Current Concepts in Carious Tissue Removal

Abstract

Purpose of Review

To summarize current concepts in carious tissue removal.

Recent Findings

Traditionally, caries has been seen as an infectious disease and was treated by attempted complete removal of all cariogenic bacteria. The logical traditional aim of carious tissue removal—removing all bacteria from carious lesions—no longer applies. The contemporary aim of carious tissue removal is to maximize restoration longevity, without unnecessarily removing sound or remineralizable dentin. This is based on recent perspectives that dental caries is a biofilm-based and lifestyle-mediated disorder. In shallow lesions, as much carious tissue as possible should be removed, with removal until hard dentin is felt around the periphery of a cavity (to maximize restoration survival and seal the cavity) while centrally firm dentin is left (to retain remineralizable dentin). For deep lesions in teeth with vital pulps (without irreversible pulpitis or pulp necrosis), maintaining pulp vitality is the priority. Dentists should aim to avoid pulp exposure and accept leaving soft or leathery dentin in areas close to the dental pulp, while at the periphery, carious tissue should be removed until hard tissue is felt, ensuring that any remaining bacteria are sealed and inactivated and that the restoration has sufficient mechanical support against masticatory forces. An alternative for deep lesions is stepwise removal. Carious tissue strategies where no carious tissue removal at all is performed include sealing using plastic materials or stainless steel crowns, or non-restorative cavity control.

Summary

A range of carious tissue removal strategies are available and should be applied according to lesion characteristics, pulp vitality, and other patient related factors. Always striving to remove carious tooth tissue until hard dentin remains is not in line with current evidence and not recommended.

https://ift.tt/2uiN6Cl

Recent Trends in Tricalcium Silicates for Vital Pulp Therapy

Abstract

Purpose of Review

Tricalcium silicates are considered as materials of choice for vital pulp therapy. Recent development improved their mechanical and bioactive properties and broadened their clinical application fields. Incorporating resins to tricalcium silicates further decreased the setting time and simplified clinical procedures but raised questions about their potential toxicity.

Recent Findings

Tricalcium silicates represent an added value in vital pulp therapy. This is ascribed to the pulp high regeneration potential, material byproducts production upon hydration and growth factor release from target cells. Adding resins to tricalcium silicates decreases their hydration and subsequently leads to pulp toxicity.

Summary

Tricalcium silicates can be successfully used for vital pulp therapy in a broad range of clinical applications. Although long-term clinical studies are still required with these new materials, adding resins to tricalcium silicates is responsible for pulp disorganization and toxicity and cannot be recommended for direct pulp capping.

https://ift.tt/2m57lzO

The Future of Payment for Dental Care

Abstract

Purpose of Review

To examine the literature on dental reimbursement methods, with emphasis on paying for value (e.g., health care outcomes) rather than procedure. To make recommendations that would facilitate the expansion of access to dental care for those most in need and improve the oral health of the US population.

Recent Findings

Although the health care system is moving toward paying for performance and outcomes, dentistry lags behind. We review publications that identify obstacles to payment for outcomes in oral health as well as moving away from traditional fee-for-service reimbursement.

Summary

Payment for value in dentistry is a long way from becoming a reality; however, the testing of models within Medicaid that set aside a small percentage of the fee for a procedure to be reimbursed based on the improved oral health of the patient and/or the population of the practice may facilitate its adoption. A similar set aside in capitation-based programs could ensure the delivery of essential services and avoid the underutilization traditionally associated with this type of reimbursement system. Similar incentives could be tested in group practices and perhaps even community health centers. Widespread adoption of diagnostics code, missing in dental records, would enable better tracking of met needs. Educational systems that foster intra- and interprofessional teamwork and the appropriate use of personnel operating at the top of their competency would increase efficiency while adding value at the same or lower cost.

https://ift.tt/2zsa3cc

Smear Layer-Deproteinization: Improving the Adhesion of Self-Etch Adhesive Systems to Caries-Affected Dentin

Abstract

Purpose of review

This paper reviews a new method of dentin surface modification, smear layer-deproteinization for self-etch adhesive systems, particularly in relation to improving the adhesion to caries-affected dentin.

Recent Findings

Remnants of smear debris, which forms hybridized smear layer with self-etch adhesives, can prevent monomer infiltration and interfere with the chemical interaction of adhesive monomers and the underlying dentin. The hybridized smear layer weakens the physical and chemical properties of the resin-dentin hybridized complex both immediately and over time. Smear layer-deproteinization with NaOCl and HOCl solutions can improve the quality of resin-dentin interface of self-etch adhesives through elimination of the hybridized smear layer, development of monomer infiltration, and enhancement of the chemical interaction of adhesive monomers with hydroxyapatite due to an increase in the mineral/organic ratio on the dentin surface. These positive effects are influenced by the types of oxidizing solution and their application time and also depend upon the adhesive materials used because compromising effects of residual oxidized-byproducts at the dentin surface on the polymerization behavior of the adhesives are different between the materials. However, applying antioxidant/reducing agents can eliminate this problem.

Summary

Smear layer-deproteinization is more effective for improving the bonding efficacy of self-etch adhesives to caries-affected dentin than normal dentin because caries-affected dentin produces a thicker organic-rich smear layer. Smear layer-deproteinization with HOCl solution, which has a rapid and broad-spectrum antimicrobial activity with less irritating and sensitizing properties, along with the subsequent application of antioxidant/reducing agents could enhance the longevity of composite restoration with self-etch adhesives.

https://ift.tt/2m3oIkC

Fracture Toughness Testing of Dental Restoratives: a Critical Evaluation

Abstract

Purpose of Review

We intend by this short critical review to highlight important aspects regarding the mechanical testing of fracture toughness. The final aim is to increase the awareness to the test sensitivity, ultimately increasing the quality and reliability of reported testing results.

Recent Findings

In a well-intended attempt to facilitate testing procedures or provide alternatives for testing material interfaces, authors are resorting to adaptation of testing methodologies without proper theoretical and experimental validation. The assumption of validity in such cases endangers the perpetration of testing strategies that are not safeguarded by sound theoretical bases. The use of improper statistical treatments based on extreme-value distributions further aggravates this scenario.

Summary

We supply here some directions for authors concerning method selection, interpretation of data scatter, statistical treatment, and possibilities for test validation.

https://ift.tt/2L0hqfo

Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluoxetine

The SHANK2 gene codes for a protein involved in organising the postsynaptic density and disruptions have been associated with autism spectrum disorders (ASDs). ASDs are frequently comorbid with intellectual disability and anxiety disorders and emerging evidence suggests potentially common aetiologies. Here, we report the case of an 18-year-old man with ASD who presented with severe anorexia due to fear of food contamination, food avoidance and stereotypies attributable to underlying obsessive compulsive disorder (OCD). The patient was found to be heterozygous for c.2518C>T (p.Pro840Ser), a likely damaging coding variant in the proline rich region of SHANK2. Interestingly, the patient's disordered eating behaviour began to improve only after high-dose fluoxetine was initiated to target OCD symptoms. Overall, this case highlights the utility of molecular genetic testing in clinical psychiatry and provides an example of how genetic information can inform clinicians in the treatment of complex neuropsychiatric syndromes.

https://ift.tt/2KWIzA4

Extremely common radiographic finding of cochlear nerve deficiency among infants with prelingual single-sided deafness and its clinical implications

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Woongsang Sunwoo, Won-Wook Lee, Byung Yoon Choi

Abstract

Objectives

To clarify the common radiographic findings of audiologically documented prelingual single-sided deafness (SSD) and identify the prevalence of cochlear nerve deficiency (CND) in SSD infants referred from the newborn hearing screening program.

Methods

Between March 2012 and March 2017, the records of all infants referred to our otology clinic after undergoing newborn hearing screening program were retrospectively reviewed. Twenty-four consecutive well infants without risk factors who had a confirmed diagnosis of prelingual SSD under the age of 1 year and who underwent internal auditory canal (IAC) magnetic resonance imaging (MRI) were included. The sizes of cochlear nerve (CN), IAC, and cochlear nerve canal (CNC) were measured on MRI. The presence of CND was visually determined by comparing the CN size to the ipsilateral facial nerve (FN) in the affected side via an oblique sagittal view of IAC MRI and defined when CN was absent or smaller than FN.

Results

CND was seen in all 24 deaf ears (100%) on MRI. There was one with incomplete partition type I, and another with combined cochleovestibular nerve absence. Twenty-four subjects demonstrated either an absent (20/24, 83.3%) or small (4/24, 16.7%) CN. When the absent and small CN groups were compared, the former group had a higher prevalence of narrow CNC and narrow IAC. Of the 20 infants without identifiable CN on the affected side, 17 (85%) had narrow IAC and 17 (85%) had narrow CNC. In the 20 ears with absent CN, only one had both normal-sized IAC and CNC.

Conclusion

The contribution of CND to prelingual SSD in Korean infants reached 100%, according to IAC MRI alone.

https://ift.tt/2Ja1IJL

Pediatric vestibular testing: Tolerability of test components in children

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Peter J. Ciolek, Elise Kang, Julie A. Honaker, Erika A. Woodson, Brandon S. Hopkins, Samantha Anne

Abstract

Introduction

Objective of the study is to define rates of successful completion of components of pediatric vestibular testing (VT).

