Nasal Instillation Research Articles

Development of a mouse model of eosinophilic chronic rhinosinusitis with nasal polyp by nasal instillation of an Aspergillus protease and ovalbumin.

One subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the development of a T-helper type 2 (Th2) response and eosinophilic infiltration. Here, we aimed to establish an eosinophilic CRSwNP murine model, which would be essential to understand the underlying pathogenesis and establish a treatment strategy. C57BL/6 mice were challenged intranasally with a mixture of an Aspergillus oryzae-derived protease (AP) and ovalbumin (OVA) for 6, 8, or 12 consecutive weeks (12 mice/group); control mice received the same volume of phosphate-buffered saline for 12weeks (n=12). Sinonasal samples were evaluated histologically, and interleukin (IL)-4, IL-5, IL-13, eotaxin, keratinocyte chemoattractant, and macrophage inflammatory protein-2 mRNA levels in sinonasal mucosa were measured by real-time PCR. Protein levels of Th2 cytokines, INF-γ, IL-17A, and chemokines in nasal lavage fluid, and total serum IgE were measured by ELISA. Greater eosinophil infiltration in the subepithelial layer was observed in the challenged groups, compared with the control group. Polypoid mucosal lesions were predominantly observed in the 12-week group, which also exhibited mucosal thickening on micro-CT scans. The IL-4, IL-5, and IL-13 mRNA and protein levels were elevated in the sinonasal mucosa and nasal lavage fluid. INF-γ and IL-17A were undetectable or not elevated relative to the control group levels. In contrast, eotaxin levels were particularly elevated in the sinonasal mucosa and nasal lavage fluid in the 12-week group. In conclusion, intranasal AP and OVA exposure successfully induced Th2-specific CRSwNP in a murine model.

MiR-541-5p regulates lung fibrosis by targeting cyclic nucleotide phosphodiesterase 1A

ABSTRACTAim of the Study: Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A (PDE1A), a Ca2+/calmodulin-stimulating PDE family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. Materials and Methods: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of PDE1A in rat lung, a nonspecific control siRNA or PDE1A-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect PDE1A and α-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. Results: In vitro studies showed that PDE1A can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-β-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. Conclusions: MiR-541-5p is a key effector in lung fibroblastsby by regulating PDE1A expression at protein translation level and its overexpression is protective against bleomycin-induced lung fibrosis.

Local delivery of siRNA-loaded calcium phosphate nanoparticles abates pulmonary inflammation

The local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach to dampen inflammation during pulmonary diseases. For the local therapeutic treatment of pulmonary inflammation, we produced multi-shell nanoparticles consisting of a calcium phosphate core, coated with siRNAs directed against pro-inflammatory mediators, encapsulated into poly(lactic-co-glycolic acid), and coated with a final outer layer of polyethylenimine. Nasal instillation of nanoparticles loaded with a mixture of siRNAs directed against different cytokines to mice suffering from TH1 cell-mediated lung inflammation, or of siRNA directed against NS-1 in an influenza infection model led to a significant reduction of target gene expression which was accompanied by distinct amelioration of lung inflammation in both models. Thus, this study provides strong evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of inflammatory disorders of the lung.

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs.

Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans.IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

Intervention effect of Qingzao Runfei Huazhuo Xingxue decoction on PM2.5-induced pulmonary injury in mice

