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Non-invasive allergic sinus congestion and resolution assessments using micro-computed tomography imaging
... The observational assessment of PSAA and sinus pathologies may be subject to subjective interpretations and observer bias. The quality and resolution of CBCT images are crucial for detailed evaluation of anatomical structures, but variations in image quality and technical limitations can hinder the clear visualization of some anatomical details [25]. Metallic artifacts and differences in imaging protocols may also affect the results. ...
Objective
This study aims to determine the anatomical relationship between the posterior superior alveolar artery (PSAA) and the lateral wall of the maxillary sinus during preoperative radiological evaluations in the posterior maxillary dental region, as well as to evaluate the prevalence of PSAA and its potential associations with sinus pathologies.
Materials and methods
This retrospective study is based on the analysis of Cone-Beam Computed Tomography (CBCT) data from 510 sinuses of 255 patients. The visibility of the PSAA vascular canal, artery diameters, vertical distance between the alveolar crest and the artery, and the distance to the sinus floor were measured in coronal sections. Additionally, the relationships between sinus pathologies and septa within the sinuses and the PSAA were evaluated.
Results
PSAA was detected bilaterally in the majority of patients (70.2%). Sinus pathologies and the presence of septa were also examined, revealing that 36.9% of the sinus pathologies were bilateral. Chi-square analyses showed no statistically significant relationship between gender and the presence of PSAA. Female patients had a higher incidence of sinus pathologies compared to males (p = 0.002). No significant relationship was found between the presence of PSAA and septa.
Conclusions
This study highlights the importance of considering the anatomical position and prevalence of the PSAA during preoperative radiological evaluations in the posterior maxillary region. This study identified the PSAA as predominantly located in the lateral wall of the maxillary sinus, an anatomical feature of critical importance during preoperative radiological evaluations to minimize vascular complications.
Clinical trial number
Not applicable.
... Odontogenic sinusitis (in contrast to rhinogenic sinusitis) has the following distinctive features: isolated lesion of one of the maxillary sinuses, pain in the tooth or in periodontal tissues, preceding the disease, disruption of the face configuration as a result of swelling of the soft tissues of the cheek, and pain on palpation of the anterolateral wall of the maxillary sinus [9][10][11]. The leading role in the diagnosis of odontogenic sinusitis still belongs to radiation methods of investigation [5,7,[12][13][14]. Traditionally, this was done using X-ray in the naso-chin projection, plain radiographs of the skull in frontal and lateral projections. ...
Individual anatomical features of the paranasal sinuses and dentoalveolar system, the complexity of physiological and pathophysiological processes in this area, and the absence of actual standards of the norm and typical pathologies lead to the fact that differential diagnosis and assessment of the severity of the course of odontogenic sinusitis significantly depend on the measurement methods of significant indicators and have significant variability. Therefore, an urgent task is to expand the diagnostic capabilities of existing research methods, study the significance of the measured indicators, and substantiate the expediency of their use in the diagnosis of specific pathologies in an automated mode. Methods of digital filtering, image segmentation and analysis, fluid dynamics, and statistical and discriminant analysis were used. Preliminary differential diagnosis of odontogenic sinusitis can be performed by densitemetric analysis of tomographic images of the maxillary sinuses, performed using frontal multiplanar reconstructions according to a given algorithm. The very manifestation of the characteristic changes in the densitography of the maxillary sinus allows for the initiation of certain pathological processes and permits the development of the effectiveness of the diagnosis of the pathology of the sinus sinuses, which can be realized automatically in real life.
The use of non-invasive imaging modalities, including micro X-ray computed tomography (micro-CT), is starting to be used extensively to investigate normal and pathological states in a variety of animal models. This increased use of in vivo imaging requires a better understanding of the radiation dose delivered during routine imaging. Our laboratory is equipped with a micro X-ray computer tomography unit (MicroCAT II (R), ImTek Inc., Knoxville, TN) with a 60 kVp X-ray source and a reconstruction volume resolution as low as 15 microns that is used for proton radiation therapy treatment planning. In order to determine the X-ray radiation dose delivered to skin and internal organs by our micro-CT we implanted new, calibrated Harshaw TLD-100 Lithium Fluoride thermo-luminescent detectors (TLDs), into five C57BL/6 male mice and ten Sprague-Dawley male rats. Implants were made into the brain, heart, right lung, liver, stomach, cecum, bladder, dorsal thoracal skin and ventral abdominal skin in each animal. Animals were each scanned once using 50 kVp at 800 mu A with 360 projections per scan with each projection lasting 400 msec. Using the TLD readings, the radiation dose from each body location was measured with the dorsal thoracal skin receiving the highest average dose (4.5 cGy, mouse; 2.8 cGy, rat) and other internal organs receiving significantly lower average doses. Therefore, knowing the radiation doses delivered during routine imaging, care can be taken to avoid significant and potentially lethal doses of radiation.
Proteases are recognized environmental allergens, but little is known about the mechanisms responsible for sensing enzyme activity and initiating the development of allergic inflammation. Because usage of the serine protease subtilisin in the detergent industry resulted in an outbreak of occupational asthma in workers, we sought to develop an experimental model of allergic lung inflammation to subtilisin and to determine the immunological mechanisms involved in type 2 responses. By using a mouse model of allergic airway disease, we have defined in this study that s.c. or intranasal sensitization followed by airway challenge to subtilisin induces prototypic allergic lung inflammation, characterized by airway eosinophilia, type 2 cytokine release, mucus production, high levels of serum IgE, and airway reactivity. These allergic responses were dependent on subtilisin protease activity, protease-activated receptor-2, IL-33R ST2, and MyD88 signaling. Also, subtilisin stimulated the expression of the proallergic cytokines IL-1α, IL-33, thymic stromal lymphopoietin, and the growth factor amphiregulin in a human bronchial epithelial cell line. Notably, acute administration of subtilisin into the airways increased lung IL-5-producing type 2 innate lymphoid cells, which required protease-activated receptor-2 expression. Finally, subtilisin activity acted as a Th2 adjuvant to an unrelated airborne Ag-promoting allergic inflammation to inhaled OVA. Therefore, we established a murine model of occupational asthma to a serine protease and characterized the main molecular pathways involved in allergic sensitization to subtilisin that potentially contribute to initiate allergic airway disease.
Copyright © 2015 by The American Association of Immunologists, Inc.
Introduction:
Effective pharmacologic treatment exists for most patients suffering from allergic rhinitis (AR). However, both in clinical trials and in real-life studies, many patients are dissatisfied with treatment. Physicians often use multiple therapies, in an attempt to improve symptom control, often with limited evidence of success. Novel treatment options are needed and must consider unmet medical needs.
