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1.  Infections caused by Klebsiella ozaenae: a changing disease spectrum. 
Journal of Clinical Microbiology  1978;8(4):413-418.
A total of 64 isolates of Klebsiella ozaenae were recovered from 36 patients during a 40-month period. Over 7,500 isolates of K. pneumoniae were isolated during the same time period. Before this decade, K. ozaenae was considered to be only a colonizer of the nasopharynx or a putative cause of ozena (atrophic rhinitis). K. ozaenae was recovered most frequently from sputum in mixed culture but was associated with infection in 12 patients (2 with bacteremia, 3 with urinary tract infection, 1 with soft tissue infection, and 6 with mucopurulent nasal discharge). The spectrum of disease caused by this organism is more extensive than has been appreciated previously.
PMCID: PMC275262  PMID: 721945
2.  Neuro-navigation: An Adjunct in Craniofacial Surgeries: Our Experience 
Purpose
Due to the destruction of osseous landmarks of the skull base or paranasal sinuses, the anatomical orientation during surgery of frontobasal or clival tumors with (para) nasal extension is often challenging. In this relation, Neuro-navigation guidance might be a useful tool. Here, we explored the use of Neuro-navigation in an interdisciplinary setting.
Methods and Materials
The surgical series consists of 3 patients who underwent Lefort-I access osteotomy and surgical decompression of the tumor. The procedures were planned and assisted by neuro-navigation techniques with image fusion of CT and MRI. Two of the patients were diagnosed to have clival chordoma and one had extensive JNA.
Results
The application of Neuro-navigation in the combined approaches was both safe and reliable for delineation of tumors and identification of vital structures hidden or encased by the tumors. There was no perioperative mortality. Tumors were either removed completely, or subtotal resection was achieved.
Conclusion
Craniofacial approaches with intra-operative neuro-navigational guidance in a multidisciplinary setting allow safe resection of large tumors of the upper clivus and the paranasal sinuses involving the anterior skull base. Complex skull base surgery with the involvement of bony structures appears to be an ideal field for advanced navigation techniques given the lack of intraoperative shift of relevant structures.
doi:10.1007/s12663-011-0245-6
PMCID: PMC3267921  PMID: 23204743
Neuro-navigation; Neuro-navigator; Lefort I access osteotomies; Clival chordoma
3.  A report on a rare case of Klebsiella ozaenae causing atrophic rhinitis in the UK 
BMJ Case Reports  2011;2011:bcr0920114812.
Ozena is a chronic disease of the nasal cavity characterised by atrophy of the mucosa and bone caused by Klebsiella ozaenae. It is endemic to subtropical and temperate regions affecting the lower socio-economic group, usually the poor who live in unhygienic conditions. It is a rare disease in the UK. There is usually a delay in diagnosis due to unfamiliarity of the disease. A 25-year-old Nigerian migrant presented with nasal obstruction with purulent nasal discharge. Isolation of the bacterium was found from cultures of nasal discharge, crusting and tissue biopsies. She was treated successfully with ciprofloxacin. It is important to consider this rare condition in cases of nasal obstruction even in non-endemic areas especially with the advances of modern travel.
doi:10.1136/bcr.09.2011.4812
PMCID: PMC3233926  PMID: 22669526
4.  Cerebral abscess caused by Klebsiella ozaenae. 
Journal of Clinical Microbiology  1987;25(8):1553-1554.
Klebsiella ozaenae is the putative cause of ozena or atrophic rhinitis. It has also been commonly isolated as a colonizing organism, but recent reports demonstrate its role as an invasive pathogen, especially in immunosuppressed hosts. We report the first known case of a cerebral abscess caused by K. ozaenae.
PMCID: PMC269269  PMID: 3624447
5.  Sinonasal phosphaturic mesenchymal tumor: Case report and systematic review 
Allergy & Rhinology  2014;5(3):e162-e167.
We report a case of sinonasal phosphaturic mesenchymal tumor (PMT) and conduct a systematic review of the literature to highlight a unique paraneoplastic syndrome associated with PMT. We used English language publications from Medline and Cochrane databases (1970–2013) as data sources. A systematic review of the literature was conducted. All reported cases of head and neck PMTs were included. The presence or absence of the associated paraneoplastic syndrome was noted. We found 33 cases of PMT in the head and neck reported in the literature, 17 of which occurred in the sinonasal area. Approximately 5% of all PMTs are located in the head and neck. Just greater than half are concentrated in the sinonasal area, and the remaining involve various bony and soft tissue structures of the head and neck. PMT is sometimes associated with a paraneoplastic syndrome of tumor-induced (oncogenic) osteomalacia (TIO) causing bone pain, muscle weakness, and pathologic fractures. We present the 18th reported case of sinonasal PMT. A smooth mucosa-covered midline intraseptal mass filling the posterior nasal cavity with destruction and erosion of the skull base was found in an adult male. The patient underwent successful endoscopic resection with wide negative margins and is without recurrence at 24-month follow-up. PMT is a benign, locally aggressive tumor with rare malignant transformation. Knowledge of the bony invasion and destruction caused by this tumor is essential in planning surgical resection with wide negative margins. Familiarity with the associated TIO is essential to investigate for and manage any associated bony morbidity.
doi:10.2500/ar.2014.5.0100
PMCID: PMC4275463  PMID: 25565053
Phosphaturic mesenchymal tumor; sinonasal; oncogenic osteomalacia; tumor-induced osteomalacia; phosphaturia; mesenchymal tumors
6.  Primary Atrophic Rhinitis: A Clinical Profile, Microbiological and Radiological Study 
ISRN Otolaryngology  2012;2012:404075.
