Macrophage polarization differs between apical granulomas, radicular cysts, and dentigerous cysts

Abstract

Objectives

Apical periodontitis can appear clinically as apical granulomas or radicular cysts. There is evidence that immunologic factors are involved in the pathogenesis of both pathologies. In contrast to radicular cysts, the dentigerous cysts have a developmental origin. Macrophage polarization (M1 vs M2) is a main regulator of tissue homeostasis and differentiation. There are no studies comparing macrophage polarization in apical granulomas, radicular cysts, and dentigerous cysts.

Materials and methods

Forty-one apical granulomas, 23 radicular cysts, and 23 dentigerous cysts were analyzed in this study. A tissue microarray (TMA) of the 87 consecutive specimens was created, and CD68-, CD11c-, CD163-, and MRC1-positive macrophages were detected by immunohistochemical methods. TMAs were digitized, and the expression of macrophage markers was quantitatively assessed.

Results

Radicular cysts are characterized by M1 polarization of macrophages while apical granulomas show a significantly higher degree of M2 polarization. Dentigerous cysts have a significantly lower M1 polarization than both analyzed periapical lesions (apical granulomas and radicular cysts) and accordingly, a significantly higher M2 polarization than radicular cysts. Macrophage cell density in dentigerous cysts is significantly lower than in the periapical lesions.

Conclusions

The development of apical periodontitis towards apical granulomas or radicular cysts might be directed by macrophage polarization. Radicular cyst formation is associated with an increased M1 polarization of infiltrating macrophages. In contrast to radicular cysts, dentigerous cysts are characterized by a low macrophage infiltration and a high degree of M2 polarization, possibly reflecting their developmental rather than inflammatory origin.

Clinical relevance

As M1 polarization of macrophages is triggered by bacterial antigens, these results underline the need for sufficient bacterial clearance during endodontic treatment to prevent a possible M1 macrophage-derived stimulus for radicular cyst formation.

http://ift.tt/2reC7Yp

Ventilator Management of Bronchopleural Fistula Secondary to Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia in a Pregnant Patient with Systemic Lupus Erythematosus

Managing mechanical ventilation in patient with bronchopleural fistula with coexisting acute respiratory distress syndrome is a challenging situation for the intensivist. We are reporting a case of a pregnant patient with systemic lupus erythematosus on immunosuppressive medications who developed methicillin-resistant Staphylococcus aureus necrotizing pneumonia complicated by bronchopleural fistula and acute respiratory distress syndrome.

http://ift.tt/2refgw2

Hypoxia-based strategies for regenerative dentistry—Views from the different dental fields

Publication date: September 2017
Source:Archives of Oral Biology, Volume 81
Author(s): Anna Sonja Müller, Klara Janjić, Bledar Lilaj, Michael Edelmayer, Hermann Agis
The understanding of the cell biological processes underlying development and regeneration of oral tissues leads to novel regenerative approaches. Over the past years, knowledge on key roles of the hypoxia-based response has become more profound. Based on these findings, novel regenerative approaches for dentistry are emerging, which target cellular oxygen sensors. These approaches include hypoxia pre-conditioning and pharmacologically simulated hypoxia. The increase in studies on hypoxia and hypoxia-based strategies in regenerative dentistry highlights the growing attention to hypoxia's role in regeneration and its underlying biology, as well as its application in a therapeutic setting.In this narrative review, we present the current knowledge on the role of hypoxia in oral tissues and review the proposed hypoxia-based approaches in different fields of dentistry, including endodontics, orthodontics, periodontics, and oral surgery.



http://ift.tt/2r4SQjK

Hypoxia-based strategies for regenerative dentistry—Views from the different dental fields

Publication date: September 2017
Source:Archives of Oral Biology, Volume 81
Author(s): Anna Sonja Müller, Klara Janjić, Bledar Lilaj, Michael Edelmayer, Hermann Agis
The understanding of the cell biological processes underlying development and regeneration of oral tissues leads to novel regenerative approaches. Over the past years, knowledge on key roles of the hypoxia-based response has become more profound. Based on these findings, novel regenerative approaches for dentistry are emerging, which target cellular oxygen sensors. These approaches include hypoxia pre-conditioning and pharmacologically simulated hypoxia. The increase in studies on hypoxia and hypoxia-based strategies in regenerative dentistry highlights the growing attention to hypoxia's role in regeneration and its underlying biology, as well as its application in a therapeutic setting.In this narrative review, we present the current knowledge on the role of hypoxia in oral tissues and review the proposed hypoxia-based approaches in different fields of dentistry, including endodontics, orthodontics, periodontics, and oral surgery.



http://ift.tt/2r4SQjK

Dupilumab Improves General Health-Related Quality-of-Life in Patients with Moderate-to-Severe Atopic Dermatitis: Pooled Results from Two Randomized, Controlled Phase 3 Clinical Trials

Abstract

Introduction

Patients with moderate-to-severe atopic dermatitis (AD) report a multidimensional disease burden that includes impaired health-related quality-of-life (HRQoL). Changes in overall health status and specific dimensions that contribute to HRQoL were evaluated in adults with moderate-to-severe AD who participated in phase 3 clinical trials of dupilumab, which is a fully human monoclonal antibody that inhibits signaling of cytokines IL-4 and IL-13.

Methods

Two dupilumab phase 3 clinical trials of identical design included the 5-dimension 3-level EuroQol (EQ-5D) as a measure of HRQoL. EQ-5D data from the two trials were pooled in an analysis that, using analysis of covariance, compared subcutaneous dupilumab 300 mg once weekly (qw) or every 2 weeks (q2w) versus placebo for EQ-5D utility score change from baseline overall and for clinical responders. The proportions of patients who reported different levels of problems on the individual dimension of the EQ-5D were also compared by treatment group.

Results

Patients (n = 1379) were 57.9% male with a mean (SD) age of 38.3 (14.3) years; baseline EQ-5D utility scores ranged from 0.611 to 0.629 across treatment groups. EQ-5D least squares mean change from baseline at week 16 was 0.031 with placebo, and was significantly greater with dupilumab qw (0.207) and q2w (0.210) (both P < 0.0001), which exceeded the minimal clinically important difference and resulted in scores that approached population norms. Changes from baseline among patients who achieved AD clinical response were greater than changes among the total population. Improvements were driven by the individual EQ-5D dimensions with the greatest burden at baseline (i.e., pain/discomfort, anxiety/depression and usual activities).

Conclusion

In adults with moderate-to-severe AD, dupilumab resulted in improvements in HRQoL that were statistically significant relative to placebo and were clinically meaningful.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.

