Resveratrol reverses the negative effect of smoking on peri‐implant repair in the tibia of rats

Abstract

Objectives

Innovative approaches capable to improve peri‐implant bone repair are relevant in the presence of smoking, a risk factor for healing around implants. This study investigated the effect of resveratrol (RESV) on peri‐implant repair and its influence on bone‐related markers in rats submitted to cigarette smoking inhalation (CSI).

Materials and Methods

One titanium implant was inserted in each tibiae of rats assigned to: CSI+RESV(n:18); CSI+ placebo(n:18); Non‐CSI(n:18). One implant was removed for counter‐torque and the peri‐implant tissue was collected for mRNA quantification of BMP‐2, OPN, Runx2, Lrp‐5, Osx, β‐catenin, Dkk1, OPG, and RANKL. The other tibia was submitted to MicroCT to measure: bone volume, bone porosity, trabecular spacing, trabecular thickness and bone‐implant contact (BIC).

Results

No differences were detected between counter‐torque in CSI+RESV and Non‐CSI group (p>0.05), whereas CSI+placebo group presented lower values when compared to the others (p<0.05). RESV improved the BIC in CSI rats without differences when compared to non‐CSI group (p>0.05), whereas CSI+placebo showed reduced BIC when compared to the other groups (p<0.05). RESV reduced RANKL/OPG and Lrp‐5 levels and increased β‐catenin in CSI rats when compared to CSI+placebo (p<0.05).

Conclusion

Although further investigations should be considered using oral models of dental implants, within the limits of the present study, it was concluded that RESV reverses the negative effects of smoking in the peri‐implant repair, benefiting the modulation of bone‐related markers.

This article is protected by copyright. All rights reserved.

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Non-contrast three-dimensional gradient recalled echo Dixon-based magnetic resonance angiography/venography in children

Abstract

Magnetic resonance imaging (MRI) has been considered a valuable diagnostic tool for noninvasive imaging of the vasculature in children and adults for more than two decades. While a variety of non-contrast MRI methods have been described for imaging of both arteries and veins (e.g., time-of-flight, phase contrast, and balanced steady-state free precession imaging), contrast-enhanced magnetic resonance angiography/venography are the most commonly employed vascular imaging techniques due to their high spatial and contrast resolutions and general reliability. In this technical innovation article, we describe a novel 3-D respiratory-triggered gradient recalled echo Dixon-based MR angiography/MR venography technique that provides high-resolution anatomical imaging of the vasculature of the neck, body and extremities without the need for intravenous contrast material or breath-holding.

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In vivo Raman spectroscopic characteristics of different sites of the oral mucosa in healthy volunteers

Abstract

Objectives

Investigate the biochemistry of in vivo healthy oral tissues through Raman spectroscopy. We aimed to characterize the biochemical features of healthy condition in oral subsites (buccal mucosa, lip, tongue, and gingiva) of healthy subjects. More specifically, we investigated Raman spectral characteristics and biochemical content of in vivo healthy tissues on Brazilian population. This characterization can be used to better define normal tissue and improve the detection of oral premalignant conditions in future studies.

Materials and methods

For spectroscopic analysis a Raman spectrometer (Kaiser Optical Systems imaging spectrograph Holospec, f / 1.8i-NIR) coupled with a laser 785 nm, 60 mW was used. Raman measurements were obtained by means of an optical fiber (EMVision fiber optic probe) coupled between the laser and the spectrometer. Three spectra per site were acquired from the lip, buccal mucosa, tongue, and gingiva of ten healthy volunteers. This resulted in 30 spectra per oral sub-site and in total 120 spectra.

Results

We report detailed biochemical information on these subsites and their relative composition based on deconvolution studies of their spectra. Finally, we also report classification efficiency of 61, 83, 41, and 93% for buccal, gingiva, lip, and tongue respectively after applying multivariate statistical tools.

Conclusions

We quantitated the contribution of various biochemicals in terms of percentage, and this will enable comparison not only across anatomical sites but also across studies. Raman spectroscopy can rapidly probe tissue biochemistry of healthy oral regions. Moreover, the study suggests the possibility of using Raman spectroscopy combined with signal processing and multivariate analysis methods to differentiate the oral sites in healthy conditions and compare with pathological conditions in future studies.