Methods

Retrospective review of VT performed on patients less than 18 years of age from 2004 to 2015.

Results

188 pediatric patients (mean age: 13.9 ± 3.56 years old, range 2–17 years) underwent testing. Thirty-five (18.6%) had abnormal test results. Pediatric patients unable to complete all aspects of VT could still complete an average of 7.9 ± 4.0 of 12 test components. The optokinetic tracking test was the most commonly omitted component of the vestibular tests. In a multivariate analysis, failure to perform Nylen-Barany positional testing (χ² 27.5, p < 0.0001) or Dix-Hallpike (5.66, p = 0.0174) testing was associated with inability to obtain final diagnosis on VT.

Conclusions

Interpretable VT may be obtained in most children, even in those that do not tolerate the full testing protocol. Spontaneous and gaze-evoked nystagmus testing maybe considered as part of initial testing protocol before attempting less well-tolerated components such as bithermal calorics or components that require VNG goggles.

https://ift.tt/2NCKCYt

Two novel homozygous missense mutations identified in the BSND gene in Moroccan patients with Bartter's syndrome

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Soukaina Elrharchi, Zied Riahi, Sara Salime, Halima Nahili, Hassan Rouba, Mostafa Kabine, Crystel Bonnet, Christine Petit, Abdelhamid Barakat

Abstract

Objectives

Hearing loss (HL) is one of the most common sensorineural disorders. In the present study, we identified two novel missense mutations in BSND gene causing Bartter syndrome type IV which is a genetic disease with an autosomal recessive transmission, characterized by hypokalaemia, metabolic alkalosis, an elevation in plasma renin activity and hyperaldosteronism as well as sensorineural deafness.

Methods

Whole-exome sequencing was performed to study the genetic causes of Hearing loss in two unrelated patients from two Moroccan families.

Results

The two novel homozygous mutations p.Arg8Gly (c.22C > G), p.Thr36Asn (c.107C > A) in exon 1 of BSND gene which encodes barttin were identified in 7 patients belonging to two unrelated families originated from central region of Morocco.

Conclusion

We identified two novel missense mutations p.Arg8Gly and p.Thr36Asn in exon 1 of BSND gene; both mutations were described for the first time in Moroccan patients with Bartter syndrome type IV.

https://ift.tt/2J9K4pH

Decreased disulphide/thiol ratio in patients with autosomal recessive non-syndromic hearing loss

Publication date: Available online 10 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Burhan Balta, Ramazan Gundogdu, Murat Erdogan, Murat Alisik, Aslihan Kiraz, Ibrahim Ozcan, Ozcan Erel

Abstract

Introduction

Oxidative stress plays a key role in the formation of age-related, noise-induced and drug-induced hearing loss. Thiols are organic compounds which can react with free radicals to protect against tissue and cell damage caused by reactive oxygen. There are no studies in literature on the association between autosomal recessive non-syndromic hearing loss(ARNSHL) including GJB2 and non-GJB2 mutations and thiol-disulphide balance. In this study, we aim to assess whether thiol-disulphide balance is disrupted in patients with ARNSHL.

Methods

Thirty-one ARNSHL patients and thirty-one healthy controls were included in this study. Patients whose parents were first degree cousins and who had at least two congenital hearing loss in the same family were included in the study. Audiological tests included air - bone pure tone audiometry and auditory brain stem response. GJB2 gene analysis was performed using sanger sequence method. Tests of thiol/disulphide homeostasis were conducted using the automated spectrophotometric method. We first investigated whether there was a significant difference between ARNSHL patients and healthy controls. Then, in order to determine the differential effect of the GJB2 gene mutations and non-GJB2 gene mutations on the thiol-disulphide balance, subjects were divided into three groups: Group 1 included patients with GJB2 mutations; Group 2 included patients with non-GJB2 mutations; Group 3 included healthy subjects.

Results

Patients with ARNSHL had significantly higher native thiol (411.6 ± 54.3 μmol/l vs. 368.0 ± 64.3 μmol/l, p = 0.006), total thiol levels (440.3 ± 56.2 μmol/l vs. 402.4 ± 65.9 μmol/l, p = 0.018), and lower disulphide levels (14.3 ± 5.7 μmol/l) vs. (17.1 ± 4.9 μmol/l), (p = 0.043) compared to the control group. Moreover, disulphide /native thiol (p < 0.001) and disulphide/total thiol (p < 0.001) were also detected lower in the ARNSHL group compared to the control group. Thiol-disulphide hemostasis parameters between all three groups showed that the native thiol and total thiol were increased in the Group 1 and Group 2. The disulphide levels decreased in Group 1 and 2, although not statistically significant.

Conclusion

It was shown that thiol levels increased and disulphide levels decreased in patients with autosomal recessive non-syndromic hearing loss. It also may suggest that there is a reverse association between ARNSHL and oxidative stress. Further studies are needed on whether or not ARNSHL cause oxidative stress limited to the inner ear and cochlea.

https://ift.tt/2NB7IP0

Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases

Publication date: Available online 10 July 2018

Source: Clinical Immunology

Author(s): Eric Espinosa, Salvatore Valitutti, Michel Laroche, Camille Laurent, Pol André Apoil, Olivier Hermine, Michel Lavit, Carle Paul, Cristina Bulai Livideanu

Abstract

There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2).

We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

https://ift.tt/2KML9sQ

Beyond JAAD - October 2018

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Andrew Bronin, Robert Phelps, Robert Sidbury

https://ift.tt/2N1x7jO

Methotrexate for alopecia areata: a systematic review and meta-analysis

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Kevin Phan, Vignesh Ramachandran, Deshan Frank Sebaratnam

Abstract

Background

Methotrexate has been used both as an adjunct for low-risk maintenance therapy after initiation with corticosteroids for alopecia areata (AA) and as standalone therapy in some investigations, based on a lack of definitive evidence/guidelines.

Objective

To (1) determine the efficacy and risks associated with methotrexate therapy for AA (2) determine differences efficacy of combination with corticosteroids versus standalone treatment, and (3) determine relative efficacy of methotrexate in adult versus pediatric populations.

Methods

A systematic review and meta-analysis was performed according to recommended PRISMA guidelines.

Results

Methotrexate has reasonable effectiveness in patients with severe AA, and that adults appear to be more responsive to methotrexate treatment compared to pediatric cases. Methotrexate in conjunction with corticosteroids result in higher good/complete response rates compared to those treated with methotrexate alone. A large proportion of recurrence rates occurred in the setting of tapering treatment. Complication rates were acceptable and similar between adults and pediatric cases.

Limitations

Studies reviewed were retrospective observational studies with heterogeneity between centers in terms of dosages/protocols for methotrexate use in AA, and adjunctive treatments with a lack of data beyond one year.

Conclusion

Methotrexate is an effective monotherapy or adjunct to corticosteroid in the treatment of severe AA.

https://ift.tt/2KIwOOd

Surgical Pearl: A Granny Sliding Knot for High Tension Closures

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Jeffrey F. Scott, Mona Ascha, Whitney Pollard, Jeremy S. Bordeaux

https://ift.tt/2N3tytt

Ustekinumab treatment for neutrophilic dermatoses associated with Crohn’s disease: a multicenter-retrospective study

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Tullia de Risi-Pugliese, Philippe Seksik, Jean-David Bouaziz, François Chasset, Philippe Moguelet, Jean-Marc Gornet, Anne Bourrier, Aurélien Amiot, Laurent Beaugerie, Camille Francès, Sarah Guégan, Ustek-CDND study group

https://ift.tt/2KOwg9O

Drug-Induced Phototoxicity: A Systematic Review

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Whan B. Kim, A.J. Shelley, K. Novice, J. Joo, H.W. Lim, S.J. Glassman

Abstract

Background

Phototoxicity has been attributed to numerous oral drugs over the past 60 years.

Objective

Determine the quality of evidence supporting suspected phototoxicity from oral drugs

Methods

MEDLINE and EMBASE databases were searched for all studies containing original data for drug-induced phototoxicity published between May 1959 and December 2016. Study quality was assessed using a modified GRADE scale.

Results

The review included 240 eligible studies with a total of 2466 subjects. There were 1134 cases of suspected phototoxicity associated with 129 drugs. Most associations were supported by either very low-quality or low-quality evidence (89.1% of the studies). Medications supported by stronger evidence were vemurafenib, non-steroidal anti-inflammatory drugs (NSAIDs), and antibiotics, specifically fluoroquinolones and tetracyclines. The most frequently reported drugs were: vemurafenib, voriconazole, doxycycline, hydrochlorothiazide, amiodarone, and chlorpromazine. Photobiologic evaluation was performed in only 56 studies (23.3%), while challenge-rechallenge was done in 10% of cases.

Limitations

Only English-language publications were reviewed. Phototoxicity cases incorrectly termed photoallergy would not have been included.

Conclusions

Most purported associations between oral drugs and phototoxicity are not supported by high-quality evidence. Despite the variable quality of data, clinicians should be aware of the possible consequences of chronic use of culprit drugs.

https://ift.tt/2N2T95T

The ALT-70 Predictive Model Outperforms Thermal Imaging for the Diagnosis of Lower Extremity Cellulitis: A Prospective Evaluation

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): David G. Li, Anna K. Dewan, Fan Di Xia, Hasan Khosravi, Cara Joyce, Arash Mostaghimi

Abstract

Background

We previously demonstrated dermatology consultation to substantially reduce cellulitis misdiagnosis rates; however, broad implementation is impractical due to existing practice patterns and reimbursement systems. Meanwhile, efforts to improve diagnostic accuracy have culminated in point-of-care tools, including the ALT-70 predictive model for lower extremity cellulitis and thermal imaging.

