We Need to Talk About Notch:Notch Dysregulation as an Epiphenomenon in Inflammatory Skin Disease

Abstract

The Notch signaling pathway is a highly evolutionarily conserved signaling pathway comprised of four type 1 transmembrane receptors. Canonical Notch signaling is stimulated by Jagged and Delta ligands resulting in translocation of the Notch Intracellular domain (ICD) to the nucleus resulting in activation of transcription factor CSL. Increased Notch activity is associated with epidermal keratinocyte maturation, proliferation and innate immune activation through maturation of dendritic cells, T cells and macrophages.

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IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Abstract

Psoriasis vulgaris (PV) results from activation of IL‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin derived pro‐inflammatory cytokines, IL‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL‐23 and IL‐36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL‐36 receptor (IL‐36R) was interrogated. Anti‐mouse IL‐36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL‐36α induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL‐36 signaling in IL‐23/Th17 pathway, the ability of anti‐IL‐36R mAbs to inhibit skin inflammation in an IL‐23 ear injection model was assessed. Inhibiting the IL‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, this data suggests a role for IL‐36 signaling in the IL‐23/Th17 signaling axis in PV.

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Diagnostik beim nichtkleinzelligen Lungenkarzinom

Zusammenfassung

Grundlage für die Behandlung des nichtkleinzelligen Lungenkarzinoms sind eingehende Kenntnisse der zugrunde liegenden Krankheitscharakteristikamerkmale und der verschiedenen Therapieoptionen. Die Ergebnisse der Diagnostik sollten in einer interdisziplinären Tumorkonferenz eingeordnet werden. Die präzise Histologie und die genaue TNM-Klassifikation sind prognoserelevant und führen zu einer individuellen und optimalen Therapie. Der vorliegende Artikel wurde basierend auf nationalen und internationalen Leitlinien sowie auf einer selektiven PubMed-Suche erstellt.

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Syringocystadenoma papilliferum of the cervix presenting as vulvar growth in an adolescent girl

Summary

Syringocystadenoma papilliferum (SCP) is a rare, benign, adnexal tumour of apocrine or eccrine differentiation. It is commonly located on head and neck region. We report the case of an 18‐year‐old woman who presented with a vulvar lobulated growth that was found to arise from the posterior lip of cervix. Histopathological examination revealed the diagnosis of SCP. To our knowledge, SCP arising from the cervix has never been reported previously in the literature, thus we believe this to be the first case of SCP arising from the posterior lip of the cervix.

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Evaluation of the efficacy of microneedle fractional radiofrequency in Turkish patients with atrophic facial acne scars

Summary

Background

Scarring is an undesirable and severe complication of acne resulting in loss of self‐esteem in young people. Although microneedle fractional radiofrequency (MFR) system has emerged as a good option to treat acne scars in recent years, it was examined in a few studies which were commonly from Asian countries.

Aims

We sought to evaluate the efficacy of MFR in Turkish patients with facial acne scars.

Methods

Nine patients with atrophic facial acne scars treated with MFR device were included in the study. The number of treatment sessions was varied from one to five (median three) with 4‐week intervals. Demographic and basal clinical features were recorded. Efficacy of the device was evaluated by the physicians' global assessment and patients' self‐assessment scales 4 weeks after the last treatment session.

Results

Of nine patients, two were male and seven were female (mean age, 31.33 years). Two patients had mild, four had moderate, and three had severe facial acne scars. Mean acne scar age was 13.22 ± 8.79 years. According to the predominant scar subtype, three patients had V‐shaped, three had U‐shaped, and three had M‐shaped atrophic acne scars. A clinical improvement of >25% has been reported in seven patients (77.7%) and eight patients (88.9%) by the physicians and patients, respectively. U‐shaped atrophic acne scars responded better to the treatment than the other types, as statistically nonsignificant. There were no severe side effects.

Conclusions

Microneedle fractional radiofrequency system showed a quite good efficacy and safety in the treatment of atrophic facial acne scars (Department of Dermato‐Cosmetology, Uludag University Medical School).

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Craniofacial and Dental Manifestations of Melnick–Needles Syndrome: Literature Review and Orthodontic Management

The aim of this article was to present a characteristic clinical image of Melnick–Needles syndrome using an example of an 11.5-year-old female patient treated at the Facial Congenital Disorders Outpatient Clinic as well as to present the actual literature review of the surgical treatment. The patient was diagnosed with several characteristics typical for Melnick–Needles syndrome: single-sided hearing loss, malocclusion, and facial dysmorphism, among others. Due to malocclusion and facial dysmorphism, the patient with Melnick–Needles syndrome requires orthodontic treatment with surgical intervention. Mandibular distraction with fixed appliance treatment is a recommended treatment protocol.