Clinical relevance

The spectral characterization of the healthy condition of oral tissues by a noninvasive, label-free, and real-time analytical techniques is important to create a spectral reference for future diagnosis of pathological conditions.

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Synthetic polymeric barrier membrane associated with blood coagulum, human allograft, or bovine bone substitute for ridge preservation: a randomized, controlled, clinical and histological trial

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Prospective evaluation of psychological burden in patients with oral cancer

The high morbidity and mortality that is associated with oral cancer places a huge psychological burden on patients. The purpose of this prospective study was to evaluate levels of depression, anxiety, and stress, at three time points using DASS-21 (Depression, Anxiety and Stress Scale-21). We also compared DASS-21 with HADS (Hospital Anxiety and Depression Scale). A total of 111 patients were enrolled and 75 of them completed the questionnaires at diagnosis, one month after treatment, and three months after discharge.

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Impact of isolated basal ganglia infarction at pretreatment DWI on outcomes after endovascular thrombectomy in acute anterior circulation stroke

Abstract

Purpose

Acute infarction confined to the basal ganglia (BG) is occasionally observed on baseline imaging before endovascular thrombectomy. This study aimed to investigate the impact of isolated BG infarction revealed on pretreatment DWI in a large cohort of patients with acute anterior circulation stroke who underwent thrombectomy.

Methods

We retrospectively analyzed clinical and DWI data from 328 patients who underwent thrombectomy for emergent occlusions of the intracranial internal carotid artery or the middle cerebral artery. Characteristics and treatment outcomes were compared between patients with isolated BG infarction and those with non-isolated BG infarction. Binary logistic regression analyses were performed to identify independent predictors of good outcome (90-day mRS 0–2).

Results

Isolated BG infarction was found in 57 patients (17.4%). Patients with isolated BG infarction had a higher incidence of underlying severe intracranial atherosclerotic stenosis (21.1% vs. 10.7%, P = 0.032) than those with non-isolated BG infarction. Successful reperfusion occurred more frequently in patients with isolated BG infarction than those with non-isolated BG infarction (93% vs. 79%, odds ratio 3.529, 95% confidence interval 1.226–10.161, P = 0.014). On multivariate logistic regression analysis, independent predictors of good outcome were age, DWI-ASPECTS, and admission NIHSS score. There was no significant difference in the rate of good outcome between the two groups (54.4% vs. 42.8%, P = 0.110).

Conclusion

Isolated BG infarction on pretreatment DWI may predict successful reperfusion after endovascular thrombectomy in patients with acute anterior circulation stroke. In addition, our study suggested a novel finding that isolated BG infarction was more frequently associated with underlying severe ICAS than non-isolated BG infarction.

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Proximal internal carotid artery stenosis associates with diffuse wall thickening in petrous arterial segment of moyamoya disease patients: a three-dimensional magnetic resonance vessel wall imaging study

Abstract

Purpose

To investigate the association between proximal internal carotid artery (ICA) luminal narrowing and diffuse wall thickening (DWT) in ipsilateral petrous ICA in moyamoya disease (MMD) patients.

Methods

Forty-one MMD (mean age 42.8 ± 11.0 years, 19 males) and 36 atherosclerotic patients (mean age 61.5 ± 7.1 years, 31 males) and 41 healthy controls were recruited and underwent carotid MR vessel wall imaging. The luminal narrowing of proximal ICA was evaluated by the diameter ratio of ICA to common carotid artery (DR_ICA/CCA). The wall thickness of petrous ICA was measured on T1-VISTA images. The enhancement degree of petrous ICA was recorded and graded into four grades (none to marked) on the CE-T1-VISTA images. The correlation between wall thickness in petrous ICA and DR_ICA/CCA was analyzed_.