Objective

To prospectively evaluate the performance of ALT-70 and thermal imaging in diagnosing lower extremity cellulitis in a head-to-head comparison.

Methods

We collected ALT-70 and thermal imaging data from patients with presumed lower extremity cellulitis and compared classification measures and accuracy for ALT-70, thermal imaging, and combination testing (ALT-70 plus thermal imaging).

Results

We enrolled 67 patients with ALT-70 and thermal imaging data. ALT-70 conferred the highest sensitivity (97.8%) and negative predictive value (90.9%), while combination testing had the highest specificity (71.4%) and positive predictive value (86.6%). ALT-70 had improved classification measures compared to thermal imaging. Combination testing conferred a marginal benefit to ALT-70 alone.

Limitations

Single-center design may limit generalizability.

Conclusion

ALT-70 outperformed thermal imaging in diagnosing lower extremity cellulitis. The accuracy of the ALT-70 was high and consistent with previously published reports. Broad implementation of ALT-70 into clinical practice may decrease misdiagnosis rates of lower extremity cellulitis.

https://ift.tt/2KN4xGf

Mohs micrographic surgery (MMS) with MART-1 immunostaining for atypical intraepidermal melanocytic proliferation (AIMP)

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Jeremy R. Etzkorn, Olivia S. Jew, Thuzar M. Shin, Joseph F. Sobanko, Donald E. Neal, Christopher J. Miller

Abstract

Background

The efficacy of Mohs micrographic surgery (MMS) for atypical intraepidermal melanocytic proliferation (AIMP) is unknown.

Objective

To ascertain the frequency of diagnostic change to melanoma (upstaging) and the frequency of local recurrence after MMS for AIMP. A secondary outcome was the frequency of subclinical spread (defined as the requirement for greater than one stage of MMS to achieve tumor-free margins).

Methods

Retrospective, cross-sectional study of 223 AIMP (with 92.4% located on the head, neck, hand, foot, or pretibial leg) treated with MMS with MART-1 immunostaining.

Results

Upstaging to unequivocal MIS or invasive melanoma was identified in 18.8% (42/223) of all AIMP. The local recurrence rate was 0% (0/223) with a mean follow-up time of 2.7 years (998 days). Subclinical spread was present in 23.8% (53/223) of AIMP.

Limitations

Single site, retrospective design, observational study, lack of objective criteria to diagnose AIMP

Conclusion

MMS with MART-1 immunostaining achieves excellent local control of specialty-site AIMP and permits definitive removal of subclinical spread prior to reconstruction. The central debulking excision should be evaluated with formalin-fixed paraffin-embedded sections, since a significant percentage of AIMP are reclassified as MIS or invasive melanoma.

https://ift.tt/2N3txWr

Pigmentation of basal cell carcinoma is inversely associated with tumor aggressiveness in Asian patients

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Hye-Rim Moon, Tae Jun Park, Ki Woong Ro, Hwa Jung Ryu, Soo Hong Seo, Sang Wook Son, Il-Hwan Kim

https://ift.tt/2KMK2JG

Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-analysis

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Samar Salman, Mohamed Shehata Ahmed, Ahmed Mohamed Ibrahim, Omar Mohamed Mattar, Hassan El-Shirbiny, Sameh Sarsik, Ahmed M. Afifi, Ruba Marwan Anis, Nadim Aiman Yakoub Agha, Abdelrahman Ibrahim Abushouk

Abstract

Background

Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging.

Objective

Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities.

Methods

We included randomized controlled trials (RCTs) comparing intralesional immunotherapeutic modalities to cryotherapy, placebo or imiquimod. All outcomes were presented as odds ratio (OR) with 95% confidence-interval. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments.

Results

Network meta-analysis of 17 RCTs (1676 patients) showed that PPD (OR=39.56), MMR (OR=17.46) and INF-β (OR=15.55) had the highest efficacy in terms of complete recovery at the primary site, compared to placebo. Regarding complete recovery at the distant site, autoinoculation (OR=79.95), PPD (OR=42.95) and MMR (OR=15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing recurrence rate at the same site.

Limitations

Relatively-small sample size in some comparisons and variability in baseline characteristics.

Conclusion

PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site, compared to cryotherapy and other immunotherapeutic modalities.

https://ift.tt/2N56cUb

Efficacy, Safety, and Comparison of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: A Systematic Review and Meta-Analysis

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Pingxing Xie, Philippe Lefrançois

Abstract

Background

Sonic Hedgehog Inhibitors (SHHi) provide an additional treatment option for basal cell carcinomas (BCC), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacking direct comparisons between molecules.

Objective

To determine the efficacy and safety of SHHi, as a class of molecules, for treating BCC, and to compare them individually.

Methods

We performed a PRISMA-compliant systematic review of studies followed by a meta-analysis.

Results

Eighteen articles were included in our meta-analysis; sixteen articles were combined for efficacy and sixteen for safety. In locally advanced BCC, Overall Response Rates (ORR) were similar for vismodegib and sonidegib (69% vs. 57%), but not Complete Response Rates (31% vs. 3%). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs. 15%). For side effects affecting a majority of patients, combined prevalences were 67.1%, 54.1% and 57.7% for muscle spasms, dysgeusia, and alopecia, respectively, in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper GI distress than patients receiving vismodegib.

Conclusions

SHHi as a class lead to partial responses for locally advanced BCC disease. Side effects are similar across molecules, common, associated with high discontinuation rates, and warrant discussion beforehand.

https://ift.tt/2KHT4Ys

Topical Glycopyrronium Tosylate for the Treatment of Primary Axillary Hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 Phase 3 Randomized Controlled Trials

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Dee Anna Glaser, Adelaide A. Hebert, Alexander Nast, William P. Werschler, Lawrence Green, Richard Mamelok, Janice Drew, John Quiring, David M. Pariser

Abstract

Background

Glycopyrronium tosylate (GT) is a topical anticholinergic developed for once-daily treatment of primary axillary hyperhidrosis.

Objective

Assess the efficacy and safety of GT for primary axillary hyperhidrosis.

Methods

ATMOS-1 and ATMOS-2 were replicate randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Patients were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. Coprimary endpoints were responder rate (≥4-point improvement from Baseline) on Item 2 (sweating severity) of the Axillary Sweating Daily Diary (ASDD), a newly developed patient-reported outcome, and absolute change from Baseline in axillary gravimetric sweat production at Week 4. Safety evaluation included treatment-emergent adverse events (TEAEs).

Results

Pooled data, consistent with individual trial results show significantly more GT-treated patients achieved ASDD Item 2 response versus vehicle (59.5% vs 27.6%) and had reduced sweat production from Baseline (-107.6mg/5min vs -92.1mg/5min) at Week 4 (P<0.001 for both coprimary endpoints). Most TEAEs were mild or moderate and infrequently led to discontinuation.

Limitations

Short trial duration and inherent challenges in gravimetrically assessing sweat production.

Conclusions

Daily, topically-applied GT over 4 weeks reduced sweating severity as measured by ASDD-Item 2, reduced sweat production as measured gravimetrically, and was generally well tolerated in primary axillary hyperhidrosis patients.

https://ift.tt/2N2l2eb

Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): Nicole M. Golbari, Martina L. Porter, Alexa B. Kimball

Abstract

Background

Hormonal therapy is a potential treatment for hidradenitis suppurativa (HS). However, little data exists describing the efficacy of spironolactone in HS treatment.

Objective

To assess whether spironolactone treatment improves HS disease severity and patient reported pain.

Methods

We performed a single center chart review of female HS patients treated with spironolactone between 2000 and 2017. Primary outcome measurements included the HS Physician Global Assessment (HSPGA), Hurley Staging, inflammatory lesion count, fistula count, and a numeric rating scale for pain.

Results

Subjects on average were exposed to 75mg of spironolactone daily over a 7.1-month follow-up period. Patients achieved significant disease improvement with regards to pain (Δ-1.5, P=.01), inflammatory lesions (Δ-1.3, P=.02), and HSPGA (Δ-0.6, P<.001). As expected, no change was found for Hurley stage (Δ0, P=.32) or fistulas (Δ0, P=.73). There was no difference in improvement between subjects who received less than 75mg daily (n= 25, average 45mg/day) and those who received greater than 100mg daily (n=21, average 112mg/day).

Limitations

Retrospective nature, limited sample size, and variations in severity measures documented were limiting factors.

Conclusions

Management of HS with spironolactone reduces lesion count, HSPGA and pain. Lower doses appear to be effective and may be an appropriate option for patients with tolerability concerns.

https://ift.tt/2KHSWrW

“Comparing the eighth and the seventh editions of the ajcc staging system and the brigham and women’s hospital alternative staging system for cutaneous squamous cell carcinoma: implications for clinical practice”

Publication date: Available online 10 July 2018

Source: Journal of the American Academy of Dermatology

Author(s): J. Cañueto, J. Burguillo, D. Moyano-Bueno, A. Viñolas-Cuadros, A. Conde-Ferreirós, Luis Antonio Corchete-Sánchez, J. Pérez-Losada, C. Román-Curto

Abstract

Background

The new 8^th edition of the American Joint Committee on Cancer (AJCC) staging system incorporates changes regarding cutaneous squamous cell carcinoma (CSCC).