Areas covered:
This article reviews the clinical data for a new AR treatment. MP29-02 (Dymista®, Meda, Solna, Sweden) contains azelastine hydrochloride (AZE) and fluticasone propionate (FP), in a novel formulation and delivered in an improved device as a single nasal spray. It has shown superior efficacy in AR patients than either commercially available AZE or FP monotherapy for both nasal and ocular symptom relief, regardless of disease severity. MP29-02 also provided more effective and rapid symptom relief than either AZE or FP monotherapy delivered in the MP29-02 formulation and device. However, the effect was less than that observed versus commercial comparators, suggesting the impact of formulation and device on clinical efficacy.
Expert opinion:
MP29-02 simplifies AR management, surpassing the efficacy of gold standard treatment, intranasal corticosteroids (INS), for the first time. It is indicated for the treatment of moderate-to-severe seasonal allergic rhinitis and perennial allergic rhinitis when monotherapy with either intranasal antihistamine or INS is NOT considered sufficient. Most patients present with moderate/severe disease, with evidence of current or previous treatment insufficiency. MP29-02 should be the treatment of choice for these patients.
Micron-scale computed tomography (micro-CT) is an essential tool for phenotyping and for elucidating diseases and their therapies. This work is focused on preclinical micro-CT imaging, reviewing relevant principles, technologies, and applications. Commonly, micro-CT provides high-resolution anatomic information, either on its own or in conjunction with lower-resolution functional imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). More recently, however, advanced applications of micro-CT produce functional information by translating clinical applications to model systems (e.g. measuring cardiac functional metrics) and by pioneering new ones (e.g. measuring tumor vascular permeability with nanoparticle contrast agents). The primary limitations of micro-CT imaging are the associated radiation dose and relatively poor soft tissue contrast. We review several image reconstruction strategies based on iterative, statistical, and gradient sparsity regularization, demonstrating that high image quality is achievable with low radiation dose given ever more powerful computational resources. We also review two contrast mechanisms under intense development. The first is spectral contrast for quantitative material discrimination in combination with passive or actively targeted nanoparticle contrast agents. The second is phase contrast which measures refraction in biological tissues for improved contrast and potentially reduced radiation dose relative to standard absorption imaging. These technological advancements promise to develop micro-CT into a commonplace, functional and even molecular imaging modality.
Rationale: Persistence of airway hyperresponsiveness and serotonergic enhancement of airway smooth muscle contraction induced by ozone plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to ozone plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for asthmatics. Objectives: To determine if previously documented airway hyperresponsiveness and serotonin-enhanced airway smooth muscle contraction in allergic monkeys exposed to ozone plus house dust mite allergen persist after prolonged recovery. Methods: Infant rhesus monkeys sensitized to house dust mite allergen were exposed to filtered air (n=6) or house dust mite allergen plus ozone (n=6) for 5 months. Monkeys were then housed in a filtered air environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested and airway smooth muscle contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin subtype receptor antagonists. Measurements and Main Results: Ozone plus house dust mite allergen exposed animals exhibited persistent airway hyperresponsiveness. Serotonin exacerbated the airway smooth muscle contraction in the exposure group, but not in the filtered air group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Conclusions: Airway hyperresponsiveness and serotonin-dependent exacerbation of cholinergic-mediated airway smooth muscle contraction induced by early-life exposure to ozone plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype.
Background:
It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses.
Methods:
610 moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses.
Results:
MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a ≥30, ≥50, ≥60, ≥75 and ≥90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the ≥60% (or higher) threshold. One in 2 MP29-02 patients achieved a ≥50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom.
Conclusions:
MP29-02 provided faster and more complete symptom control than first-line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate-to-severe AR. These measures define a new standard for assessing relevance in AR.
Asthma and allergic rhinitis are common health problems that cause major illness and disability worldwide. The prevalence of allergic rhinitis is estimated to range from 10% to 20% in the USA and Europe. Multiple factors contribute to the wide range of reported prevalence rates. These include type of prevalence rate reported (current or cumulative), study selection criteria, age of participants, differences in survey methods, varied geographic locations and socioeconomic status, any of which are significant enough to confound direct comparison between studies. There is no standard set of diagnostic criteria for allergic rhinitis. In most studies, the criteria for diagnosis are based on the subject's reporting, solely by questionnaire and rarely confirmed by skin testing. In addition, most studies focus on hay fever, leaving perennial allergic rhinitis underestimated. Sinus imaging is generally not performed and, therefore, rhinosinusitis not differentiated. Some investigators report 'current' prevalence while others report 'cumulative' or 'lifetime' prevalence. Epidemiologic studies have consistently shown that asthma and rhinitis often coexist in the same patients. The prevalence of asthma is <2% in subjects without rhinitis while it varies from 10% to 40% in patients with rhinitis. Furthermore, the majority of patients with asthma experience rhinitis, which is a factor in the risk for asthma. Despite recognition that allergic rhinitis and asthma are global health problems, there are insufficient epidemiologic data and more data are needed with regard to their etiologic risk factors and natural history. This aim of this review is to enable the reader to discuss prevalence, risk factors and prognosis of allergic rhinitis and asthma.
Allergic rhinitis is a very common disorder that affects people of all ages, peaking in the teenage years. It is frequently ignored, underdiagnosed, misdiagnosed, and mistreated, which not only is detrimental to health but also has societal costs. Although allergic rhinitis is not a serious illness, it is clinically relevant because it underlies many complications, is a major risk factor for poor asthma control, and affects quality of life and productivity at work or school. Management of allergic rhinitis is best when directed by guidelines. A diagnostic trial of a pharmacotherapeutic agent could be started in people with clinically identified allergic rhinitis; however, to confirm the diagnosis, specific IgE reactivity needs to be recorded. Documented IgE reactivity has the added benefit of guiding implementation of environmental controls, which could substantially ameliorate symptoms of allergic rhinitis and might prevent development of asthma, especially in an occupational setting. Many classes of drug are available, effective, and safe. In meta-analyses, intranasal corticosteroids are superior to other treatments, have a good safety profile, and treat all symptoms of allergic rhinitis effectively. First-generation antihistamines are associated with sedation, psychomotor retardation, and reduced academic performance. Only immunotherapy with individually targeted allergens has the potential to alter the natural history of allergic rhinitis. Patients' education is a vital component of treatment. Even with the best pharmacotherapy, one in five affected individuals remains highly symptomatic, and further research is needed in this area.