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Cochlear Ossification in a Patient with Cogan’s Syndrome Undergoing Bilateral Cochlear Implantation

We present the case of a young female patient diagnosed with Cogan's syndrome after the rapid onset of profond hearing and vestibular loss with concomitant eye symptoms. After appropriate medical treatment, her hearing did not respond and she underwent bilateral simultaneous cochlear implantation with findings of extensive cochlear ossification in both ears. The case and outcome are described in the body of the paper.

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Dividing neutrophils in subsets, reveals a significant role for activated neutrophils in the development of airway hyperreactivity

Abstract

Background

Previous research has emphasized the importance of eosinophils in allergic asthma, while paying less attention to neutrophils. The known functionality of neutrophils in the inflammatory process has recently changed and knowledge about subsets of neutrophils, as characterized by their expression of CD16 and CD62L, has surfaced. Their specific roles in asthma are still unknown.

Objective

To study the functional differences between subsets of neutrophils by characterising the impact of individual subsets on airway smooth muscle reactivity.

Methods

The direct effect of neutrophils on airway hyper‐responsiveness was assessed by co‐culturing different subsets of neutrophils (produced by LPS in vitro stimulation) with human isolated small airways or murine tracheae with subsequent evaluation of smooth muscle reactivity to bradykinin in myographs. Supernatants and tissue were saved for ELISA and immunohistochemistry.

Results

The CD16^highCD62L^dim neutrophils were found to enhance the response to bradykinin in both human isolated small airways and murine tracheae. No such effects were obtained for the other subsets. The response is due to an upregulation of bradykinin receptor 2 through release of TNFα from the neutrophil.

Conclusions & Clinical Relevance

The present study introduces a new concept regarding the role of neutrophils and defines a novel direct link between a specific activated neutrophil subset and airway smooth muscle, establishing neutrophils as important players in the development of asthmatic airway hyperactivity.

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Variability of blood eosinophils in patients in a clinic for severe asthma

Abstract

Background

Blood eosinophils are used to determine eligibility for agents targeting IL‐5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation.

Objective

To characterize variability and patterns of variability of blood eosinophil levels in a real‐world clinic for severe asthmatics.

Methods

Retrospective review of blood eosinophils measured over a 5‐year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analyzed.

Results

Patients treated in the Bellevue Hospital Asthma Clinic within a 3‐month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n= 13) of patients had levels that were consistently above 300 cells/μL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/μL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/μL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures.

Conclusion

In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability. These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.

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Traffic‐related air pollution induces non‐allergic eosinophilic airway inflammation and cough hypersensitivity in guinea pigs

Abstract

Background

The pathogenesis and pathophysiology of eosinophilia‐related chronic cough such as non‐asthmatic eosinophilic bronchitis and cough variant asthma are still not clear.

Objective

This study is to examine the potential role of traffic‐related air pollution (TRAP) in eosinophilic inflammation and cough responses.

Methods

Non‐sensitized guinea pigs were exposed to TRAP in an urban traffic tunnel or kept in a filtered air environment for 7 or 14 days. Reflexive cough was measured using citric acid and allyl isothiocyanate (AITC) challenges, respectively. Spontaneous cough counting was determined using audio recording and a waveform analysis. Airway inflammation was evaluated using differential cells in bronchoalveolar lavage fluid (BALF) and lung histopathology. To further elucidate the relationship between airway inflammation and cough hypersensitivity, a subgroup of those exposed for 14 days received a dexamethasone treatment.

Results

Compared to reflexive cough count (mean (95% confidence interval) in 10 min) provoked by the AITC challenge for the unexposed animals (3.1 (1.7‐4.5)), those were increased significantly following both the 7‐day (12.0 (6.8‐17.2), p<0.01) and the 14‐day (12.0 (6.4‐17.6), p<0.01) TRAP exposure. The effect provoked by the citric acid challenge was more profound following the 14‐day exposure (26.0 (19.5‐32.5) vs. 3.8 (1.5‐6.0) for the control, p<0.001). TRAP exposures enhanced spontaneous cough events, caused a significant increase of eosinophils and neutrophils in BALF, and resulted in a dramatic eosinophilic infiltration in submucosal layer of trachea and bronchus, which can be inhibited significantly by dexamethasone treatment.

