IκBNS induces Muc5ac expression in epithelial cells and causes airway hyperresponsiveness in murine asthma models

Abstract

Background

In allergic asthma, environmental allergens including house dust mite (HDM) trigger pattern recognition receptors and activate downstream signaling pathways including NF-κB pathways not only in immune cells but also in airway epithelial cells. Recent studies have shown that NF-κB activation is regulated positively or negatively depending on the cellular context by IκBNS (encoded by the gene Nfkbid), one of atypical IκB proteins, in the nucleus. Therefore, we hypothesized that IκBNS expressed in immune cells or epithelial cells is involved in the regulation of asthmatic responses.

Aim

To determine the roles of IκBNS in HDM-induced asthmatic responses.

Methods

Roles of IκBNS in HDM-induced airway inflammation and airway hyperresponsiveness (AHR) were examined by using IκBNS-deficient (Nfkbid^-/-) mice. Roles of IκBNS expressed in hematopoietic cells and non-hematopoietic cells were separately evaluated by bone marrow chimeric mice. Roles of IκBNS expressed in murine tracheal epithelial cells (mTEC) were examined by air-liquid interface culture.

Results

HDM-induced airway inflammation and AHR were exacerbated in mice lacking IκBNS in hematopoietic cells. In contrast, HDM-induced airway inflammation was exacerbated but AHR was attenuated in mice lacking IκBNS in non-hematopoietic cells. The induction of Muc5ac, a representative mucin in asthmatic airways, was reduced in Nfkbid^-/- mTEC, whereas the induction of Spdef, a master regulator of goblet cell metaplasia, was not impaired in Nfkbid^-/- mTEC. Moreover, IκBNS bound to and activated the MUC5AC distal promoter in epithelial cells.

Conclusion

IκBNS is involved in inducing Muc5ac expression in lung epithelial cells and causing AHR in HDM-induced asthma models.

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Allergen immunotherapy for insect venom allergy: a systematic review and meta-analysis

Abstract

Background

The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy.

Methods

We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible meta-analysed.

Results

Our searches identified a total of 16,917 potentially eligible studies of which 17 satisfied our inclusion criteria. The available evidence was limited both in volume and quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR=0.08, 95% CI 0.03 to 0.26); meta-analysis showed that it also improved disease specific quality of life (risk difference=1.41, 95% CI 1.04 to 1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modeling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life.

Conclusions

The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established.

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Prevalence of infection with the use of β-tricalcium phosphate as a bone graft substitute during Le Fort I osteotomy

Publication date: Available online 6 November 2016
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): M. Ragaey, J.E. Van Sickels
While grafting with bone substitutes has been shown to provide greater stability in maxillary advancements, infection remains a concern with any material that is placed in close proximity to the maxillary sinus. The purpose of this study was to evaluate the prevalence of infection in maxillary advancements in which a bone graft substitute (β-tricalcium phosphate; β-TCP) was placed at the time of surgery. This was a retrospective study of all maxillary osteotomies. Patients were divided into two groups: group 1 included maxillary osteotomies in which β-TCP was not used; group 2 included any maxillary osteotomy where β-TCP was used. The prevalence of infection, slow healing, and need for second surgery due to infection or non union was noted. Fisher's exact test was used to compare differences between the groups. Records were adequate for 438 patients: group 1 included 297 patients, while group 2 included 141. No infections were noted in either group. In group 2, there was one patient who had delayed union/non-union requiring a second procedure. Statically, there was no significant difference between the two groups (P=0.3219). Based on the data obtained in this study, the use of β-TCP does not increase the incidence of infection or complications when used in Le Fort I maxillary osteotomy.



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Treatment of hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII)

Abstract

Background

Hereditary angioedema with normal C1 esterase inhibitor and mutations in the F12 gene (HAE-FXII) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. It occurs nearly exclusively in women. We report our experience treating HAE-FXII with discontinuation of potential trigger factors and drug therapies.

Methods

The study included 72 patients with HAE-FXII. Potential triggers included estrogen-containing oral contraceptives (eOC), hormonal replacement therapy, or angiotensin-converting enzyme inhibitors. Drug treatment comprised plasma-derived C1 inhibitor (pdC1-INH) for acute swelling attacks and progestins, tranexamic acid and danazol for prevention of attacks.