In this paper, the field of quantitative microcomputed tomography arising from the combination of microcomputed tomography and quantitative 3D image analysis, is summarized with focus on materials science applications. Opportunities and limitations as well as typical application scenarios are discussed. Selected examples provide an insight into commonly used as well as recent methods from mathematical morphology and stochastic geometry.
Continuous isometric microfocal X-ray computed tomography (CT) scans were acquired from an AKR/J mouse, Brown-Norway rat, and Hartley guinea pig. The anatomy and volume of the paranasal sinus cavities were defined from 2-dimensional (2-D) and 3-dimensional (3-D) CT images. Realistic 3-D images were reconstructed and used to determine the anterior maxillary, posterior maxillary, and ethmoid sinus cavity airspace volumes (mouse: 0.6, 0.7, and 0.7 mm(3), rat: 8.6, 7.7, and 7.0 mm(3), guinea pig: 63.5, 46.6 mm(3), and no ethmoid cavity, respectively). The mouse paranasal sinus cavities are similar to the corresponding rat cavities, with a reduction in size, while the corresponding maxillary sinus cavities in the guinea pig are different in size, location, and architecture. Also, the ethmoid sinus cavity is connected by a common drainage pathway to the posterior maxillary sinus in mouse and rat while a similar ethmoid sinus was not present in the guinea pig. We conclude that paranasal sinus cavity airspace opacity (2-D) or volume (3-D) determined by micro-CT scanning may be used to conduct longitudinal studies on the patency of the maxillary sinus cavities of rodents. This represents a potentially useful endpoint for developing and testing drugs in a small animal model of sinusitis.
Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.
Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.
The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.
To investigate if markers of exposure to foodborne and orofecal microbes versus airborne viruses are associated with atopy and respiratory allergies.
Retrospective case-control study.
240 atopic cases and 240 non-atopic controls from a population sample of 1659 participants, all Italian male cadets aged 17-24.
Air force school in Caserta, Italy.
Serology for Toxoplasma gondii, Helicobacter pylori, hepatitis A virus, measles, mumps, rubella, chickenpox, cytomegalovirus, and herpes simplex virus type 1; skin sensitisation and IgE antibodies to relevant airborne allergens; total IgE concentration; and diagnosis of allergic asthma or rhinitis.
Compared with controls there was a lower prevalence of T gondii (26% v 18%, P=0.027), hepatitis A virus (30% v 16%, P=0.004), and H pylori (18% v 15%, P=0.325) in atopic participants. Adjusted odds ratios of atopy decreased with a gradient of exposure to H pylori, T gondii, and hepatitis A virus (none, odds ratio 1; one, 0. 70; two or three, 0.37; P for trend=0.000045) but not with cumulative exposure to the other viruses. Conversely, total IgE concentration was not independently associated with any infection. Allergic asthma was rare (1/245, 0.4%) and allergic rhinitis infrequent (16/245, 7%) among the participants (245/1659) exposed to at least two orofecal and foodborne infections (H pylori, T gondii, hepatitis A virus).
Respiratory allergy is less frequent in people heavily exposed to orofecal and foodborne microbes. Hygiene and a westernised, semisterile diet may facilitate atopy by influencing the overall pattern of commensals and pathogens that stimulate the gut associated lymphoid tissue thus contributing to the epidemic of allergic asthma and rhinitis in developed countries.
Nasal hypersecretion is predominantly caused by overaction of nasal glands, which are mainly under cholinergic control. In this work, we investigated the influence of botulinum toxin A (BTA) on the nasal mucosal tissue of the maxillary sinus turbinates of guinea pigs (n = 10) that were painlessly sacrificed 10 days (short-term group) or 3 months (long-term group) after local treatment with 20 units of BTA (Botox) or 0.2 mL of 0.9% sodium chloride (control). Histologic investigation of the nasal mucosal tissue of the BTA-treated animals (short-term group) showed degeneration of glands and ducts and apoptotic nuclei on TUNEL staining of these structures. The control animals revealed normal glandular tissue and no apoptosis. The animals of the long-term group showed almost normal glandular tissue and only a few apoptotic nuclei. In conclusion, BTA induces temporary apoptosis in the nasal glandular compartment of guinea pigs.
The year 2010 marks the centennial for the identification of histamine and the first glimpse of its many physiological functions. From these initial findings a rich tapestry of research has uncovered roles for histamine in almost every physiological process with new findings emerging every year. These diverse roles of histamine have made for fertile ground for the discovery of novel therapeutics, and these drugs have been so successful that the term “antihistamine” has entered the common lexicon. This volume is an attempt to give a snapshot in time as to the current understanding of the role of histamine in just one important therapeutic area—inflammation. The first three chapters provide some background context for the rest of the book starting out with a historical perspective by Figueroa and Shankley. Bongers et al provide an overview of the pharmacology of the four histamine receptors and the chapter by Hiroshi Ohtsu describes how histamine is synthesized as well as the insights derived from mice where this synthesis is disrupted. The next several chapters discuss disease areas where histamine is known to be involved. Chapter 4 by Thomas Taylor-Clark outlines the role of histamine in allergic rhinitis, an area were antihistamines are commonly used. This is also true for ocular allergy as discussed by Ohbayashi et al. Both of these chapters highlight aspects of these conditions that are still not well-controlled and suggest the utility of new antihistamines targeting other histamine receptors.
Diseases of the Sinuses: A Comprehensive Textbook of Diagnosis and Treatment, 2nd Edition, offers the definitive source of information about the basic science of the sinuses and the clinical approach to sinusitis. Since the widely praised publication of the first edition, understanding of sinus disease has changed dramatically, mainly as a result of recent developments and new discoveries in the field of immunology. This updated and expanded edition is divided into sections addressing, separately, the pathogenesis, clinical presentation, medical and surgical management of acute and chronic rhinosinusitis. Special entities such as autoimmune-related sinusitis, allergy and sinusitis, and aspirin-exacerbated respiratory disease are discussed in separate chapters. The role of immunodeficiency is also addressed. The management section has been fully updated to incorporate new medical modalities and surgical procedures. Developed by a distinguished group of international experts who share their expertise and insights from years of collective experience in treating sinus diseases, the book will appeal to anyone who has an interest in sinus disease, including both physicians and allied health professionals. Internists, pediatricians, allergists, otolaryngologists and infectious disease specialists will find the book to be an invaluable, comprehensive reference. Physician assistants and nurse practitioners who work with specialists who treat sinus disease will also benefit from the book.