Objectives

We aimed to compare the 8^th edition of the AJCC (AJCC-8) staging system with the previous 7^th edition (AJCC-7) and the Brigham and Women's Hospital alternative staging system, to identify their usefulness and the utility of their risk factors in defining prognostic groups in CSCC.

Methods

A series of 186 CSCCs of the head and neck was retrospectively collected. All three staging systems were compared in their ability to predict poor prognosis. Binary logistic regression models were built to determine which risk factors were most relevant.

Results

Poor prognosis was mainly associated with T2-AJCC-7, with T2b/T3-BWH's and with T3-AJCC-8. The AJCC-8 and the BWH's staging systems displayed overlap between each other in predicting poor prognosis and both were superior to the AJCC-7. The new risk factors incorporated into the AJCC-8 and the poor degree of differentiation were independently associated with poor outcome.

Limitations

Retrospective study and few cases with bone invasion.

Conclusions

The AJCC-8 is more distinctive, monotonous and homogeneous than the AJCC-7 and shows some overlap in the stratification of tumors with the BWH's system.

https://ift.tt/2MZNiy6

The joint toxicity effect of five antibiotics and dibutyl phthalate to luminescent bacteria ( Vibrio fischeri )

Abstract

Antibiotics and phthalate esters are two kinds of emerging pollutants and are ubiquitous in the aquatic ecosystem. To date, few studies analyzed the combined toxicity of the mixtures of antibiotics and phthalate esters, and their joint toxicity effect mode remains unknown. Here, we investigated the single and joint toxicity of dibutyl phthalate (DBP) and five antibiotics, namely, oxytetracycline hydrochloride (OTC), chlortetracycline hydrochloride (CTC), sulfamethazine (SMZ), sulfamerazine (SMR), and sulfadiazine (SD), to luminescent bacteria of Vibrio fischeri. The median effect concentration (EC₅₀) values of the test chemicals were ranked as CTC (6.67 mg/L) > OTC (25.12 mg/L) > SD (67.61 mg/L) > SMR (141.51 mg/L) > DBP (148.38 mg/L) > SMZ (245.07 mg/L). The joint toxicities of the binary mixtures of antibiotics and DBP were evaluated by the concentration addition (CA) and independent action (IA) models. The joint toxicity effects of CTC-DBP, OTC-DBP, SMZ-DBP, SMR-DBP, and SD-DBP all appeared to be synergism. Our study revealed that sulfonamides combined with DBP could be as toxic as or even more toxic than tetracycline. Thus, the joint toxicity effect should be considered when assessing the ecological risks of binary or multicomponent pollutants.

https://ift.tt/2zzs7kT

Several newly discovered Mo-enriched plants with a focus on Macleaya cordata

Abstract

Phytoremediation as an alternative strategy has been a widespread attention. The screening of enriched plants and hyperaccumulators is the key of the strategy. So this study examined the status of heavy metal pollution in molybdenum (Mo) mine soils, metal accumulation in plants growing on mine, and their tolerance strategies. The analysis of 14 soils and 27 plant samples in mining area showed that Mo, zinc (Zn), and cadmium (Cd) concentrations exceeded soil safety standards and their levels varied in 27 plant samples. Mo was the heavy pollution with an average total content of 256.1 mg/kg in soils. As Mo-enriched plants, Mo concentrations of Macleaya cordata (Willd.) R. Br. and Morus australis Poir. were 704.4 and 772.4 mg/kg, respectively. M. cordata was selected as the research material, due to its high biomass. Molybdenum significantly decreased the biomass and photosynthesis of M. cordata at high concentration (> 200 μmol/L), but its biomass and photosynthesis reached the maximum after 50 μmol/L Mo treatment, respectively. Analysis of the subcellular distribution and chemical speciation showed that Mo was distributed a certain way in the extracts and that this suggested that it may be present in cell wall and soluble fraction of roots (51.9–63.9%; 26.1–44.7%) or shoots (30.0–44.4%; 47.3–56.0%) and complexed to organic acid, pectate, oxalate, and protein. This might be responsible for the adaptation of M. cordata to Mo stress. Therefore, M. cordata could serve as a potential plant to utilize for the phytoremediation of Mo-contaminated soil.

https://ift.tt/2u7Epf7

Relationship between transient severe motion of the liver in gadoxetic acid or iodinated contrast agent-enhanced imaging and arterial oxygen saturation and heart rate changes

Publication date: Available online 10 July 2018

Source: Magnetic Resonance Imaging

Author(s): Akihiko Kanki, Tsutomu Tamada, Toshinori Abe, Hiroyuki Ikenaga, Koji Yoshida, Katsuyoshi Ito

Abstract

Purpose

To clarify the relationship between transient sever motion artifact in arterial phase (TSMA) and changes in peripheral capillary oxygen saturation (SpO₂) and heart rate (HR) after contrast media administration during MRI or CT of the liver.

Methods

87 patients undergoing 61 MRI examination with gadoxetic acid or 26 CT examination with iodinated contrast were included. Dynamic contrast-enhanced imaging (DCEI) was obtained at four vascular phase acquisitions. Reviewers extracted the segmental data of SpO₂ and HR in each phase from consecutive data in DCE-CT or DCE-MRI. In addition, reviewers scored for respiratory motion in each phase using 5-point scale. Patients with an arterial score of 4–5, and other phase scores of 1–2 were considered to be exhibiting TSMA.

Results

In gadoxetic acid, mean SpO₂ of arterial phase was significantly lower than three other phases (P = 0.045 to P < 0.001). However, the decrease in SpO₂ in arterial phase compared with other phases was <1%. Mean HR in gadoxetic acid or iodinated contrast agent was highest in the portal-phase. The incidence of TSM was 0% in patients with iodinated contrast agent and was 8.2% (5/61 patients; TSM group) in patients with gadoxetic acid, respectively. In addition, there was no significant difference in mean SpO₂ of arterial phase between the TSM group (97.5% ± 1.08%) and non-TSM group (96.4% ± 1.85%) (P = 0.219).

Conclusion

The slight decrease in SpO₂ in arterial phase is not associated with TSMA.

https://ift.tt/2KIvHy1

3D Printed Electrodes for Improved Gas Reactant Transport for Electrochemical Reactions

3D Printing and Additive Manufacturing, Ahead of Print.


https://ift.tt/2L4aBpZ

Emerging contaminants removal by granular activated carbon obtained from residual Macauba biomass

Abstract

The removal of emergent contaminants via adsorption on granular activated carbon, prepared from Macauba palm, has been studied, contributing to the recovery of the residual biomass, endocarp, obtained in the Macauba palm oil extraction process. The material was characterized by different techniques, such as Raman spectroscopy, thermal analysis, adsorption/desorption of N₂, zeta potential, and scanning electron microscopy. The N₂ adsorption studies showed that the material presents wide micropores and narrow mesopores, and has a surface area of 907.0 m² g⁻¹. Its maximum adsorption capacity towards the three main emerging contaminants (bisphenol A, ethinylestradiol, and amoxicillin) is much higher than that obtained with benchmark adsorbents (0.148, 0.104, and 0.072 mmol g⁻¹, respectively). The influence of temperature and pH on the adsorption was also analyzed, allowing an improved description of the adsorption mechanism and showing very promising results.

https://ift.tt/2ul2eiu

Nasenseptumplastik und Nasenmuschelbehandlung – ambulant oder stationär?

Laryngo-Rhino-Otol 2018; 97: 450-452
DOI: 10.1055/a-0621-2108

Menezes AS et al. Septal and turbinate surgery: is overnight essential? Eur Arch Otorhinolaryngol 2018; 275: 131–138 Die ambulante Operation von Nasenscheidewand und Nasenmuschel ist zunehmende Praxis. Allerdings wird dieses Thema kontrovers diskutiert. Portugiesische Kopf- und Halschirurgen überprüften anhand eigener Daten, mit welchen unerwarteten Krankenhauswiederaufnahmen und Komplikationen zu rechnen ist.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Welche Behandlung wirkt beim Hörsturz am besten?