Trial registration

ClinicalTrials.gov identifiers, NCT02277743 and NCT02277769, EudraCT Numbers 2014-001198-15 and 2014-002619-40.

http://ift.tt/2pwzoMB

Intratympanic steroid delivery by an indwelling catheter in refractory severe sudden sensorineural hearing loss

Publication date: Available online 13 May 2017
Source:Auris Nasus Larynx
Author(s): Diego Zanetti, Federica Di Berardino, Nader Nassif, Luca Oscar Redaelli De Zinis
ObjectiveMany studies over the last decade showed favorable outcomes with intratympanic (IT) steroid treatment, alone as salvage treatment or in combination with conventional systemic therapy (ST). However, in severe to profound sensorineural hearing loss resistant to ST, the optimal infusion mode, the type and concentration of the solution, the preferable drug, its total amount, and the duration and fractionation of the treatment are still debated. Aim of the study was to investigate the feasibility and the outcomes of a direct and constant IT delivery of dexamethasone (DEX) by means of a new indwelling catheter.MethodsA prospective case-control study in a tertiary referral university hospital. Ninety-nine subjects treated with ST only and 28 with additional IT DEX have been included in the study. A 4 Fr catheter inserted in a sub-annular fashion with a minimal postero-inferior tympanotomy through and endocanalar approach under local anesthesia. DEX 4mg/ml delivered daily, up to 7 days. Daily bone and air-conducted pure tone and speech audiometry were performed with a follow-up at 1, 3, 6 months after treatment.ResultsTwenty-one out of 28 patients (75%) refractory to ST gained on average 24.0dB±20.5dB HL after IT-DEX, compared to 35.4% (average 6.7dB±16.6dB HL) of those receiving only medical ST (p<0.001). No significant side effects were noted.ConclusionIn severe to profound sudden deafness refractory to conventional ST, the daily perfusion of 4mg/ml DEX through an intratympanic catheter is an easy, well accepted procedure that enables patients to receive a drug in the middle ear in a repeatable or sustained form, with minimal discomfort and a partial rescue (67.86%) and a speech recognition gain of 39%.



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Severely infected pneumoceles of the frontal sinus in patients with mental retardation and brain atrophy treated by endoscopic sinus surgery

Publication date: Available online 13 May 2017
Source:Auris Nasus Larynx
Author(s): Ichiro Tojima, Hirotaka Kikuoka, Takao Ogawa, Takeshi Shimizu
We herein present three cases of abnormally expanded frontal sinuses (pneumoceles) with severe infection in patients with mental retardation and brain atrophy. Two patients previously underwent laryngotracheal separation surgery, and bacteriological examinations of purulent nasal discharge revealed infections caused by drug-resistant bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As conservative medical treatments were ineffective, all three patients were treated by computed tomography-guided endoscopic sinus surgery. This navigation system is useful for safer surgery in the area of anatomic deformity. The clinical findings, possible etiologies and surgical treatment of these cases are discussed.



http://ift.tt/2qhqWOy

Intratympanic steroid delivery by an indwelling catheter in refractory severe sudden sensorineural hearing loss

Many studies over the last decade showed favorable outcomes with intratympanic (IT) steroid treatment, alone as salvage treatment or in combination with conventional systemic therapy (ST). However, in severe to profound sensorineural hearing loss resistant to ST, the optimal infusion mode, the type and concentration of the solution, the preferable drug, its total amount, and the duration and fractionation of the treatment are still debated. Aim of the study was to investigate the feasibility and the outcomes of a direct and constant IT delivery of dexamethasone (DEX) by means of a new indwelling catheter.

http://ift.tt/2rcZfWx

Severely infected pneumoceles of the frontal sinus in patients with mental retardation and brain atrophy treated by endoscopic sinus surgery

We herein present three cases of abnormally expanded frontal sinuses (pneumoceles) with severe infection in patients with mental retardation and brain atrophy. Two patients previously underwent laryngotracheal separation surgery, and bacteriological examinations of purulent nasal discharge revealed infections caused by drug-resistant bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As conservative medical treatments were ineffective, all three patients were treated by computed tomography-guided endoscopic sinus surgery.

http://ift.tt/2qe94WY

Component Resolved Diagnosis in Hymenoptera Anaphylaxis

Abstract

Purpose of Review

Hymenoptera anaphylaxis is one of the leading causes of severe allergic reactions and can be fatal. Venom-specific immunotherapy (VIT) can prevent a life-threatening reaction; however, confirmation of an allergy to a Hymenoptera venom is a prerequisite before starting such a treatment. Component resolved diagnostics (CRD) have helped to better identify the responsible allergen.

Recent Findings

Many new insect venom allergens have been identified within the last few years. Commercially available recombinant allergens offer new diagnostic tools for detecting sensitivity to insect venoms. Additional added sensitivity to nearly 95% was introduced by spiking yellow jacket venom (YJV) extract with Ves v 5. The further value of CRD for sensitivity in YJV and honey bee venom (HBV) allergy is more controversially discussed. Recombinant allergens devoid of cross-reactive carbohydrate determinants often help to identify the culprit venom in patients with double sensitivity to YJV and HBV. CRD identified a group of patients with predominant Api m 10 sensitization, which may be less well protected by VIT, as some treatment extracts are lacking this allergen.

Summary

The diagnostic gap of previously undetected Hymenoptera allergy has been decreased via production of recombinant allergens. Knowledge of analogies in interspecies proteins and cross-reactive carbohydrate determinants is necessary to distinguish relevant from irrelevant sensitizations.

http://ift.tt/2qdchpB

The acceptability and tolerability of nasal douching in children with allergic rhinitis: A systematic review

Publication date: July 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 98
Author(s): Nelson Gutiérrez-Cardona, Paula Sands, Graham Roberts, Jane S. Lucas, Woolf Walker, Rami Salib, Andrea Burgess, Hasnaa Ismail-Koch
BackgroundAllergic rhinitis (AR) is a significant issue in children. Treatment options include allergen avoidance, pharmacotherapy and immunotherapy. The use of nasal saline douching (NSD) in children has recently gained acceptability. However, there is limited data regarding the acceptability and tolerability of NSD in children with AR.MethodsA search was conducted using Medline and Embase databases from January 1946 until June 2015 on the use of NSD in children aged 4–12 years with AR. All publications identified that assessed the beneficial effects, acceptability and tolerability were included.Results40 studies were analyzed. Data varied considerably in terms of saline solutions used, modality of application, participant numbers, study design, follow up and outcomes. Factors that appear to influence the acceptability and tolerability of NSD include parental and health professionals' preconceptions, and characteristics of the solution.ConclusionsNasal saline douching appears to be effective, being accepted and tolerated in the majority of children (78–100%). NSD has a significant positive impact on the quality of life in children with allergic rhinitis. When used as an adjunctive treatment having mainly a cleansing property, NSD potentiates the effects and may reduce the dose required of AR medications. Among the principal factors that influence the acceptability and tolerability of NSD are the child's age, delivery system and method, and tonicity. Nasal saline douching provides an accessible, low cost, low morbidity, easy to use treatment in children with allergic rhinitis.



http://ift.tt/2rdLQ0W

Component Resolved Diagnosis in Hymenoptera Anaphylaxis

Abstract

Purpose of Review

Hymenoptera anaphylaxis is one of the leading causes of severe allergic reactions and can be fatal. Venom-specific immunotherapy (VIT) can prevent a life-threatening reaction; however, confirmation of an allergy to a Hymenoptera venom is a prerequisite before starting such a treatment. Component resolved diagnostics (CRD) have helped to better identify the responsible allergen.

