phenylephrine-hydrochloride and Disease-Models--Animal

Release of histamine from mast cells and basophils in inflammatory diseases of the nose and paranasal sinuses has been demonstrated in allergic and non-allergic processes.. A selective literature search was conducted in PubMed and Medline, and publications in German-language journals were additionally analyzed.. The histamine receptors H. H

Topics: Animals; Disease Models, Animal; Humans; Inflammation; Nose; Paranasal Sinuses; Receptors, Histamine; Receptors, Histamine H4

Viral infections of the respiratory tract can be complicated by bacterial superinfection, resulting in a significantly longer duration of illness and even a fatal outcome. In this review, we focused on interactions between S. aureus and non-influenza viruses. Clinical data evidenced that rhinovirus infection may increase the S. aureus carriage load in humans and its spread. In children, respiratory syncytial virus infection is associated with S. aureus carriage. The mechanisms by which some non-influenza respiratory viruses predispose host cells to S. aureus superinfection can be summarized in three categories: i) modifying expression levels of cellular patterns involved in S. aureus adhesion and/or internalization, ii) inducing S. aureus invasion of epithelial cells due to the disruption of tight junctions, and iii) decreasing S. aureus clearance by altering the immune response. The comprehension of pathways involved in S. aureus-respiratory virus interactions may help developing new strategies of preventive and curative therapy.

Topics: Animals; Bacterial Adhesion; Carrier State; Disease Models, Animal; Epithelial Cells; Host-Pathogen Interactions; Humans; Mice; Microbial Interactions; Nose; Picornaviridae Infections; Respiratory Syncytial Virus Infections; Respiratory System; Respiratory Tract Infections; Rhinovirus; Staphylococcal Infections; Staphylococcus aureus; Superinfection; Virus Diseases

Although human colonization by facultative bacterial pathogens, such as Staphylococcus aureus, represents a major risk factor for invasive infections, the commensal lifestyle of such pathogens has remained a neglected area of research. S. aureus colonizes the nares of approximately 30% of the human population and recent studies suggest that the composition of highly variable nasal microbiota has a major role in promoting or inhibiting S. aureus colonization. Competition for epithelial attachment sites or limited nutrients, different susceptibilities to host defence molecules and the production of antimicrobial molecules may determine whether nasal bacteria outcompete each other. In this Review, we discuss recent insights into mechanisms that are used by S. aureus to prevail in the human nose and the counter-strategies that are used by other nasal bacteria to interfere with its colonization. Understanding such mechanisms will be crucial for the development of new strategies for the eradication of endogenous facultative pathogens.

Topics: Animals; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Host-Pathogen Interactions; Humans; Microbiota; Models, Molecular; Nasal Cavity; Nose; Risk Factors; Staphylococcal Infections; Staphylococcus aureus

The morphogenesis of midfacial processes requires the coordination of a variety of cellular functions of both mesenchymal and epithelial cells to develop complex structures. Any failure or delay in midfacial development as well as any abnormal fusion of the medial and lateral nasal and maxillary prominences will result in developmental defects in the midface with a varying degree of severity, including cleft, hypoplasia, and midline expansion. Despite the advances in human genome sequencing technology, the causes of nearly 70% of all birth defects, which include midfacial development defects, remain unknown. Recent studies in animal models have highlighted the importance of specific signaling cascades and genetic-environmental interactions in the development of the midfacial region. This review will summarize the current understanding of the morphogenetic processes and molecular mechanisms underlying midfacial birth defects based on mouse models with midfacial developmental abnormalities.

Topics: Animals; Cleft Palate; Disease Models, Animal; Gene-Environment Interaction; Genome, Human; Humans; Maxilla; Mice; Nose; Signal Transduction

Staphylococcus aureus persistently colonizes the anterior nares of approximately one fifth of the population and nasal carriage is a significant risk factor for infection. Recent advances have significantly refined our understanding of S. aureus-host communication during nasal colonization. Novel bacterial adherence mechanisms in the nasal epithelium have been identified, and novel roles for both the innate and the adaptive immune response in controlling S. aureus nasal colonization have been defined, through the use of both human and rodent models. It is clear that S. aureus maintains a unique, complex relationship with the host immune system and that S. aureus nasal colonization is overall a multifactorial process which is as yet incompletely understood.

Topics: Adaptive Immunity; Animals; Bacterial Adhesion; Carrier State; Disease Models, Animal; Epithelial Cells; Host-Pathogen Interactions; Humans; Immunity, Innate; Microbial Interactions; Microbiota; Nasal Cavity; Nasal Mucosa; Nose; Risk Factors; Rodentia; Staphylococcal Infections; Staphylococcus aureus

The nasal epithelium of the mouse closely mimics the bioelectrical phenotype of the human airways. Ion transport across the nasal epithelium induces a nasal transepithelial potential difference. Its measurement by a relatively non-invasive method adapted from humans allows in vivo longitudinal measurements of CFTR-dependent ionic transport in the murine nasal mucosa. This test offers a useful tool to assess CFTR function in preclinical studies for novel therapeutics modulating CFTR activity. Here we extensively review work done to assess transepithelial transport in the murine respiratory epithelium in the basal state and after administration of CFTR modulators. Factors of variability and discriminative threshold between the CF and the WT mice for different readouts are discussed.

Topics: Animals; Biological Transport; Cystic Fibrosis; Disease Models, Animal; Epithelium; Humans; Nasal Mucosa; Nose

The pig represents a useful, large experimental model for biomedical research. Recently, it has been used in different areas of biomedical research. The aim of this study was to review the basic anatomical structures of the head region in the pig in relation to their use in current research. Attention was focused on the areas that are frequently affected by pathological processes in humans: the oral cavity with teeth, salivary gland, orbit, nasal cavity and paranasal sinuses, maxilla, mandible and temporomandibular joint. Not all of the structures have an equal morphology in the pig and human, and these morphological dissimilarities must be taken into account before choosing the pig as an experimental model for regenerative medicine.

Topics: Animals; Disease Models, Animal; Humans; Mouth; Nose; Nose Diseases; Orbital Diseases; Skull; Stomatognathic Diseases; Swine

Nonsyndromic cleft of the lip and/or palate (CLP or orofacial cleft) derives from an embryopathy with consequent failure of the nasal process and/or palatal shelves fusion. This severe birth defect is one of the most common malformations among live births. Nonsyndromic CLP is composed of two separate entities: cleft lip and palate (CL+/-P) and cleft palate only (CPO). Both have a genetic background, and environmental factors probably disclose these malformations. In CL+/-P, several loci have been identified, and, in one case, a specific gene has also been found. In CPO, one gene has been identified, but many more are probably involved. Because of the complexity of the genetics of nonsyndromic CLP as a result of the difference between CL+/-P and CPO, heterogeneity of each group caused by the number of involved genes, type of inheritance, and interaction with environmental factors, we discuss the more sound results obtained with different approaches: epidemiological studies, animal models, human genetic studies, and in vitro studies.

Topics: Animals; Chromosome Mapping; Cleft Lip; Cleft Palate; Disease Models, Animal; Environment; Epidemiologic Studies; Humans; Nose; Palate

The minimal cleft lip provides a model for study of the clefting process. Nasolabial embryogenesis can be best understood using the concept of embryonic fields in which midline structures (columella, philtrum, premaxilla, septum, vomer, and ethmoids) develop with paired, fused A fields. Anatomic features of the minimal cleft lip suggest that the actual clefting site is located at the interface between the A and B fields within the lateral piriform wall. Study of the progression of clefting, using this model, places the timing of the clefting event to Carnegie stage 14. The degree to which this initial event affects subsequent fusion of the lateral and medial nasal processes (D and C fields) determines the final morphology of the cleft. Using this model, a rational basis is presented for the surgical management of minimal clefting in its varying manifestations.

Topics: Adult; Alveolar Process; Animals; Cleft Lip; Disease Models, Animal; Embryonic and Fetal Development; Ethmoid Bone; Facial Muscles; Female; Humans; Infant; Lip; Male; Maxilla; Mesoderm; Mouth; Nose; Plastic Surgery Procedures

Topics: Animals; Disease Models, Animal; Humans; Mice; Nasopharynx; Nose; Staphylococcal Infections; Staphylococcus aureus

Small animal models are of crucial importance for assessing COVID-19 countermeasures. Common laboratory mice would be well-suited for this purpose but are not susceptible to infection with wild-type SARS-CoV-2. However, the development of mouse-adapted virus strains has revealed key mutations in the SARS-CoV-2 spike protein that increase infectivity, and interestingly, many of these mutations are also present in naturally occurring SARS-CoV-2 variants of concern. This suggests that these variants might have the ability to infect common laboratory mice. Herein we show that the SARS-CoV-2 beta variant attains infectibility to BALB/c mice and causes pulmonary changes within 2-3 days post infection, consistent with results seen in other murine models of COVID-19, at a reasonable virus dose (2 × 10

Topics: Animals; Brain; COVID-19; Disease Models, Animal; Female; Inflammation; Lung; Male; Mice, Inbred BALB C; Nose; Pulmonary Alveoli; SARS-CoV-2

Topics: Animals; Antibodies, Viral; Brain; COVID-19; Cricetinae; Disease Models, Animal; Disease Progression; Ferrets; Immunoglobulin G; Lung; Nose; Real-Time Polymerase Chain Reaction; SARS-CoV-2; Viral Load

Infection with highly pathogenic avian H5N1 influenza virus in humans often leads to severe respiratory disease with high mortality. Experimental infection in non-human primates can provide additional insight into disease pathogenesis. However, such a model should recapitulate the disease symptoms observed in humans, such as pneumonia and inflammatory cytokine response. While previous studies in macaques have demonstrated the occurrence of typical lesions in the lungs early after infection and a high level of immune activation, progression to severe disease and lethality were rarely observed. Here, we evaluated a routinely used combined route of infection via intra-bronchial, oral, and intra-nasal virus inoculation with aerosolized H5N1 exposure, with or without the regular collection of bronchoalveolar lavages early after infection. Both combined route and aerosol exposure resulted in similar levels of virus replication in nose and throat and similar levels of immune activation, cytokine, and chemokine release in the blood. However, while animals exposed to H5N1 by combined-route inoculation developed severe disease with high lethality, aerosolized exposure resulted in less lesions, as measured by consecutive computed tomography and less fever and lethal disease. In conclusion, not virus levels or immune activation, but route of infection determines fatal outcome for highly pathogenic avian H5N1 influenza infection.

Topics: Aerosols; Air Microbiology; Animals; Bronchi; Cytokines; Disease Models, Animal; Environmental Exposure; Humans; Influenza A Virus, H5N1 Subtype; Influenza, Human; Macaca fascicularis; Male; Mouth; Nose

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking. Animal models exposed to cigarette smoke (CS) are used to mimic human COPD but the use of different CS protocols makes it difficult to compare the immunological and structural consequences of using a nose-only or whole-body CS exposure system. We hypothesized that when using a standardized CS exposure protocol based on particle density and CO (carbon monoxide) levels, the whole-body CS exposure system would generate a more severe inflammatory response than the nose-only system, due to possible sensitization by uptake of CS-components through the skin or via grooming.. In this study focusing on early COPD, mice were exposed twice daily 5 days a week to CS either with a nose-only or whole-body exposure system for 14 weeks to assess lung function, remodeling and inflammation.. At sacrifice, serum cotinine levels were significantly higher in the whole-body (5.3 (2.3-6.9) ng/ml) compared to the nose-only ((2.0 (1.8-2.5) ng/ml) exposure system and controls (1.0 (0.9-1.0) ng/ml). Both CS exposure systems induced a similar degree of lung function impairment, while inflammation was more severe in whole body exposure system. Slightly more bronchial epithelial damage, mucus and airspace enlargement were observed with the nose-only exposure system. More lymphocytes were present in the bronchoalveolar lavage (BAL) and lymph nodes of the whole-body exposure system while enhanced IgA and IgG production was found in BAL and to a lesser extent in serum with the nose-only exposure system.. The current standardized CS-exposure protocol resulted in a higher internal load of serum cotinine in the whole-body exposure system, which was associated with more inflammation. However, both exposure systems resulted in a similar lung function impairment. Data also highlighted differences between the two models in terms of lung inflammation and remodelling, and potential sensitization to CS. Researchers should be aware of these differences when designing their future studies for an early intervention in COPD.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cotinine; Cytokines; Disease Models, Animal; Immunity, Humoral; Immunoglobulin A; Immunoglobulin G; Inflammation Mediators; Inhalation Exposure; Lung; Lymphoid Tissue; Male; Mice, Inbred C57BL; Nose; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoke; Time Factors; Tobacco Products

ST59 is the predominant pathotype of community-associated methicillin-resistant

Topics: Adult; Aged; Alveolar Epithelial Cells; Animals; Bacterial Proteins; Child; Child, Preschool; China; Disease Models, Animal; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Middle Aged; Nose; Phylogeny; Sepsis; Staphylococcal Skin Infections; Virulence; Virulence Factors; Whole Genome Sequencing

Topics: Animals; Antibodies, Neutralizing; COVID-19; COVID-19 Vaccines; Disease Models, Animal; Ferrets; Injections, Intramuscular; Nose; Reinfection; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Viral Load

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques (. SARS-CoV-2感染引起的新型冠状病毒肺炎疫情已成为21世纪全球最重要的公共卫生突发事件。目前，SARS-CoV-2感染非人灵长类动物模型被认为是进行新型冠状病毒肺炎病理损伤特征及致病机制研究的金标准。该研究中，我们成功构建SARS-CoV-2感染北平顶猴（

Topics: Animals; COVID-19; Disease Models, Animal; Interferon-alpha; Interleukin-1beta; Interleukin-6; Lung; Macaca nemestrina; Nose; Pharynx; Rectum; RNA, Viral; SARS-CoV-2

Swine influenza is an economically important respiratory disease in swine, but it also constantly poses a threat to human health. Therefore, developing rapid, sensitive, and efficient detection methods for swine influenza virus (SIV) is important. By aligning the haemagglutinin (HA) gene sequences of SIVs circulating in China over a 10-year period, an H1 primer-probe set targeting both Eurasian avian-like H1N1 (EA H1N1) and pandemic 2009 H1N1 ((H1N1)pdm09) lineages plus a H3 primer-probe set targeting the prevalent human-like H3N2 (HL H3N2) subtype were designed. Subsequently, a TaqMan-MGB-based duplex one-step real-time RT-PCR (RT-qPCR) assay was established and evaluated. The duplex RT-qPCR has a detection limit of 5 copies/μL of HA plasmid for EA H1N1, (H1N1)pdm09, and HL H3N2 subtype SIVs, and its overall detection sensitivity of 100% and specificity of 91.67% matches that of traditional virus isolation through chicken embryo inoculation using experimentally infected mouse lung samples. The method showed high repeatability both within run and between runs, and there was no cross-reactivity against several other porcine viruses that are commonly circulating in China. Furthermore, the duplex RT-qPCR method revealed a higher prevalence of subtype H1 than subtype H3 in 166 nasal swabs from pigs collected from one slaughterhouse between October and December 2019. This assay could be very helpful in the rapid differential detection and routine surveillance of EA H1N1, (H1N1)pdm09, and HL H3N2 SIVs in China.

Topics: Animals; China; Disease Models, Animal; Early Diagnosis; Female; Hemagglutinin Glycoproteins, Influenza Virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Mice; Multiplex Polymerase Chain Reaction; Nose; Orthomyxoviridae Infections; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Swine

Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.

Topics: Animals; Brain Stem; Disease Models, Animal; Hypersensitivity; Male; Mice, Inbred C57BL; Neurokinin B; Neurons; Neuropeptides; Nose; Reflex; RNA, Small Interfering; Sensory Receptor Cells; Sneezing; TRPV Cation Channels; Video Recording

Topics: Administration, Intranasal; Administration, Intravenous; Animals; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; Disease Models, Animal; Humans; Mouth; Nose; SARS-CoV-2; Swine; Trachea; Virus Replication

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.

Topics: Aging; Angiotensin-Converting Enzyme 2; Animals; Betacoronavirus; Brain; Coronavirus Infections; COVID-19; CRISPR-Cas Systems; Cytokines; Disease Models, Animal; Gene Knock-In Techniques; Lung; Lung Diseases, Interstitial; Mice, Inbred C57BL; Nose; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; RNA, Viral; SARS-CoV-2; Stomach; Trachea; Viral Load; Virus Replication

Human respiratory syncytial virus (HRSV) is the leading cause of severe respiratory tract disease in infants. Most HRSV infections remain restricted to the upper respiratory tract (URT), but in a small percentage of patients the infection spreads to the lower respiratory tract, resulting in bronchiolitis or pneumonia. We have a limited understanding of HRSV pathogenesis and what factors determine disease severity, partly due to the widespread use of tissue-culture-adapted viruses. Here, we studied early viral dissemination and tropism of HRSV in cotton rats, BALB/cJ mice and C57BL/6 mice. We used a novel recombinant (r) strain based on a subgroup A clinical isolate (A11) expressing EGFP [rHRSV

Topics: Animals; Bronchiolitis, Viral; Disease Models, Animal; Humans; Lung; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nose; Olfactory Mucosa; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory System; Respiratory Tract Infections; Rhinitis; Sigmodontinae; Viral Load; Viral Tropism; Virus Replication

Non-human primates form an important animal model for the evaluation of immunogenicity and efficacy of novel 'universal' vaccine candidates against influenza virus. However, in most studies a combination of intra-tracheal or intra-bronchial, oral and nasal virus inoculation is used with a standard virus dose of between 1 and 10 million tissue culture infective doses, which differs from typical modes of virus exposure in humans. This paper studies the systemic and local inflammatory and immune effects of aerosolized versus combined-route exposure to pandemic H1N1 influenza virus. In agreement with a previous study, both combined-route and aerosol exposure resulted in similar levels of virus replication in nose, throat and lung lavages. However, the acute release of pro-inflammatory cytokines and chemokines, acute monocyte activation in peripheral blood as well as increased cytokine production and T-cell proliferation in the lungs were only observed after combined-route infection and not after aerosol exposure. Longitudinal evaluation by computed tomography demonstrated persistence of lung lesions after resolution of the infection and a tendency for more lesions in the lower lung lobes after combined-route exposure versus upper and middle lung lobes after aerosol exposure. Computed tomography scores were observed to correlate with fever. In conclusion, influenza virus infection by aerosol exposure is accompanied by less immune-activation and inflammation in comparison with direct virus installation, despite similar levels of virus replication and development of lesions in the lungs.

Topics: Animals; Bronchi; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Humans; Immunity, Cellular; Immunity, Humoral; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lung; Lymphopenia; Macaca fascicularis; Male; Mouth; Nose; Orthomyxoviridae Infections; Virus Replication; Virus Shedding

Topics: Animals; Cadaver; Cattle; Costal Cartilage; Disease Models, Animal; Female; Humans; Male; Nose; Postoperative Complications; Rhinoplasty; Transplantation, Autologous

Respiratory infections are a leading cause of morbidity and mortality worldwide. Bacterial pathogens often colonize the upper respiratory tract (nose or mouth) prior to causing lower respiratory infections or invasive disease. Interactions within the upper respiratory tract between colonizing bacteria and the resident microbiota could contribute to colonization success and subsequent transmission. Human carriage studies have identified associations between pathogens such as

Topics: Animals; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Microbiota; Nasal Cavity; Nose; Pneumococcal Infections; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae

Monkeypox virus (MPXV) is a member of the genus Orthopoxvirus, endemic in Central and West Africa. This viral zoonosis was introduced into the United States in 2003 via African rodents imported for the pet trade and caused 37 human cases, all linked to exposure to MPXV-infected black-tailed prairie dogs (Cynomys ludovicianus). Prairie dogs have since become a useful model of MPXV disease, utilized for testing of potential medical countermeasures. In this study, we used recombinant MPXV containing the firefly luciferase gene (luc) and in vivo imaging technology to characterize MPXV pathogenesis in the black-tailed prairie dog in real time. West African (WA) MPXV could be visualized using in vivo imaging in the nose, lymph nodes, intestines, heart, lung, kidneys, and liver as early as day 6 post infection (p.i.). By day 9 p.i., lesions became visible on the skin and in some cases in the spleen. After day 9 p.i., luminescent signal representing MPXV replication either increased, indicating a progression to what would be a fatal infection, or decreased as infection was resolved. Use of recombinant luc+ MPXV allowed for a greater understanding of how MPXV disseminates throughout the body in prairie dogs during the course of infection. This technology will be used to reduce the number of animals required in future pathogenesis studies as well as aid in determining the effectiveness of potential medical countermeasures.