To study the effects of Qingzao Runfei Huazhuo Xingxue decoction (QRHXD) on inflammatory reaction and histopathology in mice with PM2.5-induced pulmonary injury, and to approach the possible mechanism of prevention and treatment of traditional Chinese medicine on lung injury induced by haze. Fifty healthy male C57BL/6 mice were randomly divided into five groups (n = 10): namely control, PM2.5, PM2.5 + low-, moderate-, and high-dose groups. The PM2.5 suspensions at a dosage of 40 mg/kg was respectively given to mice by the nasal instillation for reproduction of mouse model of lung injury induced by PM2.5, and the mice in control group were given the same volume of normal saline. The mice in PM2.5 + low-, moderate-, and high-dose QRHXD groups were given 15, 25, 50 mL×kg-1×d-1 QRHXD by oral perfusion daily for consecutive 21 days at the next day of model reproduction (the QRHXD included: Pear 75 g, Bulbus Fritillariae Cirrhosae 10 g, Radix Stemonae 8 g, Rhizoma Pinelliae 8 g, Radix Platycodi 6 g, Aster 10 g, Almond 5 g, Lily 6 g, Rhodiola 4 g, Lotus 3 g, Fructrs Liquidambaris 6 g, Radix Paeoniae Rubra 5 g, Semen Cassiae 6 g). The mice in control and PM2.5 groups were given equivalent volume of normal saline respectively. After treatment for 21 days, the mice were sacrificed, and the left lung was harvested for bronchoalveolar lavage, and the bronchoalveolar lavage fluid (BALF) was collected for determination of levels of acid phosphatase (ACP), alkaline phosphatase (AKP), lactic dehydrogenase (LDH), and albumin (ALB). The right lung was harvested for histopathology observation under light microscope using hematoxylin and eosine (HE) staining. After intranasal instillation of PM2.5 suspension, the levels of ACP, AKP, LDH, and ALB in PM2.5 group were significantly higher than those in control group [ACP (U/L): 3.9±0.4 vs. 1.7±0.3, AKP (U/L): 9.0±1.5 vs. 4.8±0.3, LDH (U/L): 416.7±44.4 vs. 112.5±20.3, ALB (mg/L): 198.7±32.4 vs. 65.8±21.3, all P < 0.05]. Under light microscope, the PM2.5 particles were collected, the alveolar septa were thickened, and the inflammatory cells in the alveolar cavity and pulmonary interstitium were found. On the contrary, after administration of QRHXD, a significant reduction of biochemical indexes was found, which showed a dose-dependent manner. The parameters of PM2.5 + high-dose QRHXD group were significantly lower than those in PM2.5 group [ACP (U/L): 2.1±0.8 vs. 3.9±0.4, AKP (U/L): 5.3±1.4 vs. 9.0±1.5, LDH (U/L): 146.6±29.8 vs. 416.7±44.4, ALB (mg/L): 88.5±26.7 vs. 198.7±32.4, all P < 0.05]. At the same time, the pathological changes in lung tissue were better with the increase of the dose. QRHXD can reduce the pulmonary inflammatory response and tissue damage caused by PM2.5, with the increase concentration of Chinese medicine, and the effect is more obvious. This may be related to the immune response of the human body to regulate inflammatory mediators, which provide basis for the treatment of pulmonary injury induced by PM2.5.

Effects of nasal instillation of a nitric oxide-releasing solution or parenteral administration of tilmicosin on the nasopharyngeal microbiota of beef feedlot cattle at high-risk of developing respiratory tract disease

Nitric oxide has bactericidal and virucidal properties. Nasal instillation of a nitric oxide releasing solution (NORS) on arrival at the feedlot was recently reported as inferior to a parenteral injection of tilmicosin (macrolide antibiotic) for control of bovine respiratory disease (BRD) in cattle at high-risk of developing BRD. We hypothesized that this inferiority was due to differences between treatments with regards to their effects on the nasopharyngeal microbiota. The objective was to compare nasal instillation of NORS versus parenteral administration of tilmicosin regarding their effects on the nasopharyngeal microbiota of feedlot cattle at high-risk of developing BRD. Culture-independent community profiling (16S rRNA sequencing) and culture-based methods were used to evaluate treatment effects. High-risk Angus-cross heifers (n=20) were randomly allocated to 2 treatment groups on arrival at a feedlot and received either NORS or tilmicosin for prevention of BRD. Heifers were sampled using guarded deep nasal swabs immediately prior to treatment (day 0) and on days 1, 5 and 10 after treatment. Based on culture-independent community profiling, there was a distinct shift in composition of the nasopharyngeal microbiota during the first 10 d after arrival, with 116 OTUs changing over time, but no difference between treatment groups. However, culture-based methods detected a difference between treatment groups, with more cattle culture-positive for Pasteurellaceae in the NORS group at day 5 post-treatment. This difference in ability to inhibit colonization of the nasopharynx by Pasteurellaceae may be the basis for NORS being inferior to tilmicosin for control of BRD in high-risk cattle.