CT alone has conventionally informed radiotherapy planning. It provides anatomical information for delineation and electron density for dose calculation. Integrating PET-CT for radiotherapy planning offers the opportunity to individualize treatment and improve patient outcome. PET-CT’s molecular insight of tumour biology could facilitate a move away from ‘one-size-fits-all’ prescription to more accurate personalized radiotherapy [1].
Objectives:
To (1) compare the radiation dose of low-dose computed tomography (CT) to that of standard-dose CT, (2) determine the minimum optimal radiation dose for use in patients who need endoscopic sinus surgery, and (3) assess the reliability of iterative model reconstruction.
Study design:
Prospective single-institution study.
Setting:
Tertiary care center.
Subjects and methods:
We recruited 48 adults with medically refractory sinusitis. Each patient underwent 4 scans with different CT parameters: 120 kV and 100 mAs (standard dose), 100 kV and 40 mAs (low dose), 100 kV and 20 mAs (very low dose), and 100 kV and 10 mAs (ultra-low dose). All CT scans were reconstructed via filtered back-projection, and ultra-low dose scans were additionally reconstructed through iterative model reconstruction. Radiation dose, image quality, and diagnostic performance were compared among the scans.
Results:
Radiation doses decreased to 6% (ultra-low dose), 12% (very low dose), and 22% (low dose) of the standard-dose CT. The image quality of low-dose CT was similar to that of standard-dose CT. Ultra-low-dose CT with iterative model reconstruction was inferior to standard-dose CT for identifying anatomic structures, except for the optic nerve. All CT scans had 100% agreement for diagnosing rhinosinusitis.
Conclusions:
With low-dose CT, the radiation dose can be decreased to 22% of that of standard-dose CT without affecting the image quality. Low-dose CT can be considered the minimum optimal radiation for patients who need surgery. Iterative model reconstruction is not useful for assessing the anatomic details of the paranasal sinus on CT.
Using dedicated contrast agents high-quality X-ray imaging of soft tissue structures with isotropic micrometre resolution has become feasible. This technique is frequently titled as virtual histology as it allows production of slices of tissue without destroying the sample. The use of contrast agents is, however, often an irreversible time-consuming procedure and despite the non-destructive principle of X-ray imaging, the sample is usually no longer usable for other research methods. In this work we present the application of recently developed large-area photon counting detector for high resolution X-ray micro-radiography and micro-tomography of whole ex-vivo ethanol-preserved mouse organs. The photon counting detectors provide dark-current-free quantum-counting operation enabling acquisition of data with virtually unlimited contrast-to-noise ratio (CNR). Thanks to the very high CNR even ethanol-only preserved soft-tissue samples without addition of any contrast agent can be visualized in great detail. As ethanol preservation is one of the standard steps of tissue fixation for histology, the presented method can open a way for widespread use of micro-CT with all its advantages for routine 3D non-destructive soft-tissue visualisation.
Rationale:
Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g. inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets.
Objectives:
To assess the changes in cough responses to a range of inhaled irritants in COPD, and model these in animals to investigate the underlying mechanisms.
Methods:
Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea-pig model.
Measurements and main results:
Patients with COPD had heightened cough responses to capsaicin but reduced responses to PGE2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea-pigs than in controls; similar increased responses were observed in ex-vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to PGE2 were decreased by CS-exposure.
Conclusions:
CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable to the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neuro-phenotypes in airway disease.
Objective:
Allergic rhinitis (AR) is one of the most common diseases affecting adults. It is the most common chronic disease in children in the United States today and the fifth most common chronic disease in the United States overall. AR is estimated to affect nearly 1 in every 6 Americans and generates 5 billion in direct health expenditures annually. It can impair quality of life and, through loss of work and school attendance, is responsible for as much as 4 billion in lost productivity annually. Not surprisingly, myriad diagnostic tests and treatments are used in managing this disorder, yet there is considerable variation in their use. This clinical practice guideline was undertaken to optimize the care of patients with AR by addressing quality improvement opportunities through an evaluation of the available evidence and an assessment of the harm-benefit balance of various diagnostic and management options.
Purpose:
The primary purpose of this guideline is to address quality improvement opportunities for all clinicians, in any setting, who are likely to manage patients with AR as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The guideline is intended to be applicable for both pediatric and adult patients with AR. Children under the age of 2 years were excluded from the clinical practice guideline because rhinitis in this population may be different than in older patients and is not informed by the same evidence base. The guideline is intended to focus on a limited number of quality improvement opportunities deemed most important by the working group and is not intended to be a comprehensive reference for diagnosing and managing AR. The recommendations outlined in the guideline are not intended to represent the standard of care for patient management, nor are the recommendations intended to limit treatment or care provided to individual patients.
Action statements:
The development group made a strong recommendation that clinicians recommend intranasal steroids for patients with a clinical diagnosis of AR whose symptoms affect their quality of life. The development group also made a strong recommendation that clinicians recommend oral second-generation/less sedating antihistamines for patients with AR and primary complaints of sneezing and itching. The panel made the following recommendations: (1) Clinicians should make the clinical diagnosis of AR when patients present with a history and physical examination consistent with an allergic cause and 1 or more of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing. Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes. (2) Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy. (3) Clinicians should assess patients with a clinical diagnosis of AR for, and document in the medical record, the presence of associated conditions such as asthma, atopic dermatitis, sleep-disordered breathing, conjunctivitis, rhinosinusitis, and otitis media. (4) Clinicians should offer, or refer to a clinician who can offer, immunotherapy (sublingual or subcutaneous) for patients with AR who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls. The panel recommended against (1) clinicians routinely performing sinonasal imaging in patients presenting with symptoms consistent with a diagnosis of AR and (2) clinicians offering oral leukotriene receptor antagonists as primary therapy for patients with AR. The panel group made the following options: (1) Clinicians may advise avoidance of known allergens or may advise environmental controls (ie, removal of pets; the use of air filtration systems, bed covers, and acaricides [chemical agents formulated to kill dust mites]) in patients with AR who have identified allergens that correlate with clinical symptoms. (2) Clinicians may offer intranasal antihistamines for patients with seasonal, perennial, or episodic AR. (3) Clinicians may offer combination pharmacologic therapy in patients with AR who have inadequate response to pharmacologic monotherapy. (4) Clinicians may offer, or refer to a surgeon who can offer, inferior turbinate reduction in patients with AR with nasal airway obstruction and enlarged inferior turbinates who have failed medical management. (5) Clinicians may offer acupuncture, or refer to a clinician who can offer acupuncture, for patients with AR who are interested in nonpharmacologic therapy. The development group provided no recommendation regarding the use of herbal therapy for patients with AR.