Topics: Animals; Disease Models, Animal; Female; Heart; Intestines; Kidney; Liver; Luminescent Measurements; Lung; Lymph Nodes; Male; Monkeypox virus; Mpox (monkeypox); Nose; Sciuridae

The alteration of the microbial community in the upper respiratory tract (URT) can contribute to the colonization and invasion of respiratory pathogens. However, there are no studies regarding whether the characteristics of the URT microbiota can be affected by infections in lower respiratory tract (LRT). To elucidate the microbial profiles of the URT during pneumonia, the oral, nasal, and lung microbiota was evaluated at the early phase in a murine pneumonia model by direct intratracheal inoculation of Klebsiella pneumoniae. The meta 16S rRNA sequencing of bronchoalveolar lavage fluid after K. pneumoniae inoculation presented alterations in the beta diversity of the microbes, but not in the alpha diversity. At this point, a significant increase in microbial alpha diversity was observed in the oral cavity, but not in the nasal cavity. The significant increase was observed in the family Carnobacteriaceae and family Enterococcaceae. These results suggest that characterizing the microbial community of the respiratory tract may not just involve a simple downstream relationship from the URT to the LRT. The health status of the LRT may influence the oral microbiota. Thus, evaluation of the oral microbiota may contribute towards monitoring lung health; the oral microbiota may act as a diagnostic marker of pneumonia.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Lung; Mice; Mice, Inbred C57BL; Microbiota; Mouth; Nose; Pneumonia, Bacterial; RNA, Ribosomal, 16S

Coxsackievirus A16 (CV-A16) is one of the main causative agents of hand, foot and mouth disease (HFMD) in young children and has become prevalent in the Asia-Pacific region in recent years. However, no approved vaccines or drugs are available for CV-A16 infection. CV-A16 virus-like particles (VLPs) are a potential vaccine candidate; however, whether the intranasal route of immunization is suitable for inducing immune responses against CV-A16 infection has not been clarified. In this study, the comprehensive immunogenicity and protective efficacy of the CV-A16 VLP vaccine were evaluated by multiple methods in a mouse model. In mice, a high neutralizing antibody (NTAb) titre could be elicited by intranasal immunization with CV-A16 VLPs, which produced NTAb levels similar to those induced by intranasal immunization with inactivated CV-A16. Passive immunity with NTAbs provided very good protection, as the survival rate of the immunized neonatal mice was 100% after challenges with CV-A16 at a dose of 1000 LD

Topics: Animals; Animals, Newborn; Antibodies, Neutralizing; Antibodies, Viral; Disease Models, Animal; Enterovirus A, Human; Enterovirus Infections; Female; Humans; Immunization; Mice; Mice, Inbred ICR; Nose; Viral Vaccines

The single greatest barrier to studying the lifestyle of Neisseria meningitidis stems from its exquisite adaptation to life in humans, a specialization which prevents it from infecting other animals. This barrier to modeling meningococcal infection has been overcome by the provision of factors that allow the meningococci to overcome one or more aspects of host restriction, including the use of mice expressing receptors that allow mucosal colonization and/or the inclusion of serum factors that facilitate meningococcal replication during disseminated meningococcal disease. Here we discuss these advances, consider variables that influence the outcome of infection, and detail the technical requirements to establish robust and reproducible nasal colonization or sepsis. Once established, these models can then be used to study the meningococcal lifestyle and the immune response during infection, and to facilitate development of novel drug or vaccine-based approaches to intervene in meningococcal carriage and disease.

Topics: Animals; Antigens, CD; Cell Adhesion Molecules; Disease Models, Animal; Humans; Male; Meningococcal Infections; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neisseria meningitidis; Nose; Sepsis

Patients with mutations in the ectodysplasin receptor signalling pathway genes - the X-linked ligand ectodysplasin-A (

Topics: Animals; Antibodies; Disease Models, Animal; Ear, Middle; Ectodermal Dysplasia 1, Anhidrotic; Ectodysplasins; Female; Hyalin; Male; Mice; Nasopharyngitis; Nasopharynx; Nose; Otitis Media; Phenotype; Rats; Receptors, Ectodysplasin; Rhinitis; Signal Transduction

The airway is the major entry route of pathogens due to continuous gas exchange with the environment. In particular, the nasal epithelial layer is the common site of airborne mucotropic virus infections. The inflammatory response to such infections must be tightly controlled due to its non-specific nature. Unrestrained inflammation breaks down the physiological mucosal defense system and leads to secondary bacterial or fungal infections. Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease that compromises quality of life. In spite of its importance in the initiation of inflammation, the role of interferon signaling in nasal airway epithelial cells is largely unknown. We analyzed the expression of interferon signaling genes using clinical lavage specimens and nasal airway epithelial cells collected from CRS patients and controls. Basal expression of IFNAs, IKBKE, STAT1, and some CXC chemokines was elevated in samples from CRS patients. In subsequent in vitro studies, we found IKKε to be the key molecule and augmented CXCL10 secretion. Based on our findings and review of the literature, we hypothesized that high levels of IKKε might induce intractable inflammation via CXCL10. We tested the hypothesis in an animal model and found not only that IKKε induced severe eosinophilic inflammation with CXCL10 over-production, but also that inhibition of IKKε resolved the inflammation.

Topics: Animals; Chemokine CXCL10; Chronic Disease; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation; Humans; I-kappa B Kinase; Inflammation; Interferon-alpha; Mice, Inbred BALB C; Mice, Nude; Nose; Rhinitis; Sinusitis

Influenza B virus is a main causative pathogen of annual influenza epidemics, however, research on influenza B virus in general lags behind that on influenza A viruses, one of the important reasons is studies on influenza B viruses in animal models are limited. Here we investigated the tree shrew as a potential model for influenza B virus studies.. Tree shrews and ferrets were inoculated with either a Yamagata or Victoria lineage influenza B virus. Symptoms including nasal discharge and weight loss were observed. Nasal wash and respiratory tissues were collected at 2, 4 and 6 days post inoculation (DPI). Viral titers were measured in nasal washes and tissues were used for pathological examination and extraction of mRNA for measurement of cytokine expression.. Clinical signs and pathological changes were also evident in the respiratory tracts of tree shrews and ferrets. Although nasal symptoms including sneezing and rhinorrhea were evident in ferrets infected with influenza B virus, tree shrews showed no significant respiratory symptoms, only milder nasal secretions appeared. Weight loss was observed in tree shrews but not ferrets. V0215 and Y12 replicated in all three animal (ferrets, tree shrews and mice) models with peak titers evident on 2DPI. There were no significant differences in peak viral titers in ferrets and tree shrews inoculated with Y12 at 2 and 4DPI, but viral titers were detected at 6DPI in tree shrews. Tree shrews infected with influenza B virus showed similar seroconversion and respiratory tract pathology to ferrets. Elevated levels of cytokines were detected in the tissues isolated from the respiratory tract after infection with either V0215 or Y12 compared to the levels in the uninfected control in both animals. Overall, the tree shrew was sensitive to infection and disease by influenza B virus.. The tree shrew to be a promising model for influenza B virus research.

Topics: Animals; Antibodies, Viral; Cytokines; Disease Models, Animal; Female; Ferrets; Influenza B virus; Male; Mice; Mice, Inbred BALB C; Nose; Orthomyxoviridae Infections; Respiratory System; Trees; Tupaiidae; Viral Load; Virus Replication

Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma.. We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma.. We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis.. In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function.. Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Topics: Animals; Antigens, Dermatophagoides; Asthma; Cells, Cultured; Cohort Studies; Disease Models, Animal; Female; Glycolysis; Humans; Hypersensitivity; I-kappa B Proteins; Interleukin-1beta; Lactic Acid; Lung; Male; Mice; Middle Aged; Neutrophils; Nose; Proto-Oncogene Proteins; Pyroglyphidae; Respiratory Mucosa; RNA, Small Interfering; Signal Transduction; Sputum

Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD.. The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs.. Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (. Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.

Topics: Administration, Intranasal; Animals; Brain; Disease Models, Animal; Dopamine Agonists; Drug Carriers; Drug Delivery Systems; Lactoferrin; Male; Nanoparticles; Neuroprotective Agents; Nose; Parkinson Disease; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tetrahydronaphthalenes; Thiophenes; Tissue Distribution

Our human model of nasal colonization and eradication of S. aureus is limited by safety issues. As rhesus macaques are closely related to humans and natural hosts for S. aureus, we developed an experimental decolonization and inoculation protocol in these animals. Animals were screened for nasal carriage of S. aureus and 20 carriers were selected. Decolonization was attempted using nasal mupirocin (10 animals) or mupirocin plus trimethoprim/sulfadiazine intramuscularly (10 animals) both once daily for 5 days, and checked by follow-up cultures for 10 weeks. Intranasal inoculation was performed with S. aureus strain 8325-4 in culture-negative animals. 11/20 animals, of which 5 received mupirocin and 6 the combination treatment, became culture-negative for S. aureus for 10 weeks and these 11 animals were subsequently inoculated. Swabs were taken once a week for 5 weeks to test for the presence of the inoculated strain. In 3 animals, strain 8325-4 was cultured from the nose 1 week after inoculation, indicating short-term survival of this strain only, a finding similar to that previously found in our human model. These data demonstrate that rhesus macaques may constitute a relevant animal model to perform S. aureus eradication and inoculation studies with relatively limited invasive handling of the animals.

Topics: Administration, Intranasal; Animals; Anti-Bacterial Agents; Carrier State; Disease Models, Animal; Drug Combinations; Female; Macaca mulatta; Male; Mupirocin; Nose; Staphylococcal Infections; Staphylococcus aureus; Sulfadiazine; Trimethoprim

Recent studies leveraging next-generation sequencing and functional approaches to understand the human microbiota have demonstrated the presence of diverse, niche-specific microbial communities at nearly every mucosal surface. These microbes contribute to the development and function of physiologic and immunological features that are key to host health status. Not surprisingly, several chronic inflammatory diseases have been attributed to dysbiosis of microbiota composition or function, including chronic rhinosinusitis (CRS). CRS is a heterogeneous disease characterized by inflammation of the sinonasal cavity and mucosal microbiota dysbiosis. Inflammatory phenotypes and bacterial community compositions vary considerably across individuals with CRS, complicating current studies that seek to address causality of a dysbiotic microbiome as a driver or initiator of persistent sinonasal inflammation. Murine models have provided some experimental evidence that alterations in local microbial communities and microbially-produced metabolites influence health status. In this perspective, we will discuss the clinical implications of distinct microbial compositions and community-level functions in CRS and how mucosal microbiota relate to the diverse inflammatory endotypes that are frequently observed. We will also describe specific microbial interactions that can deterministically shape the pattern of co-colonizers and the resulting metabolic products that drive or exacerbate host inflammation. These findings are discussed in the context of CRS-associated inflammation and in other chronic inflammatory diseases that share features observed in CRS. An improved understanding of CRS patient stratification offers the opportunity to personalize therapeutic regimens and to design novel treatments aimed at manipulation of the disease-associated microbiota to restore sinus health.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dysbiosis; Host Microbial Interactions; Humans; Inflammation; Microbial Interactions; Microbiota; Nasal Mucosa; Nose; Rhinitis; RNA, Ribosomal, 16S; Sinusitis

Many of the currently used models of bacterial meningitis have limitations due to direct inoculation of pathogens into the cerebrospinal fluid or brain and a relatively insensitive assessment of long-term sequelae. The present study evaluates the utility of a Streptococcus (S.) suis intranasal infection model for the investigation of experimental therapies in meningitis.. We examined the brains of 10 piglets with S. suis meningitis as well as 14 control piglets by histology, immunohistochemistry and in-situ tailing for morphological alterations in the hippocampal dentate gyrus and microglial activation in the neocortex.. In piglets with meningitis, the density of apoptotic neurons was significantly higher than in control piglets. Moreover, scoring of microglial morphology revealed a significant activation of these cells during meningitis. The slight increase in the density of dividing cells, young neurons and microglia observed in piglets suffering from meningitis was not statistically significant, probably because of the short time frame between onset of clinical signs and organ sampling.. The morphological changes found during S. suis meningitis are in accordance with abnormalities in other animal models and human autopsy cases. Therefore, the pig should be considered as a model for evaluating effects of experimental therapeutic approaches on neurological function in bacterial meningitis.

Topics: Animals; Brain; Dentate Gyrus; Disease Models, Animal; Inflammation; Meningitis, Bacterial; Microglia; Neurons; Nose; Streptococcal Infections; Streptococcus suis; Swine

Nontypeable Haemophilus influenzae (NTHi) is a commensal in the human nasopharynx and the cause of pneumonia, meningitis, sinusitis, acute exacerbations of chronic obstructive pulmonary disease and acute otitis media (AOM). AOM is the most common ailment for which antibiotics are prescribed in the United States. With the emergence of new strains of antibiotic-resistant bacteria, finding an effective and broad coverage vaccine to protect against AOM-causing pathogens has become a priority. Mouse models are a cost-effective and efficient way to help determine vaccine efficacy. Here, we describe an NTHi AOM model in C57BL/6J mice, which also utilizes a mouse-adapted H1N1 influenza virus to mimic human coinfection.. We tested our coinfection model using a protein vaccine formulation containing protein D, a well-studied NTHi vaccine candidate that can be found in the 10-valent Streptococcus pneumoniae conjugate vaccine. We verified the usefulness of our mouse model by comparing bacterial loads in the nose and ear between protein D-vaccinated and control mice.. While there was no measurable difference in nasal bacterial loads, we did detect significant differences in the bacterial loads of ear washes and ear bullae between vaccinated and control mice.. The results from this study suggest that our NTHi AOM coinfection model is useful for assessing protein vaccines.

Topics: Administration, Intranasal; Animals; Antibodies, Bacterial; Bacterial Proteins; Carrier Proteins; Coinfection; Disease Models, Animal; Female; Haemophilus Infections; Haemophilus influenzae; Haemophilus Vaccines; Humans; Immunoglobulin D; Influenza A Virus, H1N1 Subtype; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Nose; Otitis Media; Vaccines, Conjugate

Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of

Topics: Acrocephalosyndactylia; Animals; Cartilage; Cell Cycle; Cell Proliferation; Chondrocytes; Cranial Sutures; Craniofacial Dysostosis; Craniosynostoses; Disease Models, Animal; Embryo, Mammalian; Face; Gene Expression Regulation, Developmental; Mice, Inbred C57BL; Mice, Mutant Strains; Nose; Organ Specificity; Receptor, Fibroblast Growth Factor, Type 2; Respiratory System Abnormalities

Laboratory investigations of the pathogenesis of Pseudogymnoascus destructans, the fungal causal agent of bat White Nose Syndrome (WNS), presents unique challenges due to its growth requirements (4°-15°C) and a lack of infectivity in the current disease models. Pseudogymnoascus pannorum is the nearest fungal relative of P. destructans with wider psychrophilic - physiological growth range, and ability to cause rare skin infections in humans. Our broad objectives are to create the molecular toolkit for comparative study of P. destructans and P. pannorum pathogenesis. Towards these goals, we report the successful development of an invertebrate model in the greater wax moth Galleria mellonella. Both P. destructans and P. pannorum caused fatal disease in G. mellonella and elicited immune responses and histopathological changes consistent with the experimental disease.

Topics: Animals; Ascomycota; Chiroptera; Disease Models, Animal; Humans; Moths; Mycoses; Nose; Phylogeny

The whooping cough agent Bordetella pertussis coordinately regulates the expression of its virulence factors with the two-component system BvgAS. In laboratory conditions, specific chemical modulators are used to trigger phenotypic modulation of B. pertussis from its default virulent Bvg+ phase to avirulent Bvg- or intermediate Bvgi phases, in which no virulence factors or only a subset of them are produced, respectively. Whether phenotypic modulation occurs in the host remains unknown. In this work, recombinant B. pertussis strains harboring BvgS variants were tested in a mouse model of infection and analyzed using transcriptomic approaches. Recombinant BP-BvgΔ65, which is in the Bvgi phase by default and can be up-modulated to the Bvg+ phase in vitro, could colonize the mouse nose but was rapidly cleared from the lungs, while Bvg+-phase strains colonized both organs for up to four weeks. These results indicated that phenotypic modulation, which might have restored the full virulence capability of BP-BvgΔ65, does not occur in mice or is temporally or spatially restricted and has no effect in those conditions. Transcriptomic analyses of this and other recombinant Bvgi and Bvg+-phase strains revealed that two distinct ranges of virulence gene expression allow colonization of the mouse nose and lungs, respectively. We also showed that a recombinant strain expressing moderately lower levels of the virulence genes than its wild type parent was as efficient at colonizing both organs. Altogether, genetic modifications of BvgS generate a range of phenotypic phases, which are useful tools to decipher host-pathogen interactions.

Topics: Animals; Bacterial Proteins; Bordetella pertussis; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Lung; Mice; Mutation; Nose; Protein Engineering; Sequence Analysis, RNA; Transcription Factors; Virulence; Whooping Cough

The usefulness of nasal packing after endoscopic sinus surgery is still debated in the literature.. Our aim was to evaluate the effects of a new chitosan-based nasal dressing in animal model.. Standard mucosal damage was caused in both nostrils during endoscope-assisted procedure in ten rabbits. Chitosan nasal packing was inserted in a randomly selected nasal fossa of each animal, while the other side was left unpacked. Symptoms were evaluated during nasal endoscopy on the 12th postoperative week. The degree of mucosal oedema, crusting, adhesions and the nasal discharge were observed according to the modification of the grading system of Berlucchi et al. The higher scores indicated the worse complaints.. Assessing the adhesion formation, 1 point was given (mean: 0.1; standard deviation [SD]: 0.32) for the unpacked side, while in the tamponated side no adhesion formation was observed. The total score of crusting in the non-packed side was lower with 1 point (total score: 9, mean: 0.90; SD: 0.74) than in the chitosan side (total score: 10, mean 1.00; SD: 0.82). Discharge or mucosal oedema were not observed during the follow-up period. The mean rate, measured with electronmicroscopy, was 22.06% (SD: 0.25) in the chitosan side, while in the non-packed side it was 36.11% (SD: 0.48). The differences did not show any significance (p = 0.806).. During the examinations, none of the animals suffered complications. The symptoms of the packed and the non-packed nasal cavities did not differ significantly on the basis of our examinations. Orv Hetil. 2018; 159(47): 1981-1987.. Absztrakt: Bevezetés: Az endoszkópos melléküregműtétek során alkalmazott orrtamponáló módszerek hatékonysága máig ellentmondásos témakör az irodalomban. Célkitűzés: Egy új típusú, kitozánt tartalmazó orrtamponnak a gyógyulási folyamatra gyakorolt hatását vizsgáltuk állatkísérletes modellen. Módszer: Vizsgálatunkban 10 nyúlon standard nyálkahártya-sérülést okoztunk, kétoldali endoszkópos orrüregi beavatkozás során. Az egyik orrfélbe kitozán orrtampont helyeztünk, míg a másik orrfél tamponálás nélkül maradt. Az eredmények értékelése a posztoperatív 12. héten történt orrendoszkópos vizsgálatokkal, illetve szövetmintavétellel. A szövetmintákat pásztázó elektronmikroszkóppal is vizsgáltuk, ennek során a csillókkal nem rendelkező vagy elhalt hámsejteknek az épen maradt hámsejtekhez viszonyított arányát százalékban határoztuk meg. Orrendoszkópiával a nyálkahártya ödémáját, pörkösödését és az orrváladék jellegét, valamint az adhaesioképződés mértékét vizsgáltuk. A tünetek súlyosságától függően 0-tól 3-ig terjedő pontszámokat osztottunk ki Berlucchi és mtsai pontozási rendszerének módosításával. A magasabb pontszámok jelezték a kedvezőtlenebb állapotot. Eredmények: Az adhaesiót vizsgálva a nem tamponált orrfeleknél mindössze 1 pont adódott (átlag: 0,1; standard deviáció [SD]: 0,32), míg a tamponált oldalon egyáltalán nem jelentkezett ez a tünet. A nem tamponált orrfelek pörkösödése 1 ponttal bizonyult kevesebbnek (9, átlag: 0,90; SD: 0,74), mint a tamponált orrfélnél (10, átlag 1,00; SD: 0,82). Orrváladék és nyálkahártya-ödéma nem volt észlelhető. Az elektronmikroszkópos vizsgálat alapján a százalékos értékek átlaga a tamponált oldalon 22,06% (SD: 0,25), míg a nem tamponált oldalon 36,11% (SD: 0,48) volt. A különbségek nem érték el a szignifikancia szintjét (p = 0,806). Következtetés: A kitozántampon vizsgálata során egyik állatban sem tapasztaltunk műtéti szövődményt. A tamponált és a tampon nélküli orrfelek nyálkahártyájának gyógyulása között nincs szignifikáns különbség ezen állatkísérletes modell alapján. Orv Hetil. 2018; 159(47): 1981–1987.

Topics: Administration, Intranasal; Animals; Anti-Bacterial Agents; Bandages; Chitosan; Disease Models, Animal; Nose; Paranasal Sinuses; Postoperative Hemorrhage; Rabbits

Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis.

Topics: Animals; Capsid Proteins; Child; Child, Preschool; Cytokines; Disease Models, Animal; Enterovirus D, Human; Enterovirus Infections; Feces; Ferrets; Fluorescent Antibody Technique; Humans; Interleukin-17; Interleukin-5; Interleukin-8; Lung; Nose; Phylogeny; Respiratory System; Respiratory Tract Infections; Viral Load

Smokers have nasal microbiota dysbiosis, with an increased frequency of colonizing bacterial pathogens. It is possible that cigarette smoke increases pathogen acquisition by perturbing the microbiota and decreasing colonization resistance. However, it is difficult to disentangle microbiota dysbiosis due to cigarette smoke exposure from microbiota changes caused by increased pathogen acquisition in human smokers. Using an experimental mouse model, we investigated the impact of cigarette smoke on the nasal microbiota in the absence and presence of nasal pneumococcal colonization. We observed that cigarette smoke exposure alone did not alter the nasal microbiota composition. The microbiota composition was also unchanged at 12 h following low-dose nasal pneumococcal inoculation, suggesting that the ability of the microbiota to resist initial nasal pneumococcal acquisition was not impaired in smoke-exposed mice. However, nasal microbiota dysbiosis occurred as a consequence of established high-dose nasal pneumococcal colonization at day 3 in smoke-exposed mice. Similar to clinical reports on human smokers, an enrichment of potentially pathogenic bacterial genera such as

Topics: Animals; Disease Models, Animal; Dysbiosis; Fusobacterium; Gemella; Humans; Lung; Mice; Microbiota; Neisseria; Nose; Pneumococcal Infections; Pneumonia; Smoke; Streptococcus pneumoniae; Tobacco Products

The capsular polysaccharide (CPS) of

Topics: Animals; Animals, Newborn; Bacterial Capsules; Bacterial Shedding; Disease Models, Animal; Host-Pathogen Interactions; Mice; Mucus; Mutation; Nose; Pneumococcal Infections; Polysaccharides, Bacterial; Respiratory Tract Infections; Streptococcus pneumoniae

Pertussis, or whooping cough, caused by the obligate human pathogen

Topics: Animals; Bacterial Adhesion; Biofilms; Bordetella pertussis; Disease Models, Animal; Epithelial Cells; Humans; Mice; Nose; Trachea; Virulence; Whooping Cough

Zika virus (ZIKV) is primarily transmitted to humans through mosquito bites or sexual contact. The excretion and persistence of contagious ZIKV in various body fluids have been well documented in ZIKV patients; however, the risk of direct contact exposure remains unclear. Here, we show that guinea pigs are susceptible to ZIKV infection via subcutaneous inoculation route; infected guinea pigs exhibit seroconversion and significant viral secretion in sera, saliva, and tears. Notably, ZIKV is efficiently transmitted from infected guinea pigs to naïve co-caged animals. In particular, intranasal inoculation of ZIKV is fully capable of establishing infection in guinea pigs, and viral antigens are detected in multiple tissues including brain and parotid glands. Cynomolgus macaques also efficiently acquire ZIKV infection via intranasal and intragastric inoculation routes. These collective results from animal models highlight the risk of exposure to ZIKV contaminants and raise the possibility of close contact transmission of ZIKV in humans.