Pseudomonas aeruginosa Ventilator-Associated Pneumonia Induces Lung Injury through TNF-α/c-Jun NH2-Terminal Kinase Pathways.

Ventilator-associated pneumonia (VAP) is a common nosocomial infection among intensive care unit (ICU) patients. Pseudomonas aeruginosa (PA) is the most common multidrug-resistant Gram-negative pathogen and VAP caused by PA carries a high rate of morbidity and mortality. This study examined the molecular mechanism of PA VAP-induced lung injury. C57BL/6 wild-type (WT) mice and JNK1 knockout (JNK1-/-) mice received mechanical ventilation (MV) for 3 h at 2 days after receiving nasal instillation of PA. The WT and JNK1-/- mice also received MV after the induction of lung injury by instillation of supernatants from PA-stimulated alveolar macrophages (AMs). AMs isolated from WT, IκB-kinase (IKK)βΔMye (IKKβ was selectively deleted in macrophages), and JNK1-/- mice were ex vivo stimulated with live PA and supernatants were collected for cytokine assay. Intranasal instillation of 106 PA enhanced MV-induced NF-κB DNA binding activity in the lungs and nitrite levels in BALF. MV after PA instillation significantly increased the expression of ICAM and VCAM in the lungs and TNF-α, IL-1β, and IL-6 levels in bronchoalveolar lavage fluid (BALF) of WT mice, but not in JNK1-/- mice. MV after supernatant instillation induced more total protein concentration in BALF and neutrophil sequestration in the lungs in WT mice than JNK1-/- mice and cytokine assay of supernatants indicated that TNF-α is a critical regulator of PA VAP-induced lung injury. Ex vivo PA stimulation induced TNF-α production by AMs from WT as well as JNK1-/- mice but not IKKβΔMye mice. In summary, PA colonization plays an important role in PA VAP-induced lung injury through the induction of JNK1-mediated inflammation. These results suggest that the pathogenesis mechanism of PA VAP involves production of TNF-α through activation of IKK/NF-κB pathways in AMs and JNK signaling pathway in the lungs.

A standardized methanol extract of Eclipta prostrata (L.) L. (Asteraceae) reduces bronchial hyperresponsiveness and production of Th2 cytokines in a murine model of asthma

Ethnopharmacological relevanceEclipta prostrata (L.) L. (Asteraceae) has been used in Brazilian traditional medicine to treat asthma and other respiratory illnesses. Aims of the studyTo investigate the effects of different doses of a standardized extract of E. prostrata using a murine model of allergen induced asthma. Materials and methodsBalb/c mice were sensitized twice with ovalbumin (OVA) administered intraperitoneally and challenged over four alternate days with nasal instillations of OVA solution. The standardized methanol extract of E. prostrata was administered in doses of 100, 250 and 500mgkg−1 concomitantly with nasal instillation over seven consecutive days. Control animals were treated with dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, allergen sensitization, airway and lung inflammation, mucous secretion and airway remodeling were assessed. ResultsThe concentrations of chemical markers in the standardized methanol extract were 0.02% oroboside, 1.69% demethylwedelolactone and 1.71% wedelolactone. Treatment with 250mgkg−1 of extract, which provided 0.745, 4.22 and 4.30mgkg−1day−1 of oroboside, demethylwedelolactone and wedelolactone, respectively, significantly reduced (P<0.05) respiratory resistance and elastance. Such effects were comparable with those produced by dexamethasone. The total number of inflammatory cells and eosinophils in the bronchoalveolar lavage and the concentrations of interleukin (IL)-4, IL-5 and IL-13 in lung homogenate were significantly reduced (P<0.05) by the methanol extract of E. prostrata. ConclusionThe results presented herein demonstrate for the first time the anti-inflammatory activity of E. prostrata in a murine model of asthma, thereby supporting the ethnopharmacological uses of the plant.