Recent Findings

Many new insect venom allergens have been identified within the last few years. Commercially available recombinant allergens offer new diagnostic tools for detecting sensitivity to insect venoms. Additional added sensitivity to nearly 95% was introduced by spiking yellow jacket venom (YJV) extract with Ves v 5. The further value of CRD for sensitivity in YJV and honey bee venom (HBV) allergy is more controversially discussed. Recombinant allergens devoid of cross-reactive carbohydrate determinants often help to identify the culprit venom in patients with double sensitivity to YJV and HBV. CRD identified a group of patients with predominant Api m 10 sensitization, which may be less well protected by VIT, as some treatment extracts are lacking this allergen.

Summary

The diagnostic gap of previously undetected Hymenoptera allergy has been decreased via production of recombinant allergens. Knowledge of analogies in interspecies proteins and cross-reactive carbohydrate determinants is necessary to distinguish relevant from irrelevant sensitizations.

http://ift.tt/2qdchpB

Inactivation of the KSRP gene modifies collagen antibody induced arthritis

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Rudolf Käfer, Katharina Schrick, Lisa Schmidtke, Evelyn Montermann, Dominika Hobernik, Matthias Bros, Ching-Yi Chen, Hartmut Kleinert, Andrea Pautz
The KH type splicing regulatory protein (KSRP) is a nucleic acid binding protein, which negatively regulates the stability and/or translatability of many mRNA species encoding immune-relevant proteins. As KSRP is expressed in immune cells including T and B cells, neutrophils, macrophages and dendritic cells, we wanted to analyze its importance for the development of autoimmune diseases.We chose collagen antibody-induced arthritis (CAIA) as an appropriate autoimmune disease mouse model in which neutrophils and macrophages constitute the main effector cell populations. We compared arthritis induction in wild type (WT) and KSRP^−/− mice and paws were taken for histological sections and qPCR analysis. Furthermore, we determined the frequencies of spleen immune cells by flow cytometry. Cytokine levels in spleen cell supernatants were determined by cytometric bead array analyses (CBA).After CAIA induction we unexpectedly observed in WT animals much stronger swelling of the paws than in KSRP^−/− mice. In accordance, histological staining of paw sections of KSRP^−/− animals revealed much lower frequencies of infiltrating immune cells in the joints compared to WT animals. Furthermore, CAIA-treatment resulted in reduced expression of several inflammatory factors (like CXCL-1, iNOS, TNF-α and S100A8) as well as immune cell marker genes (e.g. LFA-1, CD68, Ly6G) in the joints of KSRP^−/− mice.Spleen cells of KSRP^−/− mice showed lower frequencies of myeloid cells. On cytokine level IFN-γ production was increased in spleen cells of KSRP^−/− mice compared to WT samples.These data surprisingly suggest that the absence of KSRP protects against the induction of inflammatory arthritis.



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Utilidad y versatilidad del colgajo en isla de la arteria supraclavicular en reconstrucción de cabeza y cuello

Publication date: Available online 13 May 2017
Source:Acta Otorrinolaringológica Española
Author(s): José A. González-García, Carlos M. Chiesa-Estomba, Jon A. Sistiaga, Ekhiñe Larruscain, Leire Álvarez, Xabier Altuna
IntroducciónEl colgajo supraclavicular en isla es un colgajo rotacional pediculado que puede presentar ciertas ventajas en reconstrucción de cabeza y cuello en pacientes donde una reconstrucción microvascularizada no sea factible o aconsejable.Material y métodosPresentamos nuestra experiencia durante el año 2016 en 5 casos con la aplicación de este colgajo, como alternativa a una reconstrucción microvascularizada tras resección de distintos tumores de cabeza y cuello. En 2 casos se utilizó para reconstrucción del faringostoma quirúrgico tras laringectomía total con faringectomía parcial. En un caso para reconstrucción facial lateral tras resección parcial de temporal. En un caso para reconstrucción de un defecto cutáneo tras laringectomía total ampliada y en otro para cobertura cutánea tras el cierre primario de una fístula faringocutánea. No hubo complicaciones del colgajo y el resultado final fue satisfactorio en todos los casos.ResultadosEl colgajo supraclavicular en isla presenta una utilidad y es muy versátil en reconstrucciones de cabeza y cuello. El tiempo quirúrgico en pacientes de riesgo se reducirá respecto a colgajos libres microvascularizados. Su técnica quirúrgica es relativamente sencilla y se adapta perfectamente a reconstrucciones mucosas o cutáneas.ConclusiónEl colgajo supraclavicular en isla es una opción recomendable en reconstrucción de cabeza y cuello, su uso parece estar incrementándose y supone una alternativa segura y sobre todo rápida a los colgajos libres microvascularizados en pacientes seleccionados.IntroductionThe supraclavicular island flap is a rotational pedicled flap and may have some advantages in head and neck reconstruction compared with free-tissue transfer when this kind of reconstruction is not affordable or recommended.Material and methodsWe present our experience during the year 2016 in the application of the supraclavicular island flap in five cases as an alternative to microvascular reconstruction in several defects after resection of head and neck tumours. In two patients, the flap was used to close the surgical pharyngostoma after total laryngectomy with partial pharyngectomy. In one patient, it was used in lateral facial reconstruction after partial resection of the temporal bone. In one case, it was used to close a skin defect after total laryngectomy with prelaryngeal tissue extension. And in the last case to close a neck skin defect after primary closure of a pharyngo-cutaneous fistula. There were no flap complications, and the result was satisfactory in all cases.ResultsThe supraclavicular artery island flap is useful and versatile in head and neck reconstruction. Operating room time in aged patients or those with comorbidities will be reduced compared to free flaps. The surgical technique is relatively easy and can be used for skin and mucosal coverage.ConclusionThe supraclavicular island flap could be a recommended option in head and neck reconstruction, its use seems to be increasing and provides a safe and time-saving option to free flaps in selected patients.