Topics: Animals; Disease Models, Animal; Female; Guinea Pigs; Humans; Intestines; Macaca fascicularis; Male; Mice; Nose; Saliva; Serum; Spleen; Tears; Testis; Zika Virus; Zika Virus Infection

In healthy individuals, naturally acquired infections of human cytomegalovirus (HCMV) are generally asymptomatic. Animal models mimicking the natural primary HCMV infections in infants and adults are scarce. Here, neonatal and adult BALB/c mice were inoculated oronasally with a Belgian isolate HaNa1 of murine cytomegalovirus (MCMV). None of the mice showed clinical symptoms. In neonatal mice, a typical systemic infection occurred. In adult mice, viral replication was restricted to the nasal mucosa and submandibular glands. Infectious virus was not detected in trachea, oral mucosa, pharynx, esophagus, small intestines of both neonatal and adult mice at all time points. Nose was demonstrated to be the entry site. Double immunofluorescence staining showed that in nose infected cells were olfactory neurons and sustentacular cells in olfactory epithelium and were macrophages and dendritic cells in nasopharynx-associated lymphoid tissues (NALT). Neonatal and adult mice developed similar antibody response pattern, though former magnitude was lower. In summary, we have established intranasal (without anesthesia) infections of neonatal and adult mice with murine CMV HaNa1 strain, which mimic the range and extent of virus replication during natural primary HCMV infections in healthy infants and adults. These findings might bring new insights in the pathogenesis of natural primary CMV infections.

Topics: Animal Structures; Animals; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred BALB C; Nose; Virulence; Virus Replication

Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood-brain barrier and blood-nerve barrier, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-γ and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread.

Topics: Animals; Antibodies, Viral; B-Lymphocytes; Biological Transport; Blood-Brain Barrier; Capillary Permeability; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Ganglia, Spinal; Herpes Genitalis; Herpesvirus 2, Human; Histocompatibility Antigens Class I; Immunologic Memory; Integrin alpha4; Interferon-gamma; Mice; Nerve Tissue; Nervous System; Neurons; Nose; Receptors, Fc; Spinal Cord; Vesiculovirus

Hypohidrotic ectodermal dysplasia (HED) results from mutation of the EDA, EDAR or EDARADD genes and is characterized by reduced or absent eccrine sweat glands, hair follicles and teeth, and defective formation of salivary, mammary and craniofacial glands. Mouse models with HED also carry Eda, Edar or Edaradd mutations and have defects that map to the same structures. Patients with HED have ear, nose and throat disease, but this has not been investigated in mice bearing comparable genetic mutations. We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically dilated. Accumulation of large foreign body particles in the bulla stimulates granuloma formation. Analysis of immune cell populations and myeloid cell function shows no evidence of overt immune deficiency in HED mutant mice. Our findings using HED mutant mice as a model for the human condition support the idea that ear and nose pathology in HED patients arises as a result of nasal and nasopharyngeal gland deficits, reduced mucociliary clearance and impaired auditory tube gating function underlies the pathological sequelae in the bulla.

Topics: Animals; Disease Models, Animal; Ear, Middle; Ectodermal Dysplasia 1, Anhidrotic; Ectodysplasins; Edar Receptor; Edar-Associated Death Domain Protein; Genetic Predisposition to Disease; Humans; Mice; Muramidase; Mutation; NF-kappa B; Nose; Phenotype

The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.

Topics: Animals; Anti-Bacterial Agents; Carrier State; Disease Models, Animal; Drug Resistance, Microbial; Female; Humans; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Microbiota; Nose; Peptides, Cyclic; Sigmodontinae; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus lugdunensis; Symbiosis; Thiazolidines

To establish the murine models of local allergic rhinitis (LAR) and allergic rhinitis (AR) by using ovalbumin (OVA), and to investigate the relationship between them.. Thirty BALB/c mice were divided into 5 groups, (1) the nasally sensitized group (group A1) that was challenged with OVA by a 10 d procedure, (2) the control group of A1 that was challenged with phosphate-buffered saline (PBS), (3) the nasally sensitized group (group A2) that was challenged with OVA by a 25 d procedure, (4)the control group of A2 that was challenged with PBS, (5) the intraperitoneally sensitized group (group B) .The numbers of sneezing after final challenge were counted, and the serum OVA-specific immunoglobulin E (OVA-sIgE), interleukin (IL) -4, IL-13, IL-5 levels in nasal lavage fluid were measured by ELISA. Hematoxylin-eosin staining was performed to evaluate the histological change of nose and lung tissues. Graph Pad Prism 6 software was used to analyze the data.. Nasally sensitized group A1 displayed LAR symptoms of sneezing and eosinophilic infiltrating, but without increased OVA-sIgE in serum on day 10 compared with the control group of A1(t=0.697, P>0.05), OVA-sIgE in serum of group A2(2.710±1.406)ng/ml reached to statistical significance and with airway remodeling on day 25 compared with the control group of A2((0.221±0.080)ng/ml, t=4.329, P<0.05). IL-5 and IL-13 in nasal fluid showed a significant increase in the nasally sensitized group A1, compared with the group A2(t values were 2.442, 2.804, P values were less then 0.05).. A short time intranasal instillation with OVA could establish LAR murine model, continuing OVA challenge could increase serum sIgE level and with airway remodeling. LAR mice show a unique characteristic by expressing higher IL-5 and IL-13 in nose than AR mice, but sIgE in serum remains at a normal level.

Topics: Administration, Intranasal; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eosinophils; Immunoglobulin E; Interleukin-13; Interleukin-4; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Nose; Ovalbumin; Rhinitis, Allergic; Sneezing; Sodium Chloride

Current porcine reproductive and respiratory syndrome virus (PRRSV) vaccines sometimes fail to provide adequate immunity to protect pigs from PRRSV-induced disease. This may be due to antigenic differences among PRRSV strains. Rapid production of attenuated farm-specific homologous vaccines is a feasible alternative to commercial vaccines. In this study, attenuation and efficacy of a codon-pair de-optimized candidate vaccine generated by synthetic attenuated virus engineering approach (SAVE5) were tested in a conventional growing pig model. Forty pigs were vaccinated intranasally or intramuscularly with SAVE5 at day 0 (D0). The remaining 28 pigs were sham-vaccinated with saline. At D42, 30 vaccinated and 19 sham-vaccinated pigs were challenged with the homologous PRRSV strain VR2385. The experiment was terminated at D54. The SAVE5 virus was effectively attenuated as evidenced by a low magnitude of SAVE5 viremia for 1-5 consecutive weeks in 35.9% (14/39) of the vaccinated pigs, lack of detectable nasal SAVE5 shedding and failure to transmit the vaccine virus from pig to pig. By D42, all vaccinated pigs with detectable SAVE5 viremia also had detectable anti-PRRSV IgG. Anti-IgG positive vaccinated pigs were protected from subsequent VR2385 challenge as evidenced by lack of VR2385 viremia and nasal shedding, significantly reduced macroscopic and microscopic lung lesions and significantly reduced amount of PRRSV antigen in lungs compared to the non-vaccinated VR2385-challenged positive control pigs. The nasal vaccination route appeared to be more effective in inducing protective immunity in a larger number of pigs compared to the intramuscular route. Vaccinated pigs without detectable SAVE5 viremia did not seroconvert and were fully susceptible to VR2385 challenge. Under the study conditions, the SAVE approach was successful in attenuating PRRSV strain VR2385 and protected against homologous virus challenge. Virus dosage likely needs to be adjusted to induce replication and protection in a higher percentage of vaccinated pigs.

Topics: Administration, Intranasal; Animals; Antibodies, Viral; Disease Models, Animal; Injections, Intramuscular; Nose; Porcine Reproductive and Respiratory Syndrome; Porcine respiratory and reproductive syndrome virus; Sus scrofa; Swine; Vaccine Potency; Vaccines, Attenuated; Vaccines, Synthetic; Viral Vaccines; Viremia; Virus Shedding

The main features of lung infection and inflammation are a massive recruitment of neutrophils and the subsequent release of neutrophil serine proteases (NSPs). Anti-infectious and/or anti-inflammatory treatments must be tested on a suitable animal model. Mice models do not replicate several aspects of human lung disease. This is particularly true for cystic fibrosis (CF), which has led the scientific community to a search for new animal models. We have shown that mice are not appropriate for characterizing drugs targeting neutrophil-dependent inflammation and that pig neutrophils and their NSPs are similar to their human homologues. We induced acute neutrophilic inflammatory responses in pig lungs using Pseudomonas aeruginosa, an opportunistic respiratory pathogen. Blood samples, nasal swabs and bronchoalveolar lavage fluids (BALFs) were collected at 0, 3, 6 and 24 h post-insfection (p.i.) and biochemical parameters, serum and BAL cytokines, bacterial cultures and neutrophil activity were evaluated. The release of proinflammatory mediators, biochemical and hematological blood parameters, cell recruitment and bronchial reactivity, peaked at 6h p.i.. We also used synthetic substrates specific for human neutrophil proteases to show that the activity of pig NSPs in BALFs increased. These proteases were also detected at the surface of lung neutrophils using anti-human NSP antibodies. Pseudomonas aeruginosa-induced lung infection in pigs results in a neutrophilic response similar to that described for cystic fibrosis and ventilator-associated pneumonia in humans. Altogether, this indicates that the pig is an appropriate model for testing anti-infectious and/or anti-inflammatory drugs to combat adverse proteolytic effects of neutrophil in human lung diseases.

Topics: Animals; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Disease Models, Animal; Humans; Mice; Neutrophils; Nose; Pseudomonas aeruginosa; Pseudomonas Infections; Serine Proteases; Swine

Inhaled nanoparticles can migrate to the brain via the olfactory bulb, as demonstrated in experiments in several animal species. This route of exposure may be the mechanism behind the correlation between air pollution and human neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.. This article aims to (i) estimate the dose of inhaled nanoparticles that deposit in the human olfactory epithelium during nasal breathing at rest and (ii) compare the olfactory dose in humans with our earlier dose estimates for rats.. An anatomically-accurate model of the human nasal cavity was developed based on computed tomography scans. The deposition of 1-100 nm particles in the whole nasal cavity and its olfactory region were estimated via computational fluid dynamics (CFD) simulations. Our CFD methods were validated by comparing our numerical predictions for whole-nose deposition with experimental data and previous CFD studies in the literature.. In humans, olfactory dose of inhaled nanoparticles is highest for 1-2 nm particles with ∼1% of inhaled particles depositing in the olfactory region. As particle size grows to 100 nm, olfactory deposition decreases to 0.01% of inhaled particles.. Our results suggest that the percentage of inhaled particles that deposit in the olfactory region is lower in humans than in rats. However, olfactory dose per unit surface area is estimated to be higher in humans in the 1--7 nm size range due to the larger inhalation rate in humans. These dose estimates are important for risk assessment and dose-response studies investigating the neurotoxicity of inhaled nanoparticles.

Topics: Adult; Animals; Computer Simulation; Disease Models, Animal; Female; Humans; Hydrodynamics; Inhalation Exposure; Male; Middle Aged; Models, Anatomic; Nanoparticles; Nasal Cavity; Nose; Olfactory Bulb; Olfactory Mucosa; Particle Size; Rats; Rats, Inbred F344; Reproducibility of Results

Hypoxic-ischemic encephalopathy (HIE) is a common neurological disease in infants with persistent neurobehavioral impairments. Studies found that neural stem cell (NSC) therapy benefits HIE rats; however, the mechanisms underlying are still unclear. The current study investigated the efficacy and molecular events of human embryonic neural stem cells (hNSCs) in neonatal hypoxic-ischemic (HI) rats.. PKH-26-labeled hNSCs were intranasally delivered to P7 Sprague Dawley rats 24 h after HI. Neurobehavioral tests were performed at the indicated time after delivery: righting reflex and gait testing at D1, 3, 5, and 7; grid walking at D7 and 14; social choice test (SCT) at D28; and Morris water maze from D35 to 40. Protein expression was determined by Western blot analysis. Brain damage was assessed by cresyl violet staining and MBP staining. hNSC distribution and differentiation were observed by in vivo bioluminescence imaging and immunofluorescence staining.. (1) hNSCs migrated extensively into brain areas within 24 h after the delivery, survived even at D42 with the majority in ipsi-hemisphere, and could be co-labeled with NeuN or GFAP. (2) hNSCs reduced the upregulation in cytosolic IL-1β, p-IκBα, and NF-κB p65 levels, whereas enhanced nuclear p65 expression in HI rats at D3 after the delivery. (3) hNSCs decreased HI-induced brain tissue loss and white matter injury at D42 after the delivery. (4) hNSCs improved neurological outcomes in HI rats in the tests of righting reflex (within 3 days), gait (D5), grid (D7), SCT (D28), and water maze (D42).. Intranasal delivery of hNSCs could prevent HI-induced brain injury and improve neurobehavioral outcomes in neonatal HI rats, which is possibly related to the modulation of NF-κB signaling.

Topics: Animals; Animals, Newborn; Brain; Cell Movement; Cell Survival; Choice Behavior; Disease Models, Animal; Embryonic Stem Cells; Gait; Humans; Hypoxia-Ischemia, Brain; Interleukin-1beta; Maze Learning; Motor Activity; Neural Stem Cells; NF-kappa B; Nose; Rats, Sprague-Dawley; Reflex; Social Behavior

To establish a mouse model of chronic obstructive pulmonary disease (COPD) and associated pulmonary hypertension (COPD-PH) induced by nose-only cigarette smoking exposure plus airway lipopolysaccharide (LPS) inhalation.. There were 24 male C57B6 mice divided into a control group and a model group at random. The model group was given LPS by intranasal inhalation on day 1 and day 14 and exposed to the cigarette smoke in a nose-only exposure system, while the control group was given physiological saline and exposed to normal air. The model establishment was evaluated according the following parameters: the lung function and the right heart pressure, the total and differential cell numbers in bronchial alveolar lavage fluid (BALF), and the pathological changes of lung tissues.. The functional residual capacity data of the model group and the control group were (0.402 ± 0.057) and (0.243 ± 0.064) ml respectively (P<0.05). The inspiratory resistance data of the model group and the control group were (1.056 ± 0.121) and (0.789 ± 0.063) cmH(2)O · ml(-1) · s(-1) (1 cmH(2)O=0.098 kPa) respectively (P<0.05). The static lung compliance data of the model group and the control group were (0.084 ± 0 .007) and (0.056 ± 0.004) cmH(2)O/ml respectively (P<0.05). The right ventricular mean pressure of the model group and the control group were (11.3 ± 1.3) and (7.9 ± 1.1) mmHg (1 mmHg=0.133 kPa) respectively (P<0.05), while the right ventricular hypertrophy index of the model group and the control group were (0.267 ± 0.019) and (0.195 ± 0.023) respectively (P<0.05). Moreover, the histological staining showed that goblet cell hyperplasia, lung inflammation and thickening of smooth muscle layers of bronchial and pulmonary small vessels occurred in the model group, which indicated ongoing airway and blood vessel remodeling.. A COPD-PH mouse model was established by nose-only cigarette smoking exposure plus airway LPS inhalation in a short period of time, and this method was more similar to the smoking behavior of human.

Topics: Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Hypertension, Pulmonary; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Nicotiana; Nose; Pneumonia; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoking

We have recently presented the Old Spanish Pointer dog, with a 15-20% spontaneous congenital cleft palate rate, as a unique experimental model of this disease. This study aimed to describe the cleft palate of these dogs for surgical research purposes and to determine whether congenital cleft palate influences maxillofacial growth. Seven newborn Old Spanish Pointer dogs of both sexes, comprising a cleft palate group (n = 4) and a normal palate group (n = 3), were fed using the same technique. Macroscopic photographs and plaster casts from the palate, lateral radiographs and computer tomograms of the skull were taken sequentially over 41 weeks, starting at week 5. The cleft morphology, the size and the tissue characteristics in these dogs resembled the human cleft better than current available animal models. During growth, the cleft width varies. Most of the transverse and longitudinal measures of the palate were statistically lower in the cleft palate group. The cleft palate group showed hypoplasia of the naso-maxillary complex. This model of congenital cleft palate seems suitable for surgical research purposes. A reduced maxillofacial pre- and post-natal development is associated to the congenital cleft palate in the Old Spanish Pointer dog.

Topics: Anatomic Landmarks; Animals; Animals, Newborn; Cephalometry; Cleft Palate; Dental Arch; Disease Models, Animal; Dogs; Female; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Male; Mandible; Maxilla; Maxillofacial Development; Models, Dental; Nasal Bone; Nose; Palate; Photography; Time Factors; Tomography, Spiral Computed

Respiratory syncytial virus (RSV) is a major cause of infectious lower respiratory disease in infants and the elderly. As there is no vaccine for RSV, we developed a genetic vaccine approach that induced protection of the entire respiratory tract from a single parenteral administration. The approach was based on adenovirus vectors derived from newly isolated nonhuman primate viruses with low seroprevalence. We show for the first time that a single intramuscular (IM) injection of the replication-deficient adenovirus vectors expressing the RSV fusion (F0) glycoprotein induced immune responses that protected both the lungs and noses of cotton rats and mice even at low doses and for several months postimmunization. The immune response included high titers of neutralizing antibody that were maintained ≥ 24 weeks and RSV-specific CD8+ and CD4+ T cells. The vectors were as potently immunogenic as a human adenovirus 5 vector in these two key respiratory pathogen animal models. Importantly, there was minimal alveolitis and granulocytic infiltrates in the lung, and type 2 cytokines were not produced after RSV challenge even under conditions of partial protection. Overall, this genetic vaccine is highly effective without potentiating immunopathology, and the results support development of the vaccine candidate for human testing.

Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Cell Line; Disease Models, Animal; Humans; Lung; Mice; Nose; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Sigmodontinae; T-Lymphocytes; Vaccines, Synthetic

Bordetella bronchiseptica is a Gram-negative bacterium that infects and causes disease in a wide variety of animals. B. bronchiseptica also infects humans, thereby demonstrating zoonotic transmission. An extensive characterization of human B. bronchiseptica isolates is needed to better understand the distinct genetic and phenotypic traits associated with these zoonotic transmission events. Using whole-genome transcriptome and CGH analysis, we report that a B. bronchiseptica cystic fibrosis isolate, T44625, contains a distinct genomic content of virulence-associated genes and differentially expresses these genes compared to the sequenced model laboratory strain RB50, a rabbit isolate. The differential gene expression pattern correlated with unique phenotypes exhibited by T44625, which included lower motility, increased aggregation, hyperbiofilm formation, and an increased in vitro capacity to adhere to respiratory epithelial cells. Using a mouse intranasal infection model, we found that although defective in establishing high bacterial burdens early during the infection process, T44625 persisted efficiently in the mouse nose. By documenting the unique genomic and phenotypic attributes of T44625, this report provides a blueprint for understanding the successful zoonotic potential of B. bronchiseptica and other zoonotic bacteria.

Topics: Animals; Bacterial Adhesion; Bacterial Proteins; Biofilms; Bordetella bronchiseptica; Bordetella Infections; Comparative Genomic Hybridization; Cystic Fibrosis; Disease Models, Animal; Female; Genome, Bacterial; Mice; Mice, Inbred C57BL; Microarray Analysis; Nose; Phenotype; Sequence Analysis, DNA; Virulence

The fruits of Xanthium strumarium L. (Asteraceae) have been used extensively in China for treatment of various diseases such as allergic rhinitis (AR), tympanitis, urticaria and arthritis or ozena. This study was designed to systemically investigate the effects of the caffeoylxanthiazonoside (CXT) isolated from fruits of X. strumarium on AR in rodent animals. Animals were orally administered with CXT. Anti-allergic activity of CXT was evaluated by passive cutaneous anaphylaxis test (PCA); acetic acid-induced writhing tests were used to evaluate the analgesic effects of CXT; acetic acid-induced vascular permeability tests were performed to evaluate anti-inflammatory effect of CXT. Then, the model AR in rats was established to evaluate the effects of CXT on AR with the following tests: the sneezing and nasal scratching frequencies, IgE level in serum, and histopathological examinations. Our results demonstrated that CXT had favorable anti-allergic, anti-inflammatory and analgesic effects. Additionally, we found that CXT was helpful to ameliorate the nasal symptoms and to down-regulate IgE levels in AR rats. Thus, we suggested that CXT can be treated as a candidate for treating AR.