Acute changes in murine hippocampus and olfactory bulb after nasal instillation of varying size cerium dioxide particles

ABSTRACTCerium (Ce)-containing compounds are now widely applied in medicine, agriculture, and animal breeding. However, the effects of Ce on humans, especially on the central nervous system (CNS), remain to be determined. In order to investigate whether Ce exposure affected the CNS, the aim of this study was to expose female ICR mice to varying nanoparticle sizes of 35 nm and 300 nm, and to a mixture of 1–5 µM cerium dioxide (CeO2) particles through intranasal (i.n.) instillation at daily dose of 40 mg/kg body weight. Immunohistochemical data showed that glial fibrillary acidic protein expression (GFAP) increased significantly in the hippocampus and olfactory bulb in all Ce-administered groups. The ultrastructure of olfactory bulb cells displayed chromatin reduction. In the hippocampus decreased chromatin was associated with ribosome shedding as evidenced from transmission electron microscopy (TEM). No significant differences in immunohistochemistry were noted between varying sizes of CeO2 groups. The results of inductively coupled plasma–mass spectroscopy (ICP-MS) analysis group exposed to 1–5 µM demonstrated that Ce levels were significantly higher in whole brain (0.17 ng/mg) than for the control (0.04 ng/mg). Data thus demonstrated that i.n. instillation of different sized CeO2 particles induced damage in the olfactory bulb and hippocampus and that CeO2 particle size did not appear to play a role in the observed adverse responses.

Pseudomonas aeruginosa colonization enhances ventilator-associated pneumonia-induced lung injury.

BackgroundPseudomonas aeruginosa (PA) is the single-most common pathogen of ventilator-associated pneumonia (VAP). Large quantities of PA in the trachea of ventilated patients are associated with an increased risk of death. However, the role of PA colonization in PA VAP-induced lung injury remains elusive. This study examined the effect and mechanism of PA colonization in VAP-induced lung injury.MethodsC57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1−/−) mice received mechanical ventilation for 3 h at 2 days after receiving nasal instillation of PA (1 × 106 colony forming unit) or normal saline.ResultsIntranasal instillation of PA or mechanical ventilation induced the expression of interleukin-6 (IL-6) in the lungs. Phospho-JNK protein expression in the lungs was significantly increased in mice receiving mechanical ventilation after PA instillation as compared with those receiving ventilation alone. Mechanical ventilation after PA instillation significantly increased the expression of tumor necrosis factor-α (TNF-α), IL-1β, and macrophage inflammatory protein-2 (MIP-2) proteins; neutrophil sequestration; and TNF-α, IL-1β, and IL-6 levels in the lungs of WT mice, but not in JNK1−/− mice.ConclusionPA colonization plays an important role in PA VAP-induced lung injury through the induction of JNK1-mediated inflammation. PA-induced VAP causes lung injury through JNK signaling pathway in the lungs. JNK inhibition in ICU patients with higher percentages of PA colonization may reduce VAP-induced lung injury and mortality.