Results

In total, 81 arteries of MMD patients and 64 arteries of atherosclerotic patients were included for analysis. The DR_ICA/CCA was significantly correlated with the wall thickness in petrous ICA in MMD (r = − 0.434, P < 0.001) and atherosclerotic groups (r = − 0.604, P < 0.001). Logistic regression analysis revealed that odds ratio (OR) of DR_ICA/CCA was 4.433 (95% CI 1.980–9.925, P < 0.001) and 2.212 (95% CI 1.253–3.905, P = 0.006) in MMD and atherosclerotic groups in discriminating petrous ICA DWT after adjusting for confounding factors. An increasing trend was found in prevalence of DWT and wall thickness with enhancement grades in petrous ICA in MMD (P = 0.02 and P = 0.01) and atherosclerotic groups (P < 0.001 and P < 0.001), respectively.

Conclusions

The proximal ICA luminal narrowing is significantly associated with wall thickness and diffuse wall thickening in ipsilateral petrous ICA in patients with carotid steno-occlusive diseases regardless of MMD or atherosclerosis.

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Vocal Biomarkers of Mild-to-Moderate Hearing Loss in Children and Adults: Voiceless Sibilants

Purpose

The purpose of this study was to determine if an objective measure of speech production could serve as a vocal biomarker for the effects of high-frequency hearing loss on speech perception. It was hypothesized that production of voiceless sibilants is governed sufficiently by auditory feedback that high-frequency hearing loss results in subtle but significant shifts in the spectral characteristics of these sibilants.

Method

Sibilant production was examined in individuals with mild to moderately severe congenital (22 children; 8–17 years old) and acquired (23 adults; 55–80 years old) hearing losses. Measures of hearing level (pure-tone average thresholds at 4 and 8 kHz), speech perception (detection of nonsense words within sentences), and speech production (spectral center of gravity [COG] for /s/ and /ʃ/) were obtained in unaided and aided conditions.

Results

For both children and adults, detection of nonsense words increased significantly as hearing thresholds improved. Spectral COG for /ʃ/ was unaffected by hearing loss in both listening conditions, whereas the spectral COG for /s/ significantly decreased as high-frequency hearing loss increased. The distance in spectral COG between /s/ and /ʃ/ decreased significantly with increasing hearing level. COG distance significantly predicted nonsense-word detection in children but not in adults.

Conclusions

At least one aspect of speech production (voiceless sibilants) is measurably affected by high-frequency hearing loss and is related to speech perception in children. Speech production did not predict speech perception in adults, suggesting a more complex relationship between auditory feedback and feedforward mechanisms with age. Even so, these results suggest that this vocal biomarker may be useful for identifying the presence of high-frequency hearing loss in adults and children and for predicting the impact of hearing loss in children.

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Relations Between Teacher Talk Characteristics and Child Language in Spoken Language, Deaf, and Hard-of-Hearing Classrooms

Purpose

The aim of this study was to examine relations between teachers' conversational techniques and language gains made by their deaf and hard-of-hearing students. Specifically, we considered teachers' reformulations of child utterances, language elicitations, explicit vocabulary and syntax instruction, and wait time.

Method

This was an observational, longitudinal study that examined the characteristics of teacher talk in 25 kindergarten through second-grade classrooms of 68 deaf and hard-of-hearing children who used spoken English. Standardized assessments provided measures of child vocabulary and morphosyntax in the fall and spring of a school year. Characteristics of teacher talk were coded from classroom video recordings during the winter of that year.

Results

Hierarchical linear modeling indicated that reformulating child statements and explicitly teaching vocabulary were significant predictors of child vocabulary gains across a school year. Explicitly teaching vocabulary also significantly predicted gains in morphosyntax abilities. There were wide individual differences in the teachers' use of these conversational techniques.

Conclusion

Reformulation and explicit vocabulary instruction may be areas where training can help teachers improve, and improvements in the teachers' talk may benefit their students.

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The Coexistence of Disabling Conditions in Children Who Stutter: Evidence From the National Health Interview Survey

Purpose

Stuttering is a disorder that has been associated with coexisting developmental disorders. To date, detailed descriptions of the coexistence of such conditions have not consistently emerged in the literature. Identifying and understanding these conditions can be important to the overall management of children who stutter (CWS). The objective of this study was to generate a profile of the existence of disabling developmental conditions among CWS using national data.