Topics: Acetic Acid; Analgesics; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Caffeic Acids; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Fruit; Immunoglobulin E; Inflammation; Mice, Inbred ICR; Nose; Pain; Phytotherapy; Rats, Sprague-Dawley; Rhinitis, Allergic; Sneezing; Xanthium

H6N1 avian influenza A viruses, which have spread across North America, Europe and Asia, have been shown to be infectious not only for birds but also for mammals. Because humans lack immunity to H6N1 avian influenza A viruses, the emergence of these viruses in humans would probably cause a pandemic. Replication of H6N1 avian influenza A viruses in dogs may facilitate their adaptation in humans because dogs are often in close contact with humans. However, the susceptibility of dogs to these viruses is unknown. To address this question, we infected beagles intranasally (i.n.) with an H6N1 avian influenza A virus that was isolated from a mallard. Inoculation of this virus into beagles resulted in the virus being detectable in the lung and seroconversion with no clinical signs except for a fever at 1 day post-inoculation (dpi). In addition, the virus was transiently shed from the nose and in the feces of the infected beagles. Our results suggest that dogs can be subclinically infected with H6N1 avian influenza A viruses, which, like H7N9, have low pathogenicity in birds and may serve as an intermediate host to transfer this virus to humans. Certain actions may be taken to prevent the potential transmission of these viruses, including the development of H6N1 avian influenza vaccines for prevention.

Topics: Animals; Birds; Disease Models, Animal; Dogs; Feces; Host Specificity; Influenza A virus; Influenza in Birds; Lung; Molecular Sequence Data; Nose; Orthomyxoviridae Infections; RNA, Viral; Sequence Analysis, DNA; Virus Shedding

Impaired postoperative wound healing is the second most common morbidity after synechia formation in endoscopic sinus surgery. The aim of this experimental study was to investigate the potential effects of topical phenytoin on wound healing after nasal mucosal trauma in rats.. An experimental study at the Inonu University Faculty of Medicine.. Twenty-four rats were randomized into three groups: 1) phenytoin group (n = 8), 2) control group (n = 8), and 3) vehicle group (n = 8). After damaging the right nasal cavity, in the phenytoin group, 1% topical phenytoin cream was applied for 7 days. The rats in the control group did not receive any treatment. The vehicle group was treated with daily topical cold cream for 1 week. The rats were sacrificed at the end, and the nasal cavities were excised. Tissue edema and inflammatory cell infiltration were compared among the groups. Additionally, proliferating cell nuclear antigen (PCNA) and cluster of differentiation 31 (CD31) immunoexpression levels were evaluated. Furthermore, in biochemical analysis, the tissue levels of vascular endothelial growth factor and (EGF) of the groups were investigated.. In the phenytoin group, tissue edema and inflammatory cell infiltration were significantly decreased, and PCNA and CD31 immunoexpression levels were more prominent (P < .001) and the tissue EGF levels were significantly higher (P < .01).. Topical phenytoin treatment may alter the nasal wound healing after mechanical trauma. The potential beneficial effects of topical phenytoin on nasal mucosa should be investigated by further experimental and human trials.. NA.

Topics: Administration, Topical; Animals; Anticonvulsants; Disease Models, Animal; Male; Nasal Mucosa; Nose; Phenytoin; Rats; Rats, Wistar; Wound Healing; Wounds and Injuries

Decalcification of osseous specimens is required for histological analysis; this however may cause tissue damage. In rodent models of allergic rhinitis (AR), epithelial histologic assessment necessitates prior decalcification of the nasal osseous structures. However, respiratory epithelium is highly susceptible to damage, and rat nasal architecture is elaborate and its sectioning is challenging. Nevertheless, decalcification is not standardized in experimental AR. We therefore undertook this task, in order to reduce experimental bias.. Six-to-eight week-old Wistar rats underwent an AR protocol. Subsequently, nasal structures were decalcified in the following mediums: (i) formic acid 10% for 5 and 20 days; (ii) formic acid 15% for 5 and 15 days; (iii) Morse Solution for 5 and 20 days and (iv) EDTA for 20 and 40 days. Decalcification efficiency/speed was evaluated via radiographic analysis. Furthermore, specimens were stained with hematoxylin and eosin and assessed for preservation of epithelial features.. Specimens were appropriately decalcified in 5 days in the formic acid-based mediums and in 20 days in EDTA with minimal epithelial damage. EDTA for 40 days had no unacceptable adverse effects; conversely, 15 and/or 20 days in acid-based agents provided no extra benefit for decalcification and were detrimental to the epithelium.. EDTA treatment for 20 days is appropriate for decalcification of nasal structures in rat models of allergic rhinitis; further incubation preserves epithelial integrity but is not required. When urgency is a factor, formic-acid-based decalcification for 5 days yields acceptable results.

Topics: Animals; Bone and Bones; Decalcification Technique; Disease Models, Animal; Male; Nose; Rats; Rats, Wistar; Rhinitis, Allergic

To study the effect of hypertonic seawater and isotonic seawater for nasal mucosa of allergic rhinitis mice model, and explore the possible mechanism of nasal irrigation with seawater in treatment of allergic rhinitis.. We used Der pl to make allergic rhinitis model of BALB/c mice, and divided them into three groups randomly. Nasal irrigation with hypertonic seawater (HS) or isotonic seawater (IS) in the treatment group 1-14 days after modeling, and black control (BC) group was given no treatment after modeling. Normal control (NC) group was given no treatment, the number of rubs and sneezings in each group were counted in 30 min after the last nasal irrigation. Mice were then killed 24 h after the last therapy. The noses of mice from each group were removed and fixed, then the slices were stained with hematoxylin and eosin, the others were observed by transmission electron microscope.. Mice with hypertonic seawater and isotonic seawater were significantly improved in rubs and sneezings compared to the black control group (P<0. 05); The number of eosinophiles in mucosal tissues of HS group and IS group had no significant difference with that of the black control group (P> 0. 05); Ciliated columnar epithelium cells in mucosal tissues of HS group and IS group were arranged trimly, better than that in the black control group. Morphology and microstructure in nasal mucosal of HS group was closer to the normal group than in IS group.. The injury of nasal mucosa ciliated epithelium was significantly improved by nasal irrigation with hypertonic seawater and isotonic seawater, and the former is better than the latter, the mechanism of nasal irrigation with seawater in treatment of allergic rhinitis may rely on repairing the injured nasal mucosa ciliated epithelium, thereby the symptoms of nasal was reduced.

Topics: Animals; Disease Models, Animal; Mice; Mice, Inbred BALB C; Nasal Lavage; Nasal Mucosa; Nose; Rhinitis, Allergic; Seawater

While influenza viruses are typically considered respiratory pathogens, the ocular system represents a secondary entry point for virus to establish a productive respiratory infection and the location for rare instances of virus-induced conjunctivitis. We used the ferret model to conduct a side-by-side comparison of virus infectivity, kinetics of viral replication, and induction of host responses following inoculation by either the intranasal or ocular routes with two viruses, A/Netherlands/230/03 (H7N7) and A/Panama/2007/99 (H3N2). We show that ocular inoculation resulted in delayed virus replication and reduced levels of proinflammatory cytokine and chemokine transcript in respiratory tract but not ocular tissues compared with intranasally inoculated animals. We identified numerous proinflammatory mediators with known roles in ocular disease elicited in ferret eye tissue following influenza virus infection. These findings provide a greater understanding of the modulation of host responses following different inoculation routes and underscore the risk associated with ocular exposure to influenza viruses.

Topics: Animals; Chemokines; Conjunctiva; Cytokines; Disease Models, Animal; Eye; Eye Infections, Viral; Ferrets; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N7 Subtype; Nose; Orthomyxoviridae Infections; Respiratory System; Respiratory Tract Infections; RNA, Viral; Virus Replication

To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection.

Topics: Adaptive Immunity; Administration, Intranasal; Animals; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Disease Models, Animal; Female; Immunoglobulin A; Immunoglobulin G; Mice; Mice, Inbred BALB C; Nanogels; Nose; Pneumococcal Infections; Pneumococcal Vaccines; Polyethylene Glycols; Polyethyleneimine; Streptococcus pneumoniae; Th17 Cells; Th2 Cells

Defects such as cleft lip with or without cleft palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, the underlying molecular and cellular mechanisms that result in these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease. In particular, mutations in the gene encoding the major HH receptor and negative regulator, patched1 (PTCH1), are associated with both sporadic and familial forms of clefting, yet relatively little is known about how PTCH1 functions during craniofacial morphogenesis. To address this, we analysed the consequences of conditional loss of Ptch1 in mouse neural crest cell-derived facial mesenchyme. Using scanning electron microscopy (SEM) and live imaging of explanted facial primordia, we captured defective nasal pit invagination and CL in mouse embryos conditionally lacking Ptch1. Our analysis demonstrates interactions between HH and FGF signalling in the development of the upper lip, and reveals cell-autonomous and non-autonomous roles mediated by Ptch1. In particular, we show that deletion of Ptch1 in the facial mesenchyme alters cell morphology, specifically in the invaginating nasal pit epithelium. These findings highlight a critical link between the neural crest cells and olfactory epithelium in directing the morphogenesis of the mammalian lip and nose primordia. Importantly, these interactions are critically dependent on Ptch1 function for the prevention of orofacial clefts.

Topics: Animals; Brain; Cell Death; Cell Proliferation; Cell Shape; Cleft Lip; Cleft Palate; Disease Models, Animal; Epithelial Cells; Fibroblast Growth Factors; Genetic Association Studies; Hedgehog Proteins; Mesoderm; Mice; Mice, Knockout; Morphogenesis; Nasal Mucosa; Neural Crest; Nose; Patched Receptors; Patched-1 Receptor; Phenotype; Receptors, Cell Surface; Signal Transduction; Wnt1 Protein

Annually adjusted inactivated influenza vaccines can prevent infection and limit the spread of seasonal influenza when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a rapid screening of a larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the cotton rat Sigmodon hispidus, a small laboratory animal susceptible to infection with unadapted influenza viruses, may become such a model. Cotton rats were immunized with a trivalent inactivated vaccine (TIV) FluLaval (2006/2007) and vaccine immunogenicity and antiviral efficacy was evaluated against the homologous H1N1 and a heterologous H3N2 challenge. FluLaval induced a strong virus-specific IgG and neutralizing antibody response against homologous virus, elicited sterilizing immunity in the lungs and significantly reduced viral replication in the nose of infected animals. FluLaval was efficacious in cotton rats as either a single-time or a double immunization, although higher level of protection of the upper respiratory tract was achieved following two doses of vaccine. Antibodies against a heterologous influenza strain were induced in FluLaval-vaccinated animals, but vaccine lacked antiviral efficacy and did not reduce replication of a heterologous virus. Similarity of these findings to human TIV data suggests that the cotton rat may prove to be a reliable small animal model of human influenza vaccines.

Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Disease Models, Animal; Immunoglobulin G; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza Vaccines; Lung; Nose; Orthomyxoviridae Infections; Sigmodontinae; Vaccination; Vaccines, Inactivated; Viral Load; Virus Replication

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

Topics: Animals; Axons; Disease Models, Animal; Embryo, Mammalian; Female; Fetus; Gonadotropin-Releasing Hormone; Humans; Kallmann Syndrome; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mutation; Neuropilin-1; Nose; Semaphorin-3A

We investigated whether the maxillary sinus plays a stimulatory role in nasal nitric oxide (NO) synthesis. Research on sinusitis and nasal polyps has found low NO levels in exhaled air and linked this to obstruction of the ostium. However, the major source of NO in exhaled air is thought to be the nasal mucosa. In this study, Streptococcus pneumoniae was applied to the maxillary sinus to investigate changes in NO synthesis of the nasal mucosa.. An experimental study was performed with New Zealand white rabbits. Three groups, pneumococcus, control and sham, were created. The maxillary sinus of the pneumococcal group was exposed to Streptococcus pneumoniae suspension. Before and after the exposure, bilateral biopsy specimens were taken from the inferior turbinate. Specimens were examined by RT-PCR for expressions of endothelial nitric oxide synthase (e-NOS) and inducible nitric oxide synthase (i-NOS). Physiological saline solution was administered to the maxillary sinus in the control group and biopsies were obtained. The sham group underwent only biopsy.. A significant increase in i-NOS expression of tissue samples from the pneumococcal group on the same and opposite sides were detected. There was no increase in e-NOS expression in this group. The control and sham groups had no significant change in i-NOS or e-NOS expression.. In the acute period after the maxillary sinus is exposed to a pathogen, i-NOS expression increases in the nasal mucosa, but endothelial NOS expression is not affected. Consequently, a combined response in the maxillary sinus and the nasal mucosa for nitric oxide synthesis is shown in the present study.

Topics: Animals; Disease Models, Animal; Endothelium; Maxillary Sinus; Maxillary Sinusitis; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nose; Pneumococcal Infections; Rabbits

Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59-adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine- and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving.

Topics: Adjuvants, Immunologic; Animals; Body Temperature; Body Weight; Disease Models, Animal; Female; Ferrets; Histocytochemistry; Immunization, Secondary; Immunohistochemistry; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Lung; Male; Microscopy; Nose; Orthomyxoviridae Infections; Pharynx; Polysorbates; Squalene; Vaccination; Viral Load

CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.

Topics: Animals; Cell Count; Cell Proliferation; CHARGE Syndrome; Disease Models, Animal; DNA-Binding Proteins; Embryo, Mammalian; Estrous Cycle; Female; Gene Dosage; Gene Expression Regulation, Developmental; Gonadotropin-Releasing Hormone; Hypothalamus; Mice; Neurogenesis; Neurons; Nose; Olfactory Bulb; Pituitary Gland; Puberty; Reproduction

Herpes simplex virus type 2 (HSV-2), a ubiquitous human pathogen associated with genital infections, is neurotropic. It establishes latent infections in local dorsal root ganglia from which it reactivates causing recurrent lesions and frequent episodes of viral shedding. Herpes simplex virus type 2 can also be transmitted from mother to child during birth, causing major neonatal complications including encephalitis. Animal models of HSV-2 genital infection are well described and used for testing of therapies; little is known about animal models of HSV-2-induced encephalitis. We analyzed the pathologic and immunohistochemical features of the nasal rostrum and brain tissue and correlated them with viral distribution in a mouse model of HSV-2 encephalitis induced by intranasal infection and examined viral replication in the brain tissue using quantitative polymerase chain reaction and traditional plaque assay. Our results suggest that the primary route for HSV-2 neuroinvasion after intranasal infection is via the trigeminal pathway, ultimately leading to infection of the brainstem and meningoencephalitis.

Topics: Animals; Brain Stem; Disease Models, Animal; Encephalitis; Female; Herpesvirus 2, Human; Humans; Mice; Mice, Inbred BALB C; Nose; Time Factors; Trigeminal Ganglion; Viral Plaque Assay; Viral Proteins; Virus Replication

Monkeypox virus (MPXV) is considered the most significant human public health threat in the genus Orthopoxvirus since the eradication of variola virus (the causative agent of smallpox). MPXV is a zoonotic agent endemic to forested areas of Central and Western Africa. In 2003, MPXV caused an outbreak in the United States due to the importation of infected African rodents, and subsequent sequential infection of North American prairie dogs (Cynomys ludovicianus) and humans. In previous studies, the prairie dog MPXV model has successfully shown to be very useful for understanding MPXV since the model emulates key characteristics of human monkeypox disease. In humans, percutaneous exposure to animals has been documented but the primary method of human-to-human MPXV transmission is postulated to be by respiratory route. Only a few animal model studies of MPXV transmission have been reported. Herein, we show that MPXV infected prairie dogs are able to transmit the virus to naive animals through multiple transmission routes. All secondarily exposed animals were infected with MPXV during the course of the study. Notably, animals secondarily exposed appeared to manifest more severe disease; however, the disease course was very similar to those of experimentally challenged animals including inappetence leading to weight loss, development of lesions, production of orthopoxvirus antibodies and shedding of similar levels or in some instances higher levels of MPXV from the oral cavity. Disease was transmitted via exposure to contaminated bedding, co-housing, or respiratory secretions/nasal mucous (we could not definitively say that transmission occurred via respiratory route exclusively). Future use of the model will allow us to evaluate infection control measures, vaccines and antiviral strategies to decrease disease transmission.

Topics: Animals; Communicable Disease Control; Disease Models, Animal; DNA, Viral; Enzyme-Linked Immunosorbent Assay; Humans; Monkeypox virus; Mpox (monkeypox); Nose; Polymerase Chain Reaction; Respiration; Respiratory System; Sciuridae

Little is known regarding the potential risk posed by aerosolized prions. Chronic wasting disease (CWD) is transmitted horizontally, almost surely by mucosal exposure, and CWD prions are present in saliva and urine of infected animals. However, whether CWD may be transmissible by the aerosol or nasal route is not known. To address this question, FVB mice transgenetically expressing the normal cervid PrP(C) protein [Tg(cerPrP) mice] were exposed to CWD prions by either nose-only aerosol exposure or by drop-wise instillation into the nostrils. Mice were monitored for signs of disease for up to 755 days post-inoculation (p.i.) and by examination of tissues for lesions and PrP(CWD) after necropsy. In particular, nasal mucosa, vomeronasal organ, lungs, lymphoid tissue and the brain were assessed for PrP(CWD) by Western blotting and immunohistochemistry. Six of seven aerosol-exposed Tg(cerPrP) mice developed clinical signs of neurological dysfunction mandating euthanasia between 411 and 749 days p.i. In all these mice, CWD infection was confirmed by detection of spongiform lesions and PrP(CWD) in the brain. Two of nine intranasally inoculated Tg(cerPrP) mice also developed transmissible spongiform encephalopathy associated with PrP(CWD) between 417 and 755 days p.i. No evidence of PrP(CWD) was detected in CWD-inoculated Tg(cerPrP) mice examined at pre-terminal time points. These results demonstrate that CWD can be transmitted by aerosol (as well as nasal) exposure and suggest that exposure via the respiratory system merits consideration for prion disease transmission and biosafety.

Topics: Aerosols; Animals; Blotting, Western; Brain; Disease Models, Animal; Immunohistochemistry; Lung; Lymphoid Tissue; Mice; Mice, Transgenic; Nasal Mucosa; Nose; Prions; Vomeronasal Organ; Wasting Disease, Chronic

Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer's disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused beta-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Abeta immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Electron Transport Complex IV; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; NADPH Dehydrogenase; Neurons; Nose; Olfactory Bulb; Olfactory Pathways; Plaque, Amyloid; Presynaptic Terminals; Up-Regulation

To establish the animal model with unilateral alveolar cleft and its effect on the nose growth.. 10 dogs were used. One side was selected to receive operation to create alveolar cleft, with the unoperated side as control side. The alveolar cleft was 10 mm in width. The dogs were harvested 10 weeks later. With the 3-D reconstruction of skull, cephalometric measurement was performed and analyzed with Amira software, the bilateral alar cartilage was dissected for comparison of cartilage growth.. The alveolar was not closed. The growth of alar cartilage on cleft side was poor, with asymmetric nostril. The lateral crus of alar on the cleft side was down-displaced. The nasal tip was deviated to the healthy side, with the columella to the cleft side. Histologic study showed better cartilage growth in healthy side than in cleft side.. The unnormal mechanical structure in unilateral alveolar cleft can affect the alar cartilage growth and nose shape. Early repair may improve the bony structure for alar development, as well as the soft tissue growth.

Topics: Alveolar Process; Animals; Disease Models, Animal; Dogs; Nose

Although it has been suggested that the use of tachykinin receptor antagonists might prove to be an effective treatment for allergic rhinitis (AR), they are not used clinically. Therefore, we decided to examine the effects of tachykinin receptor antagonists on AR symptoms in an appropriate experimental model.. To evaluate newly developed tachykinin receptor antagonists in a Japanese cedar pollen-induced AR model and to determine their effect on allergen-induced sneezing, nasal blockage, and nasal hyperresponsiveness (NHR).. Sensitized guinea-pigs were challenged by forced inhalation of pollen once every week. Sneezing and nasal blockage were observed after pollen challenges. NHR (nasal blockage) to an intranasal application of leukotriene D(4) was assessed 2 days after an antigen challenge. We also evaluated whether intranasal dosing with a tachykinin causes NHR. NK(1) and NK(2) receptor antagonists were administered before an intranasal treatment with antigen or tachykinin. Amounts of tachykinins present in nasal cavity lavage fluid were measured by an enzyme immunoassay.. Although an NK(1) and NK(2) receptor dual antagonist showed no effect on pollen-induced sneezing and biphasic nasal blockage, it did completely suppress the development of NHR. Experiments using specific NK(1) or NK(2) receptor antagonists revealed that NK(2) receptor activation was preferentially involved in the development of hyperresponsiveness. Increases in the levels of substance P (SP) and neurokinin A (NKA) in the nasal tissue were noted 20 min-1 h after the challenge. Intranasal instillation of either SP or NKA-induced NHR, which was almost completely inhibited by NK(2) receptor antagonists and partially inhibited by NK(1) receptor antagonists.. SP and NKA, which are released early after the challenge, mediate the development of NHR by preferentially activating NK(2) receptors. Therefore, NK(2) receptor antagonists might prove to be effective treatment of AR.