Ayurvedic Management of Acute Cerebrovascular Accident – A Case Study

Cerebro vascular accident (CVA) is the third leading cause of death in developing countries. This disease has posed a great problem to the medical field as far as its treatment is concerned. Ayurveda can offer a lot in such conditions. This is a case study of an acute CVA. An acute CVA case was admitted on 23/05/2016 at 7.30 pm, with the complaints of loss of strength in the right side of the body, loss of speech, drowsiness since 2 days. On examination Glasgowcoma scale was 8/15 (E - 2, M- 1, V-2). Investigation i.e., Computed Tomography (CT) scan of head showed on 24/05/2016: Lacunar infarcts in the Right Frontal White matter and in the Pons at the Midline. It was diagnosed as Pitta Kapha Avruta Vataja Pakshaghata (Vaama). In this case various treatment procedures like cold water pouring over forehead, application of medicated paste on anterior frontanallae, application of Shathadhouta Ghrutha all over the body, nasal instillation etc. with oral medicines were adopted at various condition of the disease. There was a remarkable improvement in the subjective and objective clinical features.

Persistence of respiratory and inflammatory responses after dermal sensitization to persulfate salts in a mouse model of non-atopic asthma.

BackgroundExposure to ammonium persulfate (AP) has been reported to be the main cause of occupational asthma in hairdressers. The aim of this study is to assess how long the asthmatic response to AP can be induced after dermal sensitization in a mouse model.MethodsBALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) (control) on days 1 and 8. They then received a single nasal instillation (challenge) of AP or saline on days 15, 22, 29, 36, 45, 60 and 90. Respiratory responsiveness to methacholine was measured 24 h after the challenge using a non-specific methacholine provocation test. Pulmonary inflammation was analysed in bronchoalveolar lavage (BAL), and total serum immunoglobulin (Ig) E, IgG1 and IgG2a were measured in serum samples. Histological analysis of lung slides was performed.ResultsMice dermally sensitized and intranasally challenged with AP showed respiratory responsiveness to methacholine as long as 45 days after initial sensitization, as well as increased percentage of neutrophils in BAL compared with the control group. At day 60, dermally sensitized mice still presented bronchial hyperresponsiveness, while the percentage of neutrophils returned to baseline levels similar to those of controls. Total serum IgE increased significantly on day 22 after dermal sensitization. Total serum IgG1 and IgG2a increased from 45 days after dermal sensitization and remained high at 90 days.ConclusionsBoth respiratory responsiveness to methacholine and airway inflammation responses decrease with increasing time between sensitization and challenge. Respiratory responsiveness to methacholine tends to persist longer than inflammation.

The effectiveness of ayurvedic oil-based nasal instillation (Nasya) medicines in the treatment of facial paralysis (Ardita)