Background. The objective of this prospective study was to evaluate the clinical profile, microbiological flora and radiological features in primary atrophic rhinitis patients and to identify their association with the etiology of primary atrophic rhinitis. Study design. Prospective case study. Materials and methods. Patients with primary atrophic rhinitis over a two years period were included in the study. Complete blood count, total protein and microbiological analysis from nasal swab were done to evaluate iron deficiency anemia, nutritional status and identification of the pathogenic bacteria respectively. Radiological evaluation was done to study the radiological features of primary atrophic rhinitis. Observations. Ninety cases of primary atrophic rhinitis were studied. The most common symptom was nasal crusting. Nasal crust, odour and atrophy of mucosa were the most consistent finding. Nasal myiasis was found in 26.6% cases. The nasal mucociliary clearance time was markedly increased. On investigation there were low value of hemoglobin and total protein in 46.6% and 25.5% patients, respectively. Pseudomonas aeruginosa (37%) was the commonest organism isolated from culture. On radiological evaluation evidence of different grade of sinusitis was seen in 87.7% case. Conclusion. The present study suggested that certain bacterial infections, anemia, poor nutrition and hereditary factor may contribute significantly to the etiology of primary atrophic rhinitis.
doi:10.5402/2012/404075
PMCID: PMC3671697  PMID: 23762613
7.  Non Allergic Rhinitis: Prevalence, Clinical Profile and Knowledge Gaps in Literature 
Oman Medical Journal  2011;26(6):416-420.
Objectives
Although Nasal symptoms induced by Non-allergic rhinitis| (NAR) are a cause of wide spread morbidity; the disease is trivialized. There is a lack of Epidemiological studies on the prevalence of non-allergic rhinitis. In spite of being one of the commonest conditions presenting to the General practitioner and otolaryngologists, the clinical profile, diagnosis, and management outcomes are unknown. The objectives of the study were to examine the prevalence and clinical profile of non-allergic rhinitis in Oman. Secondary objective was to identify Knowledge gaps in literature with the aim of directing future research.
Methods
A cross sectional study of 610 consecutive adult patients presenting to the Ear, Nose and Throat clinic at Sultan Qaboos University Hospital is presented in this paper. The diagnosis of NAR was mainly based on step wise fashion; including a thorough clinical history and exclusion of other causes of rhinitis; all consecutive patients diagnosed with rhinitis (n=113) had a detailed history, nasal endoscopy, nasal smears, CT scans and an antihistamine response trial. The prevalence of NAR with its clinical profile was subsequently determined. Primary research articles and meta-analysis evaluated for the knowledge gap study were identified through MEDLINE search of English language literature published between 2000-2011.
Results
A total of 610 consecutive patients were studied. The overall prevalence of rhinitis was 18.5% (n=113). The prevalence of NAR was 7.5% (n=46). Cases of allergic rhinitis (5.7%; n=35), Chronic rhinosinusitis (1.8%; n=11), and miscellaneous causes (3.4%; n=21) were excluded. Among the rhinitis population (n=113), the prevalence of NAR was 57% (n=46). The major presenting symptoms included nasal obstruction (93%; n=43), postnasal drainage (78%; n=36), and rhinorrhea (62%; n=29). For the knowledge gap study; 115 Medline titles were reviewed, four systematic reviews, and 34 research papers were reviewed. The text of two recent otolaryngology text books was also reviewed, and the main results of the study revealed the prevalence of NAR had not previously been studied in Oman. Although the recent text now clearly defines NAR, there is scant literature on the prevalence, diagnosis and management outcomes of NAR in the literature.
Conclusion
The study found that more than half of rhinitis patients suffered from NAR. There are no specific diagnostic tests for NAR; a thorough case history is the best diagnostic tool to date. A substantial knowledge gap exists in literature with relations to pathogenesis, clinical and laboratory diagnosis, as well as in reference to medical and surgical outcomes. Larger studies are required and management outcomes need to be studied.
doi:10.5001/omj.2011.106
PMCID: PMC3251201  PMID: 22253950
Nasal obstruction; Non allergic rhinitis; Seasonal rhinitis; NANIPER; NARES; Idiopathic rhinitis
8.  Diseases of the nose and paranasal sinuses in child 
Diseases of the pediatric nose and nasal sinuses as well as neighboring anatomical structures encompass a variety of pathologies, especially of inflammatory nature. Congenital disease, such as malformations and structural deviations of the nasal septum, as well as systemic metabolic pathologies affecting the nose and sinuses, rarely require medical therapy from an Otolaryngologist.
The immunological function of the mucosa and genetic factors play a role in the development of disease in the pediatric upper airway tract, especially due to the constantly changing anatomy in this growth phase. Disease description of the nose and nasal sinuses due to mid-facial growth must also take developmental age differences (infant, toddler, preschool, and school age) into account. Epidemiological examinations and evidence based studies are often lacking in the pediatric population.
