipA) (VCA0732), a hypothetical protein, was highly induced by AMP exposure and was dependent on a specific uncharacterized two-component system. In order to better understand role of this protein in stress relief, we examined whether it shared any of the phenotypes reported for its homologs. SipA is required for survival in the presence of two other stressors, cadmium chloride and hydrogen peroxide, and it localizes to the bacterial periplasm, similar to its homologs. We also found that SipA physically interacts with OmpA. Importantly, we found that SipA binds AMPs in the bacterial periplasm. This suggests a model where SipA may act as a molecular chaperone, binding AMPs that enter the periplasm and delivering them to OmpA for removal from the cell. While El Tor V. cholerae strains lacking SipA do not show a survival defect in the presence of AMPs, we found that Classical sipA mutants are less able to survive in the presence of AMPs. This phenotype is likely masked in the El Tor background due to a functional lipid A modification system that increases AMP resistance in these strains. In summary, we have identified a protein that contributes to a novel mechanism of stress relief in V. cholerae.

Vibrio responses to extracytoplasmic stress.

A critical factor for bacterial survival in any environment is the ability to sense and respond appropriately to any stresses encountered. This is especially important for bacteria that inhabit environments that are constantly changing, or for those that inhabit more than one biological niche. Vibrio species are unique in that they are aquatic organisms, and must adapt to ever-changing temperatures, salinity levels and nutrient concentrations. In addition, many species of Vibrio colonize other organisms, and must also deal with components of the host immune response. Vibrio infections of humans and other organisms have become more common in recent years, due to increasing water temperatures in many parts of the world. Therefore, understanding how these ubiquitous marine bacteria adapt to their changing environments is of importance. In this review, we discuss some of the ways that Vibrios sense and respond to the variety of stresses that negatively affect the bacterial cell envelope. Specifically, we will focus on what is currently known about the σE response, the Cpx response and the contributions of OmpU to extracytoplasmic stress relief.

Quantitative and Functional Antibody Responses to the 13-Valent Conjugate and/or 23-Valent Purified Polysaccharide Vaccine in Aging HIV-Infected Adults.

BACKGROUND: The number of aging human immunodeficiency virus-infected (HIV+) individuals living in the United States has substantially grown over the past two decades. Advanced age and HIV infection both increase susceptibility to Streptococcus pneumoniae infection due to B cell dysfunction. The combined impact of these factors on pneumococcal vaccine responses remains unknown. METHODS: We assessed serum immunoglobulin (Ig) G and IgM levels and opsonophagocytic killing assay (OPA) titers to pneumococcal serotypes 14 and 23F in HIV+ subjects and HIV-uninfected (HIV-) controls 50-65 years old. HIV+ individuals with CD4+ T cells/µl (CD4) >200 and ≥1 year of antiretroviral therapy (ART) received either a dose of the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine 8 weeks later (PCV/PPV) as currently recommended (n=15) or a single dose of PPV only (n=22). HIV- controls received PCV/PPV (n=14). RESULTS: HIV+ PCV/PPV and PPV groups exhibited similar increases in IgG levels and OPA titers for both serotypes after immunization. Postvaccination IgM levels for serotype 23F, but not 14, were significantly higher in HIV+ PCV/PPV compared to PPV groups. IgG and IgM levels for serotype 14 and OPA titers to serotype 23F were significantly reduced in HIV+ compared to HIV- PCV/PPV groups. Serotype-specific IgG levels correlated with OPA titers for all groups. CONCLUSIONS: Our data suggest that the recommended PCV/PPV regimen may not significantly improve quantitative or functional antibody responses compared to PPV only in aging HIV+ subjects. Continued efforts aimed at improving vaccine responses in this high risk population are warranted.

Inflammatory Markers and Immune Response to Pneumococcal Vaccination in HIV-Positive and -Negative Adults.

BACKGROUND: Members of the Tumor Necrosis Factor (TNF)-superfamily have speculated roles in the response against T-independent type II antigens (TI-II) including pneumococcal polysaccharides (PPS). Dysregulation in their expression is associated with an enhanced risk for pneumococcal disease in neonates but their expression in other high-risk populations including HIV-positive individuals remains to be elucidated. OBJECTIVE: To investigate signals that contribute towards PPS-response and identify potential anomalies that may account for diminished serological response in HIV-positive individuals post Pneumovax (PPV23) immunization. METHODS: Markers of inflammation, C-reactive protein (CRP), IL-6, sCD27 and sCD30, were assessed in HIV-positive and -negative individuals as potential predictors of PPV23 response. Serum levels of B cell activating factor (BAFF), transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), B cell maturation antigen (BCMA) and B cell expression of BAFF-R, TACI, BCMA, CD40 and CD21 were assessed in total (unselected) and PPS23F (antigen)-specific B cells of PPV23 immunized HIV-positive and -negative individuals. RESULTS: CRP, sCD27, sCD30 and BAFF were significantly elevated in the serum of HIV-positive individuals but did not adversely affect PPV23 response. Assessment of PPS-specific B cells revealed enhanced TACI and reduced BAFF-R expression compared to unselected B cells in HIV-positive and -negative individuals. Surface TACI was similar but soluble TACI was significantly lower in HIV-positive compared to HIV-negative individuals. CONCLUSION: Current studies highlight a potential role for TACI in PPV23 response based on its enhanced expression on PPS-specific B cells. Although surface levels of TACI were similar, diminished soluble TACI (sTACI) in HIV-positive compared to HIV-negative individuals could potentially decrease BAFF responsiveness and Ig response. A better understanding of the role of TNF receptors could contribute to the design of improved pneumococcal vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT02515240.

Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults.

BACKGROUND: Advanced age and human immunodeficiency virus (HIV) infection are associated with increased pneumococcal disease risk. The impact of these factors on cellular responses to vaccination is unknown. METHODS: HIV-infected (HIV+) individuals 50-65 years old with CD4(+) Tcells/µl (CD4) >200 on antiretroviral therapy (ART) ≥1 year received either the 13-valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine (PCV/PPV) or PPV only. HIV-uninfected (HIV-) controls received PCV/PPV. Phenotype distribution and surface expression of complement receptor CD21 and tumor necrosis factor superfamily receptors (TNFRs) were compared on serotype-specific B cells postvaccination. RESULTS: Postvaccination serotype-specific B cell percentages were significantly lower in HIV+ PCV/PPV compared to PPV groups, but similar between HIV+ or HIV- PCV/PPV groups. Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI)(+) serotype-specific B cell percentages were significantly decreased in HIV+ PCV/PPV compared to PPV groups. CD21(+) serotype-specific B cells were significantly higher in HIV- compared to HIV+ PCV/PPV groups. CONCLUSIONS: An initial dose of PCV reduced the frequency, but not phenotype distribution, of serotype-specific B cells and also lowered TACI expression in aging HIV+ subjects postvaccination with PPV. These findings suggest that PCV does not enhance cellular responses to revaccination with PPV.