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Early neurosyphilis presenting with facial palsy and an oral ulcer in a patient who is human immunodeficiency virus positive: a case report

Neurosyphilis is the tertiary stage of Treponema pallidum infection that involves the central nervous system, which occurs within days or weeks after an initial syphilis infection, especially in immunocompromised...

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Outcomes of multimodal management for sinonasal squamous cell carcinoma

Publication date: Available online 12 May 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Arnaud Paré, Pierre Blanchard, Silvia Rosellini, Anne Aupérin, Philippe Gorphe, Odile Casiraghi, Stéphane Temam, François Bidault, Philippe Page, Frédéric Kolb, François Janot, Antoine Moya Plana
BackgroundPoor prognosis of sinonasal cancers (SNC) is usually due to the non-specific symptoms leading to late diagnosis with locally advanced disease. However, previous prognostic studies were often based on heterogeneous cohorts because of the scarcity of SNC. With squamous cell carcinoma being the main histological subgroup, the study aimed to perform a prognostic analysis on sinonasal squamous cell carcinoma (SNSCC) particularly, and to evaluate the oncological results of a multimodal therapy.MethodsA retrospective review of 68 cases involving SNSCC treatment between 1998 and 2012 at Gustave Roussy Cancer Campus was performed. Clinical, pathological, and treatment characteristics were evaluated as prognostic markers for oncological outcomes.ResultsThe 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.1% and 52.6% respectively. Tumor downsizing under neoadjuvant chemotherapy (NACT) was observed in 82.5% of cases. The main pattern of recurrence was local with a 2- and 5-year rate of 37.3%. Decreased OS, PFS and local control were associated with involvement of the orbit, the soft tissue, and the suprastructure (p < 0.005).ConclusionPrognosis of surgically treated SNSCC remains poor. Multimodal treatment combining NACT followed by wide resection requiring complex reconstruction and adjuvant radiation therapy seems to provide promising results.



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Calcifying epithelial odontogenic tumor: An updated analysis of 339 cases reported in the literature

Publication date: Available online 12 May 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Bruno Ramos Chrcanovic, Ricardo Santiago Gomez
PurposeThe aim of this study was to integrate the available data published on calcifying epithelial odontogenic tumors (CEOT) into a comprehensive analysis of its clinical and radiologic features.Materials and MethodsAn electronic search was undertaken in May 2016. Eligibility criteria were publications having enough clinical, radiological and/or histological information to confirm definite diagnosis.ResultsA total of 362 lesions were found, 339 with enough information were analyzed. Variants clear cells (n=33) and Langerhans cells (n=10) were rarely described in the literature, as well as lesions with malignant transformation (n=8). Central lesions (n=264) were more prevalent than their peripheral counterparts (n=24). A higher prevalence characterized the mandible, posterior region, and third and fourth decades. About 40% of the peripheral lesions showed signs of underlying bone erosion, and about half of the central ones showed signs of cortical bone perforation. Recurrence was found in all lesions (12.6%), peripheral lesions (18.8%), central lesions (11.6%), clear cell (10.7%), Langerhans cell (0%), and those with malignant transformation (42.9%). Excision or curettage was associated with the highest recurrence rate. None of the variables showed a statistically significant influence on the recurrence rate.ConclusionsThe possible locally aggressive behavior of the lesions recommends a less conservative management than simple curettage. The clear cell variant shows similar demographic data and biological behavior compared to the non-variant lesions, suggesting that the presence of clear cells does not have an important clinical significance.



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The effect of chronic dental inflammation on development of stage 0 medication-related osteonecrosis of the jaw

Publication date: Available online 12 May 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Goknur Topaloglu, Osman Taha Koseoglu, Cigdem Karaca, Kemal Kosemehmetoglu
ObjectiveThe pathogenesis of medication-related osteonecrosis of jaw (MRONJ) is poorly understood. The aim of this prospective study was to determine the effect of chronic dental inflammation on the development of stage 0 MRONJ based on histopathological findings.MethodsThe study involved patients with a history of bisphosphonate use and an indication for tooth extraction. Before surgery, C-terminal telopeptide test (CTX) values were collected from all patients. All tooth extractions were performed according to a determined protocol. To detect whether any medication-related osteonecrotic changes were present in the non-exposed bone, biopsy samples were taken from the alveolar bone.ResultsA total of 50 patients were included in the study (39 women and 11 men). The patients were mean age of 57.4 ± 12.1 years. In total, 74 teeth were extracted (29 maxillary and 45 mandibular). Histologic examination of three patients (6%) revealed stage 0 MRONJ. Postoperatively, the complete mucosal healing success rate was 96%. MRONJ risk was not significantly correlated with low CTX value (p = 0.285).ConclusionsChronic inflammation may contribute to stage 0 MRONJ; however, its role may not be sufficient alone for its development. Application of a predetermined protocol for dentoalveolar processes will help to prevent MRONJ development.



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Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2 + γδ T cell cytotoxicity in a perforin-dependent manner

Abstract

Vδ2⁺ T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2⁺ T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2⁺ T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C–C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2⁺ T cell cytotoxicity. Vδ2⁺ T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive—at least in part—to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2⁺ T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

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Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model

Abstract

Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2K^b/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.

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Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma

Abstract

We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC₅₀ for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC₅₀ for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.

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Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma

Abstract

Background

Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers.

Objectives

To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA).

Methods

We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed.

Results

PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001). A similar correlation was also found for cSCC (r = 0.86; P < 0.0001). The percentage of PD-L1 + tumours was 33.3% for KA and 26.9% for cSCC. Similarly, the percentage of PD-L1 + TILs in KA and cSCC was 33.3 and 34.6%, respectively.

Conclusions

PD-L1 is differently expressed in cSCC and closely related non-melanoma skin cancer. cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD1/PD-L1 inhibitors might be beneficial in a proportion of patients with an inoperable or metastatic cSCC. Unlike AK and BD, TILs and tumour cells of KA and cSCC present very similar PD-L1 expression profiles indicating a common immune escape mechanism.

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Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments

Abstract

The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.

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Early gastric adenocarcinoma arising within foveolar-type dysplasia in a patient with Muir-Torre variant Lynch syndrome

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Local resectability assessment of head and neck cancer: Positron emission tomography/MRI versus positron emission tomography/CT

Abstract

Background

The purpose of this study was to compare the diagnostic accuracy of positron emission tomography (PET)/MRI with PET/CT for local resectability of head and neck cancer.