Conclusions & Clinical Relevance

TRAP exposures induced cough hypersensitivity and non‐allergic eosinophilic inflammation of airways in guinea pigs. This study highlights the potential mechanisms of eosinophilia‐related chronic cough that can be induced by traffic‐related air pollution.

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Antihistamine‐resistant chronic spontaneous urticaria: 1‐year data from the AWARE study

Abstract

Background

Previous reports indicate that patients with chronic spontaneous urticaria (CSU) are undertreated and that physicians show poor adherence to guideline recommendations. Awareness of CSU has improved in recent years, but it remains unclear if this has improved the management of these patients in clinical practice.

Objective

To describe disease burden, quality of life (QoL), and treatment patterns of patients with H₁‐antihistamine‐refractory CSU in Germany.

Method

AWARE (A World‐wide Antihistamine‐Refractory chronic urticaria patient Evaluation) is a global prospective, non‐interventional study of chronic urticaria in the real‐world setting, supported by the manufacturer of omalizumab. Patients (18–75 years) were included who had H₁‐antihistamine‐refractory CSU for ≥2 months. Disease characteristics, pharmacological treatments, and QoL (dermatology life quality index [DLQI], chronic urticaria QoL questionnaire, and angioedema QoL questionnaire) are reported for patients enrolled in Germany.

Results

After 1 year in AWARE, CSU remained uncontrolled (urticaria control test [UCT] score <12) in 432 of 1032 (42.2%) patients. QoL impairment remained high after one year, with 28.2% of patients reporting that CSU had a moderate/very large/extremely large effect on the DLQI. Most patients did not receive guideline‐recommended treatments at the end of the one‐year observation period. Changes in treatments were most evident at the first patient visit, with an increase in patients receiving omalizumab vs. prior therapy from 8.5% to 21.4%, and a decrease in those receiving no treatment from 29.9% to 12.8%. These changes were associated with reduced hives, angioedema, UCT scores, and QoL scores at Month 3, but only modest improvements thereafter. Of 528 patients with uncontrolled CSU and who were eligible for treatment escalation, only 3% received up‐dosing of H₁‐antihistamines and only 5% were initiated on omalizumab during one year of treatment.

Conclusions & Clinical Relevance

This study highlights a significant discrepancy between recommendations for managing CSU in international guidelines, and in real‐world clinical practice in Germany.

This article is protected by copyright. All rights reserved.

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Bidirectional roles of IL-22 in the pathogenesis of allergic airway inflammation

Publication date: Available online 10 November 2018

Source: Allergology International

Author(s): Takashi Ito, Koichi Hirose, Hiroshi Nakajima

Abstract

Asthma is the most prevalent allergic disease of the airway, which is characterized by eosinophilic inflammation, mucus hyperproduction, and airway hyper-responsiveness. Although these pathognomonic features are mainly mediated by antigen-specific Th2 cells and their cytokines, such as IL-4, IL-5, and IL-13, recent studies have revealed that other inflammatory cells, including Th17 cells and innate lymphoid cells (ILCs), also play a critical role in the pathogenesis of asthma. IL-22, one of the cytokines produced by Th17 cells and type 3 ILCs, has distinct functional properties, as IL-22 exclusively acts on non-hematopoietic cells including epithelial cells of mucosal surface and exhibits a broad range of action in regeneration and host protection. In accordance with the fact that lung epithelial cells play a critical role in the pathogenesis of asthma, we and other groups have shown that IL-22 is involved in the regulation of allergic airway inflammation. In this review, we discuss recent advances in the biology of IL-22 and its involvement in the pathogenesis of allergic airway inflammation.

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Implementing universal newborn hearing screening in the French Rhône-Alpes region. State of affairs in 2016 and the 1st half of 2017

Publication date: Available online 10 November 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Lorène Bouillot, Maurice Vercherat, Catherine Durand

ABSTRACT

Introduction

Universal newborn hearing screening (UNHS) started as public health policy in 2015 in the French Rhône-Alpes region, aiming to screen for unilateral and bilateral hearing loss. After a first and second screening (retest) in the maternity hospital, the diagnostic process occurred at a limited number of specialist centers. A deferred preliminary screening (T3) was proposed before the age of 1 month. The aims of this study were to assess implementation of the program, impact of T3, and present the incidence of hearing loss in this population.