The wide range of inflammatory diseases of the nose and paranasal sinuses, such as the acute and chronic rhinosinusitis, the allergic rhinitis, and adenoid disease, play a role in the susceptibility of a child to infection. The susceptibility to infection depends on the pediatric age structure (infant, young child) and has yet to be well defined. The acute rhinosinusitis in children develops after a viral infection of the upper airways, also referred to as the “common cold” in the literature. It usually spontaneously heals within ten days without any medical therapy. Antibiotic therapy is prudent in complicated episodes of ARS. The antibiotic therapy is reserved for children with complications or associated disease, such as bronchial asthma and/or chronic bronchitis. A chronic rhinosinusitis is defined as the inflammatory change in the nasal mucosa and nasal sinus mucosa, in which the corresponding symptoms persist for over 12 weeks. The indication for CT-imaging of the nasal sinuses is reserved for cases of chronic rhinosinusitis that have been successfully treated with medication. A staged therapeutic concept is followed in CRS based on conservative and surgical methods. Nasal sinus surgery is considered nowadays as effective and safe in children. Based on the assumption that adenoids are a reservoir for bacteria, from which recurrent infections of the nose and nasal sinus originate, the adenoidectomy is still defined as a cleansing procedure in rhinosinusitis. 69.3% of the children had benefit from adenoidectomy.
Comorbidities, such as pediatric bronchial asthma, presently play an even more important role in the therapy of rhinosinusitis; therefore, it is often wise to have the support of pediatricians. In western European countries 40% of children presently suffer from allergic rhinitis, in which pronounced nasal obstruction can cause disturbed growth in facial bones. An early therapy with SIT may prevent the development of bronchial asthma and secondary sensitization to other allergens. Therefore, SIT is recommended in treatment of allergic rhinitis whenever, if possible. The assessment of diagnostic tools is for the examiner not often possible due to the lack of evidence. Rhinosurgical approaches are often described in study reports; however, they lack the standard prospective randomized long-term study design required nowadays and can only be evaluated with caution in the literature.
doi:10.3205/cto000113
PMCID: PMC4273171  PMID: 25587370
nose; paranasal sinuses; childhood; diseases; rhinosinusitis
9.  Endoscopic Reconstruction of Skull Base Defects with the Nasal Septal Flap 
Skull Base  2008;18(6):385-394.
ABSTRACT
Objectives: Endoscopic technology is allowing larger resections of the anterior and middle skull base with resultant dural defects. A pedicled nasal septal flap (NSF) based on the posterior nasal septal artery has recently been developed for closure of these defects. We describe our initial experience with the NSF for vascularized coverage of skull base defects. Design: Retrospective review. Setting: Tertiary care skull base center. Participants: Patients undergoing endoscopic harvest of vascularized pedicled flap for skull base reconstruction. Results: Twenty-eight patients had 32 NSFs raised over 14 months for benign (7) or malignant (21) lesions. Surgical defects (mean, 4.95 cm2) were intracranial (25) and intradural (20, average defect 1.86 cm2) in the anterior (10) and central skull base (6), infratemporal fossa (4), orbit (1), or a combination of sites (9). There were no cases of meningitis or cerebrospinal fluid leak (median follow-up, 8.3 months). Two NSFs were injured intraoperatively and two necrosed postoperatively, both in patients with a prior history of radiation to the nasopharynx (p = 0.013). Conclusions: Prior radiation is a risk factor for necrosis. The NSF is easily harvested endonasally, reliably covers a range of skull base defects, and should be considered the first line closure after expanded endonasal skull base resections.
doi:10.1055/s-0028-1096202
PMCID: PMC2637073  PMID: 19412408
Nasal septal flap; skull base; endoscopic approach
10.  Clinical Course and Autopsy Findings of a Patient with Clival Chordoma Who Underwent Multiple Surgeries and Radiation during a 10-Year Period 
Skull Base  2007;17(5):331-340.
ABSTRACT
The management of clival chordoma remains problematic. We present the case of a 48-year-old woman with clival chordoma who underwent multiple surgeries and radiation therapy, including gamma knife stereotactic radiosurgery (GK-SRS), during a 10-year clinical course. The tumor was initially removed by gross total resection via the trans-sphenoidal approach, followed by external linac radiation therapy. The tumor recurred at the clivus 5 years after the initial operation. After repeated trans-sphenoidal removal of recurrent tumors, she twice underwent GK-SRS for a tumor remnant adjacent to the brainstem. Although this part of the tumor was controlled by GK-SRS, there was further tumor extension toward the sphenoid and maxillary sinuses. Ultimately, lower cranial nerve dysfunction developed due to tumor extension into the lower part of the clivus and the patient died of respiratory failure. Autopsy revealed the tumor to extend from the lower clivus to the bilateral middle fossae. The lower part of the tumor extended to the nasal cavity and to the posterior wall of the pharynx, resulting in compression of the upper pharyngeal region. The tumor around the jugular foramen compressed the lower cranial nerves bilaterally. Tumor cells did not, however, invade the intradural space microscopically. Although chordoma is not biologically malignant, this tumor can show massive extension with destruction of bony structures and extracranial invasion of connective tissues. Therefore, the optimal treatment strategy is to remove the tumor mass as extensively as possible, including normal bony structures and connective tissues surrounding the tumor, using skull base surgical techniques.
doi:10.1055/s-2007-986438
PMCID: PMC2095125  PMID: 18330432
Chordoma; autopsy; skull base surgery; gamma knife radiosurgery; proton radiation therapy
11.  Randomised trial of proton vs. carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base, clinical phase III study 
BMC Cancer  2010;10:606.
Background
Low and intermediate grade chondrosarcomas are relative rare bone tumours. About 5-12% of all chondrosarcomas are localized in base of skull region. Low grade chondrosarcoma has a low incidence of distant metastasis but is potentially lethal disease. Therefore, local therapy is of crucial importance in the treatment of skull base chondrosarcomas. Surgical resection is the primary treatment standard. Unfortunately the late diagnosis and diagnosis at the extensive stage are common due to the slow and asymptomatic growth of the lesions. Consequently, complete resection is hindered due to close proximity to critical and hence dose limiting organs such as optic nerves, chiasm and brainstem. Adjuvant or additional radiation therapy is very important for the improvement of local control rates in the primary treatment. Proton therapy is the gold standard in the treatment of skull base chondrosarcomas. However, high-LET (linear energy transfer) beams such as carbon ions theoretically offer advantages by enhanced biologic effectiveness in slow-growing tumours.