Laryngo-Rhino-Otol 2018; 97: 448-449
DOI: 10.1055/a-0621-2081

Ashtiani MK at al. Efficacy of systemic and intratympanic corticosteroid combination therapy versus intratympanic or systemic therapy in patients with idiopathic sudden sensorineural hearing loss: a randomized controlled trial. Eur Arch Otorhinolaryngol 2018; 275: 89–7 Iranische HNO-Ärzte verglichen die Heilungsraten einer Behandlung des idiopathischen Hörsturzes mit oralen und intratympanalen Kortikosteroidgaben in Mono- und Kombinationstherapien.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Prävention von Stimmstörungen

Laryngo-Rhino-Otol 2018; 97: 453-454
DOI: 10.1055/a-0626-8754

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Schonende Operationstechnik beim Attikcholesteatom vielversprechend

Laryngo-Rhino-Otol 2018; 97: 449-450
DOI: 10.1055/a-0588-9272

Presutti L et al. The Impact of the Transcanal Endoscopic Approach and Mastoid Preservation on Recurrence of Primary Acquired Attic Cholesteatoma. Otol Neurotol 2018; 39: 445–450 Die chirurgische Behandlung eines Attikcholesteatoms ist anspruchsvoll und über eine optimale Strategie wird aktuell immer noch diskutiert. Wissenschaftler haben nun untersucht, welche Faktoren einen Einfluss auf postoperative Erkrankungen eines primär erworbenen Attikcholesteatoms haben. Die Autoren nahmen an, dass minimalinvasiv, schleimhautschonende Operationstechniken einen positiven Effekt auf die Ergebnisse in Bezug auf Rezidive haben.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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„Plastische Gesichtschirurgie – Hautdefekte und Wundversorgung“

Laryngo-Rhino-Otol 2018; 97: 453-453
DOI: 10.1055/a-0625-8508

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Akute Kehlkopfentzündung

Laryngo-Rhino-Otol 2018; 97: 455-456
DOI: 10.1055/a-0589-3229

Durch die akute Laryngitis wird die Stimme heiser und ist in ihrer Leistungsfähigkeit herabgesetzt. Stimmruhe ist die sicherste Methode, Folgeschäden durch weitere Belastung zu vermeiden.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Aus der Gutachtenpraxis: Objektive Diagnostik mithilfe von Chirp-Stimuli bei stationären auditorischen Potenzialen (ASSR) in der Begutachtung von Hörstörungen

Laryngo-Rhino-Otol 2018; 97: 493-496
DOI: 10.1055/a-0589-3251

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Update Schwangerschaftsrhinitis

Laryngo-Rhino-Otol 2018; 97: 457-464
DOI: 10.1055/a-0589-3218

Als sog. Schwangerschaftsrhinitis (SSR) wird eine mehrwöchige, schwangerschaftsbegleitende nasale Obstruktion bezeichnet, die sich durch eine Schwellung der Mukosa sowie vermehrte Sekretion ohne Hinweis auf eine Entzündung, Infektion, Allergie oder Raumforderung auszeichnet und deren Symptome nach der Geburt rasch wieder verschwinden. Die SSR zählt zu den endokrinen nasalen Hyperreaktivitäten. Etwa ein Viertel aller Schwangeren ist von diesem Krankheitsbild betroffen, das zu jedem Zeitpunkt der Schwangerschaft auftreten kann. Pathophysiologisch werden vor allem hormonelle Einflüsse diskutiert, Rauchen sowie eine vorbestehende Hausstaubmilbenallergie gelten als Risikofaktoren. Nachfolgend stellen wir ein stufentherapeutisches Konzept für die Behandlung der SSR vor und diskutieren die aktuelle Literatur.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Otitis media – Definition, Pathogenese, Klinik, Diagnose und Therapie

Laryngo-Rhino-Otol 2018; 97: 497-508
DOI: 10.1055/s-0044-101327

Unter dem Begriff Otitis media werden die akute Otitis media, die rezidivierende akute Otitis media, die Otitis media mit Erguss, die chronische Otitis media mesotympanalis und die chronische Otitis media epitympanalis, das Cholesteatom, zusammengefasst. Es handelt sich um vielfältige Krankheitsbilder, die teils ineinander übergehen können und eine individuell angepasste, zielgerichtete Therapie erfordern.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Fragen für die Facharztprüfung

Laryngo-Rhino-Otol 2018; 97: 509-510
DOI: 10.1055/a-0589-3262

© Georg Thieme Verlag KG Stuttgart · New York

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Rhinoplastik

Laryngo-Rhino-Otol 2018; 97: 511-513
DOI: 10.1055/a-0589-3316

© Georg Thieme Verlag KG Stuttgart · New York

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Kommentar der Schriftleitung

Laryngo-Rhino-Otol 2018; 97: 444-445
DOI: 10.1055/a-0589-3196

© Georg Thieme Verlag KG Stuttgart · New York

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Contributors

SUJANA S. CHANDRASEKHAR, MD

https://ift.tt/2NF2WAe

Contents

Sujana S. Chandrasekhar

https://ift.tt/2L6ELJ5

Forthcoming Issues

Nasal Obstruction

https://ift.tt/2NF2O3I

CME Accreditation Page

https://ift.tt/2J9AliP

Age-Related Deficits in Taste and Smell

Disturbances in both the ability to smell and to taste are common in older persons. Such disturbances influence nutrition, safety, quality of life, and psychological and physical health. The anatomic and physiologic causes of age-related disturbances are multiple and interacting, and depend on genetic and environmental factors. Frank losses of function, distortions, and hallucinations are common. Most distortions resolve over time, although this can take months or even years. Olfactory dysfunction occurs during the earliest stages of several neurologic disorders, most notably Alzheimer's disease and Parkinson's disease, likely heralding the onset of the underlying pathologies.

https://ift.tt/2NCMvEt

Copyright

ELSEVIER

https://ift.tt/2L6EK7Z

Geriatric Otolaryngology

According to the US census publications, the US population is expected to grow by 27% between 2012 and 2050, which would be an increase from 314 million to 400 million. About 80 million in the US are expected to be over 65 years old. The projection of increased elderly population is due to several factors: increase in life expectancy, decrease in mortality, and decrease in fertility. As such, the recognition of the geriatric patient with otolaryngologic problems will present some unique challenges.

https://ift.tt/2NBCCah

Geriatric Otolaryngology

OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA

https://ift.tt/2J7YGpv

Concentrations of PCDD/Fs in the neighborhood of a hazardous waste incinerator: human health risks

Abstract

In 1996–1998, a wide surveillance program was initiated in the vicinity of a new hazardous waste incinerator (HWI) placed in Constantí (Catalonia, Spain), which started its regular operations in 1999. The program was aimed at assessing the environmental impact of the facility on the surrounding environment, as well as to evaluate the potential risks for the population living in the neighborhood. Since then, among other measurements, the concentrations of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) have been periodically determined in soil and herbage samples. This study shows the results, corresponding to the period 2013–2016. Data were compared with those obtained in the baseline survey (1996–1998), as well as with those of the previous survey (2011–2012). The median PCDD/F concentrations in soils were 0.44 and 0.33 ng toxic equivalent (I-TEQ)/kg in 2015 and 2016, respectively, with a significant decrease in relation to the baseline survey, and a non-significant decrease between 2015 and 2016. In turn, PCDD/F levels in vegetation showed some fluctuations over time, being the concentrations of PCDD/Fs in 2013 very similar to those found in 2012 (1.11 and 1.23 ng I-TEQ/kg, respectively). These concentrations notably decreased along the three last campaigns (0.16, 0.23, and 0.17 ng I-TEQ/kg in 2014, 2015, and 2016, respectively). These changes would be more related to a number of environmental factors rather than to a variation of PCDD/F emissions by the HWI. With respect to human health risks, exposure to PCDD/Fs in the area under potential influence of the HWI is not of concern, as the current environmental concentrations of PCDD/Fs do not mean additional carcinogenic or non-carcinogenic risks for the local population.

https://ift.tt/2KOesvu

Valorization of biochars from pinewood gasification and municipal solid waste torrefaction as peat substitutes

Abstract

Gasification and torrefaction have both gained significant interest as bioenergy techniques. During biomass gasification together with fuel gas, carbon-rich solid substances are produced, whereas torrefaction process is mainly used to prepare a final product with higher calorific value and carbon content than the feedstock, through a low temperature pyrolysis. Both materials (carbon wastes from gasification and torrefied product) could be classified as alternatives to biochar obtained from slow pyrolysis of biomass. The use of biochar, typically from the slow pyrolysis of biomass, as soil amendment and, more recently, as growing media components has been widely researched. However, to our knowledge, no studies have compared the use of biochar from gasification and torrefaction as growing media component for growing media formulation. The objective of this work was to study the effect of two biochars on peat-based growing media: a pinewood gasification biochar (BG) and a biochar (BT) obtained by torrefaction of the organic fraction of municipal solid waste. Growing media mixing PT (peat) with 50%vol of BG or BT were prepared and characterized according to their chemical, thermal and hydrophysical properties. Phytotoxic experiments and growth of Lolium perenne were also performed. Results indicated that peat substitution in growing media by BG and BT at a 50%vol ratio improved their hydrophysical properties. Specifically, bulk density increased more than 50%, air space increased by 43%, the increment of the total porosity was 20%, and, finally, the water holding capacity increased by 18.3%. Significantly, a positive effect on plant biomass production (yield increment: 274%) was observed after addition of BT, whereas no significant differences were observed after addition of BG biochar. Therefore, it can be concluded that both BT and BG could be used as peat substitutes in growing media formulation.

https://ift.tt/2N1hf0J

Comparative effect of organic amendments on physio-biochemical traits of young and old bean leaves grown under cadmium stress: a multivariate analysis