Topics: Allergens; Animals; Disease Models, Animal; Guinea Pigs; Humans; Nasal Lavage Fluid; Nasal Obstruction; Nasal Provocation Tests; Neurokinin A; Nose; Pollen; Receptors, Neurokinin-2; Receptors, Tachykinin; Rhinitis, Allergic, Seasonal; Sneezing; Substance P; Tachykinins

Multiple monkeypox virus (MPXV) animal models have been discussed in previous studies, but no small animal models, nor most non-human primate models, demonstrated the protracted asymptomatic incubation phase seen in systemic human orthopoxvirus illness. Herein, we characterize a black-tailed prairie dog (PD) (Cynomys ludovicianus) model of infection, via intranasal and intradermal exposures, with the two MPXV clades. Daily observations of the animals were made (food consumption, general symptoms, disease presentation), while weights and virus evaluations (ocular, nasal, oropharyngeal, faeces, blood) were obtained/made every third day. Generalized rash became apparent 9-12 days post-infection for all animals. Individual animals demonstrated a range of symptoms consistent with human monkeypox disease. Measurable viraemias and excretas were similar for both clade-representative strains and persisted until at least day 21. Greater morbidity was observed in Congo Basin strain-challenged animals and mortality was observed only in the Congo Basin strain-challenged animals. The PD model is valuable for the study of strain-dependent differences in MPXV. Additionally, the model closely mimics human systemic orthopoxvirus disease and may serve as a valuable non-human surrogate for investigations of antivirals and next generation orthopoxvirus vaccines.

Topics: Africa, Western; Animals; Antiviral Agents; Blood; Disease Models, Animal; Eye; Feces; Humans; Monkeypox virus; Mouth; Nose; Poxviridae Infections; Sciuridae; Viral Vaccines

Anatomical visualization of airspace-containing organs in intact small animals has been limited by the resolution and contrast available from current imaging methods such as X-ray, micro-computed tomography and magnetic resonance imaging. Determining structural relationships and detailed anatomy has therefore relied on suitable fixation, sectioning and histological processing. More complex and informative analyses such as orthogonal views of an organ and three-dimensional structure visualizations have required different animals and image sets, laboriously processed to gather this complementary structural information. Precise three-dimensional anatomical views have always been difficult to achieve in small animals. Here we report the ability of phase-contrast synchrotron X-ray imaging to provide detailed two- and three-dimensional visualization of airspace organ structures in intact animals. Using sub-micrometre square pixel charge-coupled device array detectors, the structure and anatomy of hard and soft tissues, and of airspaces, is readily available using phase-contrast synchrotron X-ray imaging. Moreover, software-controlled volume-reconstructions of tomographic images not only provide unsurpassed image clarity and detail, but also selectable anatomical views that cannot be obtained with established histological techniques. The morphology and structure of nasal and lung airways and the middle ear are illustrated in intact mice, using two- and three-dimensional representations. The utility of phase-contrast synchrotron X-ray imaging for noninvasively localizing objects implanted within airspaces, and the detection of gas bubbles transiting live airways, are other novel features of this visualization methodology. The coupling of phase-contrast synchrotron X-ray imaging technology with software-based reconstruction techniques holds promise for novel and high-resolution non-invasive examination of airspace anatomy in small animal models.

Topics: Animals; Disease Models, Animal; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Lung; Mice; Mice, Inbred C57BL; Nasopharynx; Nose; Respiratory System; Synchrotrons; Tomography, X-Ray Computed

We examined the role of prostanoid DP receptor in nasal blockage in an experimental allergic rhinitis model in guinea pigs. Local inhalation of prostaglandin D(2) (PGD(2)) to the nasal cavity resulted in an increase in intranasal pressure in guinea pigs actively sensitized by repeated antigen exposure but not in non-sensitized guinea pigs. Nasal hyperresponsiveness was observed when the guinea pigs were exposed to histamine and U-46619 (11alpha, 9alpha-epoxymethano-PGH(2); a thromboxane (TX) A(2) mimetic) after repeated antigen exposure. S-5751 ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid), a prostanoid DP receptor antagonist, inhibited not only PGD(2)-induced nasal blockage but also nasal hyperresponsiveness to histamine and U-46619 in sensitized guinea pigs. Combined exposure of the nasal cavity of guinea pigs to an aerosol of PGD(2) with histamine or U-46619 at sub-threshold concentrations synergistically caused a marked increase in intranasal pressure. These responses were significantly suppressed by S-5751. These results suggest that PGD(2) plays a critical role in the increase in intranasal pressure via prostanoid DP receptor, probably through synergistically enhancing the nasal response with other chemical mediators released from mast cells and other inflammatory cells activated by allergens.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Intranasal; Allergens; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Guinea Pigs; Histamine; Male; Nasal Mucosa; Nasal Obstruction; Nose; Ovalbumin; Pressure; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Perennial; Thiophenes; Time Factors

It is not known whether the progressive airway changes in cystic fibrosis (CF) are all secondary to infection and inflammation. The CF mouse nose shares electrophysiologic and cellular properties with human CF airway epithelium. In the present work, we tested the hypothesis that structural abnormalities in the nasal mucosa of CF mice develop independent of infection and inflammation. We performed nasal lavage and subsequent serial coronal section through the nasal tissue of adult CF (mutations Cftr(TgHm1G551D) and Cftr(tm1Unc)-TgN((FABPCFTR))) and wild-type mice raised under normal housing conditions. Nasal tissue was also obtained from Day 17 embryos and newborn pups. Detailed histologic examination of the respiratory and olfactory epithelium within the nasal cavity was performed. Bacterial culture, cell count, and macrophage inflammatory protein-2 (MIP-2) concentration were assessed in nasal lavage fluid. Significantly thickened respiratory epithelium and increased mucous cell density was found in adult CF mice of both mutations compared with wild-type animals. In contrast, the olfactory epithelium was thinner, with a decreased cell density. Areas of lymphoid aggregates were found in CF mice but not in non-CF mice. There were no differences in bacterial growth, cell count, or MIP-2 concentrations. No genotype differences were observed in the embryonic or newborn periods. There are significant histologic changes in the nasal mucosa of adult CF mice, not associated with increased lumenal inflammation or bacterial content, and which are not present perinatally. These may be novel therapeutic targets.

Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Genotype; Homozygote; Humans; Infections; Inflammation; Mice; Mice, Mutant Strains; Mice, Transgenic; Nose; Olfactory Mucosa; Polymorphism, Single Nucleotide; Respiratory Mucosa

La Crosse virus (LACV), family Bunyaviridae, was first identified as a human pathogen in 1960 after its isolation from a 4 year-old girl with fatal encephalitis in La Crosse, Wisconsin. LACV is a major cause of pediatric encephalitis in North America and infects up to 300,000 persons each year of which 70-130 result in severe disease of the central nervous system (CNS). As an initial step in the establishment of useful animal models to support vaccine development, we examined LACV infectivity, pathogenesis, and immunogenicity in both weanling mice and rhesus monkeys.. Following intraperitoneal inoculation of mice, LACV replicated in various organs before reaching the CNS where it replicates to high titer causing death from neurological disease. The peripheral site where LACV replicates to highest titer is the nasal turbinates, and, presumably, LACV can enter the CNS via the olfactory neurons from nasal olfactory epithelium. The mouse infectious dose50 and lethal dose50 was similar for LACV administered either intranasally or intraperitoneally. LACV was highly infectious for rhesus monkeys and infected 100% of the animals at 10 PFU. However, the infection was asymptomatic, and the monkeys developed a strong neutralizing antibody response.. In mice, LACV likely gains access to the CNS via the blood stream or via olfactory neurons. The ability to efficiently infect mice intranasally raises the possibility that LACV might use this route to infect its natural hosts. Rhesus monkeys are susceptible to LACV infection and develop strong neutralizing antibody responses after inoculation with as little as 10 PFU. Mice and rhesus monkeys are useful animal models for LACV vaccine immunologic testing although the rhesus monkey model is not optimal.

Topics: Animals; Antibodies, Viral; Antigens, Viral; Cell Line; Central Nervous System; Chlorocebus aethiops; Disease Models, Animal; Encephalitis, California; Female; Humans; La Crosse virus; Lethal Dose 50; Macaca mulatta; Mice; Neutralization Tests; Nose; Peritoneum; Vero Cells; Virus Replication

Staphylococcus aureus nasal colonization is a well-known risk factor for development of S.aureus infections in humans, but despite this established association, we are only beginning to understand the factors, both host and pathogen, that play a role in the colonization of the nares by S. aureus. The cotton rat is a model for many human respiratory pathogens and has proved its utility as a robust model for S. aureus nasal colonization. In this animal model, S. aureus is instilled in the nostrils of adult cotton rats, the bacteria rapidly colonize, and 7 days later S. aureus nasal colonization is enumerated by surgical removal of the nose and recovery of the colonizing S. aureus. This model is an excellent animal model to allow for the evaluation of the efficacy of various therapies, including semi-solid formulations, for determination of their ability to eradicate S. aureus nasal colonization. Further, the cotton rat model allows for assessment of the ability of defined genetic mutants of S. aureus to colonize mucosal surfaces. Finally, this model has demonstrated its utility for the assessment of various antigens as vaccine candidates to protect against S. aureus nasal colonization. This chapter will discuss in detail the method to establish nasal colonization, treatment and eradication of colonization, and recovery of the colonizing bacteria from the nose.

Topics: Animals; Disease Models, Animal; Humans; Nose; Rats; Staphylococcal Infections; Staphylococcus aureus; Time Factors

This report describes an alternative technique to inoculate rabbits and to reproduce infection by Bovine herpesvirus 1 and 5. First, the nostrils are anaesthetized by aspersion with local anaesthetic. A few seconds later, and after proving the insensitivity of the zone, the rabbits are put on their back legs with their nostrils upwards and the inoculum is introduced slowly into each nostril by using disposable droppers. Clinical signs, viral isolation from nasal swabs, histological lesions found, positive polymerase chain reaction and antibodies production confirm the infection. This very simple and bloodless technique, where the animals are exposed to minor distress, may be useful for evaluating the virulence of BoHV-1 and BoHV-5 strains, to study the establishment of latent virus infection and to test the potential of experimental vaccines or properties of antiviral drugs. It may be also suitable for experimental infection with other respiratory viruses in this animal model.

Topics: Administration, Intranasal; Animals; Antibodies, Viral; Disease Models, Animal; Encephalitis, Viral; Female; Herpesviridae Infections; Herpesvirus 1, Bovine; Herpesvirus 5, Bovine; Liver; Lung; Male; Meningoencephalitis; Nose; Rabbits; Virology

Mouse models have been widely used to test candidate vaccines against Chlamydophila abortus infection in mice. Although the induction of a systemic infection by endogenous or intraperitoneal inoculation is a useful tool for understanding the immune mechanism involved in the protection conferred by the vaccination, a different approach is necessary to understand other factors of the infection, such as mucosal immunity or the colonization of target organs. To test whether C. abortus intranasal model of infection in mice is a useful tool for testing vaccines in a first group of experiments mice, were infected intranasally with C. abortus to characterize the model of infection. When this model was used to test vaccines, two inactivated experimental vaccines, one of them adjuvated with QS-21 and another with aluminium hydroxide, and a live attenuated vaccine (strain 1B) were used. Non-vaccinated control mice died within the first 8 days, after displaying substantial loss of weight. Histologically, the mice showed lobar fibrinopurulent bronchointerstitial pneumonia. Prior immunization with QS-21 adjuvated vaccine or 1B vaccine presented mortality and the recipients showed a greater number of T cells in the lesions, especially CD8(+) T cells, than the control mice and mice immunized with vaccine adjuvated with aluminium hydroxide. The results confirm that the C. abortus intranasal model of infection in mice is a useful tool for testing vaccines.

Topics: Abortion, Veterinary; Animals; Bacterial Vaccines; CD8-Positive T-Lymphocytes; Chlamydophila; Chlamydophila Infections; Disease Models, Animal; Female; Immunophenotyping; Liver; Lung; Mice; Mice, Inbred C57BL; Nose; Saponins; Vaccination

To investigate the characteristics of wound healing in the mouse naso-labial region in both the fetal and neonatal stages, histological and immunohistochemical analyses were performed using a newly established laser burn wound healing system.. Fetal mice at embryonic day 14 (E 14) were wounded as a model of fetal wound healing. To compare it, neonatal mice at day 5 after birth (d 5) were adopted as a model of neonatal wound healing. The healing process was examined by van Gieson staining and immunohistochemistry for fibronectin and tenascin.. Relatively large damage remained after wound healing even in fetal mice. In both types of wound healing, rapid regeneration of muscle tissues were observed. Fibronectin and tenascin immunostaining was detected not only in wound healing region, but also in the endomysium of regenerating muscle tissues. Especially, tenascin showed a restricted expression pattern.. Rapid regeneration of muscle tissues in the naso-labial region in both the fetal and neonatal mice seemed to leave relatively large damage even in the fetal wound healing. Contracted force exerted by muscle tissues may be a reason for this phenomenon. Fibronectin and tenascin were closely related to the wound healing process including muscle regeneration in this region.

Topics: Animals; Animals, Newborn; Coloring Agents; Disease Models, Animal; Extracellular Matrix Proteins; Facial Muscles; Female; Fetus; Fibronectins; Gestational Age; Lasers; Lip; Mice; Mice, Inbred ICR; Nose; Pregnancy; Prenatal Injuries; Regeneration; Tenascin; Wound Healing

The 1918 influenza pandemic was a catastrophic series of virus outbreaks that spread across the globe. Here, we show that only a modest change in the 1918 influenza hemagglutinin receptor binding site alters the transmissibility of this pandemic virus. Two amino acid mutations that cause a switch in receptor binding preference from the human alpha-2,6 to the avian alpha-2,3 sialic acid resulted in a virus incapable of respiratory droplet transmission between ferrets but that maintained its lethality and replication efficiency in the upper respiratory tract. Furthermore, poor transmission of a 1918 virus with dual alpha-2,6 and alpha-2,3 specificity suggests that a predominant human alpha-2,6 sialic acid binding preference is essential for optimal transmission of this pandemic virus. These findings confirm an essential role of hemagglutinin receptor specificity for the transmission of influenza viruses among mammals.

Topics: Amino Acid Substitution; Animals; Cell Line; Disease Models, Animal; Dogs; Ferrets; Galactose; Glycoconjugates; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lung; Male; Mutation; Nose; Receptors, Virus; Respiratory System; Sialic Acids; Virulence; Virus Replication; Virus Shedding

Respiratory infection with the neurovirulent vaccinia virus (VV) strain Western Reserve (WR) results in an acute infection of the lung followed by dissemination of the virus to other organs and causes lethality in mice. The mechanisms of lethality are not well-understood. In this study, we analyzed virus replication and host immune responses after intranasal infection with lethal and non-lethal doses of VV using the WR strain and the less virulent Wyeth strain.. The WR strain replicated more vigorously in the lung and in the brain than the Wyeth strain. There were, however, no differences between the virus titers in the brains of mice infected with the higher lethal dose and the lower non-lethal dose of WR strain, suggesting that the amount of virus replication in the brain is unlikely to be the sole determining factor of lethality. The WR strain grew better in primary mouse lung cells than the Wyeth strain. Lethal infection with WR strain was associated with a reduced number of lymphocytes and an altered phenotype of the T cells in the lung compared to non-lethal infections with the WR or Wyeth strains. Severe thymus atrophy with a reduction of CD4 and CD8 double positive T cells was also observed in the lethal infection.. These results suggest that the lethality induced by intranasal infection with a high dose of the WR strain is caused by the higher replication of virus in lung cells and immune suppression during the early phase of the infection, resulting in uncontrolled virus replication in the lung.

Topics: Animals; Atrophy; Brain; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Disease Models, Animal; Female; Immune Tolerance; Lung; Lymphocyte Count; Mice; Mice, Inbred C57BL; Nose; Respiratory Tract Infections; Thymus Gland; Vaccinia; Vaccinia virus; Virulence; Virus Replication

Cleft palate is a congenital deformity with soft tissue and hard tissue defects. Normal cleft palate repairing surgery only repairs soft tissue defects, whereas bone defects in the hard palate still exist. Therefore, we conducted this study in beagles to observe the influence of bone grafting at primary surgery on craniofacial growth and occlusal relationships in individuals with complete cleft palate and to provide experimental evidence for optimal surgical procedures for cleft palate. Using 60 beagle puppies as subjects, we tested the effects of bone grafting in surgically induced palatal defect. The animals were randomly and equally divided into four groups: (1) unoperated controls; (2) surgically induced unilateral cleft palate, not repaired; (3) two-flap palatoplasty used to close the soft defect of the surgically induced cleft palate; (4) autogenous bone (a piece of rib bone) implanted into the palatal defect before two-flap palatoplasty was performed.Cephalometric roentgenography and plaster casts of the maxillary were taken preoperatively and every 4 weeks after surgery. Sixty metric cranial variables were measured directly from the cleaned skulls after the animals were killed the 34th week postoperatively. The measurement results indicated that bone grafting may reduce the disturbance of maxillary growth caused by the cleft palate and the denuded bone, but it may cause other maxillary deformities. This finding suggests that surgeons should be careful in choosing the method of primary bone grafting in repairing complete cleft palate.

Topics: Animals; Bone Transplantation; Cephalometry; Cleft Palate; Dental Arch; Dental Occlusion; Disease Models, Animal; Dogs; Female; Male; Maxilla; Maxillofacial Development; Nose; Palate, Hard; Periosteum; Plastic Surgery Procedures; Random Allocation; Ribs; Surgical Flaps; Time Factors

Relapsing polychondritis (RP) is a human autoimmune disease of unknown etiology in which cartilaginous sites are destroyed by cyclic inflammatory episodes beginning, most commonly, during the fourth or fifth decade of life. We have previously described collagen-induced polychondritis that closely mirrors RP occurring in young (6-8 weeks old) HLA-DQ6alphabeta 8alphabeta transgenic Abeta0 mice, following immunization with heterologous type II collagen (CII). We present evidence here that transgenic strains expressing the DQ6alpha8beta transgene develop spontaneous polychondritis (SP) at the mouse equivalent of human middle age (4.5-6 months and 40-50 years old, respectively) and display polyarthritis, auricular chondritis and nasal chondritis--three of the most common sites affected in RP. Auricular chondritis in SP, like RP but unlike CII-induced polychondritis, exhibited a relapsing/remitting phenotype, requiring several inflammatory cycles before the cartilage is destroyed. Elevated serum levels of total IgG corresponded with the onset of disease in SP, as in RP and CII-induced polychondritis. No CII-specific immune response was detected in SP, however--more closely mirroring RP, in which as few as 30% of RP patients have been reported to have CII-specific IgG. CII-induced polychondritis displays a strong CII-specific immune response. SP also demonstrated a strong female preponderance, as some workers have reported in RP but has not observed in CII-induced polychondritis. These characteristics of SP allow for the examination of the immunopathogenesis of polychondritis in the absence of an overwhelming CII-specific immune response and the strong adjuvant-induced immunostimulatory influence in CII-induced polychondritis. This spontaneous model of polychondritis provides a new and unique tool to investigate both the initiatory events as well as the immunopathogenic mechanisms occurring at cartilaginous sites during the cyclic inflammatory assaults of polychondritis.

Topics: Animals; Cartilage; Disease Models, Animal; Ear Cartilage; Female; HLA-DQ Antigens; Immunoglobulin G; Male; Mice; Mice, Transgenic; Nose; Phenotype; Polychondritis, Relapsing; Sex Factors; Transgenes

Chitin in the form of microparticles (chitin microparticles, CMP) has been demonstrated to be a potent stimulator of macrophages, promoting T-helper-1 (Th1) activation and cytokine response. In order to examine the mucosal adjuvant effect of CMP co-administered with influenza hemagglutinin (HA) vaccine against influenza infection, CMP were intranasally co-administered with influenza HA vaccine prepared from PR8 (H1N1) virus. Inoculation of the vaccine with CMP induced primary and secondary anti-HA IgA responses in the nasal wash and anti-HA IgG responses in the serum, which were significantly higher than those of nasal vaccination without CMP, and provided a complete protection against a homologous influenza virus challenge in the nasal infection influenza model. In addition, CMP-based immunization using A/Yamagata (H1N1) and A/Guizhou (H3N2) induced PR8 HA-reactive IgA in the nasal washes and specific-IgG in the serum. The immunization with A/Yamagata and CMP resulted in complete protection against a PR8 (H1N1) challenge in A/Yamagata (H1N1)-vaccinated mice, while that with A/Guizhou (H3N2) and CMP exhibited a 100-fold reduction of nasal virus titer, demonstrating the cross-protective effect of CMP and influenza vaccine. It is suggested that CMP provide a safe and effective adjuvant for nasal vaccination with inactivated influenza vaccine.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Antibodies, Viral; Chitin; Disease Models, Animal; Female; Hemagglutinin Glycoproteins, Influenza Virus; Immunoglobulin A; Immunoglobulin G; Influenza Vaccines; Mice; Mice, Inbred BALB C; Nose; Orthomyxoviridae Infections; Vaccination

The pathogenesis of holoprosencephaly is multifactorial, and blockage of Sonic hedgehog signaling is one of the most important causative factors in animal models and human cases. In this study, the authors analyzed facial anomalies of mouse embryos, which were cultured in vitro and exposed to cyclopamine, an alkaloid blocker of Sonic hedgehog signaling. When cultured with cyclopamine for embryonic day 8.5 to 10.5, the whole body size was smaller than normal, and the distance and angle between the nasal placodes were remarkably reduced. Extension of the cranial surface vessels also was noted. No cyclopia was observed. Migration of the cranial neural crest cells seemed to be intact. Expressions of Patched-1 and Gli-1, downstream genes of Sonic hedgehog signaling, also were down-regulated in in situ hybridization and real-time reverse transcriptase-polymerase chain reaction analyses. The authors consider that these facial anomalies represent milder phenotypes of holoprosencephaly.