Methods

Sequential contrast-enhanced PET/CT-MRI was performed in 58 patients referred for the staging or restaging of head and neck cancer. Tumors were assessed with PET/CT and PET/MRI for the presence of resectability-defining factors: T4b status (mediastinal invasion, invasion of the prevertebral space, and vascular encasement), and another 8 findings that would imply obstacles for surgical cure (invasion of the laryngeal cartilage, invasion of the preepiglottic fat pad, perineural spread, orbital invasion, bone infiltration, skull base invasion, dural infiltration, and invasion of the brachial plexus).

Results

The sensitivity/specificity/accuracy of local resectability-defining factors of PET/CT and PET/MRI was 0.92/0.99/0.98 and 0.98/0.99/0.99 (P = .727), respectively, per lesion, and 0.96/0.87/0.91 and 0.96/0.90/0.93 (P = .687), respectively, per patient.

Conclusion

Both contrast-enhanced PET/MRI and contrast-enhanced PET/CT can serve as reliable examinations for defining local resectability of head and neck cancer.

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Cover Image

The cover image, by Jonathan M. Bernstein et al., is based on the Original Article Survival outcomes for cutaneous angiosarcoma of the scalp versus face, DOI: 10.1002/hed.24747.

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Issue Information - Contents

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Fallen eyeball injury

Publication date: Available online 13 May 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Seiji Hosokawa, Katsuyoshi Suzuki, Katsura Hakamada, Yasuhiro Hayashi, Hiroyuki Mineta




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Free tissue flaps in head and neck reconstruction: clinical application and analysis of 93 patients in a single institute

Publication date: Available online 13 May 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Jiwang Liang, Tao Yu, X. Wang, Yuejiao Zhao, Fengqin Fang, Wei Zeng, Zhendong Li
IntroductionReconstruction with a free flap is routine in head and neck surgery because of better functional outcomes, improved esthetics, and generally higher success rates.ObjectiveTo evaluate the clinical outcomes in patients undergoing different microvascular free flap reconstructions.MethodsThis was a retrospective study of 93 patients undergoing reconstructions with free flaps from 2007 to 2015. Four types of free flap were performed: Anterolateral Thigh (76.3%), Radial Forearm (16.1%), Fibula (4.3%) and Jejunum (3.3%). Patients' demographic data were collected, and the outcomes measured included flap survival and complications. Postoperative functional and oncological outcome were also analyzed.ResultsThe patients included 73 men and 20 women, with a mean age of 56.1 years. The most common tumor location was tongue. Squamous cell carcinoma represented the vast majority of the diagnosed tumors (89.2%). The most common recipient vessels were the superior thyroid artery (77.4%) and the internal jugular vein (91.4%). Nine patients required emergent surgical re-exploration and the overall flap success rate was 90.3%. Venous thrombosis was the most common cause for re-exploration. Other complications included wound infection (5.4%), wound dehiscence (1.1%), partial flap necrosis (9.7%), fistula formation (10.8%), and 1 bleeding (1.1%). Majority of patients had satisfactory cosmetic and functional results of both donor site and recipient site after 46.7 months of mean follow-up.ConclusionMicrosurgical free flap is shown to be a valuable and reliable method in head and neck surgery. It can be used safely and effectively with minimal morbidity in selected patients. The reconstruction can be performed by appropriately skilled surgeons with acceptable outcomes. Success rate appears to increase as clinical experience is gained.



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Nd:YAG laser irradiation associated with fluoridated gels containing photo absorbers in the prevention of enamel erosion

Abstract

This study evaluated the combined effect of Nd:YAG laser irradiation and fluoridated gels containing photo absorbers against enamel erosion. Enamel specimens from bovine teeth were polished, eroded (10 min, with 1% citric acid, pH = 2.6), and randomly allocated into the experimental groups (n = 8), according to the different surface treatments: fluoridated gels (F: 9047 ppm F and F + Sn: 9047 ppm F and 3000 ppm Sn), with or without photo absorbers (E: erythrosine and MB: methylene blue), and associated or not with Nd:YAG laser irradiation (in contact; 0.5 W; 50 mJ; ~41.66 J/cm²; 10 Hz; 40 s; pulse duration of 120 μs). A placebo gel (PLA) associated or not with laser was used as control. All gels had pH = 4.5 and were applied for 2 min. Laser irradiation was performed during gel application. The specimens were then submitted to a 5-day erosion-remineralization cycling model using 0.3% citric acid (pH = 2.6), 4×/day. Enamel surface loss (SL) was analyzed by optical profilometry in the end of the cycling (in μm). Data were analyzed by ANOVA and Tukey tests (α = 0.05). Means (SD) of SL for the groups were the following (different superscript letters imply significant difference among groups): PLA (21.02 ± 1.28)^a, PLA + laser (19.20 ± 0.96)^ab, laser (17.47 ± 1.50)^b, F + Sn + E + laser (13.69 ± 0.62)^c, F + E + laser (13.52 ± 1.16)^c, F (13.10 ± 1.08)^c, F + laser (11.94 ± 1.44)^cd, F + Sn + MB + laser (11.90 ± 4.02)^cd, F + MB + laser (11.42 ± 1.42)^cd, F + Sn (11.12 ± 1.20)^cd, and F + Sn + laser (10.35 ± 0.89)^d. In conclusion, all fluoridated gels and the Nd:YAG laser irradiation reduced erosion development, but the combination of treatments did not promote further protection. The addition of photo absorbers to the fluoridated gels did not influence the anti-erosive effect of the combination of laser plus fluoridated gels.

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Red tattoos, ultraviolet radiation and skin cancer in mice

Abstract

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously.

Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured.

All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumour was identical in the red tattooed group compared with the control group (182 vs. 186 days and 196 vs. 203 days, p=ns). Statistically, the third tumour appeared slightly faster in the red tattooed group than in the controls (214 vs 224 days, p=0.043). For the second and third tumour the growth rate was faster in the red tattooed group compared with the control (31 vs 49 days, p=0.009 and 30 vs 38 days, p=0.036).

In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumour onset regarding the third tumour, and faster growth rate of the second and third tumour indicating red ink acts as a co-carcinogen with UVR. The co-carcinogenic effect was weak and may not be clinically relevant.

This article is protected by copyright. All rights reserved.