Methods/Design
The study is a prospective randomised active-controlled clinical phase III trial. The trial will be carried out at Heidelberger Ionenstrahl-Therapie (HIT) centre as monocentric trial.
Patients with skull base chondrosarcomas will be randomised to either proton or carbon ion radiation therapy. As a standard, patients will undergo non-invasive, rigid immobilization and target volume definition will be carried out based on CT and MRI data. The biologically isoeffective target dose to the PTV (planning target volume) in carbon ion treatment will be 60 Gy E ± 5% and 70 Gy E ± 5% (standard dose) in proton therapy respectively. The 5 year local-progression free survival (LPFS) rate will be analysed as primary end point. Overall survival, progression free and metastasis free survival, patterns of recurrence, local control rate and morbidity are the secondary end points.
Discussion
Up to now it was impossible to compare two different particle therapies, i.e. protons and carbon ions, directly at the same facility in connection with the treatment of low grade skull base chondrosarcomas.
This trial is a phase III study to demonstrate that carbon ion radiotherapy (experimental treatment) is not relevantly inferior and at least as good as proton radiotherapy (standard treatment) with respect to 5 year LPFS in the treatment of chondrosarcomas. Additionally, we expect less toxicity in the carbon ion treatment arm.
Trial Registration
ClinicalTrials.gov identifier: NCT01182753
doi:10.1186/1471-2407-10-606
PMCID: PMC2991309  PMID: 21050498
12.  Transcranial Combined Neurorhinosurgical Approach to the Paranasal Sinuses for Anterior Skull Base Malignancies 
Skull Base  2009;19(2):151-158.
ABSTRACT
Objective: Various transcranial and transfacial approaches have been described and each claims to provide the best exposure to the anterior skull base. Similarly, each approach claims the best outcomes following the resection of anterior skull base malignancies. We have always advocated a combined neurorhinological approach for the management of paranasal sinus malignancies that infiltrate the skull base, such as esthesioneuroblastomas. Materials and methods: At the outset, the technique was developed on cadaver specimens, imitating the limitations that might be imposed in the real-life situation when undertaking endoscopic sinus surgery. Additional exposure of the anterior cerebral fossa was achieved using a classical bifrontal approach. Starting with endoscopic or microscopic unroofing of the ethmoids, all relevant landmarks were identified. The frontal, sphenoid, and maxillary sinuses were then opened using endoscopic techniques. Results: The dissections proved that a broad exposure of the anterior skull base could be combined with clear endoscopic visualization of the nasal cavity and of all the paranasal sinuses from above. This facilitated complete eradication of lesions from the sinuses cavities, their walls, and the intracranial tumor. Discussion: The combined neurorhinosurgical transcranial approach to the anterior skull base and nasal and paranasal sinuses, avoiding trans-facial approaches, enables a multidiciplinary team to resect malignant tumors of the anterior skull base directly without unnecessary destruction of facial structures. It appears to provide better access than other more destructive methods like midfacial degloving or subfrontal approaches. Our single-stage approach also facilitates safe and effective reconstruction of the skull base. The technique can be employed for tumors of all sizes and is also used for orbital resections and decompression of the optic nerve and chiasma.
doi:10.1055/s-0028-1096200
PMCID: PMC2671301  PMID: 19721771
Transcranial; paranasal sinus; skull base; rhinosurgery
13.  [68Ga]-DOTATOC-PET/CT for meningioma IMRT treatment planning 
Purpose
The observation that human meningioma cells strongly express somatostatin receptor (SSTR 2) was the rationale to analyze retrospectively in how far DOTATOC PET/CT is helpful to improve target volume delineation for intensity modulated radiotherapy (IMRT).
Patients and Methods
In 26 consecutive patients with preferentially skull base meningioma, diagnostic magnetic resonance imaging (MRI) and planning-computed tomography (CT) was complemented with data from [68Ga]-DOTA-D Phe1-Tyr3-Octreotide (DOTATOC)-PET/CT. Image fusion of PET/CT, diagnostic computed tomography, MRI and radiotherapy planning CT as well as target volume delineation was performed with OTP-Masterplan®. Initial gross tumor volume (GTV) definition was based on MRI data only and was secondarily complemented with DOTATOC-PET information. Irradiation was performed as EUD based IMRT, using the Hyperion Software package.
Results
The integration of the DOTATOC data led to additional information concerning tumor extension in 17 of 26 patients (65%). There were major changes of the clinical target volume (CTV) which modify the PTV in 14 patients, minor changes were realized in 3 patients. Overall the GTV-MRI/CT was larger than the GTV-PET in 10 patients (38%), smaller in 13 patients (50%) and almost the same in 3 patients (12%). Most of the adaptations were performed in close vicinity to bony skull base structures or after complex surgery. Median GTV based on MRI was 18.1 cc, based on PET 25.3 cc and subsequently the CTV was 37.4 cc. Radiation planning and treatment of the DOTATOC-adapted volumes was feasible.