Materials and methods

The retrospective observational study was based on data transmitted routinely by the 51 maternities to the regional organization responsible for newborn screening, in 2016 and first half of 2017.

Results

All the facilities implemented the UNHS protocol, with 47 out of 51 using the recommended techniques. 99.7% of the 115,435 newborns were screened (excluding 0.2% of parental refusals). A retest was required for 10.2% of the babies. Among babies who didn't pass retest, 7.7% were lost to follow-up. 2.2% of the newborns were referred to diagnostic centers. The rate of T3 was 31.3% of newborns who did not pass retest. 88.6% of the infants passed T3. In the perinatal network making extensive use of T3 (75.8 % versus 14.9% elsewhere), 0.6 % of the infants were referred to a diagnostic center, versus 2.9% in the rest of the region (2016, p<0.001). For 2016, the outcomes at 6 months revealed an overall hearing loss rate of 1.7‰ (4.7‰ for neonatal care unit babies), and bilateral hearing loss in 1.2‰.

Conclusion

In Rhône-Alpes, the national and regional objectives for UNHS were exceeded, although limiting the number of infants lost to follow-up remains essential. Repeating an automated test around 2-4 weeks after birth improves the program by decreasing the false positives of the screening. It considerably limits the number of infants referred to specialist centers, without increasing the number of patients lost to follow-up.

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A 3-Dimensional Bioprinted Tracheal Segment Implant Pilot Study: Rabbit Tracheal Resection with Graft Implantation

Publication date: Available online 10 November 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Rachel Kaye, Todd Goldstein, Daniel A. Grande, David Zeltsman, Lee P. Smith

Abstract

Objectives

Surgical reconstruction of tracheal disease has expanded to include bioengineering and three dimensional (3D) printing. This pilot study investigates the viability of introducing a living functional tracheal replacement graft in a rabbit animal model.

Methods

Seven New Zealand White rabbits were enrolled and six completed participation (one intraoperative mortality). Tracheal replacement grafts were created by impregnating 3D printed biodegradable polycaprolactone (PCL) tracheal scaffolds with rabbit tracheal hyaline chondrocytes. 2cm of native trachea was resected and the tracheal replacement graft implanted. Subjects were divided into two equal groups (n=3) that differed in their time of harvest following implantation (three or six weeks). Tracheal specimens were analyzed with intraluminal telescopic visualization and histopathology.

Results

The two groups did not significantly differ in histopathology or intraluminal diameter. All sections wherein the implant telescoped over native trachea (anastomotic ends) contained adequate hyaline cartilage formation (i.e. chondrocytes within lacuna, surrounding extracellular matrix, and strong Safranin O staining). Furthermore, the PCL scaffold was surrounded by a thin layer of fibrous tissue. All areas without membranous coverage contained inadequate or immature cartilage formation with inflammation. The average intraluminal stenosis was 83.4% (range 34.2-95%).

Conclusions

We report normal cartilage growth in a tracheal replacement graft when chondrocytes are separated from the tracheal lumen by an intervening membrane. When no such membrane exists there is a propensity for inflammation and stenosis. These findings are important for future construction and implantation of tracheal replacement grafts.

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Beals Syndrome with Middle and Inner Ear Dysplasia and Encephalocele: A Case Report and Review of Imaging Findings

Publication date: Available online 10 November 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Elizabeth K. Weidman, Peter F. Morgenstern, C. Douglas Phillips, Jeffrey P. Greenfield, Theodore H. Schwartz, Linda A. Heier

Abstract

A 10-year-old male with history of Beals syndrome presented with hearing loss and was found to have middle and inner ear dysplasia and left temporal encephalocele on imaging. Beals syndrome is a rare autosomal dominant connective tissue disorder caused by a mutation in the fibrillin-2 gene. Skeletal manifestations of Beals have been reported, including anomalies of the long bones, calvarium, and spine. External ear abnormalities with "crumpled ear" deformity are seen in the majority of patients. This is the first case to report imaging findings of the middle and inner ear in a patient with Beals.