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Analysis of serum markers of cellular immune activation in patients with bullous pemphigoid

Abstract

Experimental models of bullous pemphigoid (BP), the most frequent subepidermal autoimmune bullous disease, revealed that the immune response leading to blister formation represents an incompletely understood complex process involving different inflammatory cells. In contrast to previous reports commonly focusing on limited molecular and cellular phenotypes of the disease, the aim of this study was to investigate a broad spectrum of markers of cellular immune activation in patients with BP. We found that serum levels of soluble CD4, myeloperoxidase, S100A12, eosinophil cationic protein, and soluble P-selectin were significantly elevated in patients with active BP compared with normal controls. Mast cell tryptase and neopterin serum levels significantly decreased at the time of clinical remission of the patients. Additionally, serum concentrations of soluble IL-2 receptor, mast cell tryptase, and soluble P-selectin were significantly associated with levels of circulating anti-BP180 autoantibodies. Our findings confirm and extend previous reports suggesting some concomitant involvement of a panel of molecules representative for a wide spectrum of cellular players (T cells, mast cells, neutrophils, eosinophils, macrophages, and platelets) orchestrating the inflammatory reaction in BP. These data may favor the employment of broad-spectrum or combined immunosuppressants, potentially together with an anticoagulant treatment, over cell- or molecule-specific targeted therapy in patients with this disorder.

This article is protected by copyright. All rights reserved.

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Evaluation of photoaging scales in an elderly male population

Abstract

Photo-induced aging is a natural part of the aging process, but represents a common complaint of both medical and cosmetic dermatology patients. There are many photonumeric grading scales used to assess photo-induced aging, including several based on ethnicity (Caucasians, Asians), and cosmetic units of the face (1), however those specifically validated for older men are lacking. Current photonumeric scales were created using predominantly female subjects age 45 and younger (2-4). Our study sought to evaluate the inter-rater reliability of commonly used photonumeric grading scales in a population of elderly male subjects.

This article is protected by copyright. All rights reserved.

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Disseminated cutaneous nocardiosis with ocular involvement

Abstract

A 45-year-old Japanese woman presented with a five-day history of multiple papular eruptions and a fever >38°C. For the past 10 years, she had been treated with oral prednisolone (10 mg/day) and cyclosporine (100 mg/day) to treat mixed connective tissue disease and autoimmune hepatitis. On physical examination, multiple papules and pustules were observed on her face, trunk, and extremities. Some lesions had dermal or subcutaneous nodules.

This article is protected by copyright. All rights reserved.

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Self limited membranous glomerulonephritis due to syphilis

Abstract

Syphilis is known as "the great mimic" owing to the wide range of clinical presentations. Primary syphilis usually presents as a highly contagious ulcerated lesion that appears 9-90 days after infection (1). Secondary syphilis manifests after hematogenous and lymphatic dissemination.

This article is protected by copyright. All rights reserved.

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TNF receptor-associated periodic syndrome (TRAPS) mimicking chronic spontaneous urticaria

Abstract

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare (about one per million) autosomal dominant autoinflammatory disease being typically characterized by recurrent fever episodes accompanied by variable gastrointestinal, musculoskeletal, neurological, lymphoid, urogenital and skin symptoms (table 1) [1-3].

We report on a 21 year old non atopic male with prediagnosed IgA deficiency, Marfan syndrome and hypothyroidism who first presented in our university allergy centre with three year history of antihistamine resistant, only slightly itching urticarial rash being accompanied by fatigue. Histology showed superficial perivascular lymphocytic dermatitis with eosinophils and intravascular neutrophil granulocytes. Routine laboratory parameters were within normal range but due to persistently elevated antistreptolysin-titers, without any focal infection detectable, he unsuccessfully received antibiotic treatment. Urticarial rash was only improved by recurrent cycles of systemic methylprednisolone. Under the diagnosis of chronic spontaneous urticaria (CSU) we then treated him with omalizumab subcutaneously (300-600mg once monthly). Symptoms initially seemed to improve during summer time but therapy was stopped after 18 months due to complete recurrence of urticarial rash and persistence of fatigue.

This article is protected by copyright. All rights reserved.

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Dysregulation of the MEK/ERK/MNK1 signaling cascade by middle T antigen of the trichoydsplasia spinulosa polyomavirus

Abstract

Background

Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumor (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown.

Objective

The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies.

Methods

A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE, and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen.

Results

We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK, and MNK1. Our findings suggest that dysregulation of these key signaling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs.

Conclusion

Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.

This article is protected by copyright. All rights reserved.

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Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction

Publication date: Available online 13 May 2017
Source:Clinical Immunology
Author(s): Kazuhiro Ishiguro, Osamu Watanabe, Masanao Nakamura, Takeshi Yamamura, Masanobu Matsushita, Hidemi Goto, Yoshiki Hirooka
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-α stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-κB and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction.

Graphical abstract

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Regulatory B cells in rheumatoid arthritis: Alterations in patients receiving anti-TNF therapy

Publication date: Available online 12 May 2017
Source:Clinical Immunology
Author(s): Zsuzsanna Bankó, Judit Pozsgay, Tamás Gáti, Bernadette Rojkovich, Ilona Ujfalussy, Gabriella Sármay
Cytokines, including tumor necrosis factor alpha (TNFα) are involved in Rheumatoid arthritis (RA) pathogenesis by augmenting autoimmunity, sustaining long term inflammation in the synovium, and promoting joint damage. Anti-TNF therapy is one of the most efficient and widely used therapies for RA, although its mechanism is not clarified yet. Earlier we demonstrated that RA patients have a reduced number of IL-10 producing regulatory B cells (B10 cells) as compared to healthy individuals and they are functionally impaired. Our aim was to study the influence of anti-TNF therapy on B10 cells in RA, to follow the alteration of B cell activation markers (CD25, CD69) and to monitor the level of citrullinated peptid-specific antibodies and the secreted IL-10 in patients' sera during the therapy.We have observed that at six month after starting the therapy the frequency of B10 cells remarkably increased, while the expression of the activation marker, CD69 decreased on B cells. In contrast, serum levels of IL-10 and anti-citrullinated peptide antibodies did not change post-treatment.ConclusionThe reduced activation state of B cells and the increasing number of regulatory B10.cells might contribute to the therapeutic efficacy of anti-TNF agents in RA.



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A confirmed case of sugammadex-induced anaphylaxis in a UK hospital

We report the first published case of confirmed anaphylaxis to sugammadex in a UK hospital. The patient was given a bolus of sugammadex at the end of surgery. Four minutes later, he developed hypotension and a widespread erythematous rash. Multiple epinephrine boluses were administered and a continuous intravenous infusion of epinephrine commenced. The patient later reported auditory awareness, which occurred while the diagnosis of anaphylaxis was being made and initial treatment initiated. Serial serum tryptase levels were consistent with a type I hypersensitivity reaction. Skin prick and intradermal testing were performed 6 months later confirming allergy to sugammadex. This case restates the potential for hypersensitivity reactions to develop following the administration of sugammadex and makes clinicians aware that such reactions may require prolonged treatment with intravenous infusions of epinephrine. Finally, this case highlights the importance of maintaining or re-establishing anaesthesia while managing the emergent situation in order to avoid unintentional awareness.