Topics: Animals; Body Size; Disease Models, Animal; Down-Regulation; Embryo Culture Techniques; Eye Proteins; Gene Expression Regulation; Hedgehog Proteins; Holoprosencephaly; Homeodomain Proteins; Intracellular Signaling Peptides and Proteins; Kruppel-Like Transcription Factors; Membrane Proteins; Mice; Nose; Paired Box Transcription Factors; Patched Receptors; Patched-1 Receptor; PAX6 Transcription Factor; Receptors, Cell Surface; Repressor Proteins; Signal Transduction; Teratogens; Trans-Activators; Transcription Factors; Veratrum Alkaloids; Zinc Finger Protein GLI1

Dynamics of anti-M antibody response following intranasal infection with group A Streptococcus (GAS) M-18 were investigated in a Swiss albino mouse model. Mice arranged in three groups were inoculated intranasally with 2.0x10(7) c.f.u. ml-1 of GAS M-18 on 1, 2 alternate and 3 alternate days. Plasma collected from the retro-orbital plexus was tested for antibodies by an in-house indirect ELISA. The antibody titres of the plasma samples varied from 1 : 8 to 1 : 1024 in the 1 day dose, from 1 : 4 to 1 : 256 in the 2 day dose and from 1 : 4 to 1 : 128 in the 3 day dose. Peak titres were seen on day 42 or 56 and in all cases the titres had declined by day 84. Swiss albino mouse can thus serve as a useful animal model to study different aspects of type-specific anti-M immune responses against GAS disease when designing candidate streptococcal vaccines.

Topics: Animals; Antibodies, Bacterial; Antigens, Bacterial; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Mice; Nose; Streptococcal Infections; Streptococcus pyogenes

Despite structural and functional differences between the initial sites of contact with allergens in the gastrointestinal and nasal tracts, few animal models have examined the influence of the mucosal routes of sensitization on host reactivity to food or environmental antigens. We compared the oral and nasal routes of peanut sensitization for the development of a mouse model of allergy. Mice were sensitized by administration of peanut proteins in the presence of cholera toxin as adjuvant. Antibody and cytokine responses were characterized, as well as airway reactivity to nasal challenge with peanut or unrelated antigens. Oral sensitization promoted higher levels of IgE, but lower IgG responses, than nasal sensitization. Both orally and nasally sensitized mice experienced airway hyperreactivity on nasal peanut challenge. The peanut challenge also induced lung eosinophilia and type 2 helper T-cell-type cytokines in orally sensitized mice. In contrast, peanut challenge in nasally sensitized mice promoted neutrophilia and higher levels of lung MAC-1(+) I-A(b low) cells and inflammatory cytokines. In addition, nasal but not oral, sensitization promoted lung inflammatory responses to unrelated antigens. In summary, both oral and nasal peanut sensitization prime mice for airway hyperreactivity, but the initial mucosal route of sensitization influences the nature of lung inflammatory responses to peanut and unrelated allergens.

Topics: Animals; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Lung; Mice; Mouth; Nose; Ovalbumin; Peanut Hypersensitivity; T-Lymphocytes, Helper-Inducer

CD4 T cells are important for development of long-term immunity to bacterial infections. Here we describe construction of a group A streptococcus (GAS) strain that expresses the model ovalbumin epitope (OVA) on its surface, and the use of this strain in adoptive transfer experiments to study CD4 T cell response to bacterial infection in nasal-associated lymphoid tissue (NALT), which was previously shown to be a specific target for GAS colonization. The OVA(+) GAS, but not the wild-type strain was shown to activate CD4 T cells in an antigen-specific manner both in vitro and in vivo. After intranasal infection of mice with this strain, OVA-specific CD4 T cells were first activated in NALT, which is functionally equivalent to human tonsils, rather than in the cervical lymph nodes. During localized infection, OVA(+) GAS induced rapid and prolonged activation of CD4 T cells at higher magnitudes in the NALT than in draining lymph nodes and spleen, where CD4 T cells underwent little or no activation. In contrast, systemic infection induced significantly higher activation of CD4 T cells in both lymph nodes and spleens, compared to when the infection was localized in NALT. Further investigation of cellular immune responses in NALT during GAS infection using adoptive T cell transfer, combined with the model antigen on the pathogen may ultimately shed light on mechanisms for failure of children to develop protective immune responses following streptococcal tonsillitis.

Topics: Adoptive Transfer; Animals; Antigens, Bacterial; Bacterial Outer Membrane Proteins; Carrier Proteins; CD4-Positive T-Lymphocytes; Disease Models, Animal; Flow Cytometry; Lymphocyte Activation; Lymphoid Tissue; Mice; Nose; Ovalbumin; Polymerase Chain Reaction; Recombinant Fusion Proteins; Streptococcal Infections; Streptococcus pyogenes

Matix protein 2 (M2) is a transmembrane protein of influenza type A virus. It contains a 23 aa long ectodomain (M2e) that is highly conserved amongst human influenza type A viruses. M2e-specific antibodies have been shown to restrict virus growth in vitro and in vivo and thus have the potential of providing cross-reactive resistance to influenza type A virus infection. We attempted to induce M2e-specific protection with synthetic multiple antigen peptide (MAP) constructs that contained covalently linked M2e- and Th-determinant peptides. Mice, vaccinated twice by the intranasal (i.n.) route with adjuvanted M2e-MAPs exhibited significant resistance to virus replication in all sites of the respiratory tract. Compared to mice primed by two consecutive heterosubtypic infections, resistance was of similar strength in nasal and tracheal tissue but lower in pulmonary tissue. Importantly, the protection in M2e-MAP- and infection-immunized mice appeared to be mediated by distinct immune mechanisms. This suggests that stronger protection may be achievable by combining both protective activities.

Topics: Amino Acid Sequence; Animals; Antibodies, Viral; Antibody Formation; CD4-Positive T-Lymphocytes; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunity, Innate; Influenza A virus; Influenza Vaccines; Lung; Lymphocyte Activation; Mice; Molecular Sequence Data; Nose; Orthomyxoviridae Infections; Protein Structure, Secondary; Time Factors; Vaccines, Synthetic; Viral Matrix Proteins

Long-lasting protective antibody is not normally generated in children following primary respiratory syncytial virus (RSV) infection, frequently leading to reinfection. We used the BALB/c mouse model to examine the role of the nasal-associated lymphoid tissue and the bone marrow in the generation of RSV-specific long-lasting plasma cells, with a view to further understanding the mechanisms responsible for the poorly sustained RSV antibody levels following primary infection. We show here that substantial numbers of RSV-specific plasma cells were generated in the bone marrow following challenge, which were maintained thereafter. In contrast, in the nasal-associated lymphoid tissue, RSV-specific plasma cell numbers waned quickly both after primary infection and after challenge and were not maintained at a higher level after boosting. These data indicate that the inability to generate a robust local mucosal response in the nasal tissues may contribute substantially to the likelihood of subsequent reinfection and that the presence of serum anti-RSV antibody without local protection is not enough to protect against reinfection.

Topics: Animals; Antibodies, Viral; Disease Models, Animal; Female; Immunoglobulin G; Lung; Lymphoid Tissue; Mice; Mice, Inbred BALB C; Nose; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human

The vaccinia virus (VV) N1L gene encodes a protein of 14 kDa that was identified previously in the concentrated supernatant of virus-infected cells. Here we show that the protein is present predominantly (>90%) within cells rather than in the culture supernatant and it exists as a non-glycosylated, non-covalent homodimer. The N1L protein present in the culture supernatant was uncleaved at the N terminus and was released from cells more slowly than the VV A41L gene product, a secreted glycoprotein that has a conventional signal peptide. Bioinformatic analyses predict that the N1L protein is largely alpha-helical and show that it is conserved in many VV strains, in other orthopoxviruses and in members of other chordopoxvirus genera. However, database searches found no non-poxvirus proteins with significant amino acid similarity to N1L. A deletion mutant lacking the N1L gene replicated normally in cell culture, but was attenuated in intranasal and intradermal murine models compared to wild-type and revertant controls. The conservation of the N1L protein and the attenuated phenotype of the deletion mutant indicate an important role in the virus life-cycle.

Topics: Animals; Cell Line; Computational Biology; Dermis; Dimerization; Disease Models, Animal; Female; Fluorescent Antibody Technique; Gene Deletion; Humans; Immunoblotting; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Nose; Recombination, Genetic; Vaccinia; Vaccinia virus; Viral Proteins; Virulence; Virus Replication

Despite the documented disease burden of respiratory syncytial virus (RSV) in the elderly, little is known about the underlying risk factors or pathogenesis of RSV in a geriatric population. This report describes an age-dependent change of RSV clearance in the lung and nose of the cotton rat. Six days postinfection with RSV, lung and nose viral titers were significantly higher in all older age groups as compared with 4- to 6-week old cotton rats (P < 0.05). When comparing the 4- to 6-week old animals to the 15- to 16-month old animals 6 days postinfection, there was over an 800- and 100-fold increase in lung and nose viral titers, respectively. The cotton rat may prove to be a useful model in eliciting mechanisms of severe RSV disease in the elderly.

Topics: Aging; Animals; Disease Models, Animal; Female; Humans; Lung; Male; Nose; Rats; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Sigmodontinae; Virus Replication

The nasopharyngeal bacterial flora of healthy rhesus macaques was surveyed for the presence of Neisseria and Haemophilus species, as well as Moraxella catarrhalis. M. catarrhalis was found both in healthy rhesus macaques and in possibly immunocompromised rhesus macaques. Several Haemophilus spp. that are part of the normal nasopharyngeal bacterial flora of humans were found in many animals; these Haemophilus species included H. parahaemolyticus, H. segnis, and H. parainfluenzae. While Haemophilus influenzae was not identified, it is possible that the identification of H. influenzae types may have been thwarted by the growth of less fastidious species. A number of animals harbored Neisseria spp. such as N. sicca. However, Neisseria meningitidis was not found. In summary, it appears as though the rhesus macaque may be used as a model for M. catarrhalis infections. Moreover, in view of the susceptibility of macaques to organisms of the Haemophilus and Neisseria genera, it is possible that these animals may also accurately model nontypeable H. influenzae and N. meningitidis infections.

Topics: Animals; Disease Models, Animal; Gram-Negative Bacterial Infections; Haemophilus; Macaca mulatta; Moraxella catarrhalis; Nasopharynx; Neisseria; Nose; Pharynx

Intracranial bleeding damages the surrounding tissue in a complex fashion that involves contamination by blood-borne products and loss of ionic homeostasis. We used electrophysiological techniques to examine the functional changes in the developing intracerebral bleed and in surrounding regions using an in vivo swine model. Intracerebral hemorrhage (ICH) was induced by collagenase injection into the primary somatosensory cortex (SI). Somatic evoked potential (SEP) elicited by electrical stimulation of the contralateral snout as well as changes in DC-coupled potential were monitored in the SI from the time of collagenase injection in order to measure the effects of ICH. The SEP decreased in amplitude within minutes of the intracerebral injection. Its short-latency component was abolished within the first hour after collagenase injection without any sign of recovery for the duration of the experiment. As the SEP started decreasing in amplitude, we observed spontaneous, recurring episodes of cortical spreading depression (SD) as early as 20 min post-injection. The timing of SDs in SI is consistent with our interpretation that SDs were initially generated at multiple sites adjacent to the lesion core and propagated into the surrounding area. With time, SD became less frequent near the injection site, shifting to more distant electrodes in the surrounding area. Our results indicate that ICH leads to the reduction in SEP amplitude and induces spontaneous episodes of SD. Loss of ionic homeostasis is most likely the physiological basis for the SEP change and for the induction of SD. Recurring SD spontaneously generated in experimental ICH needs further study in humans with ICH.

Topics: Animals; Brain Mapping; Cerebral Hemorrhage; Collagenases; Cortical Spreading Depression; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Evoked Potentials, Somatosensory; Microelectrodes; Nose; Recurrence

The design and synthesis of a new potent and selective inhibitor of the respiratory syncytial virus are described. This compound, RFI-641, emerged from analysis of the structure-activity relationship in a series of biphenyl triazine anionic compounds possessing specific anti-RSV activity. The key synthetic step involves coupling of diaminobiphenyl 11 with two equivalents of chlorotriazine 10 under microwave conditions. RFI-641 inhibited RSV in vitro and in vivo models.

Topics: Animals; Antiviral Agents; Cells, Cultured; Chlorocebus aethiops; Cytomegalovirus; Disease Models, Animal; Drug Design; Enzyme-Linked Immunosorbent Assay; Herpesvirus 1, Human; Humans; Inhibitory Concentration 50; Mice; Nose; Rats; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Sensitivity and Specificity; Structure-Activity Relationship; Sulfonamides; Triazenes; Triazines

Intranasal infection of BALB/c mice with the WR strain of vaccinia virus leads to pneumonia, profound weight loss and death. Five days after intranasal inoculation, virus from untreated mice was recovered from 11 organs, tissues and whole blood. The highest titres [>10(8) plaque forming units (pfu)/g] were in lungs and nose/sinus tissue, with about 10(7) pfu/g in spleen and blood. Seven other organs contained 30- to > or = 50-fold lower amounts of virus. Mice infected with the related cowpox virus (for comparative purposes) had the majority of virus located in the respiratory tract. The vaccinia mouse model was used to study the efficacy of cidofovir treatments on the infection. Subcutaneous injections of 30 or 100 mg/kg/day, given on days 1 and 4 after virus challenge, reduced mortality by 60-100%. However, lung virus titres on days 2-5 were reduced no more than 10-fold by these treatments. A moderate improvement in drug efficacy occurred with daily treatments for 5 days. The efficacy of cidofovir also increased as the virus challenge dose decreased, where subcutaneous or intraperitoneal treatment routes showed similar degrees of protection. Although it has been known for many years that the WR strain of vaccinia virus can cause lethal infections by intranasal route, its application to antiviral therapy represents a new model for studying anti-orthopoxvirus agents.

Topics: Administration, Intranasal; Animals; Antiviral Agents; Cidofovir; Cowpox virus; Cytosine; Disease Models, Animal; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Injections, Subcutaneous; Lung; Mice; Mice, Inbred BALB C; Nose; Organ Specificity; Organophosphonates; Organophosphorus Compounds; Paranasal Sinuses; Pneumonia, Viral; Spleen; Vaccinia; Vaccinia virus; Viral Load; Viremia

Since its first description, the A strain of mice have been utilized extensively as models to study the processes involved in clefting of the midfacial region. Of the A substrains, the A/WySn has a spontaneous rate of clefting of the lip of about 20% to 30%. The A/WySn mouse model was utilized in this study to analyze and compare the phenotypic and molecular changes in the midfacial region of embryos with and without cleft.. Scanning electron microscopy and skeletal and cartilage preparations of newborn A/WySn pups showed the presence of bilateral and unilateral clefts of the lips and the disruption of the skeletal and cartilaginous components of the mice with clefts of the lip. The expression of the msx1 homeobox gene was analyzed by whole mount in situ hybridization of A/WySn embryos at different stages of midfacial development. The results showed that there was misregulation of the expression of the msx1 gene in embryos with cleft, with a persistence of expression in the distal growing tips of the midfacial processes and in areas that have fused in normal embryos without cleft.. Although the genetic defect in A/WySn mice is not known, a possible candidate gene has been mapped to a corresponding human chromosome carrying retinoic acid receptor alpha, and there exists a possibility that msx1 is in the same genetic pathway affected by the mutation of the gene in A/WySn.

Topics: Animals; Cartilage; Chromosome Mapping; Cleft Lip; Disease Models, Animal; Facial Bones; Gene Expression Regulation, Developmental; Genes, Homeobox; Gestational Age; Homeodomain Proteins; Humans; In Situ Hybridization; Maxilla; Mice; Mice, Inbred A; Mice, Inbred Strains; Microscopy, Electron, Scanning; MSX1 Transcription Factor; Mutation; Nose; Palate; Phenotype; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Skull Base; Transcription Factors

Attenuated Salmonella enterica serovar Typhi live vector vaccine strains are highly immunogenic in mice following intranasal but not orogastric inoculation. To elucidate the relationship between organs within which vaccine organisms are found and the induction of specific serum immunoglobulin G (IgG) antibodies, we examined the in vivo distribution of serovar Typhi vaccine strain CVD 908-htrA following intranasal administration. Vaccine organisms were cultured from the nasal lymphoid tissue (NALT), lungs, and Peyer's patches 2 min after intranasal inoculation. Vaccine organisms persisted longer in NALT than in other organs. By decreasing the volume of intranasal inoculum containing 10(9) CFU (from a single 30- or 10-microl dose to four 2.5-microl doses given over the course of 1 h), we were able to significantly reduce the number of vaccine organisms isolated from the lungs (P < 0.05) without reducing the number of vaccine organisms in NALT. Reducing the number of vaccine organisms in the lungs resulted in a significant decrease in the serum tetanus antitoxin response elicited by CVD 908-htrA expressing tetanus toxin fragment C under the control of the redox-responsive nir15 promoter. In contrast, a similar construct expressing tetanus toxin fragment C under control of the constitutive lpp promoter stimulated a strong serum IgG tetanus antitoxin response with both inoculation regimens. The data suggest that following intranasal inoculation, NALT is a sufficient inductive site for elicitation of an immune response against both the live vector and heterologous antigen and, as occurs following oral inoculation of humans, attenuated serovar Typhi vaccine organisms elicit serum IgG responses.

Topics: Administration, Intranasal; Administration, Oral; Animals; Antibodies, Bacterial; Antibody Specificity; Bacterial Vaccines; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Immunologic; Female; Immunity, Mucosal; Immunoglobulin G; Lung; Lymphoid Tissue; Mice; Mice, Inbred BALB C; Nose; Peyer's Patches; Salmonella typhi; Serotyping; Typhoid Fever; Vaccines, Attenuated

Oral respiration associated with an obstructed nasal airway is common in orthodontic patients. For several years chronic oral respiration has been implicated as a prime causative factor in the development of "adenoid facies or the "long-face syndrome. The animal experiment reported here begins a series designed to study, as separate variables, the 2 components of chronic oral respiration: (1) chronic absence of active nasal respiration and 2) chronic mouth opening to find out what dentofacial changes can be attributed to chronic absence of active nasal respiration alone. In this pilot study, 5 growing dogs underwent tracheotomy so that significant active nasal respiration was not possible and oral respiration was not essential.

Topics: Animals; Cephalometry; Chronic Disease; Dental Arch; Disease Models, Animal; Dogs; Facial Bones; Facies; Female; Male; Malocclusion; Mandible; Maxilla; Mouth Breathing; Nasal Obstruction; Nose; Palate; Pilot Projects; Respiration; Skull; Syndrome; Tracheotomy; Zygoma

The increase in systemic blood pressure after an obstructive apnea is due, in part, to sympathetically mediated vasoconstriction. We questioned whether upper airway (UA) receptors could contribute reflexly to this vasoconstriction. Four unanesthetized dogs were studied during wakefulness and non-rapid-eye-movement (NREM) sleep. The dogs breathed via a fenestrated tracheostomy tube sealed around the tracheal stoma. The snout was sealed with an airtight mask, thereby isolating the UA when the fenestration was closed and exposing the UA to negative inspiratory intrathoracic pressure when it was open. The blood pressure response to three UA perturbations was studied: 1) square-wave negative pressures sufficient to cause UA collapse with the fenestration closed during a mechanical hyperventilation-induced central apnea; 2) tracheal occlusion with the fenestration open vs. closed; and 3) high-frequency pressure oscillations (HFPO) with the fenestration closed. During NREM sleep, 1) blood pressure response to tracheal occlusion was similar with the fenestration open or closed; 2) collapsing the UA with negative pressures failed to alter blood pressure during a central apnea; and 3) application of HFPO to the UA during eupnea and resistive-loaded breaths increased heart rate and blood pressure. However, these changes were likely to be secondary to the effects of HFPO-induced reflex changes on prolonging expiratory time. These findings suggest that activation of UA pressure-sensitive receptors does not contribute directly to the pressor response associated with sleep-disordered breathing events.

Topics: Airway Obstruction; Airway Resistance; Animals; Blood Pressure; Disease Models, Animal; Dogs; Electromyography; Female; Heart Rate; Hemodynamics; Larynx; Nose; Polysomnography; Pressure; Sleep; Sleep Stages; Snoring; Trachea

If creating an obstructive uropathy early in glomerulogenesis produces MCDK (Multicystic Dysplastic Kidney), then a very early obstruction may produce Potter's Syndrome (PS) with oligohydramnios.. Fetal lambs at 50 days' gestation underwent urethral and urachal ligation using fine SILASTIC (Dow Corning, Midland, MI) tubing and were delivered by cesarean section at 145 days' gestation. At the time of death, kidney weight, length, and lung volumes were measured. These samples were examined histologically. Urinary sodium, chloride, potassium, and osmolarity also were measured. These were compared with normal-term fetuses.. One ewe miscarried. Two of 3 of 50-day obstructive uropathy lambs survived. The 2 survivors had dysplastic kidneys. One with large gastroschisis did not have PS but the other had renal, pulmonary, and chest wall hypoplasia. Both male lambs had undescended testes with a large bladder. Kidney weights were 2 g in the PS lamb and 16 g in controls. Lung volume was 84 mL in the PS lamb and 340 mL in controls. The lamb's face was compressed and the fetus was hydropic. Urine sodium, potassium, and osmolarity levels were higher than that of controls.. This is the first successful model ligating the penile urethra and urachus in a 50-day lamb. The authors' previous 60-day model did not have PS, but an earlier obstructive uropathy caused MCDK with PS.