Results

Discontinuation of eOC was effective in 25/28 (89.3%) of women and led to a reduction of number of attacks (about 90%). After ending hormonal replacement therapy three of 8 women became symptom-free. Three women with exacerbation of HAE-FXII during intake of quinapril or enalapril had no further HAE-FXII attacks after discontinuation of those drugs. Eleven women were treated with pdC1-INH for 143 facial attacks. The duration of the treated facial attacks (mean 26.6 hrs.; SD 10.1 hrs.) was significantly shorter than that of the previous 88 untreated facial attacks in the same women (mean 64.1 hrs.; SD 28.0 hrs.) (P < 0.01). The mean reduction in attack frequency was 99.8% under progestins after discontinuing eOC (16 women), 93.8% under tranexamic acid (4 women) and 100% under danazol (3 women).

Conclusions

For patients with HAE-FXII various treatment options are available which completely or at least partially reduce the number or duration of attacks.

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Pediatric rhinoplasty: A discussion of perioperative considerations and systematic review

Publication date: January 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 92
Author(s): Amar Gupta, Peter F. Svider, Hani Rayess, Anthony Sheyn, Adam J. Folbe, Jean Anderson Eloy, Giancarlo Zuliani, Michael A. Carron
ObjectivesPediatric rhinoplasty has traditionally raised numerous concerns, including its impact on growth as well as the psychological sequelae of undergoing a potentially appearance-altering procedure. Our objective was to critically evaluate available individual patient data relevant to pediatric rhinoplasty, and further discuss perioperative considerations.MethodsA systematic review was conducted using PubMed/MEDLINE databases. Data extracted and analyzed from included studies included patient demographics, surgical indications, operative approaches, outcomes, complications, revision rates, and other clinical considerations.ResultsSeven studies encompassing 253 patients were included, with age ranging from 7 months to 19 years. Two-thirds of patients were male. 41.7% reported antecedent trauma, and common overall surgical indications included "functional aesthetic" (24.5%) followed by cleft lip nasal deformity (15.8%). The majority (79.1%) underwent open approaches, and 71.1% of patients underwent concomitant septal intervention. The most frequently used grafting materials were septal cartilage (52.8%) and conchal cartilage (16.5%). Surgical outcomes were heterogeneous among these studies. Complication rates were only specified in 5 of the 7 studies and totaled 57 patients (39.6%). Aesthetic dissatisfaction (11.8%) and postoperative nasal obstruction (5.6%) were the most commonly reported complications. Revisions were performed in 13.5%.ConclusionRhinoplasty is safe in the pediatric population, although revisions rates appear greater than those reported in adults. This study of 253 represents the largest pooled sample size to date; nonetheless, non-standardized outcome measures, minimal long-term followup data, and lack of discussion regarding psychological sequelae all contribute to the need for further high-quality studies evaluating this topic.



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The effect of the TLR9 ligand CpG-oligodeoxynucleotide on the protective immune response to radiation-induced lung fibrosis in mice

Publication date: December 2016
Source:Molecular Immunology, Volume 80
Author(s): Jing Chen, Xiaoli Tian, Zijie Mei, Yacheng Wang, Ye Yao, Shimin Zhang, Xin Li, Hui Wang, Junhong Zhang, Conghua Xie
CpG-oligodeoxynucleotide (CpG-ODN) is not only reported to protect against airway hyper responsiveness but is also known as a potent vaccine adjuvant for anti-tumor therapy. Little is known about the effect of CpG-ODN in mice with radiation-induced lung fibrosis (RILF), a common late stage form of tissue damage that occurs after thorax radiotherapy (RT). Here, we evaluated the immunomodulatory effects of CpG-ODN on the development of RILF. Mice were divided into four groups: (1) RT, single dose of 12Gy to the whole thorax; (2) CpG, only intraperitoneal injection of CpG-ODN for total 5 weeks; (3) RT+CpG, irradiation plus CpG-ODN treatment before and after irradiation for total 5 weeks; and (4) control (CTL): No RT or CpG-ODN treatment. In this study, we found that CpG-ODN treatment attenuated lung fibrosis and collagen deposition by increasing the number of M1 macrophagocytes, levels of Type-2 cytokines and TGF-β. CpG-ODN administration up-regulated the expression of TLR9 and STAT1 phosphorylation and reversed the expression of Type-2 immune response key transcription factor GATA-3. Activation of the JAK-STAT1 signaling pathway further enhanced M1 macrophage differentiation and Type-1 cytokine production. This study reveals the mitigating effect of early exposure to CpG-ODN on lung injury caused by irradiation in mice. The potential mechanism of action may be related to enhancement of Type-1 immunity. In conclusion, CpG-ODN may be a potential therapeutic target to treat RILF.