Ardita (facial paralysis) is a medical condition that disfigures or distorts the facial appearance of the sufferer causing facial asymmetry and malfunction. Ardita patients may benefit from considering alternative treatments such as Ayurveda, including Taila Nasya (nasal instillation of medicated oil). To synthesize the best available evidence on the effectiveness of different Nasya oils in the treatment of Ardita. Studies conducted on adult sufferers (18-70 years) of Ardita (chronic or acute) in any setting were considered. Studies including participants who were pregnant or suffered allergic rhinitis, fever, intracranial tumor/hemorrhage and bilateral facial palsy were excluded. Standalone treatment of Nasya (at all dosages and frequencies) compared to Nasya in combination with other Ayurvedic treatments was considered. Comparisons between different interventions including Taila Nasya alone, Taila Nasya in combination with other Ayurvedic interventions and Ayurvedic interventions that did not include Taila Nasya were also considered. Changes in Ardita symptoms, including facial distortion, speech disorders and facial pain, were measured. All quantitative study designs (experimental, quasi-experimental and observational) were considered. Relevant studies were identified following a comprehensive literature search. References provided within these key studies identified additional resources. Indian universities were also contacted for results of Ardita studies undertaken in their institutions.A three-step search strategy aimed to find studies of published and unpublished studies was undertaken. Studies published in the English language were considered for inclusion, irrespective of publication date/year. Following an initial limited search of MEDLINE and CINAHL, the text words contained in the title and abstract, and of the index terms used to describe each articles were analyzed. From the identified keywords and index terms, searches were undertaken across all relevant databases such as PubMed, CINHAL, Cochrane (CENTRAL), Scopus, Centre for Review and Dissemination databases, Turning Research into Practice (TRIP), EMBASE, EBM Reviews, DHARA, Google Scholar, MedNar and ProQuest Dissertations. Finally, reference lists of identified theses and articles were searched for additional studies. Universities and website operators related to Ayurvedic research in India were contacted, including the National Institute of Ayurveda for relevant studies. Besides this, the University of Adelaide librarian was contacted to retrieve those studies identified in the reference lists of theses and articles. Studies were critically assessed by the review author and a secondary reviewer prior to inclusion in the review using the standardized critical appraisal instrument from the Joanna Briggs Institute. Data was extracted by the primary reviewer using the standardized data extraction tool from the Joanna Briggs Institute. Different interventions and comparators across studies precluded meta-analysis. Narrative synthesis was performed. Only two pseudo randomized studies with a small number of participants met inclusion criteria and were included in the review. One study with 20 participants, divided equally into two groups compared the effectiveness of two nasal instillations in alleviating four Ardita symptoms. The second study of 15 participants each in two groups compared the effectiveness of nasal instillation with placement of medicated oil on the head on seven Ardita symptoms. Observational measurements of Ardita symptoms were graded as Mild, Moderate or Marked at baseline and after one month. The study conducted on 30 participants using Nasya intervention showed participants had better relief from the symptoms of facial pain, speech disorder and earache within the range of 78.2% to 90.9%, graded as Marked. Along with statistical data available in the studies, this review found low levels of evidence favoring Taila Nasya intervention. The review did not include any studies examining effectiveness of Nasya compared to conventional treatment for Ardita. This review presents extremely limited evidence from only two small experimental studies that administration of Nasya oil alone may provide some relief from Ardita symptoms of facial distortion, speech disorder, inability to shut eyelids/upward eye rolling and dribbling of saliva in adult patients. No strong conclusions may be drawn from the evidence included in the review due to the limited number of studies, limited number of participants and poor quality of studies. Practitioners should advice Ardita patients that there is extremely limited evidence suggesting the potential effectiveness of Nasya oils alone or Nasya in conjunction with other Ayurvedic treatments in managing symptoms. However, given the absence of a strong evidence base, practitioners should be guided by clinical wisdom and patient preference. Well controlled clinical trials comparing standalone Nasya therapy to other Ayurvedic treatments and/or conventional medicine for Ardita symptoms need to be conducted to examine the relative effectiveness of different Nasya oils in treating Ardita.

Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

In Vitro and in Vivo Antistaphylococcal Activity Determination of the New Recombinant Lysostaphin Protein.

Background:Bacterial infection by antibiotic-resistant Staphylococcus aureus strains is a worldwide concern and the development of novel antistaphylococcal agents is acutely needed. Lysostaphin, an example of such novel agents, is a bacteriocin secreted by S. simulans to kill S. aureus through proteolysis of the Staphylococcus cell wall.Objectives:The aim of this study was to evaluate the in vitro and in vivo antistaphylococcal activity of recombinant lysostaphin.Materials and Methods:The in vitro study of the recombinant lysostaphin activity against S. aureus was determined by turbidimetric assay. For in vivo investigation, two groups of rats were inoculated with 1.4 × 109 CFU S. aureus. Five days after the nasal instillation of S. aureus, treatment in one of the groups was performed with a single dose (200 μg/dose) of recombinant lysostaphin formulated in Eucerin-based cream.Results:Recombinant lysostaphin at 100 μg/mL concentration showed a significant decrease of the optical density compared to the control samples. The in vivo study demonstrated that a single dose (200 μg/dose) of recombinant lysostaphin cream significantly reduced nasal colonization in all the treated animals compared to the untreated ones.Conclusions:These results demonstrated that the recombinant lysostaphin produced in this study was able to kill nasal S. aureus in rats. It can be recommended for human clinical trial studies.