Topics: Abnormalities, Multiple; Animals; Disease Models, Animal; Face; Female; Fetal Diseases; Gestational Age; Immunohistochemistry; Kidney; Lung; Male; Nose; Oligohydramnios; Organ Size; Pregnancy; Pregnancy, Animal; Reference Values; Risk Assessment; Sheep; Syndrome; Ureteral Obstruction

Cleft lip/palate (CLP) is a common human congenital defect in which the maxillary lateral incisors are often absent, malformed, and malpositioned. The present study was designed to examine the origin of the upper primary lateral incisor relative to the medial nasal process (MNP) and maxillary process (MP) fusion area and to the premaxillary/maxillary (incisive) suture in monkeys.. Scanning electron microscopy, histology, skeletal staining, and drying techniques were used to study facial development in embryo and fetal monkey specimens. A teratogenic dose of cyclophosphamide was administered to pregnant monkeys prior to fusion of the MNP and MP and fetuses were examined for CLP.. Formation of the anterior maxilla involved fusion of the MNP and MP at stages 14-18. At stages 18-20, the palatal portion of the MNP had formed the medial and lateral incisive mounds. By stage 22, the upper primary lateral incisor has formed within the MP, lateral to the MNP/MP fusion area and to the ossifying premaxilla. Ossification of the premaxilla begins in the MNP and subsequently spreads laterally across the MNP/MP fusion area into the MP. Accordingly, the lateral incisor undergoes a complex positional shift (mainly medial) relative to the incisive suture both prenatally and postnatally and is finally located medial to the suture. Examination of the cyclophosphamide-induced CLP fetuses showed that the lateral incisor is located lateral to the alveolar cleft and does not shift medial to the incisive suture.. Understanding the origin of the lateral incisor (the tooth closest to the cleft) and the shift after its formation provides clues to high incidence of malformations and ectopia of this incisor in cleft patients.

Topics: Alveolar Process; Animals; Cleft Lip; Cleft Palate; Coloring Agents; Cranial Sutures; Cyclophosphamide; Disease Models, Animal; Embryonic and Fetal Development; Face; Female; Humans; Incisor; Macaca fascicularis; Macaca mulatta; Maxilla; Microscopy, Electron, Scanning; Nose; Odontogenesis; Osteogenesis; Palate; Pregnancy; Teratogens; Tooth Migration

Capsaicin and analogues are valuable analgesic agents when administered to mammals, including humans. However, their pungency and the effects on the cardiovascular and respiratory systems through their general activation of small calibre (nociceptive) primary afferents severely limit their use. Recently, structure activity analysis revealed that the initial pungent and general excitatory effects can be prevented by structural modifications in such a way that the analgesic activity is retained. In this paper we present SDZ 249-665, a capsaicin analogue which produced analgesia in the mouse and anti-hyperalgesic effects in the rat and guinea pig. SDZ 249-665 was administered p.o., s.c. and i.v. in models of nociceptive pain, such as tail flick latency in response to a noxious thermal stimulus and acetic acid-induced writhing in mice, and in models of inflammatory mechanical hyperalgesia induced by turpentine or carrageenan in the rat and guinea pig, respectively. SDZ 249-665 was effective in the tail flick and the writhing assays and produced significant anti-hyperalgesic effects in the inflammatory models. The efficacy of SDZ 245-665 was similar to that of capsaicin, however, it was significantly more potent. SDZ 249-665 did not produce any irritancy in a nose wipe assay in guinea pigs or an eye irritancy assay in rats, while capsaicin was clearly irritant in both cases. Furthermore, unlike capsaicin, SDZ 249-665 did not produce unwanted side effects such as bronchoconstriction and blood pressure changes in the analgesic/anti-hyperalgesic dose range. Thus, a clear analgesic therapeutic window exists for SDZ 249-665. In summary, SDZ 249-665 is a potent orally active, analgesic/anti-hyperalgesic agent in mouse, rat and guinea pig. It lacks the excitatory effects associated with capsaicin and other close analogues, and therefore provides a clear therapeutic window for use in painful conditions. In addition to this favourable profile, no sign of tolerance was detected after a 5 day repeated dose treatment.

Topics: Analgesics; Animals; Behavior, Animal; Blinking; Blood Pressure; Bronchoconstriction; Capsaicin; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Eye; Female; Ganglia, Spinal; Guinea Pigs; Hindlimb; Hyperalgesia; Irritants; Male; Mice; Mice, Inbred Strains; Nociceptors; Nose; Odorants; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Turpentine; Urea

The precise effects of therapeutic occlusion of the internal maxillary artery (IMA) on distal nasal mucosal perfusion are unknown. A better understanding of these effects has important implications regarding the rationale and expected efficacy of certain therapeutic interventions for epistaxis management. The authors developed an animal model to assess these issues.. The effects of "proximal" and progressively more "distal" occlusions of the IMA on nasal mucosal blood flow (NBF) were assessed in anesthetized swine using continuous laser Doppler flowmetry. The levels of arterial occlusion were selected to simulate clinical therapeutic occlusions used for the management of epistaxis.. Nineteen swine were entered into one of four experimental groupings: proximal IMA occlusion using platinum micro-coils (n = 6), mid-grade distal IMA occlusion with polyvinyl alcohol particulate (PVA) suspensions (300 to 500 microns, n = 5), high-grade distal IMA occlusion with polyvinyl alcohol particulate suspensions (50 to 150 microns, n = 5), and sham control (n = 2).. All embolizations resulted in acute decreases in average NBF from 120 mL/min per 100 g to 40 mL/min per 100 g (P < .05 for all groups). NBF returned to baseline in all three treated groups within 2 to 8 days after therapeutic embolization, depending on the level of occlusion (coils, 2 d; mid-grade PVA, 2-3 d; high-grade PVA, 8 d). Follow-up angiography showed recanalization and collateralization as possible methods of reestablishing NBF.. This study supports the rationale for performing distal IMA occlusion with transarterial particulate embolization, in order to provide a longer period of time of diminished NBF. This theoretically should promote hemostasis within an injured portion of the nasal mucosa by decreasing perfusion pressure within the capillary bed. However, the benefits of distal IMA embolization must be balanced against potential ischemic complications, as may be more commonly seen with high-grade particulate embolization.

Topics: Animals; Disease Models, Animal; Embolization, Therapeutic; Female; Hemostasis, Surgical; Maxillary Artery; Nose; Regional Blood Flow; Swine

Respiratory syncytial virus (RSV) has emerged as a leading cause of pneumonia, with high mortality, in bone marrow transplant (BMT) recipients, as well as in other profoundly immunocompromised patients, such as myelosuppressed adults with leukemia. We tested the efficacy of immunoglobulin with high anti-RSV neutralizing antibody levels (RSVIG) for prophylaxis and therapy of RSV infection in cotton rats undergoing prolonged immunosuppression with cyclophosphamide. These animals experience persistent infection, a model which is similar to the disease seen in post-BMT humans. Both prophylaxis and therapy reduced pulmonary viral replication over 500-fold to nearly undetectable levels. In animals receiving continual immunosuppression, the use of multiple therapeutic doses of RSVIG was able to prevent rebound viral replication, though virus was not completely eliminated.

Topics: Animals; Antibodies, Viral; Cyclophosphamide; Disease Models, Animal; Dose-Response Relationship, Immunologic; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lung; Nose; Rats; Rats, Inbred Strains; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Sigmodontinae; Virus Replication

To develop a mouse model of acute bacterial rhinosinusitis.. Study mice (C57BL6/J) were inoculated intranasally with Streptococcus pneumoniae, ATCC 49619 suspended in trypticase soy broth, and controls were inoculated with trypticase soy broth alone. After 2, 5, or 14 days, intranasal cultures were obtained and mice were killed. The sinuses were prepared for histological investigation.. Animal care facility at a tertiary, academic institution.. The histological sections of the sinuses were examined in a blinded manner for the percentage of sinus cavity occupied by neutrophil clusters, and for the number of neutrophils per square millimeter of sinus mucosa.. Infected mice killed at 5 days had significantly more sinus area occupied by neutrophil clusters, significantly more neutrophils within the mucosa, and significantly more S pneumoniae growth in the intranasal cultures compared with controls (15/15 vs 0/6; P<.01). The amount of inflammation had decreased at 2 weeks.. Streptococcus pneumoniae induces acute bacterial rhinosinusitis in C57BL6/4 mice as measured by culture and influx of neutrophils, and can be used as a model of acute bacterial rhinosinusitis.

Topics: Animals; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred C57BL; Neutrophils; Nose; Paranasal Sinuses; Pneumococcal Infections; Rhinitis; Sinusitis; Streptococcus pneumoniae

To examine the role of disturbed upper airway reflexes in aspiration, we administered 20 microliters of the adenovirus (Ad) vector Ad-CMV-LacZ or 20 microliters of phosphate buffered saline (PBS) intranasally to C57 black mice. We investigated expression of the LacZ gene by this Ad vector in the nostrils of each mouse, with or without anesthesia. Under anesthesia, LacZ gene expression was detected in the lungs of every mouse given the Ad vector. However, no LacZ gene expression was found in the trachea or lungs of mice given the Ad vector without anesthesia. In mice given PBS or wild-type adenovirus transnasally during anesthesia, there was no LacZ gene expression in the nostrils, trachea, or lungs, suggesting that with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) staining, blue-stained cells indicated transferred LacZ gene expression. These results suggested that aspiration of intranasal solution into lower airways was caused by disturbed upper airway reflexes during anesthesia. This process can be analyzed by the distribution of LacZ gene expression in airways. We next examined the effect of age on anesthesia-induced aspiration. Twenty-six-mo-old mice exhibited more LacZ gene expression in their lungs than did 6-mo-old mice at a concentration of 0.5 to 4.0% halothane in 100% oxygen. This suggests that light anesthesia may depress upper airway reflexes and cause aspiration in older animals. This novel model of aspiration, generated with the Ad-CMV-LacZ vector, may be useful for elucidating the mechanism of development of aspiration pneumonia in relation to age-related impairment of upper airway reflexes.

Topics: Adenoviridae; Age Factors; Anesthetics, General; Anesthetics, Inhalation; Animals; beta-Galactosidase; Chromogenic Compounds; Coloring Agents; Disease Models, Animal; DNA, Recombinant; Galactosides; Gene Expression Regulation, Viral; Gene Transfer Techniques; Genetic Vectors; Halothane; Indoles; Lac Operon; Lung; Male; Mice; Mice, Inbred C57BL; Nose; Oxygen; Pneumonia, Aspiration; Reflex, Abnormal; Trachea

This study reports intraspecific variations of native isolates of Leishmania (Viannia) braziliensis from patients with leishmaniasis from Salta, Argentina. These isolates induced skin lesions in golden hamsters, initially showing rapid development, reaching their largest size between 28 and 35 days postinfection (PI). Thereafter, the infections were self-limiting and total regression was observed at 80-150 days PI. The majority of the native isolates were characterized by low infectivity in the experimental animals, and a classic pattern of dissemination to systemic organs was established. However, unusual features for L. braziliensis were displayed by two isolates; one showed evidence of high infectivity in hamsters characterized by a short prepatent period and larger, severe and persistent lesions at the inoculation site. The other isolate, of low infectivity, showed cutaneous metastasis and recurrent systemic dissemination in the same animals, suggesting dissociation between infectivity and pathogenicity. Metastasis has been frequently described in hamsters infected with L. (V) guyanensis and L. (V) panamensis, but not in infections induced by L. (V) braziliensis, as was observed in this study. Active and/or regressive histopathologic lesions were observed, depending on the stage of the infection. An exudative and mixed inflammatory pattern with microabscesses and necrotic areas was observed during early infection, while well-defined granulomas and collagen formation were the predominant features detected at a later time. Amastigotes were easily detected in the tissues, although in low numbers. Schaumann bodies were always detected. The characterization of the unique features of these native isolates, and the verification of their reproducibility in vitro and in vivo will be useful tools in tests related to immunoprophylaxis and chemotherapy.

Topics: Animals; Argentina; Cricetinae; Disease Models, Animal; Granuloma; Humans; Leishmania braziliensis; Leishmaniasis, Cutaneous; Macrophages; Mesocricetus; Necrosis; Nose; Skin

The trisomy 16 mouse is a widely accepted animal model for the study of the embryonic development of human trisomy 21. While the development of the brain and heart has been thoroughly studied, there are hardly any data on the development of sensory organs like the eye, nose and ear. By studying scanning electron microscopic pictures and semithin sections from the tenth to the 15th day of development, we found delayed development of the nose, and, in particular, of the vomer. Sensory structures of the otic vesicle also showed a marked developmental delay. Pigmentation of the outer layer of the otic cup starts later in trisomic animals. Cleared specimens on day 16 showed retarded development of ossification centres in all areas of the skull. These findings correspond with the abnormal facial morphology found in Down's syndrome and may also provide new insights into the hearing impairment commonly found. The observations in the eye and skull bones indicate that neural crest tissue maldevelopment is not the sole cause of malformations.

Topics: Animals; Chromosome Mapping; Disease Models, Animal; Down Syndrome; Ear; Embryonic and Fetal Development; Eye; Female; Humans; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Microscopy, Electron, Scanning; Nasal Septum; Nose; Skull; Trisomy

In adult mammals, the path of a swallowed bolus of solid food crosses the laryngeal opening, so that coordination between respiration and deglutition is critical for airway protection. The nature of such coordination in preterm, low-birth-weight infants with immature nervous systems, is not clear. Using preterm pigs as a model, two measures of respiration were recorded and then coordinated with a high-resolution cineradiographic record of swallowing. Swallows, divided into three distinct events, began before inhalation ended, but expiration did not start until after the milk had passed around the laryngeal opening. These results support the idea that a high degree of coordination between swallowing and respiration exists in preterm infant pigs, although other aspects of the nervous system have not fully matured.

Topics: Animals; Cineradiography; Deglutition; Disease Models, Animal; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Larynx; Nervous System Physiological Phenomena; Nose; Pharynx; Pulmonary Ventilation; Respiration; Sucking Behavior; Swine; Swine, Miniature

The SCID (severe combined immunodeficient) mouse lacks both B and T cells and tolerates injected mononuclear cells from humans, the principal hosts of Mycobacterium leprae. A SCID mouse model of leprosy could be useful to investigate potential vaccine strategies using human cells in a context in which the growth of the organism is monitored. Initial experiments determined that SCID mice are more susceptible than normal mice to infection and dissemination of M. leprae. Cells from humans, either BCG vaccinated or from countries where leprosy is endemic, were stimulated in vitro with a number of mycobacterial antigens--whole M. leprae, M. leprae cell walls, purified protein derivative of M. tuberculosis, and Mycobacterium bovis BCG--and tested for proliferation and production of interleukin-6, tumor necrosis factor alpha, and gamma interferon. Cell walls were the most efficient and consistent in inducing all of these activities. In vitro-activated human cells retain function better after injection into SCID mice than nonactivated cells. To test the ability of cells to affect the growth of M. leprae in the footpads of SCID mice, cells from a known responder to mycobacterial antigens and from a nonresponder were activated by M. leprae cell wall antigens. The cells were harvested and coinjected with fresh M. leprae into the right hind footpads of SCID mice. After 3 months, there was no growth of M. leprae in the footpads of mice coinjected with cells from the mycobacterial antigen responder, while growth was uninhibited in mice receiving cells from the nonresponder. Future experiments will determine requirements for antigen specificity in inhibiting M. leprae multiplication.

Topics: Animals; Antibodies, Bacterial; Antigens, Bacterial; Cytokines; Disease Models, Animal; Disease Susceptibility; Extremities; Humans; Immunotherapy, Adoptive; Leprosy; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphoid Tissue; Lymphotoxin-alpha; Mice; Mice, Inbred Strains; Mice, SCID; Nose

Mycoplasma pulmonis or Myc. pneumoniae were inoculated intranasally to C.B-17 scid/scid mice (severe combined immunodeficient (SCID) mice). Immunocompetent C.B-17 mice were inoculated as controls. During the observation period of 5 weeks the mice were killed and necropsied. Mycoplasma pulmonis was recovered from all of the inoculated mice, and dissemination to various tissues increased with time. SCID mice, unlike immunocompetent mice, did not show lung lesions but exhibited severe inflammatory changes of the joints. Mycoplasma pulmonis, however, was isolated both from the lungs and the articular lesions. In addition, SCID mice infected for more than 3 weeks suffered from a pronounced loss of weight and emaciation. In the experiment with Myc. pneumoniae the agent could be reisolated, but lesions were not found in any of the infected mice. Mycoplasma pulmonis infection in SCID mice may be useful as a model of arthritis in immunodeficient humans.

Topics: Administration, Intranasal; Animals; Arthritis, Infectious; Chronic Disease; Disease Models, Animal; Immunocompetence; Male; Mice; Mice, SCID; Mycoplasma; Mycoplasma Infections; Nose

While nasal cancer is relatively rare among the general population, workers in the nickel refining, leather manufacturing, and furniture building industries exhibit increased incidences of nasal cancer. To investigate the causes of nasal cancer and to design ameliorative strategies, an appropriate animal model for the human upper respiratory regions is required. The present report describes, compares, and assesses the anatomy and physiology of the nasal passages and upper airways of humans, rats, and monkeys for the purpose of determining a relevant animal model in which to investigate potential causes of nasal cancer. Based on the mode of breathing, overall geometry of the nasal passages, relative nasal surface areas, proportions of nasal surfaces lined by various epithelia, mucociliary clearance patterns, and inspiratory airflow routes, the rat, which is very different from humans, is a poor model. In contrast, the monkey exhibits many similarities to humans. Although the monkey does differ from humans in that it exhibits a more rapid respiratory rate, smaller minute and tidal volumes, larger medial turbinate, and a vestibular wing that creates an anterior vortex during inspiration, it offers a more appropriate model for studying the toxic effects of inhaled substances on the nasal passages and extrapolating the findings to humans.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Haplorhini; Humans; Monkey Diseases; Nasal Mucosa; Nose; Nose Neoplasms; Pulmonary Ventilation; Rats; Respiratory Physiological Phenomena; Respiratory System; Respiratory Tract Neoplasms

The aim of this study was to examine the pathophysiological role of capsaicin-sensitive sensory nerves in an animal model of nasal allergy. In ovalbumin (OA)-sensitized guinea pigs, a significant increase in nasal total airway resistance (TAR) was noted for at least 180 min after topical antigen challenge. The TAR response to antigen challenge was significantly inhibited for 120 min by general capsaicin pretreatment (167 +/- 12.1 vs. 113 +/- 5.0%, p < 0.001, and 186 +/- 14.9 vs. 119 +/- 6.6%, p < 0.001, control vs. capsaicin pretreatment group at 20 and 90 min after challenge, respectively). However, TAR was significantly though slightly affected even after general capsaicin pretreatment. Following nasal capsaicin challenge, TAR increased for 90 min, and nasal secretion for 30 min. Both the TAR and secretory responses to nasal capsaicin challenge were significantly greater in OA-sensitized guinea pigs than in nonsensitized animals (171 +/- 12.1 vs. 137 +/- 7.4% at 30 min, p < 0.05, and 82.3 +/- 8.6 vs. 13.4 +/- 1.7 mg/10 min, p < 0.05, TAR and secretory response to 300 microM nasal capsaicin challenge, respectively). These results suggest that capsaicin-sensitive sensory nerve reflexes play an important role in the occurrence of early-phase nasal symptoms following topical antigen exposure and are accelerated in OA-sensitized guinea pigs.

Topics: Airway Resistance; Animals; Capsaicin; Disease Models, Animal; Guinea Pigs; Immunization; Male; Nasal Mucosa; Neurons, Afferent; Nose; Ovalbumin; Reflex; Rhinitis

The purpose of this study was to determine the frequency of immunoglobulin deposition in the haired skin, footpads, and nasal planums of 10 WHV-infected woodchucks with chronic hepatitis and hepatocellular carcinoma and compare these results with those reported in humans. Immunoglobulin deposition was detected in the skin samples of 3 of 10 woodchucks. Granular deposits were revealed in the superficial dermal blood vessels of the nasal planum, lateral thoracic skin, and footpads in 1 animal each. In 1 of these animals, (lateral thorax) immunoglobulin deposition was concurrently present at the basement membrane zone.

Topics: Animals; Biopsy, Needle; Carcinoma, Hepatocellular; Chronic Disease; Disease Models, Animal; Female; Fluorescent Antibody Technique; Foot; Hair; Hepadnaviridae; Hepatitis, Viral, Animal; Immunoglobulins; Liver Neoplasms; Male; Marmota; Nose; Skin

In order to clarify the pathophysiological role of the chemical mediators, the releases of kinins, histamine and leukotriene C4(LTC4) into the nasal cavity were measured following nasal allergic challenge in ovalbumin(OA)-sensitized guinea pigs, or following nasal stimulation with one of these chemical mediators in OA-non-sensitized animals. In sensitized animals, an increased vascular permeability of nasal mucosa was recognized immediately after antigenic stimulation and lasted for 60-90 minutes. Releases of kinins and LTC4 into the nasal lavage fluid augmented not only immediately after the antigenic challenge, but also during 60 to 90 minutes after the stimulation. Release of histamine into the nasal lavage fluid was observed only immediately after the antigenic stimulation. In non-sensitized guinea pigs, nasal stimulation with bradykinin accelerated nasal vascular permeability. Nasal stimulation with histamine or LTC4 resulted in increase of nasal vascular permeability and of kinins concentration in the nasal lavage fluid. These results suggest that kinins might be concerned with the immediate and later vascular permeability during the allergic response.

Topics: Animals; Bradykinin; Capillary Permeability; Disease Models, Animal; Guinea Pigs; Histamine; Kinins; Male; Nose; Rhinitis, Allergic, Perennial; SRS-A

Thirty-five male Sprague-Dawley rats were divided into 3 groups, including 1 control and 2 experimental groups, in order to compare the efficacy of using cortisone acetate alone or in addition to intranasal inoculation of Pneumocystis carinii organisms for the purpose of inducing acute P. carinii pneumonia. The presence of P. carinii was monitored in nasal secretions on a weekly basis and in lungs at autopsy. Titers of IgG antibody were also monitored by enzyme-linked immunosorbent assay. No rat receiving cortisone acetate injections alone and only 2 of the rats receiving both cortisone and intranasal inoculation of P. carinii organisms showed Pneumocystis organisms in the lungs. However, Pneumocystis cysts did appear in the nasal secretions of 3 of the 5 control rats, all 8 rats receiving cortisone acetate injections only, and 12 of 18 rats receiving both cortisone acetate injections and an intranasal inoculum. IgG titers of both cortisonized groups remained less than 1:4 throughout the course of the experiment. The titer of the control group increased from negative to 13 (geometric mean).