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Blue Ear Cyst: A Rare Eccrine Hidrocystoma of the Ear Canal and Successful Endoscopic Excision

Aims. Hidrocystomas are benign cystic growths of the apocrine and eccrine sweat glands. These cystic lesions have been well documented on the face, head, and neck, but rarely in the external auditory canal. Presentation of Case. A 67-year-old woman presented with a bluish cystic mass partially occluding the external auditory canal and interfering with hearing aid use. Lesion was excised completely via a transcanal endoscopic approach with excellent cosmetic results, no canal stenosis, and no recurrence at 1-year follow-up. Discussion. We present a rare eccrine hidrocystoma of the external auditory canal and successful excision of this benign lesion. We describe the surgical management using a transcanal endoscopic approach and follow-up results. An eccrine gland cyst that presents as a mass occluding the external auditory canal is quite rare. There are only a few such cases reported in the literature. These masses can be mistaken for basal cell carcinomas or cholesterol granulomas but can be easily differentiated using histopathology. Conclusion. Eccrine hidrocystoma is a cystic lesion of sweat glands, rarely found in the external auditory canal. A characteristic bluish hue aids in diagnosis and surgical excision using ear endoscopy provides excellent control.

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Giant Coronary Artery Aneurysm Causing Acute Anterior Myocardial Infarction

A 70-year-old man with hypertension was admitted to our coronary ICU with acute anterior MI. Emergent primary PCI was planned and coronary angiography was performed. LAD artery was totally occluded in the proximal segment just after a huge 32 × 26 mm sized aneurysm. Emergent CABG operation was performed in 75 minutes because of multivessel disease including the RCA and left circumflex artery. Aneurysm was ligated and coronary bypass was performed using LIMA and saphenous grafts. The postoperative course of the patient was uneventful. He was discharged with medical therapy including ASA, clopidogrel, and atorvastatin. He was asymptomatic at his polyclinic visit in the first month.

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Becker’s Nevus Syndrome in a Pediatric Female Patient

Becker's nevus syndrome is part of the epidermal nevus syndromes and has been described with a phenotype that includes Becker's nevus, ipsilateral breast hypoplasia, and variable skeletal malformations. It is more frequent in males than in females (5 : 1) but is more relevant in females. The diagnosis is clinically based and the skin lesion must be present and no other numbered criteria have been established, but with more criteria being present the possibility of the diagnosis is higher. Regarding the treatment of breast hypoplasia, the use of antiandrogen medication has demonstrated adequate clinical response in a dose of 50 mg/day of spironolactone.

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A Teenage Girl with Acute Dyspnea and Hypoxemia during Red Blood Cell Transfusion

Transfusion-related acute lung injury (TRALI) can cause morbidity and mortality. We present the case of teenager who developed dyspnea and hypoxemia few hours after red cell transfusion. After being admitted for close monitoring and oxygen therapy, her symptoms spontaneously resolved. Message: dyspnea during red cell transfusion should raise the suspicion of TRALI.

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A Case of Ameloblastic Fibroodontoma Extending Maxillary Sinus with Erupted Tooth: Is Transcanine Approach with Alveolectomy Feasible?

Ameloblastic fibroodontoma (AFO) is a rare entity of mixed odontogenic tumors and frequently arises from posterior portion of the maxilla or mandible in first two decades of life. Herein, a 35-year-old woman with a noncontributory medical history who presented with a progressive left maxillary toothache, left maxillary first molar tooth mobility, and swelling in the left maxillary molar area for the last 2 months was reported. Radiologically, a tumor that originated from periapical area of the second mature molar teeth of maxilla was seen and additively unerupted tooth was not detected. The histopathologic examination revealed AFO. The patient is disease-free for five years after treated with limited segmental alveolectomy combining with Caldwell-Luc procedure.