Method

Six years of data from the National Health Interview Survey (2010–2015) were analyzed for this project. The sample consisted of children whose respondents clearly indicated the presence or absence of stuttering. Chi-square tests of independence were used for comparing categorical variables; and independent-samples t tests, for comparing continuous variables. Multiple logistic regression analyses were used for determining the odds of having a coexisting disabling developmental condition.

Results

This study sample included 62,450 children, of which 1,231 were CWS. Overall, the presence of at least 1 disabling developmental condition was 5.5 times higher in CWS when compared with children who do not stutter. The presence of stuttering was also associated with higher odds of each of the following coexisting developmental conditions: intellectual disability (odds ratio [OR] = 6.67, p < .001), learning disability (OR = 5.45, p < .001), attention-deficit hyperactivity disorder/attention-deficit disorder (OR = 3.09, p < .001), seizures (OR = 7.52, p < .001), autism/Asperger's/pervasive developmental disorder (OR = 5.48, p < .001), and any other developmental delay (OR = 7.10, p < .001).

Conclusion

Evidence from the National Health Interview Survey suggests a higher prevalence of coexisting developmental disabilities in CWS. The existence of coexisting disabling developmental conditions should be considered as part of an overall management plan for CWS.

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The Accuracy of Smartphone Sound Level Meter Applications With and Without Calibration

Purpose

The purpose of this study is to determine the accuracy of smartphone sound level meter applications (SLMAs) with calibration features across stimulus levels and for ambient room noise measures in the clinical setting.

Method

The accuracy of 3 iOS-based smartphone SLMAs (SLMA1: Analyzer [Version 2.7.2, DSP Mobile], SLMA2: Sound Level Meter Pro [Version 2.2, Mint Muse LLC], and SLMA3: SPL Meter [Version 9.3, Andrew Smith, Studio Six Digital]), using a single smartphone device (iPhone 6S Model A1688, iOS 9.3.4, Apple), was evaluated with and without calibration using a 1000-Hz narrowband noise (NBN) and white noise (WN) stimuli over a range of sound levels (20–100 dB) and in ambient noise measures of 8 speech and hearing room environments. A simultaneous and corresponding SLMA and Type 1 sound level meter (SLM) measure per condition were documented with a photo image; each condition was replicated 5 times. Mean SLMA and SLM measures were compared. SLMA measures were considered accurate if within ± 2 dB of the SLM.

Results

Measures of NBN and WN signals using these SLMAs were accurate at levels above 40–50 dB when calibrated. NBN and WN signals using some SLMAs were significantly (p < .05) more accurate with calibration at levels > 40 to 50 dB. SLMA measures with or without calibration adjustment were inaccurate and overestimated room ambient noise levels < 50 dB.

Conclusions

These findings suggest that some SLMAs are accurate for measuring NBN and WN stimuli within the range of 50–100 dB in sound-treated environments when calibrated. However, outcomes indicated that some SLMAs, even with calibration, overestimated low ambient noise levels and may not accurately verify quiet room environments < 50 dB for clinical services. These results should not be generalized for all smartphone types, and continued research on SLMAs using next-generation smartphone devices is warranted.

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Speech Impairment in Boys With Fetal Alcohol Spectrum Disorders

Background

Fetal alcohol spectrum disorders (FASD) are a highly prevalent spectrum of patterns of congenital defects resulting from prenatal exposure to alcohol. Approximately 90% of the cases involve speech impairment. Yet, to date, no detailed symptom profiles nor dedicated treatment plans are available for this population.

Purpose

This study set out to chart the speech and speech motor characteristics in boys with FASD to profile the concomitant speech impairment and identify possible underlying mechanisms.

Method

Ten boys with FASD (4.5–10.3 years old) and 26 typically developing children (4.1–8.7 years old; 14 boys, 12 girls) participated in the study. Speech production and perception, and oral motor data were collected by standardized tests.

