Staphylococcus aureus (SA), an opportunistic pathogen colonizing the anterior nares in approximately 30% of the human population, causes severe hospital-associated and community-acquired infections. SA nasal carriage plays a critical role in the pathogenesis of staphylococcal infections and SA eradication from the nares has proven to be effective in reducing endogenous infections. To understand SA nasal colonization and its relation with consequent disease, assessment of nasal carriage dynamics among a diverse population and determining factors responsible for SA nasal carriage have become major imperatives. Here, we report on an extensive longitudinal monitoring of SA nasal carriage in 109 healthy individuals over a period of up to three years to assess nasal carriage dynamics. Phylogenetic analyses of SA housekeeping genes and hypervariable virulence genes revealed that not only were SA strains colonizing intermittent and persistent nasal carriers genetically similar, but no preferential colonization of specific SA strains in these carriers was observed over time. These results indicated that other non-SA factors could be involved in determining specific carriage states. Therefore, to elucidate host responses during SA nasal carriage, we performed human SA nasal recolonization in a subset of SA nasal carriers within our cohort. In these studies, SA colonization levels were determined, and nasal secretions were collected and analyzed for host immune factors responsible for SA nasal carriage. Interestingly, we observed that stimulation of host immune responses lead to clearance of SA while sustained SA colonization was observed in hosts that did not mount a response during carriage. Further, analysis of nasal secretions from hosts revealed that proinflammatory cytokines and chemokines were significantly induced during SA nasal clearance suggesting that innate immune effectors influence carriage. SA utilizes a repertoire of surface and secreted proteins to evade host immune response and successfully colonize the nose. Analysis of the most abundant immunoevasive proteins in the exoproteome of SA nasal carrier strains revealed that expression levels of Staphylococcal protein A (SPA) produced by SA nasal carrier strains in vitro corresponded to the level of persistence of SA in the human nose. To determine if SPA is involved in modulating the host's response to SA colonization, a subset of participants in our cohort was nasally recolonized with equal concentrations of both wild-type (WT) and spa-disrupted (?spa) autologous strains of SA. Interestingly, ?spa strains were eliminated from the nares significantly faster than WT when the host mounted an immune response, suggesting that the immunoevasive role of SPA is a determinant of carriage persistence. Collectively, this report augments our understanding of SA nasal carriage dynamics, in addition to identifying important host and microbial determinants that influence SA nasal colonization in humans. Better understanding of this phenomenon can lead to improved preventative strategies to thwart carriage-associated SA infections.

Staphylococcus aureus (SA) is a major human pathogen that colonizes the anterior nares in 30% of the human population. Though nasal carriage of SA is a known risk factor for the subsequent spread of SA infections, the dynamics of SA nasal colonization is poorly understood. Our research focuses on understanding the host and bacterial factors that might contribute to the human nasal colonization by SA. In an attempt to elucidate the host response to SA, we performed an autologous human in vivo nasal colonization study, which showed decreased survival rates of SA in hosts who elicited a robust immune response. We also identified a significant correlation between SA nasal colonization and the expression of host proinflammatory, chemotactic and growth factors. Additionally, we functionally disrupted a major autolysin, atl a surface expressed bacterial protein that plays multiple roles in cell separation, adhesion and biofilm formation of SA. Microscopic analysis of the ∆atl strains showed phenotypic differences, including cell clumping and cluster formation due to defective cell separation, which confirmed the functional loss of atl. Subsequent analysis of the ∆atl and wild-type strains revealed that there was no significant difference in their ability to adhere to human nasal epithelial cells (hNEC) in an ex vivo hNEC model. Similarly, our competitive in vivo human nasal colonization study, in which equal colony-forming units of each wild-type and ∆atl SA strain were inoculated in the anterior nares of donors, showed similar survival rates between wild-type and ∆atl. These results suggest that Atl might not be directly involved in the adherence and colonization of SA to the anterior nares. Furthermore, our study suggests that host factors might play a predominant role in determining SA colonization to human anterior nares.

A 10-month-old male SaarloosWolfdog was presented with a history of multiple neurologic deficits that had acutely progressed. Neurologic examination findings localized signs to the cerebrum and brainstem.Magnetic resonance imaging revealed markedly enlarged and gas-filled lateral ventricles with amass effect leading to cerebellar herniation. A right-sided defect of the cribriform plate with a dysplastic ethmoturbinate was identified as the inlet of air and origin of the intraventricular tension pneumocephalus. Surgical findings were consistent with a ruptured, congenital, nasal meningocele.

Osteoarthritis the quality and span of life in horses. Previous studies focused on nasal cartilage as a possible source for autologous chondrocyte implantation (ACI) in cartilage defects in humans. “HOX gene-negative” nasal chondrocytes adapted articular HOX patterns after implantation into caprine joint defects and produced cartilage matrix proteins. We compared the HOX gene profile of equine chondrocytes of nasal septum, anterior and posterior fetlock to identify nasal cartilage as a potential source for ACI in horses. Cartilage was harvested from seven horses after death and derived chondrocytes were cultured in a monolayer to fourth subcultivation. HOX A3, D1, D8 and chondrocyte markers COL2 and SOX9 were analyzed with qPCR in chondrocytes of three different locations obtained during passage 0 and passage 2. HOX gene expression showed no significant differences between the locations but varied significantly between the horses. HOX genes and SOX9 remained stable during culturing. Cultured nasal chondrocytes may be a target for future research in cell-based regenerative therapies in equine osteoarthritis. The involvement of HOX genes in the high regenerative and adaptive potential of nasal chondrocytes observed in previous studies could not be confirmed.