The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components.
Objective
To validate the applicability of the PVDF nasal sensor to assess the nasal airflow, in healthy subjects and patients with nasal obstruction. Also, to correlate the results with the score of Visual Analogue Scale (VAS).
Methods
PVDF nasal sensor and VAS measurements were carried out in 50 subjects (25-healthy subjects and 25 patients). The VAS score of nasal obstruction and Peak-to-Peak amplitude (Vp-p) of nasal cycle measured by PVDF nasal sensors were analysed for Right Nostril (RN) and Left Nostril (LN) in both the groups. Spearman’s rho correlation was calculated. The relationship between PVDF nasal sensor measurements and severity of nasal obstruction (VAS score) were assessed by ANOVA.
Results
In healthy group, the measurement of nasal airflow by PVDF nasal sensor for RN and LN were found to be 51.14 ± 5.87% and 48.85 ± 5.87%, respectively. In patient group, PVDF nasal sensor indicated lesser nasal airflow in the blocked nostrils (RN: 23.33 + 10.54% and LN: 32.24 + 11.54%). Moderate correlation was observed in healthy group (r = -0.710, p < 0.001 for RN and r = -0.651, p < 0.001 for LN), and moderate to strong correlation in patient group (r = -0.751, p < 0.01 for RN and r = -0.885, p < 0.0001 for LN).
Conclusion
PVDF nasal sensor method is a newly developed technique for measuring the nasal airflow. Moderate to strong correlation was observed between PVDF nasal sensor data and VAS scores for nasal obstruction. In our present study, PVDF nasal sensor technique successfully differentiated between healthy subjects and patients with nasal obstruction. Additionally, it can also assess severity of nasal obstruction in comparison with VAS. Thus, we propose that the PVDF nasal sensor technique could be used as a new diagnostic method to evaluate nasal obstruction in routine clinical practice.
Background and purpose:
CT performed with Veo model-based iterative reconstruction has shown the potential for radiation-dose reduction. This study sought to determine whether Veo could reduce noise and improve the image quality of low-dose sinus CT.
Materials and methods:
Twenty patients consented to participate and underwent low- and standard-dose sinus CT on the same day. Standard-dose CT was created with filtered back-projection (120 kV[peak], 210 mA, 0.4-second rotation, and 0.531 pitch). For low-dose CT, mA was decreased to 20 (the remaining parameters were unchanged), and images were generated with filtered back-projection and Veo. Standard- and low-dose datasets were reconstructed by using bone and soft-tissue algorithms, while the low-dose Veo reconstruction only had a standard kernel. Two blinded neuroradiologists independently evaluated the image quality of multiple osseous and soft-tissue craniofacial structures. Image noise was measured by using multiple regions of interest.
Results:
Eight women and 12 men (mean age, 63.3 years) participated. Volume CT dose indices were 2.9 mGy (low dose) and 31.6 mGy (standard dose), and mean dose-length products were 37.4 mGy-cm (low dose) and 406.1 mGy-cm (standard dose). Of all the imaging series, low-dose Veo demonstrated the least noise (P < .001). Compared with filtered back-projection low-dose CT using soft-tissue and bone algorithms, Veo had the best soft-tissue image quality but the poorest bone image quality (P < .001).
Conclusions:
Veo significantly reduces noise in low-dose sinus CT. Although this reduction improves soft-tissue evaluation, thin bone becomes less distinct.
Neutrophils, eosinophils, and basophils play essential roles during microbe-induced and sterile inflammation. The severity of such inflammatory processes is controlled, at least in part, by factors that regulate cell death and survival of granulocytes. In recent years, major progress has been made in understanding the molecular mechanisms of granulocyte cell death and in identifying novel damage- and pathogen-associated molecular patterns as well as regulatory cytokines impacting granulocyte viability. Furthermore, an increased interest in innate immunity has boosted our overall understanding of granulocyte biology. In this review, we describe and compare factors and mechanisms regulating neutrophil, eosinophil, and basophil lifespan. Because dysregulation of death pathways in granulocytes can contribute to inflammation-associated immunopathology, targeting granulocyte lifespan could be therapeutically promising.
Background
Micro-computed tomography (micro-CT) offers numerous advantages for small animal imaging, including the ability to monitor the same animals throughout a longitudinal study. However, concerns are often raised regarding the effects of X-ray dose accumulated over the course of the experiment.PurposeTo scan C57BL/6 mice multiple times per week for 6 weeks, in order to determine the effect of the cumulative dose on pulmonary and cardiac tissue at the end of the study.Material and MethodsC57BL/6 male mice were split into two groups (irradiated group = 10, control group = 10). The irradiated group was scanned (80 kVp/50mA) three times weekly for 6 weeks, resulting in a weekly dose of 0.84 Gy, and a total study dose of 5.04 Gy. The control group was scanned on the final week. Scans from week 6 were reconstructed and the lungs and heart were analyzed.ResultsOverall, there was no significant difference in lung volume or lung density or in left ventricular volume or ejection fraction between the control group and the irradiated group. Histological samples taken from excised lung and myocardial tissue also showed no evidence of inflammation or fibrosis in the irradiated group.Conclusion
This study demonstrated that a 5 Gy X-ray dose accumulated over 6 weeks during a longitudinal micro-CT study had no significant effects on the pulmonary and myocardial tissue of C57BL/6 mice. As a result, the many advantages of micro-CT imaging, including rapid acquisition of high-resolution, isotropic images in free-breathing mice, can be taken advantage of in longitudinal studies without concern for negative dose-related effects.
Histamine is a biogenic amine that exerts its biological effects as a neurotransmitter and local mediator via four histamine receptor (HR) subtypes (H(x)Rs) - H(1)R, H(2)R, H(3)R, and H(4)R - belonging to the superfamily of G-protein-coupled receptors (GPCRs). All four H(x)Rs exhibit pronounced differences in agonist and/or antagonist pharmacology among various species orthologs. The species differences constitute a problem for animal experiments and drug development. This problem applies to GPCRs with diverse ligands. Here, we summarize our current knowledge on H(x)R orthologs as a case study for species-dependent activity of GPCR ligands. We show that species-specific pharmacology also provides unique opportunities to study important aspects of GPCR pharmacology in general, including ligand-binding sites, the roles of extracellular domains in ligand binding and receptor activation, agonist-independent (constitutive) receptor activity, thermodynamics of ligand/receptor interaction, receptor-activation mechanisms, and ligand-specific receptor conformations.