Conclusion
DOTATOC-PET/CT information may strongly complement patho-anatomical data from MRI and CT in cases with complex meningioma and is thus helpful for improved target volume delineation especially for skull base manifestations and recurrent disease after surgery.
doi:10.1186/1748-717X-4-56
PMCID: PMC2785827  PMID: 19922642
14.  Regeneration of toxigenic Pasteurella multocida induced severe turbinate atrophy in pigs detected by computed tomography 
Background
Atrophic rhinitis is a widely prevalent infectious disease of swine caused by Bordetella bronchiseptica and Pasteurella multocida. The course of the disease is considered to be different depending on the principal aetiological agents distinguishing B. bronchiseptica induced non-progressive and toxigenic P. multocida produced progressive forms. In order to compare the pathological events of the two forms of the disease, the development of nasal lesions has longitudinally been studied in pigs infected by either B. bronchiseptica alone or B. bronchiseptica and toxigenic P. multocida together using computed tomography to visualise the nasal structures.
Results
B. bronchiseptica infection alone caused moderately severe nasal turbinate atrophy and these lesions completely regenerated by the time of slaughter. Unexpectedly, complete regeneration of the bony structures of the nasal cavity was also observed in pigs infected by B. bronchiseptica and toxigenic P. multocida together in spite of seeing severe turbinate atrophy in most of the infected animals around the age of six weeks.
Conclusions
B. bronchiseptica mono-infection has been confirmed to cause only mild to moderate and transient lesions, at least in high health status pigs. Even severe turbinate atrophy induced by B. bronchiseptica and toxigenic P. multocida combined infection is able to be reorganised to their normal anatomical structure. Computed tomography has further been verified to be a useful tool to examine the pathological events of atrophic rhinitis in a longitudinal manner.
doi:10.1186/1746-6148-9-222
PMCID: PMC3818441  PMID: 24171824
Atrophic rhinitis; Bordetella bronchiseptica; Pasteurella multocida; Computed tomography
15.  Orbital metastases as first sign of metastatic spread in breast cancer: Case report and review of the literature 
Head & Neck Oncology  2011;3:37.
Background
Intraorbital metastases of breast cancer is rare with only 3-10% of all ocular metastases. We report a case of orbital metastases as first sign of systemic metastatic spread in a female patient with breast cancer.
Methods
The patient had been diagnosed with breast cancer 3 years before. Her present complain was local pain, diplopia and periorbital swelling. A CT scan revealed extensive bony destruction of the orbital roof/anterior skull base. Bone scintigraphy demonstrated additional uptake at the level of the skull base, cervical spine, ilium and ribs suggesting metastatic spread to the skeleton. A navigation-assisted intraorbital biopsy from the orbital roof revealed a metastasis of breast cancer. With the confirmed diagnosis of metastatic breast cancer the patient was refered to the oncologist for further tumor staging. As further treatment she received systemic palliative chemotherapy in addition to intravenous treatment with bisphosphonates.
Conclusion
In patients with a previous history of breast cancer who complain even of mild ophthalmologic symptoms such as local pain, periorbital edema, it is important to consider ocular or orbital metastatic disease. Adequate 3D-Imaging followed by a biopsy will usually confirm the diagnosis.
doi:10.1186/1758-3284-3-37
PMCID: PMC3184093  PMID: 21859452
Orbital metastasis; breast cancer; navigation-assisted surgery
16.  Pasteurella Multocida Toxin Prevents Osteoblast Differentiation by Transactivation of the MAP-Kinase Cascade via the Gαq/11 - p63RhoGEF - RhoA Axis 
PLoS Pathogens  2013;9(5):e1003385.
The 146-kDa Pasteurella multocida toxin (PMT) is the main virulence factor to induce P. multocida-associated progressive atrophic rhinitis in various animals. PMT leads to a destruction of nasal turbinate bones implicating an effect of the toxin on osteoblasts and/or osteoclasts. The toxin induces constitutive activation of Gα proteins of the Gq/11-, G12/13- and Gi-family by deamidating an essential glutamine residue. To study the PMT effect on bone cells, we used primary osteoblasts derived from rat calvariae and stromal ST-2 cells as differentiation model. As marker of functional osteoblasts the expression and activity of alkaline phosphatase, formation of mineralization nodules or expression of specific transcription factors as osterix was determined. Here, we show that the toxin inhibits differentiation and/or function of osteoblasts by activation of Gαq/11. Subsequently, Gαq/11 activates RhoA via p63RhoGEF, which specifically interacts with Gαq/11 but not with other G proteins like Gα12/13 and Gαi. Activated RhoA transactivates the mitogen-activated protein (MAP) kinase cascade via Rho kinase, involving Ras, MEK and ERK, resulting in inhibition of osteoblast differentiation. PMT-induced inhibition of differentiation was selective for the osteoblast lineage as adipocyte-like differentiation of ST-2 cells was not hampered. The present work provides novel insights, how the bacterial toxin PMT can control osteoblastic development by activating heterotrimeric G proteins of the Gαq/11-family and is a molecular pathogenetic basis for understanding the role of the toxin in bone loss during progressive atrophic rhinitis induced by Pasteurella multocida.
Author Summary
Pasteurella multocida causes as a facultative pathogen various diseases in men and animals. One induced syndrome is atrophic rhinitis, which is a form of osteopenia, mainly characterized by facial distortion due to degradation of nasal turbinate bones. Strains, which especially affect bone tissue, produce the protein toxin P. multocida toxin (PMT). Importantly, PMT alone is capable to induce all symptoms of atrophic rhinitis. To cause osteopenia PMT influences the development and/or activity of specialized bone cells like osteoblasts and osteoclasts. Recently, we could identify the molecular mechanism of PMT. The toxin constitutively activates certain heterotrimeric G proteins by deamidation. Here, we studied the effect of PMT on the differentiation of osteoblasts. We demonstrate the direct action of PMT on osteoblasts and osteoblast-like cells and as a consequence inhibition of osteoblastic differentiation. Moreover, we revealed the underlying signal transduction pathway to impair proper osteoblast development. We show that PMT activates small GTPases in a Gαq/11 dependent manner via a non-ubiquitously expressed RhoGEF. In turn the mitogen-activated protein kinase pathway is transactivated leading to inhibition of osteoblastogenesis. Our findings present a mechanism how PMT hijacks host cell signaling pathways to hinder osteoblast development, which contributes to the syndrome of atrophic rhinitis.
doi:10.1371/journal.ppat.1003385
PMCID: PMC3656108  PMID: 23696743
17.  Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies 
PLoS Medicine  2014;11(10):e1001748.
Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders.
Please see later in the article for the Editors' Summary
Background
The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Methods and Findings
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time.
Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
Conclusions
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Our immune system protects us from viruses, bacteria, and other pathogens by recognizing specific molecules on the invader's surface and initiating a sequence of events that culminates in the death of the pathogen. Sometimes, however, our immune system responds to harmless materials (allergens such as pollen) and triggers allergic, or atopic, symptoms. Common atopic symptoms include eczema (transient dry itchy patches on the skin), wheeze (high pitched whistling in the chest, a symptom of asthma), and rhinitis (sneezing or a runny nose in the absence of a cold or influenza). All these symptoms are very common during childhood, but recent epidemiological studies (examinations of the patterns and causes of diseases in a population) have revealed age-related changes in the proportions of children affected by each symptom. So, for example, eczema is more common in infants than in school-age children. These findings have led to the idea of “atopic march,” a natural progression of symptoms within individual children that starts with eczema, then progresses to wheeze and finally rhinitis.
Why Was This Study Done?
The concept of atopic march has led to the initiation of studies that aim to prevent the development of asthma in children who are thought to be at risk of asthma because they have eczema. Moreover, some guidelines recommend that clinicians tell parents that children with eczema may later develop asthma or rhinitis. However, because of the design of the epidemiological studies that support the concept of atopic march, children with eczema who later develop wheeze and rhinitis may actually belong to a distinct subgroup of children, rather than representing the typical progression of atopic diseases. It is important to know whether atopic march adequately describes the natural history of atopic diseases during childhood to avoid the imposition of unnecessary strategies on children with eczema to prevent asthma. Here, the researchers use machine learning techniques to model the developmental profiles of eczema, wheeze, and rhinitis during childhood in two large population-based birth cohorts by taking into account time-related (longitudinal) changes in symptoms within individuals. Machine learning is a data-driven approach that identifies structure within the data (for example, a typical progression of symptoms) using unsupervised learning of latent variables (variables that are not directly measured but are inferred from other observable characteristics).
What Did the Researchers Do and Find?
The researchers used data from two UK birth cohorts—the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Manchester Asthma and Allergy Study (MAAS)—for their study (9,801 children in total). Both studies enrolled children at birth and monitored their subsequent health at regular review clinics. At each review clinic, information about eczema, wheeze, and rhinitis was collected from the parents using validated questionnaires. The researchers then used these data and machine learning methods to identify groups of children with similar patterns of onset of eczema, wheeze, and rhinitis over the first 11 years of life. Using a type of statistical model called a latent disease profile model, the researchers found that the data were best described by eight latent classes—no disease (51.3% of the children), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%).
What Do These Findings Mean?
These findings show that, in two large UK birth cohorts, the developmental profiles of eczema, wheeze, and rhinitis were heterogeneous. Most notably, the progression of symptoms fitted the profile of atopic march in fewer than 7% of children with symptoms. The researchers acknowledge that their study has some limitations. For example, small differences in the wording of the questions used to gather information from parents about their children's symptoms in the two cohorts may have slightly affected the findings. However, based on their findings, the researchers propose that, because eczema, wheeze, and rhinitis are common, these symptoms often coexist in individuals, but as independent entities rather than as a linked progression of symptoms. Thus, using eczema as an indicator of subsequent asthma risk and assigning “preventative” measures to children with eczema is flawed. Importantly, clinicians need to understand the heterogeneity of patterns of atopic diseases in children and to communicate this variability to parents when advising them about the development and resolution of atopic symptoms in their children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001748.
The UK National Health Service Choices website provides information about eczema (including personal stories), asthma (including personal stories), and rhinitis
The US National Institute of Allergy and Infectious Diseases provides information about atopic diseases
The UK not-for-profit organization Allergy UK provides information about atopic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on eczema, wheezing, and rhinitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and asthma (in English and Spanish)
Information about ALSPAC and MAAS is available
Wikipedia has pages on machine learning and latent disease profile models (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001748
PMCID: PMC4204810  PMID: 25335105
18.  Management of Rhinitis: Allergic and Non-Allergic 
Rhinitis is a global problem and is defined as the presence of at least one of the following: congestion, rhinorrhea, sneezing, nasal itching, and nasal obstruction. The two major classifications are allergic and nonallergic rhinitis (NAR). Allergic rhinitis occurs when an allergen is the trigger for the nasal symptoms. NAR is when obstruction and rhinorrhea occurs in relation to nonallergic, noninfectious triggers such as change in the weather, exposure to caustic odors or cigarette smoke, barometric pressure differences, etc. There is a lack of concomitant allergic disease, determined by negative skin prick test for relevant allergens and/or negative allergen-specific antibody tests. Both are highly prevalent diseases that have a significant economic burden on society and negative impact on patient quality of life. Treatment of allergic rhinitis includes allergen avoidance, antihistamines (oral and intranasal), intranasal corticosteroids, intranasal cromones, leukotriene receptor antagonists, and immunotherapy. Occasional systemic corticosteroids and decongestants (oral and topical) are also used. NAR has 8 major subtypes which includes nonallergic rhinopathy (previously known as vasomotor rhinitis), nonallergic rhinitis with eosinophilia, atrophic rhinitis, senile rhinitis, gustatory rhinitis, drug-induced rhinitis, hormonal-induced rhinitis, and cerebral spinal fluid leak. The mainstay of treatment for NAR are intranasal corticosteroids. Topical antihistamines have also been found to be efficacious. Topical anticholinergics such as ipratropium bromide (0.03%) nasal spray are effective in treating rhinorrhea symptoms. Adjunct therapy includes decongestants and nasal saline. Investigational therapies in the treatment of NAR discussed include capsaicin, silver nitrate, and acupuncture.