Abstract

The current study investigated the influence of organic amendments on cadmium (Cd) uptake and its effects on biochemical attributes of young and old leaves of bean. Bean seedlings were exposed to two levels of Cd (25 and 100 μM) in the presence and absence of different levels of ethylenediaminetetraacetic acid (EDTA) and citric acid (CA). An increase in Cd concentration in growth medium significantly enhanced Cd accumulation in bean roots and shoot. Cadmium stress increased the production of H₂O₂ which resulted in lipid peroxidation and decreased chlorophyll contents. The presence of organic amendments significantly affected Cd accumulation and toxicity to bean plants. Application of EDTA alleviated Cd toxicity in terms of chlorophyll contents, H₂O₂ contents, and lipid peroxidation possibly by chelating toxic Cd ions, and as such forming Cd-EDTA complexes. The presence of CA decreased Cd toxicity by decreasing its uptake. The biochemical responses (H₂O₂ contents, lipid peroxidation, and chlorophyll contents) of bean plants were more severely affected by Cd treatments in old leaves compared to young leaves. This study shows that the effect of CA and EDTA on biochemical behavior of Cd varies greatly with applied levels of Cd and amendments as well as the age of leaves. Based on the results, it is proposed that the presence of organic amendments can greatly affect biogeochemical behavior of Cd in the soil-plant system (ecosystem).

https://ift.tt/2L2KSOF

Severity strata for POEM, PO-SCORAD and DLQI in US adults with atopic dermatitis

Patient-Oriented Eczema Measure (POEM) is the preferred patient-reported outcome (PRO) for assessing symptoms of atopic dermatitis (AD). Dermatology Life Quality Index (DLQI) is commonly used to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing AD symptoms, yet severity strata are not established.

https://ift.tt/2L01Jlc

Effect of chitosan nanoparticles on the inhibition of Candida spp. biofilm on denture base surface

Publication date: Available online 9 July 2018

Source: Archives of Oral Biology

Author(s): Brenna Louise Cavalcanti Gondim, Lúcio Roberto Cançado Castellano, Ricardo Dias de Castro, Giovanna Machado, Hugo Lemes Carlo, Ana Maria Gondim Valença, Fabíola Galbiatti de Carvalho

Abstract

Objectives

Chitosan nanoparticles (ChNPs) have antifungal effects, however there is a lack of information about the effects of ChNPs against Candida biofilm on denture base surface. This study investigated the ChNPs effect against C. albicans biofilm adhesion and formation, and against Candida spp. biofilm on heat-cured acrylic resin.

Design

The ChNPs were synthetized (3,800 µg/mL) and characterized by infra-red spectrophotometry and transmission electron microscopy. The minimum inhibitory/fungicidal concentrations (MIC/MFC) against Candida spp. were determined. The time-kill assay and changes on C. albicans micromorphology were evaluated. The % inhibition of ChNPs on C. albicans biofilm formation and reduction were investigated using 1 min and 8 h exposure. Candida biofilm was developed on resin surfaces and ChNPs were applied every 8 h for 5 days. After, fungal cells were counted (CFU/mL) and the surface roughness (Ra) and vickers microhardness (HV) of resin were analysed. For all experiments, sodium hypochlorite (NaOCl) was used as control. Data were analyzed by ANOVA, Tukey and paired t-tests (α = 0.05).

Results

The MIC_80% of ChNPs was 30.1 µg/mL. ChNPs at 4 MIC showed complete inhibition in the time-kill assays. Blastoconidia cells were predominant after ChNPs application. The % inhibition ChNPs on C. albicans was proportional to its concentration, regardless of the exposure time. ChNPs decreased the CFU/mL of Candida spp. and showed lower alteration of HV and Ra values of resin surface compared to NaOCl.

Conclusions

The ChNPs inhibited C. albicans biofilm, reduced Candida biofilm on resin and caused small changes in roughness and hardness of acrylic resin surface.

Graphical abstract

https://ift.tt/2N0Y1Z6

Severity strata for POEM, PO-SCORAD and DLQI in US adults with atopic dermatitis

Publication date: Available online 9 July 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): JI Silverberg, JM Gelfand, D Margolis, L Fonacier, M Boguniewicz, LB Schwartz, EL Simpson, M Grayson, PY Ong, ZC Chiesa Fuxench

Abstract

Background

Patient-Oriented Eczema Measure (POEM) is the preferred patient-reported outcome (PRO) for assessing symptoms of atopic dermatitis (AD). Dermatology Life Quality Index (DLQI) is commonly used to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing AD symptoms, yet severity strata are not established.

Objective

We sought to confirm previously developed strata for POEM and DLQI, and develop strata for the PO-SCORAD in a population-based cohort of adults with AD.

Methods

A cross-sectional, population-based study of 8,217 adults was performed using a structured questionnaire. A diagnosis of AD was determined using modified UK Diagnostic Criteria for AD (N=602). AD severity was assessed using self-reported global AD severity (anchoring question), POEM, PO-SCORAD, and DLQI. Strata were selected using an anchoring approach based on patient-reported disease severity.

Results

We confirmed the existing strata for DLQI (mild=0-5, moderate=6-10, severe=11-30) (kappa=0.446). However, the preferred strata for POEM was mild=0-7, moderate=8-19 and severe=20-28 (kappa=0.409) and PO-SCORAD was mild=1-27, moderate=28-56, severe=57-104 (kappa=0.444).

Conclusion

Existing strata for DLQI performed well in a population-based cohort of adult AD. The optimal severity strata for the POEM in our AD population varies slightly from those previously published for AD. This may suggest that different strata may be optimal in different study settings and cohorts. Finally, we proposed new strata for PO-SCORAD in adult AD.

https://ift.tt/2zqQGA8

Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa

Antiandrogen therapy has been reported as an effective treatment for hidradenitis suppurativa. This study evaluated both physician and patient reported hidradenitis suppurativa severity outcomes for patients treated with spironolactone. Antiandrogen therapy with spironolactone may be a useful treatment option for reducing inflammatory lesions and pain for female patients with HS.

https://ift.tt/2m8AhXI

Surgical Pearl: A Granny Sliding Knot for High Tension Closures

https://ift.tt/2zvqkgG

Topical Glycopyrronium Tosylate for the Treatment of Primary Axillary Hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 Phase 3 Randomized Controlled Trials

Current treatment options for hyperhidrosis are limited. The topical anticholinergic, glycopyrronium tosylate, results in significant reductions in sweating severity/production and favorable tolerability in two phase 3, randomized, vehicle-controlled trials in primary axillary hyperhidrosis. These results suggest glycopyrronium tosylate may provide a non-invasive, once-daily, topical treatment option for primary axillary hyperhidrosis.

https://ift.tt/2m4G0xC

Efficacy, Safety, and Comparison of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: A Systematic Review and Meta-Analysis

Sonic hedgehog inhibitors are systemic treatments for locally advanced and metastatic basal cell carcinomas. In locally advanced disease, overall response rate is similarly significant for sonidegib and vismodegib; complete response rate is significant for vismodegib only. Rates of major side effects do not differ between vismodegib and sonidegib. Patients should expect partial responses in locally advanced disease.

https://ift.tt/2uikclN

Ustekinumab treatment for neutrophilic dermatoses associated with Crohn’s disease: a multicenter-retrospective study

https://ift.tt/2m8A86C

Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-analysis

Although intralesional immunotherapy is commonly used for wart treatment, selection among existing immunotherapeutic modalities remains challenging. PPD and MMR are the most effective modalities for lesion clearance at primary and distant sites (along with autoinoculation), and also reduce recurrence. PPD and MMR may be considered as first-line treatments for warts.

https://ift.tt/2zvpXCO

Methotrexate for alopecia areata: a systematic review and meta-analysis

There is lack of synthesised data regarding methotrexate in AA, Good response was observed in 63% of patients and complete response in 36% of patients, Initial regrowth is observed after 3 months of treatment and takes 6-12 months to achieve complete regrowth, The pooled recurrence rate of AA was 47.7%

https://ift.tt/2m7BFda

The ALT-70 Predictive Model Outperforms Thermal Imaging for the Diagnosis of Lower Extremity Cellulitis: A Prospective Evaluation

Point-of-care diagnostic tools may decrease misdiagnosis rates and unnecessary care associated with lower extremity cellulitis. In our prospective study, the ALT-70 predictive model for lower extremity cellulitis outperformed thermal imaging in diagnostic accuracy. The high negative predictive value of ALT-70 effectively allows clinicians to rule out lower extremity cellulitis.

https://ift.tt/2zvpS1Y

Pigmentation of basal cell carcinoma is inversely associated with tumor aggressiveness in Asian patients

https://ift.tt/2m8zOoq

Drug-Induced Phototoxicity: A Systematic Review

Numerous oral drugs are implicated in phototoxicity; however, the level of evidence for most has not been assessed. Vemurafenib, NSAIDs, and antibiotics (fluoroquinolones, tetracyclines) have strongest evidence for phototoxicity. Most associations are not supported by robust evidence. Improved documentation of phototoxicity testing is required before labelling oral drugs as phototoxic.

https://ift.tt/2uj4K9g

“Comparing the eighth and the seventh editions of the ajcc staging system and the brigham and women’s hospital alternative staging system for cutaneous squamous cell carcinoma: implications for clinical practice”

The new 8th edition of the American Joint Committee on Cancer (AJCC) staging system incorporates changes regarding cutaneous squamous cell carcinoma (CSCC).

https://ift.tt/2m8zIgy

Mohs micrographic surgery (MMS) with MART-1 immunostaining for atypical intraepidermal melanocytic proliferation (AIMP)

Surgical outcomes for AIMP are unknown. Upstaging to unequivocal melanoma was identified in 18.8% of AIMP. No local recurrences occurred with a mean follow-up of 2.7 years. 23.8% of AIMP required greater than one stage of MMS. MMS may be an effective treatment option for AIMP.