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Lung Ultrasound in Early Diagnosis of Neonatal Ventilator Associated Pneumonia before Any Radiographic or Laboratory Changes

Neonatal pneumonia is reported to be the primary cause of neonatal respiratory failure and one of the common causes of neonatal hospitalization and death in developing countries. Chest X-ray was considered the gold standard for diagnosis of neonatal pneumonia. Lung ultrasonography has been described as a valuable noninvasive tool for the diagnosis of many neonatal pulmonary diseases. We report a case of ventilation associated neonatal pneumonia with very early diagnosis using lung ultrasound before any significant radiographic changes in chest X-ray or laboratory findings suggestive of infection.

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ORMDL3 transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide

Publication date: Available online 5 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Marina Miller, Peter Rosenthal, Andrew Beppu, Ruth Gordillo, David H. Broide

Teaser

ORMDL3 is highly linked to asthma in genetic association studies. Mice with increased human ORMDL3 expression have reduced levels of sphingolipids. ORMDL3 regulation of sphingolipid levels may play a role in the pathogenesis of asthma.


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Prenatal phthalate exposure associates with low regulatory T cell numbers and atopic dermatitis in early childhood – results from the LINA mother-child study

Publication date: Available online 5 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Gunda Herberth, Arkadiusz Pierzchalski, Ralph Feltens, Mario Bauer, Stefan Röder, Sven Olek, Denise Hinz, Michael Borte, Martin von Bergen, Irina Lehmann

Teaser

Exposure to high concentrations of the phthalate metabolite mono-isobutyl phthalate (MiBP) in the prenatal period is a risk factor for atopic dermatitis in early childhood, presumably by inhibiting the development of regulatory T cells.


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Occurrence and fumonisin B 2 producing potential of Aspergillus section Nigri in Brazil nuts

Abstract

Bertholletia excelsa is the tree that produces Brazil nuts which have vast economic importance in the Amazon region and as an export commodity. The aim of this study was to assess the presence of Aspergillus section Nigri in Brazil nut samples at different stages of its production chain and to verify the toxigenic potential for fumonisin B₂ (FB₂) production of these isolates along with the presence of this mycotoxin in Brazil nut samples. The fungal infection ranged from 0 to 80% at the different stages of the harvest and processing chain and the water activity of the nuts from 0.273 to 0.994. A total of 1052 A. section Nigri strains were isolated from Brazil nuts and 200 strains were tested for their ability to produce FB₂: 41 strains (20.5%) were FB₂ producers with concentrations ranging from 0.09 to 37.25 mg/kg; 2 strains (1%) showed traces of FB₂, less than the detection limit (0.08 mg/kg); and 157 (78.5%) were not FB₂ producers. Although several samples showed high contamination by A. section Nigri, no sample was contaminated by FB₂.

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Septooptic Dysplasia with an Associated Arachnoid Cyst

A 4-week-old male infant presented with hypothermia, hypoglycemia, and hyperbilirubinemia. His medical history was remarkable for hydrocephalus secondary to an arachnoid cyst, intermittent hypoglycemia, hypothermia, and poor feeding requiring nasogastric tube for nutrition. Physical exam revealed retrognathia, mild hypotonia, micropenis, and clinodactyly. Ophthalmologic exam demonstrated bilateral optic nerve hypoplasia (ONH). Laboratory data confirmed inadequate cortisol and growth hormone response to hypoglycemia, a low thyroxine level, and direct hyperbilirubinemia. Magnetic resonance imaging of the brain confirmed the known history of arachnoid cyst with hydrocephalus but also revealed anterior pituitary hypoplasia, absence of the posterior pituitary bright spot, a thin pituitary stalk, and bilateral optic nerve hypoplasia. A diagnosis of septooptic dysplasia (SOD) was made. Hormone replacement with hydrocortisone and levothyroxine was started with improvement in the infant's glycemic control, thermoregulation, feeding, and cholestasis. This case reinforces the importance of careful physical examination and laboratory review in a patient with known history of arachnoid cyst which has been previously described as an associated feature of optic nerve hypoplasia and hypopituitarism.

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