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Maternal bradycardia occurring prior to onset of HELLP syndrome in a woman with pre-eclampsia

A 36-year-old nulliparous woman developed pre-eclampsia at gestational week (GW) 28^–6/7. Cardiac status was checked regularly. Heart rate of 93 beats per minute (bpm) with left atrial diameter (LAD) of 35 mm, left ventricular hypertrophy and inferior vena cava diameter (IVCD) of 8 mm at GW 32^–0/7 decreased to 48 bpm with an expanded IVCD to 25 mm, dilated left atrium (LAD to 39 mm), increased pulmonary arterial pressure, increased systemic vascular resistance (approximate 3000 dyn s/cm⁵) and biphasic intrarenal venous flow pattern 3.5 hours prior to childbirth at GW 32^–3/7. Epigastralgia, tachycardia (160 bpm) and marked hypertension (201/111 mm Hg) occurring 2 hours after echocardiography necessitated caesarean section, with subsequent development of HELLP syndrome. Acute fluid shift from the splanchnic vasculature to central vasculature may have occurred causing HELLP syndrome as a result from vasospasm associated with sympathetic hyperactivity. The cause of bradycardia prior to tachycardia remains unclear.

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The vanishing duodenal polyp: mesenteric invagination presenting as duodenal pseudopolyp

Duodenal polypoid masses are an uncommon finding mainly diagnosed incidentally at endoscopy or surgery. We report a 39-year-old female patient with symptoms of intermittent stabbing pain in the upper right abdominal quadrant and an iron deficiency anaemia, without complaints of weight loss, haematemesis or melaena. A duodenal polyp and acute duodenitis have been described during endoscopic examinations and CT and ultrasound. Surgical excision of the polyp was advised. Intraoperatively, an elongated duodenum was remarkable; however, at duodenotomy, no polyp was found, nor during intraoperative endoscopy. Looking back at the endoscopy and imaging results, it was noted that the polyp varied in size and location. It was therefore concluded that we dealt with the pseudopolyp phenomenon, caused by invagination of the duodenal wall and its mesentery into the duodenum, presenting as a lipomatous pseudopolyp. Telescopic invagination of the duodenal wall was facilitated by the elongated hypermobile duodenum.

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Urothelial papilloma: a rare cause of gross haematuria in childhood

Bladder urothelial papilloma is extremely rare in the paediatric population. It usually presents as painless gross haematuria and its diagnosis implies a high index of suspicion as other causes of haematuria predominate in this age range. We describe a 9-year-old boy with two episodes of gross haematuria occurring 1 year apart with spontaneous resolution after 2 days. Bladder ultrasound revealed an endovesical papillary lesion of 24x24 mm suggestive of bladder tumour. The diagnosis was confirmed by histopathological examination of the specimen obtained by cystoscopy with transurethral resection. After 3 years of follow-up with ultrasound and cystoscopy, there are no signs of recurrence. Due to the low prevalence of urothelial papilloma, paediatric guidelines for appropriate management and follow-up are unavailable, making this a challenging entity.

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Vedolizumab: a novel medical intervention in the treatment of primary sclerosing cholangitis

Description

Primary sclerosing cholangitis (PSC) is an idiopathic and insidious cholestatic liver disease characterised by persistent inflammation of the biliary tree, leading to fibrosis and stricturing.1 Often associated with inflammatory bowel disease, pathogenesis may be related to activated intestinal T-cells expressing the integrin cell surface receptor α₄β₇. These T-cells are recruited to the liver parenchyma resulting in persistent biliary inflammation.1 Patients typically remain asymptomatic until a diagnosis is attained by detection of elevated liver enzymes.2 No effective medical management exists, and the progressive fibrotic nature of the disease usually results in the necessity of liver transplantation.

We present a case of a male in his 40s with a 30-year history of ulcerative colitis and newly diagnosed PSC, who demonstrated an improvement in inflammation and stricturing of the biliary tree with vedolizumab (figure 1). On routine follow-up our patient was found to...

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Inhibition of mast cell infiltration in an LL-37-induced rosacea mouse model using topical brimonidine tartrate 0.33% gel

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Altered expression of four miRNA (miR-1238-3p, miR-202-3p, miR-630 and miR-766-3p) and their potential targets in peripheral blood from vitiligo patients

Abstract

Vitiligo is an acquired skin disease with pigmentary disorder. Autoimmune destruction of melanocytes is thought to be major factor in the etiology of vitiligo. miRNA-based regulators of gene expression have been reported to play crucial roles in autoimmune disease. Therefore, we attempt to profile the miRNA expressions and predict their potential targets, assessing the biological functions of differentially expressed miRNA. Total RNA was extracted from peripheral blood of vitiligo (experimental group, n = 5) and non-vitiligo (control group, n = 5) age-matched patients. Samples were hybridized to a miRNA array. Box, scatter and principal component analysis plots were performed, followed by unsupervised hierarchical clustering analysis to classify the samples. Quantitative reverse transcription polymerase chain reaction (RT–PCR) was conducted for validation of microarray data. Three different databases, TargetScan, PITA and microRNA.org, were used to predict the potential target genes. Gene ontology (GO) annotation and pathway analysis were performed to assess the potential functions of predicted genes of identified miRNA. A total of 100 (29 upregulated and 71 downregulated) miRNA were filtered by volcano plot analysis. Four miRNA were validated by quantitative RT–PCR as significantly downregulated in the vitiligo group. The functions of predicted target genes associated with differentially expressed miRNA were assessed by GO analysis, showing that the GO term with most significantly enriched target genes was axon guidance, and that the axon guidance pathway was most significantly correlated with these miRNA. In conclusion, we identified four downregulated miRNA in vitiligo and assessed the potential functions of target genes related to these differentially expressed miRNA.

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Inflammatory Marker Analysis in Psoriatic Skin Under topical Phospodiesterase 4 Inhibitor Treatment

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Lennart M. Roesner, Petra Kienlin, Gabriele Begemann, Oliver Dittrich-Breiholz, Thomas Werfel

Teaser

Topical formulations of the two PDE4i roflumilast and TAK-084 lead to a reduction of inflammatory markers and infiltrating cells in psoriatic lesional skin.