Patient-reported Outcomes from A National, Prospective, Observational Study of Emergency Department Acute Pain Management With an Intranasal Nonsteroidal Anti-inflammatory Drug, Opioids, or Both.

Patient compliance and satisfaction with analgesics prescribed after emergency department (ED) care for acute pain are poorly understood, largely because of the lack of direct patient follow-up with the ED provider. Our objective was to compare patient satisfaction with three analgesia regimens prescribed for post-ED care-a nasally administered nonsteroidal anti-inflammatory drug (NSAID), an opioid, or combination therapy-by collecting granular follow-up on analgesic use, pain scores, side effects, work activity levels, and overall satisfaction directly from patients. We designed a prospective registry linking ED assessment and analgesic management for acute pain of specific musculoskeletal or visceral etiologies with self-reported automated telephonic follow-up daily for the 4days post-ED discharge. Patients were prescribed a specific NSAID (SPRIX, ketorolac tromethamine for nasal instillation) only, an oral opioid only, or both with the opioid clearly defined as rescue therapy, at the ED provider's discretion. There were 824 evaluable subjects. Maximum pain scores improved day to day more effectively with a ketorolac-based approach. Self-reported rates of return to work and work effectiveness were higher with SPRIX than with opioids or combination therapy. Adverse effects of nausea, constipation, drowsiness, and abdominal pain were higher each day among patients taking an opioid; nasal irritation was more common with SPRIX. Overall satisfaction at the end of the follow-up period was higher with SPRIX-based treatment than with opioid monotherapy. Automated telephonic follow-up of ED patients prescribed short-term analgesia is feasible. Ketorolac-based analgesia after an ED visit for many acute pain syndromes was associated with favorable patient outcomes and higher satisfaction than opioid-based therapy. SPRIX, an NSAID that is not available over the counter and has a novel delivery approach, may be useful for short-term post-ED outpatient analgesia.

Randomized, non-inferiority trial comparing a nitric oxide releasing solution with a macrolide antibiotic for control of bovine respiratory disease in beef feedlot calves at high-risk of developing respiratory tract disease

Nitric oxide, a molecule produced in most mammalian cells, has bactericidal and virucidal properties. Nasal instillation of a nitric oxide releasing solution (NORS) on arrival at the feedlot was recently reported as non-inferior to a parenteral injection of a macrolide antibiotic, tilmicosin, for control of bovine respiratory disease (BRD) in cattle at low-to-moderate risk of developing BRD. The objective of this study was to evaluate whether NORS was non-inferior to tilmicosin for control of BRD in cattle at high-risk of developing BRD (the target population for many BRD control programs). High-risk Angus-cross heifers (n=840) were randomly allocated to 2 treatment groups on arrival at a feedlot and received either NORS or tilmicosin for BRD control. Non-inferiority was assessed by calculating the difference in prevalence of heifers diagnosed with BRD during the first 40d after arrival between NORS and tilmicosin treatment groups. The non-inferiority margin (δ) was set at 8.5%. Thirty-six and 19% of heifers were diagnosed with BRD in the NORS and tilmicosin groups, respectively. Because the lower bound of the 2-sided 95% confidence interval (CI) of the difference in BRD prevalence between the 2 treatment groups (17%; 95% CI=11–23%) was higher than δ, an inferiority of NORS was concluded. Although on-arrival nasal administration of NORS can be viewed as a more rational control strategy than parental injection of antibiotics, further research is needed to improve NORS efficacy before it can be recommended to prevent BRD in high-risk cattle.