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Beyond JAAD - October 2018

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The diagnostic accuracy of increased late night salivary cortisol for Cushing’s syndrome: a real-life prospective study

Abstract

Introduction and aim

A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS).

Materials and methods

We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS.

Results

LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC.

Conclusions

LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

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Human Naive T Cells Express Functional CXCL8 and Promote Tumorigenesis [TUMOR IMMUNOLOGY]

Naive T cells are thought to be functionally quiescent. In this study, we studied and compared the phenotype, cytokine profile, and potential function of human naive CD4⁺ T cells in umbilical cord and peripheral blood. We found that naive CD4⁺ T cells, but not memory T cells, expressed high levels of chemokine CXCL8. CXCL8⁺ naive T cells were preferentially enriched CD31⁺ T cells and did not express T cell activation markers or typical Th effector cytokines, including IFN-, IL-4, IL-17, and IL-22. In addition, upon activation, naive T cells retained high levels of CXCL8 expression. Furthermore, we showed that naive T cell–derived CXCL8 mediated neutrophil migration in the in vitro migration assay, supported tumor sphere formation, and promoted tumor growth in an in vivo human xenograft model. Thus, human naive T cells are phenotypically and functionally heterogeneous and can carry out active functions in immune responses.

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Early Generated B-1-Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma-like Neoplasia in Aged Mice [TUMOR IMMUNOLOGY]

In mice, fetal/neonatal B-1 cell development generates murine CD5⁺ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a V_H11/D/J_H knock-in mouse line (V_H11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity–deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eμ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgM^hiIgD^loCD5⁺CD23^–CD43⁺ cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma–like neoplasia in aged mice.

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PD-1 Blockade Unleashes Effector Potential of Both High- and Low-Affinity Tumor-Infiltrating T Cells [TUMOR IMMUNOLOGY]

Antitumor T cell responses involve CD8⁺ T cells with high affinity for mutated self-antigen and low affinity for nonmutated tumor-associated Ag. Because of the highly individual nature of nonsynonymous somatic mutations in tumors, however, immunotherapy relies often on an effective engagement of low-affinity T cells. In this study, we studied the role of T cell affinity during peripheral priming with single-peptide vaccines and during the effector phase in the tumor. To that end, we compared the antitumor responses after OVA_257–264 (N4) peptide vaccination of CD8⁺ T cells carrying TCRs with high (OT-1) and low (OT-3) avidity for the N4 peptide in B16.N4 tumor-bearing C57BL/6 mice. Additionally, we assessed the response of OT-1 cells to either high-affinity (B16.N4) or low-affinity (B16.T4) Ag-expressing tumors after high-affinity (N4) or low-affinity (T4) peptide vaccination. We noticed that although low-affinity tumor-specific T cells expand less than high-affinity T cells, they express lower levels of inhibitory receptors and produce more cytokines. Interestingly, tumor-infiltrating CD8⁺ T cells show similar in vivo re-expansion capacity to their counterparts in secondary lymphoid organs when transferred to tumor-free hosts, suggesting that T cells in tumors may be rekindled upon relief of tumor immunosuppression. Moreover, our results show that αPD-1 treatment enhances tumor control of high- and low-affinity ligand-expressing tumors, suggesting that combination of high-affinity peripheral priming by altered peptide ligands and checkpoint blockade may enable tumor control upon low-affinity Ag recognition in the tumor.

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A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression [TUMOR IMMUNOLOGY]

Tumor hypoxia–driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A₂ adenosine receptors (A₂R) on tumor-reactive effector T cells, but there remains a need for careful evaluation of the limiting factors and properties of A₂R blockade–enabled antitumor immunity. In studies of A_2AR and/or A_2BR gene–deficient mice, we found that A_2AR deletion—but not A_2BR deletion—liberates endogenous CD8⁺ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A_2AR^–/–, A_2BR^–/–, or A_2AR^–/–/A_2BR^–/– tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A_2AR on CD8⁺ T cells. Treatment with A_2AR antagonist mimicked A_2AR gene deletion in adoptive T cell immunotherapy. This therapeutic benefit of targeting A_2AR was independent of the anatomical location of tumor growth. The enhanced antitumor reactivity also led to the eradication of established intracranial tumors, which was associated with mouse survival and the maintenance of long-lasting, tumor-specific immunological memory. The blockade of the A_2AR on adoptively transferred T cells by synthetic A_2AR antagonist led to higher levels of IFN- secretion by tumor-infiltrating CD8⁺ T cells. These data clarify the mechanism of hypoxia-driven immunosuppression in the tumor microenvironment by A_2AR on tumor-reactive CD8⁺ T cells and show that selective A_2AR antagonists can be effective in improving the outcomes of T cell–based immunotherapies. Demonstration of the T cell dose dependency of tumor rejection points to a major limitation of current cancer immunotherapies, in which the presence of sufficient numbers of tumor-reactive T cells in a patient is not known.

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Leukocyte-Associated Ig-like Receptor 1 Inhibits Th1 Responses but Is Required for Natural and Induced Monocyte-Dependent Th17 Responses [TRANSPLANTATION]

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas T_h1 responses were enhanced as predicted, T_h17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal T_h17 responses to collagen type (Col)V. For pre-existing "natural" T_h17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive T_h17 and T_h1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased T_h1 responses in a dose-dependent manner, but it had no effect on T_h17 responses. In IL-17–dependent murine organ transplant models of chronic rejection, LAIR1^+/+ but not LAIR1^–/– littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human T_h17 cells as compared with T_h1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors T_h17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors T_h17 over T_h1 development, posing a risk to long-term graft survival.

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Dual Roles for Ikaros in Regulation of Macrophage Chromatin State and Inflammatory Gene Expression [SYSTEMS IMMUNOLOGY]

Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. The transcription factor Ikaros has been shown to play a critical role in lymphoid cell development and differentiation; however, its function in myeloid cells and innate immune responses is less appreciated. Using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility, we describe unexpected dual repressor and activator functions for Ikaros in the LPS response of murine macrophages. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1^–/– macrophages showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of many delayed LPS response genes, and chromatin immunoprecipitation sequencing analyses support a key role for Ikaros in sustained NF-B chromatin binding. Decreased Ikaros expression in Ikzf1^+/– mice and human cells dampens these Ikaros-enhanced inflammatory responses, highlighting the importance of quantitative control of Ikaros protein level for its activator function. In the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin remodeling, gene expression, and cytokine responses. Together, our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.

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Epithelial IL-15 Is a Critical Regulator of {gamma}{delta} Intraepithelial Lymphocyte Motility within the Intestinal Mucosa [MUCOSAL IMMUNOLOGY]

Intraepithelial lymphocytes (IELs) expressing the TCR ( IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates IEL migration into cultured epithelial monolayers, and inhibition of IL-2Rβ significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2Rβ signaling induced IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating T cell localization within the intestinal mucosa and regulating IEL motility and patrolling behavior as a critical component of host defense.

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Mucosal Immunity in the Female Murine Mammary Gland [MUCOSAL IMMUNOLOGY]

The mammary gland is not classically considered a mucosal organ, although it exhibits some features common to mucosal tissues. Notably, the mammary epithelium is contiguous with the external environment, is exposed to bacteria during lactation, and displays antimicrobial features. Nonetheless, immunological hallmarks predictive of mucosal function have not been demonstrated in the mammary gland, including immune tolerance to foreign Ags under homeostasis. This inquiry is important, as mucosal immunity in the mammary gland may assure infant and women's health during lactation. Further, such mucosal immune programs may protect mammary function at the expense of breast cancer promotion via decreased immune surveillance. In this study, using murine models, we evaluated mammary specific mucosal attributes focusing on two reproductive states at increased risk for foreign and self-antigen exposure: lactation and weaning-induced involution. We find a baseline mucosal program of RORT⁺ CD4⁺ T cells that is elevated within lactating and involuting mammary glands and is extended during involution to include tolerogenic dendritic cell phenotypes, barrier-supportive antimicrobials, and immunosuppressive Foxp3⁺ CD4⁺ T cells. Further, we demonstrate suppression of Ag-dependent CD4⁺ T cell activation, data consistent with immune tolerance. We also find Ag-independent accumulation of memory RORT⁺ Foxp3⁺ CD4⁺ T cells specifically within the involution mammary gland consistent with an active immune process. Overall, these data elucidate strong mucosal immune programs within lactating and involuting mammary glands. Our findings support the classification of the mammary gland as a temporal mucosal organ and open new avenues for exploration into breast pathologic conditions, including compromised lactation and breast cancer.

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Bcl2L12 Contributes to Th2-Biased Inflammation in the Intestinal Mucosa by Regulating CD4+ T Cell Activities [MUCOSAL IMMUNOLOGY]

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4⁺ T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4⁺ T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4⁺ T cells from UC patients. Naive CD4⁺ T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4⁺ T cells. CD4⁺ T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation.