Results

The boys with FASD showed reduced scores on all tasks as well as a deviant pattern of correlations between production and perception tasks and intelligibility compared with the typically developing children. Speech motor profiles showed specific problems with nonword repetition and tongue control.

Conclusions

Findings indicate that the speech impairment in boys with FASD results from a combination of deficits in multiple subsystems and should be approached as a disorder rather than a developmental delay. The results suggest that reduced speech motor planning/programming, auditory discrimination, and oral motor abilities should be considered in long-term, individually tailored treatment.

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Plasma Asprosin Levels Are Associated with Glucose Metabolism, Lipid, and Sex Hormone Profiles in Females with Metabolic-Related Diseases

Asprosin is a white adipose tissue-derived hormone that increases abnormally in mammals with insulin resistance. However, the role of asprosin in polycystic ovary syndrome (PCOS), a disease partly characterized by insulin resistance, and its potential connection with type 2 diabetes mellitus (T2DM) and PCOS has not been thoroughly elucidated to date. To investigate the association of asprosin with metabolic profiles, sex-related hormones, or inflammation in females with T2DM or PCOS, plasma asprosin and metabolic indicators were measured in 66 healthy females, 53 female patients with T2DM, and 41 patients with PCOS. Spearman's correlation analysis and binary logistic regression analysis models were used. Plasma asprosin was significantly higher in T2DM females than in healthy subjects () and was positively correlated with fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and HOMA-IR (). Asprosin in PCOS subjects was also higher than in healthy subjects () but lower than in T2DM subjects (), and it was positively correlated with FBG, HbA1c, HOMA-IR, LDL-c, APOB, APOE, and testosterone (). The BMI-categorized subgroups of PCOS subjects also showed correlations of asprosin with metabolic profiles and sex-related hormones. Binary logistic regression analysis revealed that plasma asprosin level acted as an independent risk factor for T2DM or PCOS. These findings suggest the correlation of plasma asprosin level with glucose metabolism, lipid metabolism, sex-related hormones, and inflammation in females, supporting asprosin as a potential predictive factor for females with metabolic-related diseases. This trial is registered with ChiCTR-ROC-17010719.

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The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Sheng Gao, Yongdong Yi, Guojun Xia, Chengyang Yu, Chenmin Ye, Fuyang Tu, Leibin Shen, Wenqian Wang, Chunyan Hua

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.

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Target Therapy in SLE

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Matthias Schneider

Abstract

The intention of this paper is to review actual developments in target therapy in SLE. Target therapy includes both the objective of intervention and the aim of treatment. The objective should be linked to the pathophysiologic process of SLE; the aim has to be in any case an improved outcome.

The current therapeutic in SLE is guided mostly by secondary prevention. In SLE, besides a BASIC concept with antimalarials, bone and sun protection, vaccination and cardiovascular risk minimising, treatment waits for new manifestations to be started to prevent secondarily damage. With the new treatment target remission, treatment should aim at ensuring long-term survival, preventing organ damage and optimizing health-related quality-of-life by controlling disease activity and minimising comorbidities and drug toxicity. First examples show that some patients are in remission and that those patients have a better outcome. But for treat-to-target a strategy needs to be developed that needs to be evaluated.

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Dampness and mold hypersensitivity syndrome and vaccination as risk factors for chronic fatigue syndrome

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Tamara Tuuminen, Tiina Jääskeläinen, Kirsi Vaali, Olli Polo

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Adrenal Insufficiency in Systematic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS): A Systematic Review

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Keum Hwa Lee, HyunJeong Lee, Cheol-hun Lee, Jin Yeong Kim, Jong Min Kim, Se Seung Kim, Seungmin Jeong, In Sung Hwang, Namsoo Kim, Na Eun Kim, Soogeun Shin, Dongkwan Shin, Joo Sang Song, Dong Hyun Shin, Jung Dong Kim, Jeehoon Kim, Yong Seok Lee, Hansung Kang, Dong Ha Kim, So Hyun Moon

Abstract

Background: Adrenal insufficiency (AI) is associated with high morbidity and mortality. The aim of this systematic review was to enhance diagnostic approaches and summarize therapeutic strategies in the management of AI in patients with an underlying prior disease history.