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ImmunoCAP cellulose displays cross-reactive carbohydrate (CCD) epitopes and can cause false-positive test results in patients with high anti-CCD IgE antibody levels

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Wolfgang Hemmer, Friedrich Altmann, Friedrich Holzweber, Clemens Gruber, Felix Wantke, Stefan Wöhrl
RationaleCross-reactive carbohydrate determinants (CCDs) in plants and insect venoms are a common cause of irrelevant positive test results during in-vitro allergy diagnosis. We observed that some CCD-positive sera show non-specific IgE-binding even with CCD-free recombinant allergens when using the Phadia ImmunoCAP platform.ObjectiveWe investigated if cellulose used as allergen carrier in the ImmunoCAP harbors residual N-glycans causing non-specific background-binding in CCD-positive sera.MethodsIgE binding to six samples of blank ImmunoCAPs coupled with either streptavidin (SA-CAP 1-2) or non-allergenic maltose-binding protein (MBP-CAP 1-4) and to a panel of four recombinant allergens was compared in CCD-positive sera before and after inhibition with a CCD inhibitor (MUXF-HSA).ResultsOut of 52 CCD-positive sera (bromelain 1.01-59.6 kUa/L) tested on SA-CAP-1, 35 (67%) showed IgE-binding greater than 0.35 kUa/L (0.41-4.22 kUa/L). Among those with anti-CCD IgE levels >7.0 kUa/L, 90% (26/29) were positive. IgE-binding to SA-CAP-1 correlated with IgE-binding to bromelain (r=0.68) and was completely abolished by serum pre-incubation with the CCD inhibitor (n=15). Binding scores with SA-CAP-2 and MBP-CAPs 1-4 were generally lower but strongly correlated with SA-CAP-1 and bromelain. IgE reactivity of 10 CCD-positive sera (14.0-52.5 kUa/L) with the recombinant allergens rPhl p12, rFel d1, rAra h2, and rPru p3 was positive to at least one allergen in 8/10 (0.36-1.63 kUa/L) and borderline in 2/10 (0.21-0.25 kUa/L). Binding correlated with antibody binding to bromelain (r=0.61) and to all blank ImmunoCAPs (r>0.90) and could be completely blocked by the CCD inhibitor. Overall, mean background-binding to cellulose CCDs corresponded to 2-3% of the reactivity seen with bromelain.ConclusionsCellulose used as a solid phase allergen carrier may contain varying amounts of CCDs sufficient to cause false-positive test results up to 2 kUa/L with non-glycosylated recombinant allergens in patients with high levels of anti-CCD IgE antibodies.

Teaser

Cellulose-based IgE assays may deliver false-positive test results of up to 2 kUa/L with recombinant allergens in strongly CCD-positive patient sera due to the presence of glycoproteins in the cellulose matrix.


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Expression of Semaphorin 3E Is Suppressed in Severe Asthma

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Hesam Movassagh, Lianyu Shan, Jamila Chakir, John F. McConville, Andrew J. Halayko, Latifa Koussih, Abdelilah S. Gounni
The level of a previously unknown mediator, Semaphorin 3E, is diminished in the airways of severe allergic asthmatic patients. This study suggests a potential role of Semaphorin3E in the pathogenesis of asthma severity.



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A short course of gamma-tocopherol mitigates LPS-induced inflammatory responses in humans ex vivo

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Allison J. Burbank, Charity G. Duran, Martha Almond, Heather Wells, Sha'Leema Jenkins, Qing Jiang, Chao Yang, Ting Wang, Haibo Zhou, Michelle L. Hernandez, David B. Peden

Teaser

Vitamin E, gamma-tocopherol (γT), possesses unique anti-inflammatory activities. A short course of γT supplementation in healthy adults reduced inflammatory cytokine production and gene expression following ex vivo LPS challenge of PBMCs.


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Pulmonary Inflammation in COPD Patients with Higher Blood Eosinophil Counts

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Umme Kolsum, Gautam Damera, Tuyet-Hang Pham, Thomas Southworth, Sarah Mason, Pradeep Karur, Paul Newbold, Dave Singh

Teaser

The different nature of airway inflammation in COPD patients with higher blood eosinophil counts supports the concept of eosinophilic COPD being a subgroup of patients with distinct characteristics.


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Phase 2 to Phase 3 Clinical Trial Transitions: Reasons for Success and Failure in Immunologic Diseases

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Dhavalkumar D. Patel, Christian Antoni, Steven J. Freedman, Marc C. Levesque, John S. Sundy




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Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells

Publication date: Available online 12 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Veronique Schulten, Victoria Tripple, Grégory Seumois, Yu Qian, Richard H. Scheuermann, Zheng Fu, Michela Locci, Sandy Rosales, Pandurangan Vijayanand, Alessandro Sette, Rafeul Alam, Shane Crotty, Bjoern Peters
Follicular helper T cells (Tfh cells) are a CD4 T cell subset essential for germinal center formation and B cell responses, although their role in allergy and allergen-specific immunotherapy (AIT) is unclear. Here, we show that AIT-treated patients have a higher ratio of regulatory Tfh cells (Tfr) to follicular T cells (Tfh) and hypothesize an IL-2 dependent mechanism.



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The clinical spectrum of xanthomatous lesions of the eyelids

Abstract

Yellowish papules, nodules, or plaques, namely "xanthomatous" lesions, may be seen on the eyelids in the course of various disorders. The prototype is "xanthelasma palpebrarum" (XP) that is localized only to the eyelids and may be associated with hyperlipidemia. On the other hand, different types of normolipemic disorders may also cause xanthomatous eyelid lesions. Among these, Langerhans cell histiocytosis, diffuse normolipemic xanthoma, and non-Langerhans cell histiocytoses (papular xanthoma, juvenile xanthogranuloma, xanthoma disseminatum, adult-onset xanthogranuloma, adult-onset asthma and periocular xanthogranuloma, necrobiotic xanthogranuloma, Erdheim-Chester disease, Rosai-Dorfman disease, and reticulohistiocytosis) can be listed. The eyelid findings of this heterogeneous group of disorders are challenging to differentiate from each other due to common clinical aspects that may even sometimes mimic XP. Nodularity, induration, ulceration, diffuse eyelid involvement, and extension from eyelids to the neighboring skin may represent the clinical features of xanthomatous lesions other than XP. It is necessary to obtain a thorough history and exclude XP and then perform detailed dermatological and systemic examination, biopsy for histopathologic confirmation, and appropriate specific imaging screens. As some of the conditions may be associated with other systemic disorders, especially malignancies, the differentiation of xanthomatous eyelid lesions has a critical importance, and clinical signs can be guiding.

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