Mast cells are regularly found in the nasal mucosa of healthy persons. Their number increases in allergic and infections rhinitis. With the help of immunohistochemical techniques, cell surface-bound IgE antibodies within a nasal specimen in allergic rhinitis can be distinguished from other non-IgE-associated pathomechanisms. Using conventional mast cell staining techniques together with immunohistochemistry, we were able to demonstrate that IgE-associated cells within the allergic nasal mucosa predominantly resemble mast cells. They increase in number and migrate into the respiratory epithelium due to allergen exposure and show a high cell turnover and degranulation rate. Their number does not correlate with serum IgE levels. These findings suggest that mast cells not only represent the major mediator cells in Type I allergic reactions, but also the transport media for IgE antibodies produced in regional lymphoid tissues.
Micro-computed tomography imaging technology allows for the whole-mount investigation of skeletal structures in preclinical specimens at both fetal and postnatal time points. The imaging process is nondestructive to the specimen and can be performed at various resolutions to derive the region of interest information most relevant to individual researchers. In addition to qualitative imaging of skeletal samples, accurate and desirable metrics such as bone mineral density (BMD), discrete cortical and trabecular bone analysis, and milligrams hydroxyapatite per unit volume (mgHA/cc) are also achievable depending upon scanner platform. Additional benefits to the method include digitally archivable files, in vivo and ex vivo scanning options, and volumetric or slice-thru presentation of data in standard histological or oblique orientations. Some drawbacks to the method include long scan times at higher spatial resolutions, large file sizes, and limitation to imaging of highly dense biological structures (i.e., bone), though several groups have attempted to expand the modality to include soft tissue imaging in ex vivo specimens.
State-of-the-art documents like ARIA and EPOS provide clinicians with evidence-based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline-directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment-related, diagnosis-related and/or patient-related factors. Treatment-related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom-oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient-related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain.
Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.
In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.
This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.
The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.
Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.
The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.
To optimize micro-CT protocols with respect to x-ray spectra and thereby reduce radiation dose at unimpaired image quality.
Simulations were performed to assess image contrast, noise, and radiation dose for different imaging tasks. The figure of merit used to determine the optimal spectrum was the dose-weighted contrast-to-noise ratio (CNRD). Both optimal photon energy and tube voltage were considered. Three different types of filtration were investigated for polychromatic x-ray spectra: 0.5 mm Al, 3.0 mm Al, and 0.2 mm Cu. Phantoms consisted of water cylinders of 20, 32, and 50 mm in diameter with a central insert of 9 mm which was filled with different contrast materials: an iodine-based contrast medium (CM) to mimic contrast-enhanced (CE) imaging, hydroxyapatite to mimic bone structures, and water with reduced density to mimic soft tissue contrast. Validation measurements were conducted on a commercially available micro-CT scanner using phantoms consisting of water-equivalent plastics. Measurements on a mouse cadaver were performed to assess potential artifacts like beam hardening and to further validate simulation results.
The optimal photon energy for CE imaging was found at 34 keV. For bone imaging, optimal energies were 17, 20, and 23 keV for the 20, 32, and 50 mm phantom, respectively. For density differences, optimal energies varied between 18 and 50 keV for the 20 and 50 mm phantom, respectively. For the 32 mm phantom and density differences, CNRD was found to be constant within 2.5% for the energy range of 21-60 keV. For polychromatic spectra and CMs, optimal settings were 50 kV with 0.2 mm Cu filtration, allowing for a dose reduction of 58% compared to the optimal setting for 0.5 mm Al filtration. For bone imaging, optimal tube voltages were below 35 kV. For soft tissue imaging, optimal tube settings strongly depended on phantom size. For 20 mm, low voltages were preferred. For 32 mm, CNRD was found to be almost independent of tube voltage. For 50 mm, voltages larger than 50 kV were preferred. For all three phantom sizes stronger filtration led to notable dose reduction for soft tissue imaging. Validation measurements were found to match simulations well, with deviations being less than 10%. Mouse measurements confirmed simulation results.
Optimal photon energies and tube settings strongly depend on both phantom size and imaging task at hand. For in vivo CE imaging and density differences, strong filtration and voltages of 50-65 kV showed good overall results. For soft tissue imaging of animals the size of a rat or larger, voltages higher than 65 kV allow to greatly reduce scan times while maintaining dose efficiency. For imaging of bone structures, usage of only minimum filtration and low tube voltages of 40 kV and below allow exploiting the high contrast of bone at very low energies. Therefore, a combination of two filtrations could prove beneficial for micro-CT: a soft filtration allowing for bone imaging at low voltages, and a variable stronger filtration (e.g., 0.2 mm Cu) for soft tissue and contrast-enhanced imaging.
Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macroparasites. Here we present arguments to suggest that allergic immunity has an important role in host defence against noxious environmental substances, including venoms, haematophagous fluids, environmental xenobiotics and irritants. We argue that appropriately targeted allergic reactions are beneficial, although they can become detrimental when excessive. Furthermore, we suggest that allergic hypersensitivity evolved to elicit anticipatory responses and to promote avoidance of suboptimal environments.
Laboratory systems for microscopic computed tomography (micro-CT) have recently evolved from specialized prototype tools to become essential components of many research laboratories. The availability of commercial systems with almost microscopic resolution and the capability to image live animals has opened up entirely new applications for micro-CT in laboratory investigation. This review describes the technical aspects of micro-CT and highlights some current research applications. Micro-CT has the potential to replace serial histology as the reference standard in many in vitro studies, and provides a practical approach to obtain quantitative information during some longitudinal investigations in vivo.
The aim of functional septorhinoplasty is to create an esthetically elegant nose and harmony in the face by preserving nasal function as well as maintaining or restoring adequate airway. Since nasal complaints are usually subjective, it may be difficult to evaluate the functions objectively. In the present study, we aimed to investigate the alterations in nasal function associated with septorhinoplasty by using both objective and subjective methods. The study population consisted of 40 patients who underwent septorhinoplasty and 40 healthy controls. Before and after the operation, visual analog scale, acoustic rhinometry, rhinomanometry, and Odiosoft-Rhino test were applied to all patients and controls. There were significant differences in all parameters both before and after the operation. While a significant difference was obtained between the patient and control groups in terms of preoperative values, no significant difference was found between postoperative values of these groups. Both objective and subjective methods are important in evaluations.