Methods: A literature search of PubMed and EMBASE databases was performed and 91 publications containing 105 cases were included for the final analysis.

Results: The following frequency of clinical signs and symptoms was noted: abdominal pain (39.04%) was the leading symptom, followed by fever (33.33%), vomiting (23.81%), and nausea (19.05%). Antiphospholipid syndrome (APS) was present in 73%, systematic lupus erythematosus (SLE) in 17% of the patients, while 2% had a diagnosis of both, SLE and APS. ACTH stimulation test (ACTHst) was performed in 18% of cases and 76.6% of them were unresponsive towards stimulation. Variable treatment approaches were used: hydrocortisone was most commonly used (38.09%), followed by fludrocortisone (26.67%), prednisolone (20.00%) and volume replacement treatment (11.43%), respectively.

Conclusions: This analysis highlights the importance of an early diagnosis and initiation of therapeutic management when AI is suspected. In line, signs and symptoms related to autoimmune diseases in patients with AI should be reviewed crtitically.

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Liver-Associated Immune Abnormalities

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Eyal Grunebaum, Yaron Avitzur

Abstract

In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn's syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions.

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Arthritis in primary Sjögren's syndrome: Characteristics, outcome and treatment from French multicenter retrospective study

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Adrien Mirouse, Raphaèle Seror, Eric Vicaut, Xavier Mariette, Maxime Dougados, Anne-Laure Fauchais, Alban Deroux, Azeddine Dellal, Nathalie Costedoat-Chalumeau, Guillaume Denis, Jérémie Sellam, Jean-Benoît Arlet, Christian Lavigne, Geoffrey Urbanski, Dominique Fischer-Dumont, Abdou Diallo, Olivier Fain, Arsène Mékinian, on behalf of Club Rhumatismes Inflammation and SNFMI

Abstract

Objective

To describe the characteristics and the outcome of primary Sjögren Syndrome (pSS) associated arthritis and to compare the efficacy of different therapeutic regimen.

Methods

We conducted a retrospective study using Club Rhumatisme and Inflammation (CRI) and French Internal Medicine Society (SNFMI) networks. All patients with a diagnosis of pSS and at least one episode of clinical and/or echographic synovitis were included. Patients with synovitis (cases) were compared to pSS patients without synovitis (controls).

Results

57 patients (93% women) were included with a median age of 54 years [45–63]. Patients with synovitis had more frequently lymph node enlargement (12.3% vs. 1.8%, p = .007) and a higher ESSDAI score (8 [[6], [7], [8], [9], [10], [11], [12]] vs. 2 [[1], [2], [3], [4]], p < .0001). There was no difference concerning CRP levels, rheumatoid factor and cyclic citrullinated peptide (CCP)-antibodies positivity. Among 57 patients with synovitis, 101 various treatment courses have been used during the follow-up of 40 [22.5–77] months. First treatment course consisted in steroids alone (3.5%), steroids in association (79%) with hydroxychloroquine (HCQ) (49%), methotrexate (MTX) (35%), rituximab (RTX) (5.3%) or other immunosuppressive drugs (7%). HCQ, MTX, and RTX were associated with a significant reduction of tender and swollen joint count, and a significant steroids-sparing effect. No difference could be shown for the joint response between these treatment regimens.

Conclusion

pSS articular manifestations may include synovitis which could mimic rheumatoid arthritis but differ by the absence of structural damage. Even if the use of HCQ, MTX, and RTX seem to be effective for joint involvement, the best regimen remains to be determined.

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VALIDATION and meta-analysis of kappa index biomarker in multiple sclerosis diagnosis

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Paloma Menéndez-Valladares, Maria Isabel García-Sánchez, Myriam Adorna Martínez, Jose Luis García De Veas Silva, Carmen Bermudo Guitarte, Guillermo Izquierdo Ayuso

Abstract

The importance of studying the cerebrospinal fluid (CSF) in Multiple Sclerosis (MS) is included in the last McDonald criteria (2018). The study of oligoclonal IgG bands (OCGB) assay is strongly recommended in some situations in which MS diagnosis is uncertain. New biomarkers are developed during the last years. Kappa free light chains (FLC) can predict conversion to MS in patients with Clinically Isolated Syndrome (CIS).