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New insights into immune cells cross-talk during IgG4-related disease

Publication date: Available online 10 November 2018

Source: Clinical Immunology

Author(s): Fahd Touzani, Agnieszka Pozdzik

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a newly acknowledged entity, characterized by an immune-mediated fibro-inflammatory process affecting virtually all organs, with infiltration of IgG4⁺ bearing plasma cells. Until today the pathogenesis of IgG4-RD remains unknown. Treatment with anti-CD20 monoclonal antibodies efficiently induced remission and attenuated the secretory phenotype of myofibroblasts responsible of uncontrolled collagen deposition. This supports the pathogenic role of the adaptive immunity, particularly B cell compartment and B cell/T cell interaction. Latest studies have also highlighted the importance of innate immune system that has been underestimated before and the key role of a specific T cell subset, T follicular helper cells that are involved in IgG4-class-switching and plasmablast differentiation. In this review, we aim to review the most recent knowledge of innate immunity, T and B cells involvement in IgG4-RD, and introduce tertiary lymphoid organs (TLO) as a potential marker of relapse in this condition.

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A comparison of the 7th and 8th editions of the AJCC staging system in terms of predicting recurrence and survival in patients with papillary thyroid carcinoma

Publication date: December 2018

Source: Oral Oncology, Volume 87

Author(s): Sung Hoon Nam, Mi Rye Bae, Jong-Lyel Roh, Gyungyup Gong, Kyung-Ja Cho, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim

Abstract

Objectives

The recently published 8th edition of the American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) staging system was significantly updated following the thyroid cancer-related guidelines to provide better predictability of survival but not focus on recurrence. Therefore, we compared the predictive values of the 7th and 8th editions of the AJCC staging systems for recurrence-free survival (RFS) and overall survival (OS) after thyroidectomy for papillary thyroid carcinoma (PTC).

Methods

This retrospective study included 2930 patients who underwent thyroidectomy and neck dissection for previously untreated PTC between 2006 and 2014. TNM stage was defined according to 7th and 8th editions. Univariate and multivariate Cox proportional hazard regression analyses were used to identify associations between variables and RFS or OS. Multivariate models for the AJCC TNM stages were adjusted for clinical and pathological variables.

Results

A significant number of patients classified as T3 with overall TNM stages II–IV in the AJCC 7th edition were down-staged in the 8th edition. Unadjusted T classification and overall TNM staging in both the 7th and 8th editions were significantly associated with RFS and OS rates (P < 0.001). After adjustment for clinicopathological factors, the overall TNM stage according to the AJCC 8th edition, but not the 7th edition, remained significantly associated with RFS and OS (P < 0.05), with better predictability of recurrence and survival, in patients with PTC.

Conclusions

The 8th edition AJCC staging system down-staged a large proportion of PTC patients, resulting in better predictability of recurrence and survival compared to the previous staging system.

Condensed abstract

This study compared the abilities of the 7th and 8th edition AJCC staging systems to predict recurrence and overall survival in 2930 patients with papillary thyroid carcinoma. The updated guidelines down-staged a large proportion of patients, resulting in better prediction of recurrence and survival than the previous staging system.

https://ift.tt/2Fh1iog

Potential application of tumor suppressor microRNAs for targeted therapy in head and neck cancer: A mini-review

Publication date: December 2018

Source: Oral Oncology, Volume 87

Author(s): Isaac Olatunji

Abstract

Head and neck cancer remains a leading cause of death worldwide. Most common available treatment methods which include surgery, radiotherapy, and chemotherapy are associated with numerous side effects. MicroRNA therapeutics is an emerging form of gene therapy with potential for use in treatment of head and neck cancer. MicroRNAs are short nucleotide RNAs that target mRNAs (messenger RNA) to regulate gene expression at the post-transcription level. They may act as either tumor suppressor or oncogene in cancer. In the past, their potential use in cancer management (diagnosis, treatment, prognosis prediction), based on their deregulation have been demonstrated and written about but summaries on their application for targeted therapy are limited. This article aims at discussing the potential of some known tumor suppressor microRNAs for treatment of head and neck cancer, either alone or in combination with other treatment forms. It also aims at highlighting some obstacles against their use. The search for literature was done on PubMed using the search term: "MicroRNA based head and neck cancer treatment". Only free full text original articles on specific microRNAs and their tumor suppressive abilities in head and neck cancer, written in English language were used. Most of the studies demonstrated the ability of microRNAs to inhibit tumor growth by targeting specific oncogenes in cancer cells. Tumor suppressor microRNAs show promise for the treatment of head and neck cancer but more researches are needed to further clear areas of concern.

https://ift.tt/2qBp58i