Asthma is characterized by reversible bronchoconstriction and airway hyperreactivity. Although M(3) muscarinic receptors mediate bronchoconstriction, non-selective muscarinic receptor antagonists are not currently recommended for chronic control of asthma. We tested whether selective blockade of M(3) receptors, at the time of antigen challenge, blocks subsequent development of airway hyperreactivity in antigen-challenged guinea-pigs.
Ovalbumin-sensitized guinea-pigs were pretreated with 1 µg·kg(-1) of a kinetically selective M(3) receptor antagonist, tiotropium, or 1 mg·kg(-1) of a non-selective muscarinic receptor antagonist, atropine, and challenged with inhaled ovalbumin. Animals were anaesthetized, paralyzed, ventilated and vagotomized 24 h later. We measured vagally mediated bronchoconstriction and i.v. ACh-induced bronchoconstriction.
Electrical stimulation of both vagus nerves induced frequency-dependent bronchoconstriction in sensitized animals that was significantly increased after antigen challenge. Antigen-induced hyperreactivity was completely blocked by tiotropium pretreatment but only partially blocked by atropine pretreatment. Surprisingly, although tiotropium blocked bronchoconstriction induced by i.v. ACh, it did not inhibit vagally-induced bronchoconstriction in sensitized controls, suggesting that tiotropium does not block hyperreactivity by blocking receptors for vagally released ACh. Rather, tiotropium may have worked through an anti-inflammatory mechanism, since it inhibited eosinophil accumulation in the lungs and around nerves.
These data confirm that testing M(3) receptor blockade with exogenous ACh does not predict vagal blockade. Our data also suggest that selective blockade of M(3) receptors may be effective in asthma via mechanisms that are separate from inhibition of bronchoconstriction.
Ovalbumin-induced guinea pig model of rhinitis was assessed for its utility in the studies of rhinitis. Systemic sensitization and challenge with ovalbumin-induced rhinitis symptoms and an increase in anti-OVA-IgE and IgG titers, positive skin reactions and nasal lavage IL-4 concentration. Histopathology of nasal mucosa showed infiltration of eosinophils and other inflammatory cells consistent with the symptoms. Topical sensitization of ovalbumin yielded inconsistent symptoms of rhinitis. In systemic sensitization model, repeated challenge of ovalbumin caused similar response for at least 3 consecutive challenges. The symptoms were affected by relative humidity in the air and dosing volume of topical drugs. Sneezing and lacrimation were reduced by acute oral administration of the H1 receptor antagonists and steroids or the prophylactic oral administration of cysteinyl leukotriene (CysLT1) receptor antagonist montelukast or acute topical antihistamines, mast cell stabilizer sodium cromoglycate and anticholinergic agent ipratropium bromide, but not by a topical steroid. Nose rubbing was reduced significantly by some oral and topical antihistamines. Oral steroids offered excellent protection against all symptoms. Dexamethasone and montelukast also inhibited nasal lavage IL-4 concentration and inflammatory cell infiltration. Treatment with topical steroid fluticasone for 2 weeks had no effect on sneezing or rubbing. However, it caused complete inhibition of congestion. The cyclooxygenase inhibitor indomethacin had no effect on symptoms of rhinitis. The adrenergic alpha receptor agonist-decongestant oxymetazoline caused reduction in congestion. These results suggest that differential responsiveness to symptoms of rhinitis by a new agent can be very well profiled in the model in congruence with the mediation pathways and mechanism of action of drugs. The model provides complete symptomatic characterization of rhinitis and is a good tool for its study.
Micro-CT provides non-invasive anatomic evaluation of small animals. Serial micro-CT measurements are, however, hampered by the severity of ionizing radiation doses cumulating over the total period of follow-up. The dose levels may be sufficient to influence experimental outcomes such as animal survival or tumor growth.
This study was designed to evaluate the radiation dose of micro-CT and to optimize the scanning protocol for longitudinal micro-CT scans.
Normal C57Bl/6 mice were euthanized. Radiation exposure was measured using individually calibrated lithium fluoride thermoluminescent dosimeters (TLDs). Thirteen TLDs were placed in the mice at the thyroid, lungs, liver, stomach, colon, bladder and near the spleen. Micro-CT (SkyScan 1178) was performed using two digital X-ray cameras which scanned over 180 degrees at a resolution of 83 microm, a rotation step of 1.08 degrees , 50 kV, 615 microA and 121 s image acquisition time. The TLDs were removed after each scan. CTDI(100) was measured with a 100 mm ionization chamber, centrally positioned in a 2.7 cm diameter water phantom, and rotation steps were increased to reduce both scan time and radiation dose.
Internal TLD analysis demonstrated median organ dose of 5.5 +/- 0.6 mGy per mA s, confirmed by CTDI(100) with result of 6.6 mGy per mA s. A rotation step of 2.16 resulted in qualitatively accurate images. At a resolution of 83 microm the scan time is reduced to 63 s with an estimated dose of 2.9 mGy per mA s. At 166 microm resolution, the scan time is limited to 27 s, with a concordant dose of 1.2 mGy per mA s.
The radiation dose of a standard micro-CT scan is relatively high and could influence the experimental outcome. We believe that the presented adaptation of the scan protocol allows for accurate imaging without the risk of interfering with the experimental outcome of the study.
Histamine, which is stored mainly in mast cells and basophils, is a prominent contributor to allergic disease. Elevations in plasma or tissue histamine levels have been noted during anaphylaxis and experimental allergic responses of the skin, nose, and airways. Of the four cardinal signs of asthma (bronchospasm, edema, inflammation, and mucus secretion), histamine is capable of mediating the first two through its H1 receptor and mucus secretion through its H2 receptor. Of the five cardinal signs of allergic rhinitis (pruritus, mucosal edema, sneezing, mucus secretion, and late-phase inflammatory reactions), histamine is capable of mediating the first three through its H1 receptor. In the nose, mucus secretion can be reflexively mediated by H1 and possibly also by H2 receptors. In the skin the cardinal features of urticaria (vasodilation, vascular permeability, and pruritus) can be mediated by stimulation of the H1 receptor. In anaphylaxis histamine H1-receptor stimulation can mediate vascular permeability, smooth muscle contraction, and tachycardia, whereas H2-receptor stimulation can mediate mucus secretion. Stimulation of both receptors can mediate vasodilation and reduce peripheral vascular resistance. Thus although histamine is only one of many mediators of allergic disease, it plays a primary role in allergic rhinitis, urticaria, anaphylaxis, and to a lesser degree, asthma.