doi:10.4168/aair.2011.3.3.148
PMCID: PMC3121056  PMID: 21738880
Allergic rhinitis; nonallergic rhinitis; intranasal corticosteroids; immunotherapy; intranasal antihistamines; oral antihistamines
19.  173 Relationship Between Allergic Rhinitis and Dental-Facial Abnormalities 
Background
Allergic rhinitis (AR) affects 10 to 25% of the general population and is of great importance for the impact on quality of life and school performance.1 Rhinitis has been associated with craniofacial abnormalities due to the high frequency of mouth breathing, oral breathing syndrome occurs when the child replaces the correct pattern of breathing caused by nasal obstruction resulting from allergic disease.2
Objective
To establish the type of relationship between allergic rhinitis and dental-facial abnormalities in the pediatric population of Veracruz ISSSTE Hospital General in 2009.
Methods
A case-control study, cases (25) were patients aged 6 to 18 years of age with allergic rhinitis. Controls (25) were entitled 6 to 18 years, informed consent, were referred to the dental service, where he underwent medical history and oral examination. For data analysis descriptive statistics were used, and chi-square test statistic (X2) and t test.
Results
The average age of cases was 12 ± 3.5 years, mean bodyweight 44.33 kg, age of controls was 12.6 ± 3.8 years, weight 48.23 kg. 16% of the cases has any oral habit (finger, tongue), in controls 36% assumed the habit. The predominant type of skull was normocéfalo controls (84%), where was dolichocephalic (63%). In dental abnormalities (dry lips, deep palate, malocclusion) 100% of cases had at least one, 90% have deep palate, in controls 32% had impaired and 24% with deep palate. We found a statistically significant difference P = 0.007, in the variable Inadequate Respirator Syndrome Nasal.
Conclusions
There is a partnership between the patient with allergic rhinitis and dental-facial abnormalities.
doi:10.1097/01.WOX.0000411930.26815.44
PMCID: PMC3512852
20.  Study of Histopathological Changes in Primary Atrophic Rhinitis 
ISRN Otolaryngology  2011;2011:269479.
Primary atrophic rhinitis is a progressive chronic nasal disease and histopathologically characterized by squamous metaplasia and two characteristic types of vascular involvement (type I and type II). Despite its chronicity and squamous transformation, nothing is known about the occurrence of malignancy in atrophic rhinitis. The present work was undertaken to study the histopathological characteristics in primary atrophic rhinitis and identify whether it has any association with malignant transformation. Nasal biopsies obtained from 90 patients diagnosed as primary atrophic rhinitis were studied. Squamous metaplasia was noted in 89% of patients, and type I and type II vascular involvement were seen in 67% and 33% of patients, respectively. This preliminary report suggests that there is no association between atrophic rhinitis and precancerous lesions of nasal cavity despite squamous metaplasia and confirms the presence of two types of vascular changes in the disease which is helpful to decide the treatment modality.
doi:10.5402/2011/269479
PMCID: PMC3658637  PMID: 23724252
21.  Converging paths to progress for skull base chordoma: Review of current therapy and future molecular targets 
Background:
Chordomas of the skull base are rare locally aggressive neoplasms with a predilection for encapsulating critical neurovascular structures, bony destruction and irregular growth patterns, and from which patients succumb to recurrence and treatment failures.
Methods:
A review of the medical literature is performed, using standard search engines and identifying articles related to skull base chordomas, surgery, radiation therapy, chemotherapy, molecular genetics, and prospective trials.
Results:
A synthesis of the literature is presented, including sections on pathology, treatment, molecular genetics, challenges, and future directions.
Conclusion:
Beyond an understanding of the current treatment paradigms for skull base chordomas, the reader gains insight into the collaborative approach applied to orphan diseases, of which chordomas is a prime exemplar.
doi:10.4103/2152-7806.112822
PMCID: PMC3683175  PMID: 23776758
Chordomas; cell lines; radiation therapy; review; skull base neoplasms; surgery
22.  Allergic and non-allergic rhinitis: relationship with nasal polyposis, asthma and family history 
SUMMARY
Rhinitis and rhinosinusitis (with/without polyposis), either allergic or non-allergic, represent a major medical problem. Their associated comorbidities and relationship with family history have so far been poorly investigated. We assessed these aspects in a large population of patients suffering from rhinosinusal diseases. Clinical history, nasal cytology, allergy testing and direct nasal examination were performed in all patients referred for rhinitis/rhinosinusitis. Fibre optic nasal endoscopy, CT scan and nasal challenge were used for diagnosis, when indicated. A total of 455 patients (60.7% male, age range 4-84 years) were studied; 108 (23.7%) had allergic rhinitis, 128 (28.1%) rhinosinusitis with polyposis, 107 (23.5%) non-allergic rhinitis (negative skin test); 112 patients had associated allergic and non-allergic rhinitis, the majority with eosinophilia. There was a significant association between non-allergic rhinitis and family history of nasal polyposis (OR = 4.45; 95%CI = 1.70-11.61; p = 0.0019), whereas this association was no longer present when allergic rhinitis was also included. Asthma was equally frequent in non-allergic and allergic rhinitis, but more frequent in patients with polyposis. Aspirin sensitivity was more frequent in nasal polyposis, independent of the allergic (p = 0.03) or non-allergic (p = 0.01) nature of rhinitis. Nasal polyposis is significantly associated with asthma and positive family history of asthma, partially independent of the allergic aetiology of rhinitis.