The aim of this work is to validate the clinical usefulness of the kappa index, and to establish the actual state of knowledge for kappa index as a biomarker of conversion in CIS patients by a meta-analysis. Kappa index seems more relevant than the mere concentration of kappa FLC in CSF.

In the validation study, 334 patients were included; in which 100 were CIS patients. Patients were divided in two groups according kappa index cut-off of 10.62: group 1 (kappa index>10.62); group 2 (kappa index<10.62). In group 1 more patients had positive OCGB, IgG index>0.56 and fulfilled magnetic resonance imaging (MRI) criteria. In contrast, in group 2, more patients showed negative OCGB, IgG index<0.56 and did not fulfilled MRI criteria. While 67.6% of patients from group 1 converted to MS, only 12.5% of patients from group 2 converted to MS. An HR of 6.02 was obtained in the Kaplan-Meier analysis.

In the meta-analysis, 8 studies were finally included. The SROC curve revealed a high diagnostic performance for the kappa index as a MS diagnostic biomarker. Despite heterogeneity found between studies, the global OR revealed a good discriminatory capacity of kappa index.

In conclusion, kappa index has a great clinical sensitivity and specificity as a support in MS diagnosis. High kappa index increase the probability of CIS to MS conversion. A correct sample processing in the preanalytical stage is key to obtain right results and to allow establishing comparison between laboratories.

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X chromosome and female bias in systemic lupus erythematosus: Focus on population-based evidence

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Dongsheng Di, Hui Yuan, Linlin Zhang, Xiaoxiao Wu, Haifeng Pan, Dongqing Ye, Ruixue Leng

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Multi-phase 3D arterial spin labeling brain MRI in assessing cerebral blood perfusion and arterial transit times in children at 3T

Publication date: Available online 6 November 2018

Source: Clinical Imaging

Author(s): Houchun H. Hu, Jerome A. Rusin, Ruiyue Peng, Xingfeng Shao, Mark Smith, Ramkumar Krishnamurthy, Bhavani Selvaraj, Danny J.J. Wang

Abstract

Background

3D pseudocontinuous arterial spin labeling (pCASL) with a single post-labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi-phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT).

Purpose

To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines.

Material & methods

Forty patients (average age: 8.6 y, 5 d–22.4 y) referred for routine brain MRI underwent additional 5–7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients.

Results

All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97–0.99 across the measured regions (p < 0.05). Correlation coefficients for ATT ranged from 0.87–0.96 (p < 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients.

Conclusion

Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients.

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Clinical, mammographic, and ultrasonographic characteristics of diabetic mastopathy: A case series

Publication date: Available online 6 November 2018

Source: Clinical Imaging

Author(s): Voraparee Suvannarerg, Torpong Claimon, Panitta Sitthinamsuwan, Shanigarn Thiravit, Kobkun Muangsomboon, Pornpim Korpraphong

Abstract

Purpose

Diabetic mastopathy (DMP) is a rare benign breast lesion that mimics breast cancer on ultrasound. Our aims were to identify patient characteristics and imaging features of the disease.

Methods

We conducted retrospective searches of our database for DMP lesions that were pathologically confirmed between January 2004 and November 2015. Mammographic and ultrasound features were reviewed by two experienced radiologists.

Results

Twelve women were identified with 16 lesions. Most patients (83%) had type 2 diabetes mellitus (DM) and over half were insulin-dependent (58.3%), with a mean time of 16.9 years between the diagnosis of DM and that of DMP. There were negative findings on mammography for 46.7% of the lesions, including larger-sized lesions. Ultrasound revealed various features, including irregular shape (81.3%), indistinct margins (100%), parallel orientation to the chest wall (93.8%), marked hypoechogenicity (87.5%), and posterior shadowing (62.5%).