In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function. We present a novel method assessing inflammatory markers in the upper airways’ epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1b, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1b and IL-6 significantly declined 2.29-fold (2.97!1.30 pg/mL), and 1.13-fold (6.48!5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably. This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy.

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Introduction: The purpose of this study was to subclassify the types of facial asymmetries present in a pre-surgical dentofacial deformity patient population to determine the prevalence of each subcategory. Associations between the craniofacial characteristics of each asymmetry and pre-surgical Jaw Pain and Function Questionnaire (JPFQ) scores, diagnosis of temporomandibular disorders (TMD), and posterior facial asymmetry (PFA) as determined by nasal septum deviation were analyzed. In addition, the data will aid in the development of a phenomics database to allow for subsequent genotyping and gene expression evaluation from patient saliva and masseter muscle samples that were obtained at the time of corrective orthognathic surgery. Methods: Pre-surgical posterio-anterior (PA) cephalograms, submentovertex (SMV) and panoramic (PAN) radiographs from 92 pre-surgical dentofacial deformity patients at the Department of Oral and Maxillofacial Surgery, University of Lille, France were collected to evaluate facial asymmetry. PAs were traced and analyzed according to the Grummons Simplified Frontal analysis and Ramal Height analysis (Dolphin Imaging). SMVs were analyzed by the refined clinical system of the Ritucci and Burstone analysis proposed by Arnold et al along with original angular measurements for maxillary, mandibular, and nasal septum deviations (ImageJ). PFA was determined by a nasal septum deviation greater than 15 degrees. Lastly, PANs were evaluated visually for condylar pathologies. A comprehensive diagnostic decision tree for facial asymmetry was formulated based upon the current literature for normal variation of landmarks and the study design. Patient diagnosis via the decision tree was compared to visual examination of the appropriate x-rays to verify accuracy. Using this decision tree, patients were classified into subtypes and prevalence of each was calculated to form a phenomics database for future research on genotyping and gene expression. Associations between the subclassifications, mean pre-surgical JPFQ scores, temporomandibular joint (TMJ) clinical examination results (TMD+ or TMD-), and the diagnosis of posterior facial asymmetry (PFA+ or PFA-) were completed. Results: Sixty-two patients were able to fulfill all radiographic requirements to arrive at a diagnosis. Eighteen patients demonstrated facial asymmetry that fell within normal biological variation while the other 44 were diagnosed as having a form of facial asymmetry – Cranial Base Asymmetry: 11 female, 6 male; Non-Condylar Mandibular Asymmetry: 5 female, 3 male; Hemimandibular Elongation: 2 female, 3 male; Maxillary Asymmetry: 3 female, 1 male; Idiopathic Condylar Resorption: 3 female, 1 male; Atypical Asymmetry: 3 female, 1 male; Hemimandibular Hyperplasia: 1 female, 0 male; and Maxillary Base & Mandibular Body Asymmetry: 0 female, 1 male. JPFQ scores for symmetric patients ((x ) ̅= 5.33) and asymmetric patients (x ̅= 4.57) were non-significant overall, however, differences between gender were noted (female symmetric (x ) ̅= 6.13, male symmetric (x ) ̅= 1.33, female asymmetric (x ) ̅= 5.36, male asymmetric (x ) ̅= 3.19). TMD was diagnosed by pre-surgical TMJ examinations and MRIs. Four symmetric patients (3 female, 1 male) were positively diagnosed with TMD while 14 asymmetric patients (11 female, 1 male) also were diagnosed. PFA was diagnosed when nasal septum deviation was greater than 15 degrees – 25⁰ to ≤35⁰: 9 patients; >35⁰ to ≤45⁰: 3 patients; >45⁰: 1 patient. Twenty patients with a positive PFA were asymmetric while the other 8 symmetric. Twenty-one patients with PFA were female while the other 7 were male. Conclusion: A comprehensive diagnostic decision tree for facial asymmetry classification was formulated and validated. With it, it was found that: Females have increased JPFQ scores and clinical diagnosis of TMD versus males. Asymmetric females have decreased JPFQ scores, but increased prevalence of TMD. Presence of PFA does not appear to be a strong influence on development of facial asymmetry but is significantly linked to the presence of TMD. PFA is present in nearly half of all dentofacial deformity subjects. Mandibular asymmetry is most commonly associated with increased JPFQ scores and presence of TMD. However, Hemimandibular Hyperplasia, a particular and less common form of mandibular asymmetry, never associated with TMD. One form of mandibular and mid-facial asymmetry, Atypical Asymmetry, had a relatively high prevalence of TMD. Future directions for this research include continuation of genotypic description of IGF1 and Nodal biologic pathways to determine how gene expression levels in masseter muscle and patient genotypes differ in the eight subclassifications of craniofacial asymmetry compared to the symmetric population. / Oral Biology

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