PMCID: PMC3970223  PMID: 24711681
Allergic rhinitis; Non-allergic rhinitis; Nasal polyposis; Nasal cytology; Family history; Atopy
23.  Increased Expression and Role of Thymic Stromal Lymphopoietin in Nasal Polyposis 
Purpose
Nasal polyposis is a chronic inflammatory disease of the upper airways often associated with asthma and characterized by markedly increased numbers of eosinophils, Th2 type lymphocytes, fibroblasts, goblet cells and mast cells. Previous studies have shown elevated levels of thymic stromal lymphopoietin (TSLP) in atopic diseases like asthma, atopic dermatitis and mainly in animal models of allergic rhinitis (AR). Here, we investigated the expression of TSLP in nasal polyps from atopics and non-atopics in comparison with the nasal mucosa and its potential role in nasal polyposis.
Methods
Messenger RNA expression for TSLP, thymus and activation-regulated chemokine (TARC) and macrophage derived chemokine (MDC) in nasal polyps and nasal mucosa of atopics and non-atopics was analyzed by real time PCR. Immunoreactivity for TSLP in nasal polyps and in the nasal mucosa of patients with AR and non-allergic rhinitis (NAR) was analyzed by immunohistochemistry. Eosinophil counts was analyzed by Wright-Giemsa staining and nasal polyp tissue IgE, by ELISA.
Results
Messenger RNA expression for TSLP,TARC and MDC was markedly higher in nasal polyps as compared to the allergic nasal mucosa. Immunoreactivity for TSLP was detected in epithelial cells, endothelial cells, fibroblasts and inflammatory cells of the nasal mucosa and nasal polyps. The number of TSLP+ cells was significantly greater in the nasal mucosa of AR than NAR patients. The number of TSLP+ cells in nasal polyps from atopics was significantly greater than that of non-atopics and that in the allergic nasal mucosa. The number of TSLP+ cells correlated well with the number of eosinophils and the levels of IgE in nasal polyps.
Conclusions
The high expression of TSLP in nasal polyps and its strong correlation to eosinophils and IgE suggest a potential role for TSLP in the pathogenesis of nasal polyps by regulating the Th2 type and eosinophilic inflammation.
doi:10.4168/aair.2011.3.3.186
PMCID: PMC3121060  PMID: 21738884
Nasal polyps; Th2 cytokines; TSLP; eosinophils; IgE
24.  The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma 
BMC Cancer  2007;7:229.
Background
Nasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites.
Methods
We immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report.
Results
Overall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%.
Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them.
Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027).
Conclusion
Positive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.
doi:10.1186/1471-2407-7-229
PMCID: PMC2238761  PMID: 18093334
25.  Long-Term Outcome of Endonasal Endoscopic Skull Base Reconstruction with Nasal Turbinate Graft 
Skull Base  2008;18(5):297-308.
ABSTRACT
Objective: To study the long-term outcome of endonasal endoscopic skull base reconstruction with nasal turbinate tissue free graft. Patients and Methods: This study included 55 consecutive patients who underwent endonasal endoscopic skull base reconstruction with nasal turbinate graft and were available for follow-up. They were 30 patients with pituitary adenomas, 20 with cerebrospinal fluid (CSF) rhinorrhea of different etiologies, three with meningoencephalocele, and two with skull base meningiomas. Autologous nasal turbinate tissue materials were used in reconstructing the skull base defect. Clinical follow-up with endoscopic nasal examination was done routinely 1, 3, 6, and 12 months after surgery. Computed tomography and magnetic resonance imaging were performed when indicated. The follow-up period ranged from 6 months to 8 years. Results: There were no major operative or postoperative complications. Nasal turbinate graft was effective in sealing of intraoperative CSF leak, obliteration of dead space, and anatomic reconstruction of the skull base. There was no evidence of graft migration or inflammatory changes. Starting from 3 months after surgery to the rest of the follow-up period, endonasal endoscopic view of the site of duraplasty showed that: with small skull base defect (less than 5 mm), there was neither dural pulsation nor prolapse; with moderate-sized defect (5 to 10 mm), there was dural pulsation without prolapse; with larger defect (> 10 mm), there was dural pulsation and prolapse. These finding were constant regardless of the etiology of the lesion and the reconstruction material used. Conclusions: This long-term study demonstrated the efficacy of nasal turbinate graft in sealing of CSF leak without any delayed complications. Other rigid materials may be considered in reconstruction of large skull base defect (more than 10 mm) to prevent dural prolapse and herniation. For any future endonasal procedure for those patients, who had previous endonasal endoscopic duraplasty, the surgeons should be fully aware of the state of duraplasty (e.g., dural prolapse) to avoid any intraoperative complication (e.g., penetration of the prolapsed dura during nasal packing).
doi:10.1055/s-0028-1086055
PMCID: PMC2637066  PMID: 19240829
Endonasal; endoscopic; skull base; nasal turbinate

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