Topics: Animals; Antibodies, Protozoan; Body Weight; Cortisone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Lung; Male; Nose; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains

In a study of swine congenital anomalies, nine newborn piglets with varying degrees of optic hypotelorism including cyclopia were collected. Nasal and maxillary development were abnormal in all animals regardless of the degree of eye fusion. All animals except one had intact upper lips and hard palates that carried two or three small extopic teeth. The "snout" was only a medial wedge-shaped rudiment projecting from the upper lip. It was distally covered by a typical snout-like glabrous epithelium and carried small vibrissae. Six animals also had a tubular proboscis dorsal to the eye. The distal tip of the proboscis was covered by glabrous epithelium. External nares and nasal passageways, albeit blind-ended, were prominent in the proboscis. The nasofrontal bones projected into the base of the proboscis. Seven piglets were hairless except for fine vibrissae and some eyebrow hairs. All animals had some degree of ear abnormalities, e.g., malposition and absence of external auditory meatus. In all animals the brain was malformed. This abnormality varied from complete absence of the forebrain to an alobar structure with gyri. The remainder of the body of each animal was normal. Developmental anomalies of the nose and eye generally reflect malformations of the forebrain, although the etiology of these defects is unclear. The cyclopia associated with the medial proboscis suggests that both the telencephalon and diencephalon are dysplastic. The presence of glabrous epithelium in two regions on the face suggests that studies of the development of the midline face in the swine will help to elucidate the etiology of the holoprosencephalic series. In this way the pig may prove to be an excellent modeling system for human holoprosencephaly.

Topics: Abnormalities, Multiple; Animals; Brain; Disease Models, Animal; Eye Abnormalities; Face; Female; Male; Maxilla; Medial Forebrain Bundle; Nose; Radiography; Swine

A strain of Cryptococcus neoformans that was isolated from the cerebrospinal fluid of a human diagnosed as having acquired immunodeficiency syndrome (AIDS), and that produced cutaneous lesions in experimentally infected, normal mice is described. Although no unusual cutaneous manifestations were noted in the patient's records, this isolate of C. neoformans proved to be dermotropic when injected intravenously into CD-1 mice. The LD50 at 28 days post infection ranged from 3.6-7.5 X 10(5) cells per mouse, and in vitro growth rate studies demonstrated that this isolate grew well at 35 degrees C and at 37 degrees C, but did not grow at 40 degrees C and higher. This isolate was rhinotropic producing large granulomatous lesions in the nasal tissues. Other cutaneous tissues affected were the periocular tissues, ears, feet and tail, although the granulomas were nodular in structure and less necrotic than the nasal lesions. The brain, lungs, liver, kidneys and spleen also were culture positive for C. neoformans. Histopathologically, each affected tissue examined had large densities of yeast cells and a chronic, granulomatous host response. Animals surviving the infection appeared to develop a commensal-type relationship with the infective yeast. This is the first report of an isolate of C. neoformans from an AIDS patient that has caused cutaneous manifestations in an animal model. The model described in this report may be useful for elucidating pathogenic mechanisms of cryptococcosis, particularly cutaneous manifestations of the disease.

Topics: Acquired Immunodeficiency Syndrome; Adult; Animals; Cerebrospinal Fluid; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Dermatomycoses; Disease Models, Animal; Female; Humans; Male; Mice; Nose; Skin

The effectiveness of two aerosol delivery systems, nose-only and whole-body, were compared using Swiss-Webster mice and two pathogens, Klebsiella pneumoniae and Venezuelan equine encephalitis (VEE) virus. With K. pneumoniae the median lethal dose (LD50) and the mean time to death correlated with the inhaled dose. An LD50 value of 335 colony forming units (cfu) for nose-only exposure was significantly less than the LD50 value of 3741 cfu obtained for whole-body exposure. The LD50 values obtained with VEE virus for nose-only exposure [8 plaque forming units (pfu)] and whole-body exposure (11 pfu) were similar to each other. Following a 10-min nose-only exposure, concentrations of K. pneumoniae approximating 10(4)/g were present after 24 hr in the upper respiratory tract (URT) and lungs. The numbers of bacteria reached a peak at 72 hr, when resolution of the infection began. Detectable levels of bacteria in the blood and tissues were delayed in mice given whole-body exposure, plus there was a decreased concentration of bacteria per gram of tissue. Major pathological lesions induced by K. pneumoniae were mild suppurative rhinitis and minimal suppurative bronchopneumonia. Viremia was greatest at 96 hr following aerosol exposure to VEE. Virus concentrations in the URT, lungs, cerebrum, spleen and mesenteric lymph nodes reached maximum titers earlier for mice exposed by nose-only than for mice exposed to whole-body aerosols.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aerosols; Animals; Disease Models, Animal; Encephalomyelitis, Venezuelan Equine; Female; Klebsiella Infections; Klebsiella pneumoniae; Lethal Dose 50; Mice; Nose; Respiratory Tract Infections

The susceptibility of four species of East African nonhuman primates to experimental infection with Leishmania major was investigated. Four Syke's monkeys (Cercopithecus mitis), two vervet monkeys (Cercopithecus aethiops), two baboons (Papio cynocephalus), and two brown bushbabies (Galago garnettii) were each inoculated intradermally on the left eyelid, left ear, and nose with 0.1 ml of medium containing 1 x 10(7) promastigotes of a characterized L. major strain. All the nonhuman primates except the bushbabies developed erythema and conspicuous nodules on the eyelids and ears by 3 weeks PI. The nodules increased rapidly in size and ulceration was evident on the eyelids and ears by 49 days PI in the vervets, Syke's, and baboons. The aspirates were positive in culture or smears at 35, 49, 63, and 77 days PI. No parasites were observed in cultures or smears at 92, 105, 128, 147, and 161 days PI. The lesions in these animals began resolving by 84 days PI and were completely healed by 112 days PI. The exception was one baboon in which lesion healing did not start until around 147 days and was completely healed by 182 days PI. Cultures from the liver failed to demonstrate visceralization of the parasite in any of the animals throughout the 68 weeks of the experiment. Challenge with the same strain of L. major 6 months PI, corresponding to about 3 months after self cure, failed to produce infection in any of these experimental hosts. All the nonhuman primates except the bushbaby when challenged with the same strain of L. major at 12 months PI developed lesions and were positive for parasites at 14 and 28 days PI. Positive cultures were obtained from the eyelid and ear of one vervet up to 42 days PI. However, the lesion sizes in all these animals were smaller than in the initial infection and did not ulcerate. The nodules disappeared within 6 to 8 weeks as compared to 16 weeks in the initial infection. The histopathological appearance of the lesions varied from diffuse infiltration of plasma cells and lymphocytes which increased progressively to granulomata with epitheloid cells. This study shows that the vervets, Syke's, and the baboons are equally susceptible to L. major infection, while bushbabies are refractory. The vervets, Syke's, and baboons demonstrate a self-healing phenomenon within about 3 months which is comparable to that observed in humans infected with L. major. These three species of nonhuman primates are therefore considered as suitable models fo

Topics: Animals; Cercopithecus; Chlorocebus aethiops; Disease Models, Animal; Ear, External; Eyelids; Galago; Leishmania tropica; Leishmaniasis; Mice; Mice, Inbred BALB C; Monkey Diseases; Nose; Papio

Mice have been infected by intranasal instillation of Bordetella pertussis and the infection monitored by determining numbers of bacteria isolated from the lungs. Outer membrane proteins, filamentous hemagglutinin, toxoided-lymphocytosis promoting factor and agglutinogens (fimbriae) actively protect mice against intranasal infection and antibodies of the antigens neutralize infectivity. The neutralization of infection by agglutinins is serospecific. In general, antigens that actively protect mice against intracerebral infections also protect against intranasal infections but some antigens, such as filamentous hemagglutinin and agglutinogens, protect only against intranasal infections. The intranasal protective potency of antigens can be enhanced by including low levels of active lymphocytosis promoting factor in the preparations. The relevance of the intranasal test to the potency testing of pertussis vaccines is discussed.

Topics: Animals; Antigens, Bacterial; Bacterial Outer Membrane Proteins; Bordetella pertussis; Disease Models, Animal; Fimbriae, Bacterial; Hemagglutinins; Lung; Mice; Nose; Pertussis Toxin; Pertussis Vaccine; Respiratory Tract Infections; Virulence Factors, Bordetella; Whooping Cough

Neonatal cotton rats were treated with cyclophosphamide parenterally for three weeks before intranasal inoculation of live respiratory syncytial virus (RSV). Immunosuppressive therapy resulted in severe depletion of lymphocytes from the peripheral circulation, the spleen, and the thymus. In contrast to normal rats, immunosuppressed animals developed severe pulmonary pathology with marked infiltration of foamy macrophages. Persistent degeneration and regeneration of bronchial epithelial cells were also observed, in which RSV antigens could be demonstrated by the immunoperoxidase technique. In addition, large quantities of live virus were recovered from the respiratory tract of these animals for as long as six weeks after infection. Systematic dissemination of RSV, which has never been documented in immunocompetent control rats, was found in four of the cyclophosphamide-treated animals. These results support clinical observations that cellular immunity may be very important in the pathogenesis of RSV infection in the human host.

Topics: Animals; Antigens, Viral; Arvicolinae; Cyclophosphamide; Disease Models, Animal; Humans; Immunity, Cellular; Immunosuppression Therapy; Leukocyte Count; Lymphocytes; Nose; Respiratory Syncytial Viruses; Respirovirus Infections; Spleen; Thymus Gland; Virus Replication

Topics: Animals; Child; Disease Models, Animal; Dogs; Facial Bones; Humans; Mandible; Mouth Breathing; Nose; Respiration; Skull; Tracheotomy

Infection of guinea-pigs by intranasal (i.n.) instillation of 10(9) viable organisms of two newly isolated strains of Legionella pneumophila (74/81, serogroup 1; 166/81, serogroup 3) did not induce disease, but 10(4) organisms administered as a small particle aerosol (less than 5 microns diameter) produced a fatal widespread broncho-pneumonia within 3 days. Milder illness and less extensive bronchopneumonia were also produced in rhesus monkeys and marmosets by one of these two strains (74/81). Mice were resistant to induction of disease by aerosols of both these two strains, though organisms did persist in the lungs for at least 4 days. Both of these L. pneumophila strains were pathogenic for guinea-pigs by aerosol infection over a wide range of doses but the serogroup 1 type strain (NCTC 11192) was not. There was no mortality after infection of guinea-pigs by intranasal instillation of any of these strains but all proved to be fatal after intraperitoneal (i.p.) injection of large doses. Guinea-pigs, rhesus monkeys and marmosets exposed to aerosol infection with L. pneumophila provide relevant models for studying the pathogenesis of Legionnaires' disease.

Topics: Aerosols; Animals; Antibodies, Bacterial; Callitrichinae; Disease Models, Animal; Female; Guinea Pigs; Legionella; Legionnaires' Disease; Lung; Macaca fascicularis; Macaca mulatta; Male; Mice; Nose; Peritoneum

Topics: Animals; Disease Models, Animal; Female; Leishmaniasis; Leukocytes; Lymphocytes; Macrophages; Mice; Mice, Inbred Strains; Nose; Plasma Cells; Senegal; Skin; Species Specificity; Virulence

Respiratory syncytial virus infected the nose and lungs of each of 20 strains of inbred mice, with viral titers varying 100-fold from least permissive to most permissive strains. Viral titers appeared to be under genetic control, but did not correlate with the H-2 haplotype.

Topics: Animals; Disease Models, Animal; Lung; Mice; Mice, Inbred Strains; Nose; Respiratory Syncytial Viruses; Respirovirus Infections; Species Specificity; Viral Plaque Assay; Virus Replication

A total of 28 cebus monkeys were inoculated intratracheally or intranasally with 10(6) 50% tissue culture infective doses of A/New Jersey/76 virus or 10(7) 50% tissue culture infective doses of A/Victoria/75 virus, and 8 additional monkeys received sterile allantoic fluid. Each of the animals became infected as evidenced by a serological response and/or shedding of the virus. Of the 10 animals inoculated intratracheally with A/Victoria/75 virus, 8 developed a systemic illness, and pulmonary infiltration was detected by X-ray in 7 of the 8. Administration of A/New Jersey/76 virus intratracheally to 10 monkeys produced a mild systemic illness in 2 animals and an upper respiratory tract illness in 6, but no illness developed in the remaining 2 monkeys; none of the animals developed X-ray evidence of lower respiratory tract disease. Intranasal administration of either virus failed to induce any illness or produced, at most, mild illness confined to the upper respiratory tract. These studies demonstrate that cebus monkeys are susceptible to respiratory tract infection with influenza A viruses and that the development of pulmonary disease is reflected in the appearance of easily recognizable radiological changes.

Topics: Animals; Disease Models, Animal; Haplorhini; Hemagglutination Inhibition Tests; Influenza A virus; Nose; Respiratory Tract Diseases; Trachea

Porcine infectious atrophic rhinitis is a disease of swine which ought to be of considerable interest to rhinologists. We have reviewed some aspects of human atrophic rhinitis, and some aspects of etiology incidence, pathology and physiology of porcine infectious atrophic rhinitis. Swine with this nasal problem fail rather dramatically, to gain as much weight as unaffected animals. We have speculated on several reasons for this including altered nasal physiology and trigeminal reflexes and reduced olfaction. Photographs of infected pigs are included.

Topics: Animals; Disease Models, Animal; Humans; Nasal Mucosa; Nose; Rhinitis, Atrophic; Swine; Swine Diseases

After intranasal instillation into ferrets, the "swine" influenza virus A/New Jersey/8/76(Hsw1 N1) had a 50% minimal infectious dose similar to that of previously tested A/PR/8-A/England (H3 N2) recombinants virulent and attenuated for man. A/New Jersey produced only a mild upper respiratory tract infection. However, higher titres of virus were recovered from the lungs over a longer period than experienced previously with Asian and Hong Kong virus strains. There was a diphasic pyrexia the second and higher peaks of which correlated with peak titres of virus in lung macerates. These results suggest that A/New Jersey has a pneumotropic potential in ferrets and, if the animal model is valid, possible in man.

Topics: Animals; Carnivora; Disease Models, Animal; Ferrets; Fever; Humans; Influenza A virus; Influenza, Human; Lung; Nose; Pneumonia, Viral; Virulence

Although the portal of entry and mode of spread of M. leprae in human leprosy are still uncertain, it is widely held that direct person-to-person skin contact is important. This assumption has ignored the fact that patients with highly bacilliferous leprosy have nasal as well as dermal infection and that, since M. leprae is shed predominantly from the nose, leprosy might be an airborne infection. The present study was designed to investigate this possibility with mice exposed to airborne infection with M. leprae. The conditions are described in which thymectomised-irradiated CBA strain mice exposed to M. leprae aerosols sustained an immediate lung retention of 1 X 10(5) bacteria. Fourteen to 24 months later, 33% (10 of 30) of the mice had countable numbers of acid-fast bacilli (greater than 2 X 10(4)) with the characteristics of M. leprae in one or more homogenates prepared from ears, foot pads, nose or lungs. Evidence is presented from the distribution of M. leprae that the infection had arisen from systemic spresd of bacilli initially entering the lungs rather than from multiplication of organisms locally retained there, or in the nose, at the time of airborne infection. The relevance of these results to the possible route of infection of leprosy in man is discussed.

Topics: Aerosols; Air Microbiology; Animals; Disease Models, Animal; Ear; Female; Foot; Leprosy; Lung; Mice; Mice, Inbred CBA; Mycobacterium leprae; Nose

The excessive accumulation of gas in the gastrointestinal tracts was invariably induced on experimental animals (mice, rats, guinea pigs, hamsters and rabbits) by simply obstructing nasal passages. The analysis of the gas showed the almost identical composition to the ambient air or flutus which was largely due to swallowed air. Also the numerous small foams were found on and underneath the epithelial lining of small intestine. The pathological evaluation was done both macroscopically and microscopically. Dying animals after nasal obstruction showed hemorrhagic and necrotic changes in the jejunum and ileum. This observation may cast some light to the pathogenesis of necrotizing enterocolitis in human neonatal.

Topics: Aerophagy; Air; Animals; Cricetinae; Digestive System; Disease Models, Animal; Enterocolitis, Pseudomembranous; Female; Guinea Pigs; Humans; Male; Mice; Mouth Breathing; Nose; Rabbits; Rats; Respiratory Insufficiency

The antibody response and immunity to challenge infection were determined in ferrets immunized with inactivated influenza vaccine in saline or adjuvant. Adjuvanated vaccines induced variable titres of serum antibody, and the degree of immunity to challenge infection was directly related to the titre of serum HI antibody induced by these vaccines. Conventional doses of saline vaccine did not induce serum HI antibody, and the ferrets were completely susceptible to challenge infection. Infection with live virus produced a more solid immunity to challenge infection than immunization with a adjuvant vaccines, even though immunization induced higher titres of serum HI antibody. Ferrets previously infected with a heterotypic influenza A virus, but not other viruses, produced serum HI antibody in response to subsequent immunization with inactivated influenza vaccine. Similar results were obtained in hamsters and mice. Thus, the failure of animals to produce antibody in response to immunization with saline inactivated vaccines was due to the absence of a previous priming infection; this prior experience would be a feature of most volunteers. Live virus infection produced nasal antibody in ferrets, but inactivated vaccines only induced serum antibody. This may explain the more solid immunity observed following infection; however, at the time of challenge infection, no nasal wash antibody could be detected. Immunization with inactivated vaccine in Freund's complete adjuvant and influenza virus infection both produced a cell-mediated immune response; thus, the difference in the degree of immunity induced by these two immunization procedures are probably not due to differences in the cell-mediated immune response. However, cell-mediated immunity was measured by skin tests and by macrophage migration inhibition tests with spleen cells; the reaction of cells from the respiratory tract may be more important, but was not measured in these studies.

Topics: Administration, Intranasal; Animals; Antibodies, Viral; Antigens, Viral; Cricetinae; Disease Models, Animal; Ferrets; Hemagglutination Inhibition Tests; Immunity; Immunity, Cellular; Immunoelectrophoresis; Immunoglobulin G; Influenza Vaccines; Mice; Neutralization Tests; Nose; Orthomyxoviridae; Orthomyxoviridae Infections; Recurrence; Serum Albumin; Vaccination

Topics: Adenoma; Animals; Disease Models, Animal; Environmental Exposure; Filtration; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nicotiana; Nose; Plants, Toxic; Respiration; Smoke

Rhesus monkeys (Macaca mulatta) exposed to small-particle aerosols of the Aichi strain of type A2 influenza virus responded by shedding virus from the nasopharynx for 7 to 9 days and by seroconversion (hemagglutination inhibition) 8 or 9 days after exposure. After rechallenge with the homologous virus, no replication of the organism was observed, and a serological anamnestic reaction occurred. The data indicate that the rhesus monkey is a useful primate model for evaluating induced immunity to influenza virus infection.

Topics: Aerosols; Animals; Disease Models, Animal; Erythrocytes; Guinea Pigs; Haplorhini; Hemagglutination Inhibition Tests; Immunization, Secondary; Immunodiffusion; Immunoglobulin A; Macaca; Mucus; Nose; Orthomyxoviridae; Orthomyxoviridae Infections; Pharynx

Topics: Animals; Disease Models, Animal; Leprosy; Mice; Mycobacterium leprae; Nasal Mucosa; Nose

Topics: Airway Obstruction; Animals; Disease Models, Animal; Dogs; Frontal Sinus; Microscopy, Electron; Mucocele; Nasal Mucosa; Nose; Osteotomy; Radiography; Sinusitis; Turbinates

Topics: Animals; Cleft Palate; Disease Models, Animal; Female; Haplorhini; Macaca; Male; Malocclusion; Maxillofacial Development; Nasal Septum; Nose; Nose Deformities, Acquired

Topics: Animals; Antigens, Bacterial; Arthritis, Infectious; Bacteriological Techniques; Complement Fixation Tests; Culture Media; Disease Models, Animal; Female; Fermentation; Fluorescent Antibody Technique; Glucose; Immunodiffusion; Mycoplasma; Nose; Primates; Rats; Saliva

Topics: Airway Resistance; Animals; Denervation; Diagnosis, Differential; Disease Models, Animal; Dogs; Electromyography; Eosinophils; Intercostal Muscles; Leukocyte Count; Nasal Mucosa; Nose; Rhinitis; Rhinitis, Allergic, Seasonal; Sympathectomy; Vasomotor System

Topics: Africa, Eastern; Animals; Disease Models, Animal; Female; Fungi; Mycoses; Nose; Nose Diseases; Pan troglodytes; Potassium Iodide; Pyrimidines; Sulfamethoxazole; Sulfonamides; Trimethoprim

Topics: Aerosols; Animals; Antibodies; Carrier State; Digestive System; Disease Models, Animal; Hemagglutination Tests; Humans; Intubation, Gastrointestinal; Lung; Male; Mice; Nose; Respiratory System; Salmonella; Salmonella Infections, Animal; Salmonella typhimurium; Spleen; Virulence; Zoonoses

Topics: Aerosols; Bacteria; Bacteriolysis; Cilia; Disease Models, Animal; Environmental Exposure; Epithelium; Gases; Infections; Lung; Lung Diseases; Macrophages; Models, Biological; Mouth; Mucous Membrane; Mucus; Nose; Phagocytosis; Pulmonary Alveoli; Time Factors