The major pathological changes in rhinitis are vascular, with blood sinus congestion, transudation and oedema, and glandular, with mucus secretion. Both block the nose. Mediators released by antigen-antibody reactions and by inflammatory processes will disrupt nasal function in three main ways. First, mediators such as histamine, bradykinin and leukotrienes will act directly on blood vessels and submucosal glands, causing mucosal thickening and secretion. Second, the same mediators will excite terminals of sensory nervous receptors in the nose, setting up axon reflexes with release of neuropeptides from other branches of the nervous receptors. Neurokinins, such as substance P, will augment vasodilatation and transudation and may modulate the secretions from submucosal glands. Third, the same sensory receptors when stimulated will set up central nervous reflex actions. The responses include sneezing and nasal irritation (both prominent features of rhinitis) reflex nasal vasodilatation and mucus secretion, and actions on the lower airways. The relative importance of these three mechanisms is difficult to assess in man. Successful therapy may act by preventing one of the undesirable motor constituents of rhinitis, or may have a more general action in lessening inflammation or immunological responses.
We have been able to model the lung damage caused by paraquat in our mice and have found a dose-related increase in lung damage after PQ. Unfortunately we have not found a radiation dose or optimum time for irradiation which shows a reduction of the PQ lung damage.
A morphologic description of the airways of the guinea pig was developed from measurements of casts of the lungs and nasal cavity and from measurements of frozen sections of the lungs. The lengths, diameters, branching pattern, and numbers of elements of the respiratory tract formed the basis for a representative model of the system. The branching pattern is irregular to the pulmonary region but regularly dichotomous thereafter. The nasopharyngeal-tracheobronchial region contributes 2.64 cm3 of the total respiratory volume of 21.62 cm3. The alveoli contribute 16.31 cm3 of the 18.98 cm3 pulmonary region. The nasal region consists of convoluted and irregular airways with a functional volume of 0.48 cm3.
Development of nasal blockage and sneezing during repeated inhalation challenges with Japanese cedar pollens was evaluated in guinea pigs.
Male Hartley guinea pigs.
Guinea pigs were sensitized by intranasal instillation of cedar pollen extracts + Al(OH)3 2 times a day for 7 days. The animal was then forced to inhale the pollens for challenge, which was restrictively trapped in the upper airways, once a week.
Change of specific airway resistance (sRaw), sneezing frequency, and titers of anaphylactic antibodies in the serum were measured after each of the 30 challenges.
At the first challenge, no obvious increase in sRaw was observed. However, the second and third challenges to the animals caused modest biphasic elevations of sRaw, with peaks at the first and the fourth to sixth hour. At the fourth to tenth challenges, marked elevations of sRaw were observed. However, with repetition of the inhalation challenge, the early and the late responses became almost indistinguishable because of partial overlapping as the responses expanded. All guinea pigs sneezed immediately after each pollen inhalation challenge. Apparent increases of both circulating gamma1 and IgE antibodies were seen after the seventh challenge.
These results indicate that the experimental allergic rhinitis established in the present study can be a valuable model for analyzing the pathogenesis of the disease and developing new therapeutic drugs.
This document is the result of the work and discussion of the Standardization Committee on Acoustic Rhinometry and presents guidelines for quality control and optimal application of acoustic rhinometry at its present stage. It is suggested that: 1. A well-defined standard nose is used for testing and optimising the equipment (data for a standard nose is given in the paper). 2. Procedures for evaluation of accuracy and repeatability of the measurements in the standard nose are presented, and error limits are defined for the area-distance curve as a whole, for the minimum cross-sectional area and for the volume from 0-5 cm into the nose. 3. Publication of results should include the volume 0-5 cm into the nose (volume from 2-5 cm for mucosal changes) the minimum cross-sectional area or preferably the two first minima and the distances to those areas. 4. The operator should be trained, follow a standard operating procedure and the environmental conditions (temperature and noise) be controlled. 5. Attention should be given to the nosepiece and the coupling between the equipment and the nose to obtain correct position, and sufficient seal without disturbing the anatomy. 6. The manufacturer should give information about the performance of the equipment, calibration procedures and maintenance, hygiene, environmental and safety standards.
An immunotherapeutic vaccine for allergy was produced by designing IgE-based synthetic peptide immunogens and selecting them for functional immunogenicity. The vaccine targets the binding site on IgE for the high affinity receptor Fc epsilon RI, by active immunization. The peptide target site on IgE heavy chain was selected from among the amino acid sequences for the C epsilon 2, C epsilon 3, and C epsilon 4 domains. These were characterised by epitope mapping studies for cross-reactivity to IgE and functional antigenicity. A peptide, modified from positions 413-435 of a loop region of C epsilon 3 and subjected to conformational constraint, elicited anti-IgE antibodies that blocked IgE-mediated histamine release. It was immunopotentiated by linkage to a promiscuous T helper site to produce a wholly synthetic chimaeric immunogen. This immunogen was shown to induce polyclonal site-specific anti-IgE antibodies that obstruct binding to Fc epsilon RI, inhibit histamine release by IgE-sensitised basophils, inhibit passive cutaneous anaphylaxis, and do not signal degranulation. Immunized dogs experienced significant reductions in total serum IgE.
An increasing number of studies have used acoustic rhinometry (AR) for study of pharmacological interventions on nasal cavity dimensions in dogs and cats, but there have been no attempts to validate AR in these species. This is done in the present study. We compared area-distance relationships of nasal cavities from five decapitated dogs (3.5-41 kg) and cats (3.8-6 kg). AR was compared with magnetic resonance (MR) imaging and a fluid-displacement method (FDM) using perfluorocarbon. AR measured 88% (98-79%) (mean and 95% confidence interval) of nasal cavity volume in dogs determined by FDM and 71% (83-59%) in cats. AR markedly underestimated nasal cavity dimensions when minimum areas were below 0.1 cm2 in dogs and 0.05 cm2 in cats. AR underestimation increased with the severity of the constriction and with distance. Cross-sectional areas in the deeper parts of the cavity measured 76% (99-54%) of FDM in dogs and 52% (66-39%) in cats. AR agreed well with MR, especially in the deeper part of the cavity. MR images showed that the nasal cavities had a very complex structure not expected to be reproduced by AR. MR could not be considered a "gold standard" because definition of the cross-sectional area of the lumen depended critically on subjective choices. FDM produced repeatable measurements and possibly offers the most adequate reference in future evaluation of AR. AR underestimated what we believed were the most correct cross-sectional areas determined by FDM, especially in the deeper part of the dog and cat nasal cavities. Despite these difficulties, AR has been shown to be useful to describe qualitative changes in cross-sectional area.