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Evidence for the Existence of a CXCL17 Receptor Distinct from GPR35 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The chemokine CXCL17 is associated with the innate response in mucosal tissues but is poorly characterized. Similarly, the G protein–coupled receptor GPR35, expressed by monocytes and mast cells, has been implicated in the immune response, although its precise role is ill-defined. A recent manuscript reported that GPR35 was able to signal in response to CXCL17, which we set out to confirm in this study. GPR35 was readily expressed using transfection systems but failed to signal in response to CXCL17 in assays of β-arrestin recruitment, inositol phosphate production, calcium flux, and receptor endocytosis. Similarly, in chemotaxis assays, GPR35 did not confirm sensitivity to a range of CXCL17 concentrations above that observed in the parental cell line. We subsequently employed a real time chemotaxis assay (TAXIScan) to investigate the migratory responses of human monocytes and the monocytic cell line THP-1 to a gradient of CXCL17. Freshly isolated human monocytes displayed no obvious migration to CXCL17. Resting THP-1 cells showed a trend toward directional migration along a CXCL17 gradient, which was significantly enhanced by overnight incubation with PGE₂. However, pretreatment of PGE₂-treated THP-1 cells with the well-characterized GPR35 antagonist ML145 did not significantly impair their migratory responses to CXCL17 gradient. CXCL17 was susceptible to cleavage with chymase, although this had little effect its ability to recruit THP-1 cells. We therefore conclude that GPR35 is unlikely to be a bona fide receptor for CXCL17 and that THP-1 cells express an as yet unidentified receptor for CXCL17.

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C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca²⁺-dependent, the molecular identity of the Ca²⁺ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca²⁺ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca²⁺ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca²⁺-dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.

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Opposing Effects of IL-1Ra and IL-36Ra on Innate Immune Response to Pseudomonas aeruginosa Infection in C57BL/6 Mouse Corneas [INNATE IMMUNITY AND INFLAMMATION]

Pseudomonas aeruginosa keratitis is characterized by severe corneal ulceration and may lead to blindness if not treated properly in a timely manner. Although the roles of the IL-1 subfamily of cytokines are well established, as a newly discovered subfamily, IL-36 cytokine regulation, immunological relevance, and relation with IL-1 cytokines in host defense remain largely unknown. In this study, we showed that P. aeruginosa infection induces the expression of IL-36α and IL-36, as well as IL-1β and secreted IL-1Ra (sIL-1Ra), but not IL-36Ra. Downregulation of IL-1Ra increases, whereas downregulation of IL-36Ra decreases the severity of P. aeruginosa keratitis. IL-1R and IL-36Ra downregulation have opposing effects on the expression of IL-1β, sIL-1Ra, IL-36, S100A8, and CXCL10 and on the infiltration of innate immune cells. Administration of recombinant IL-1Ra improved, whereas IL-36Ra worsened the outcome of P. aeruginosa keratitis. Local application of IL-36 stimulated the expression of innate defense molecules S100A9, mouse β-defensin 3, but suppressed IL-1β expression in B6 mouse corneas. IL-36 diminished the severity of P. aeruginosa keratitis, and its protective effects were abolished in the presence of S100A9 neutralizing Ab and partially affected by CXCL10 and CXCR3 neutralizations. Thus, our data reveal that IL-1Ra and IL-36Ra have opposing effects on the outcome of P. aeruginosa keratitis and suggest that IL-36 agonists may be used as an alternative therapeutic to IL-1β–neutralizing reagents in controlling microbial keratitis and other mucosal infections.

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ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3 [INNATE IMMUNITY AND INFLAMMATION]

Ataxin-3 (ATXN3) belongs to the Josephin family of deubiquitinases. So far, ATXN3 is majorly linked to the neurodegenerative disease, Machado–Joseph disease. The role of ATXN3 in the antiviral function has not been explored, and the in vivo deubiquitinating activity of ATXN3 remains largely unknown. In this study, we report that ATXN3 is an important positive regulator of type I IFN (IFN-I)–mediated antiviral activity in murine primary lung cells and human epithelial and fibroblast cell lines. We clarify that ATXN3 does not promote IFN-I production, but enhances the IFN-I–mediated signaling pathway. Furthermore, ATXN3 physically interacts with histone deacetylase 3 (HDAC3) and upregulates the level of HDAC3 protein. Moreover, ATXN3 deubiquitinates HDAC3, thereby enhancing HDAC3 protein stability. Interestingly, the interaction between ATXN3 and HDAC3 increases during viral infection, which promotes IFN-I–induced signaling in murine primary lung cells. Finally, we reveal the ATXN3/HDAC3 axis–mediated regulation of IFN-I antiviral response. These findings reveal a novel biological function of ATXN3 and an important antiviral mechanism by which the deubiquitinase ATXN3 positively regulates IFN-I antiviral response, and they may provide a novel strategy for enhancing IFN-based antiviral therapy.

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Myeloid Cell-Restricted STAT3 Signaling Controls a Cell-Autonomous Antifibrotic Repair Program [INNATE IMMUNITY AND INFLAMMATION]

Myeloid cells can be beneficial as well as harmful in tissue regenerative responses. The molecular mechanisms by which myeloid cells control this critical decision of the immune system are not well understood. Using two different models of physiological acute or pathological chronic skin damage, in this study we identified myeloid cell–restricted STAT3 signaling as important and an injury context–dependent regulator of skin fibrosis. Targeted disruption of STAT3 signaling in myeloid cells significantly accelerated development of pathological skin fibrosis in a model of chronic bleomycin-induced tissue injury, whereas the impact on wound closure dynamics and quality of healing after acute excision skin injury was minor. Chronic bleomycin-mediated tissue damage in control mice provoked an antifibrotic gene signature in macrophages that was characterized by upregulated expression of IL-10, SOCS3, and decorin. In contrast, in STAT3-deficient macrophages this antifibrotic repair program was abolished whereas TGF-β1 expression was increased. Notably, TGF-β1 synthesis in cultured control bone marrow–derived macrophages (BMDMs) was suppressed after IL-10 exposure, and this suppressive effect was alleviated by STAT3 deficiency. Accordingly, coculture of IL-10–stimulated control BMDMs with fibroblasts suppressed expression of the TGF-β1 downstream target connective tissue growth factor in fibroblasts, whereas this suppressive effect was lost by STAT3 deficiency in BMDMs. Our findings highlight a previously unrecognized protective role of myeloid cell–specific STAT3 signaling in immune cell–mediated skin fibrosis, and its regulatory pathway could be a potential target for therapy.

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Down Syndrome as an Indicator for Pediatric Otolaryngologic Procedures

Publication date: Available online 9 July 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Terral A. Patel, Shaun A. Nguyen, David R. White

Abstract

Objective

Down Syndrome (DS) is the most common chromosome abnormality in humans. Due to the phenotype associated with DS, there are many disease states that require otolaryngologic procedures. Our goal is to use national data to study otolaryngologic procedures, their association with DS, and the degree of difference in risk profiles encountered with DS.

Methods

Data was obtained from the 2012-2015 American College of Surgeons' National Surgical Quality Improvement Program-Pediatric public use files. ENT procedure CPT codes were used to query the database and DS patients were identified using ICD-9 code 758.0. The ENT procedures were grouped into 18 categories and their frequency in DS patients as well as outcomes were analyzed. Postoperative outcomes were measured by complication rates, readmission rates, operation time, anesthesia time, and total length of stay.

Results

Results showed that DS patients are significantly (p<0.05) over-represented in the following categories: Tracheostomy, Endoscopy, Laryngoscopy, Tracheoplasty, Myringoplasty, Tympanoplasty with Mastoidectomy, and Tympanoplasty without Mastoidectomy. DS patients are under-represented in the following categories: Abscess, Palatoplasty, Excision of Congenital Neck Cyst, and Cochlear Implantation. Logistic regression analysis showed that DS patients were significantly (p<0.05) more likely to undergo procedures in the over-represented categories and were significantly (p<0.05) less likely to undergo procedures in the under-represented categories as listed above. Outcomes analysis yielded no pattern of significance.

Conclusion

Our data showed that DS may predispose patients to require certain procedures over others.

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SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages [INNATE IMMUNITY AND INFLAMMATION]

There is increasing evidence that proton-coupled oligopeptide transporters (POTs) can transport bacterially derived chemotactic peptides and therefore reside at the critical interface of innate immune responses and regulation. However, there is substantial contention regarding how these bacterial peptides access the cytosol to exert their effects and which POTs are involved in facilitating this process. Thus, the current study proposed to determine the (sub)cellular expression and functional activity of POTs in macrophages derived from mouse bone marrow and to evaluate the effect of specific POT deletion on the production of inflammatory cytokines in wild-type, Pept2 knockout and Pht1 knockout mice. We found that PEPT2 and PHT1 were highly expressed and functionally active in mouse macrophages, but PEPT1 was absent. The fluorescent imaging of muramyl dipeptide–rhodamine clearly demonstrated that PEPT2 was expressed on the plasma membrane of macrophages, whereas PHT1 was expressed on endosomal membranes. Moreover, both transporters could significantly influence the effect of bacterially derived peptide ligands on cytokine stimulation, as shown by the reduced responses in Pept2 knockout and Pht1 knockout mice as compared with wild-type animals. Taken as a whole, our results point to PEPT2 (at plasma membranes) and PHT1 (at endosomal membranes) working in concert to optimize the uptake of bacterial ligands into the cytosol of macrophages, thereby enhancing the production of proinflammatory cytokines. This new paradigm offers significant insight into potential drug development strategies along with transporter-targeted therapies for endocrine, inflammatory, and autoimmune diseases.

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Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169⁺ macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169⁺ macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2–related factor 2–dominant, cytoprotective/antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation.

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