Peptidergic innervation of the olfactory bulb: a sleep/wake-regulatory route through the nose

Olfactory epithelium receptor neurons in the nasal cavity, which are exposed to the external environment, reach the olfactory bulb (OB), representing a direct port of entry to the brain. Through retrograde axonal transport, pathogens, toxins and misfolded proteins can reach brain cell groups which innervate the OB and result in functional alterations. Indeed, influenza virus nasal instillation was found to target brainstem and hypothalamic cell groups and result in narcoleptic-like sleep/wake changes [1]. These cell groups included the wake-promoting orexin (OX)-containing neurons, and the sleep-promoting melanin-concentrating hormone (MCH)-containing neurons [1]. Orexinergic innervation of the OB has been reported, but OX and MCH neurons innervating the OB have never been visualized. OX immunoreactivity in the mouse olfactory receptor neurons has been ascribed to the olfactory mucosa. Sources of input to the OB have been studied [2] before the discovery of OX in 1998. Orexinergic innervation of the prefrontal cortex is instead well established. Aim of this study was to reveal OX- and MCH-containing neurons projecting to the OB. Unilateral injections of the retrograde fluorescent tracer Fluoro-Gold (FG) confined to the OB of adult mice were combined with immunophenotyping and quantitative analysis of retrogradely labeled neurons. The findings were compared with those obtained after FG injections in the prefrontal cortex. Following FG injections in the OB, labeled neurons were found in the ipsilateral lateral hypothalamus, and included intermingled OX-A- or MCH-immunoreactive cells. About 8% of orexinergic neurons were labeled when the tracer was confined to the OB. This proportion increased (13±2.49 %) in cases in which a faint halo of tracer diffusion to the lateral portion of the prefrontal cortex was observed. Preliminary data indicate retrograde labeling from the OB of almost 15% of MCH-containing neurons. The findings demonstrate that OX and MCH neurons reach the OB directly, thus providing to environmental agents a route to sleep/wake-regulatory nodes via the nasal cavity.

Treatment Effectiveness for Symptoms of Patulous Eustachian Tube: A Systematic Review.

To determine the effectiveness of currently available medical and surgical interventions for treating symptoms of Patulous Eustachian Tube (PET). A comprehensive search of MEDLINE (January 1948 to July 8, 2015), EMBASE (January 1974 to July 8, 2015), gray literature, hand searches, and cross-reference checking. Original published reports evaluating an intervention to treat the symptoms of patulous eustachian tube in patients 18 years and older. Quality-of-case reviews were assessed with the National Institute of Health (NIH) Quality Assessment Tool for Case Series Studies. The search strategy identified 1,104 unique titles; 39 articles with 533 patients are included. The available evidence consists of small case series and case reports. The most common medical treatment was nasal instillation of normal saline. Surgical treatments were categorized as mass loading of the tympanic membrane, eustachian tube plugging, and manipulation of eustachian tube musculature. The available evidence for management of patients with PET is poor in quality and consists predominantly of small case series. Further research is needed to determine the comparative efficacy of the current treatments.

Acute effects of therapeutic 1-MHz ultrasound on nasal unblocking of subjects with chronic rhinosinusitis

AbstractLow-intensity ultrasound therapy (LIUST) has been described as a plausible treatment for chronic rhinosinusitis (CRS).Aims: To evaluate the short-term effects of continuous 1MHz LIUST on nasal obstruction in subjects with CRS.Material and Method: A cohort placebo-controlled study comprising 26 CRS adults (10 men, 16 women), sequentially allocated into two groups: control-placebo (CP, n= 12) and treated with LIUST (US, n= 14). The treatment consisted of: ISATA = continuous 1MHz, 1W.cm-2 for four minutes in the maxillary sinuses and nasal septum. The equipment was switched off in the CP group. The degree of obstruction was assessed by the total volume of secretion expelled (VSEx) after nasal instillation of 5 mL saline solution (NaCl-0.9%) followed by nasal lavage. The volume of expired air (VEA) was assessed with a Glatzel mirror.Results: The data showed an increase (p<0.01) in VSEx and VEA after ultrasound therapy, suggesting a 64% improvement of nasal obstruction compared with the CP group.Conclusions: Continuous LIUST reduced nasal obstruction and congestionç it may be used effectively in the respiratory therapy of CRS patients.