Conclusions

DMP was more common in patients with longstanding DM; in particular, type 2 DM and insulin-dependent patients. DMP lesions were usually occult on mammography, despite the relatively large size of DMP, which may help distinguish DMP from invasive cancer. Ultrasound detected several features that are also present in invasive cancer, making tissue sampling necessary to distinguish these.

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Social Media and Radiology Education: Are We #Ready?

Publication date: Available online 6 November 2018

Source: Academic Radiology

Author(s): Joshua P Nickerson

Social media has become integrated into the lives of millions of people, but it has only recently been explored as a potential teaching tool. There is a body of literature to suggest that today's learners desire use of these interactive platforms for learning and that they result in higher degrees of student satisfaction, although it is not yet clear that a greater degree of knowledge transfer or retention is achieved. There are barriers to implementation in a curriculum, but as we learn to overcome these barriers and find new and creative ways to leverage social media we as educators will meet our students needs in the era of "web 2.0" and the digital native generation.

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“What program directors think IV”: Results of the 2017 Annual Survey of the Association of Program Directors in Radiology

Publication date: Available online 5 November 2018

Source: Academic Radiology

Author(s): Anna Rozenshtein, Brent Griffith, Tan-Lucien H. Mohammed, Darel E. Heitkamp, Linda A. Deloney, Angelisa M. Paladin, Stacy E. Smith, Ernest F. Wiggins, III, Jonathan O. Swanson

Rationale and objectives

The Association of Program Directors in Radiology (APDR) regularly surveys its members to gather information regarding a broad range of topics related to radiology residency. The survey results provide insight into the opinions of residency program leadership across the country.

Materials and methods

This is an observational cross-sectional study using a web-based survey posed to the APDR membership in the fall of 2017. The final survey consisted of 53 items, 48 multiple choice questions and five write-in comments. An invitation to complete the survey was sent to all 319 active APDR members.

Results

Deidentified responses were collected electronically, tallied utilizing Qualtrics software, and aggregated for the purposes of analysis and reporting at the 66th annual meeting of the Association of University Radiologists. The response rate was 36%.

Conclusion

Over the past 16 years, more PDs have assistant and APDs to administer growing residency programs, but the time allocation for these APDs has come from the PD's protected time. An overwhelming majority of PDs consider independent call beneficial to residents and most think a call assistant is desirable. The vast majority of PDs support a unified fellowship match and allow resident moonlighting. Most fourth year residents are actively or moderately involved in clinical work and teaching. The majority of PDs have lost or expect to lose DR training positions to the new IR/DR programs. In a competitive match, PDs do not rely on residency interviews in their selection process.

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Biological activation of bone grafts using injectable platelet-rich fibrin

Publication date: Available online 6 November 2018

Source: The Journal of Prosthetic Dentistry

Author(s): Rucha Shah, Triveni Mavinakote Gowda, Raison Thomas, Tarun Kumar, Dhoom Singh Mehta

Abstract

Platelet-rich fibrin (PRF) is gaining acceptance as a bioactive surgical additive in regenerative dentistry. However, PRF has only been available in gel or membrane form and is not suitable for injection. Recently, however, a liquid, injectable PRF has been introduced. This paper introduces the concept of injectable PRF and discusses its applications for biologic activation of bone grafts.

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Repair bond strength and nanoleakage of artificially aged CAD-CAM composite resin

Publication date: Available online 6 November 2018

Source: The Journal of Prosthetic Dentistry

Author(s): Carmen Arpa, Laura Ceballos, María Victoria Fuentes, Jorge Perdigão

Abstract

Statement of problem

The polymerization of computer-aided design and computer-aided manufacturing (CAD-CAM) composite resins during their manufacture enhances their physical properties and biocompatibility but might compromise their reparability.

Purpose

The purpose of this in vitro study was to determine the microtensile bond strength and nanoleakage (NL) of aged LAVA Ultimate (LU) CAD-CAM composite resin after different repair protocols.

Material and methods

Fifty-eight LU miniblocks were prepared, thermocycled (10 000 cycles, 5°C to 55°C), and assigned to 10 surface pretreatment and bonding protocols: (1) tribochemical silica coating (CoJet, CoJet Sand; 3M ESPE)+Scotchbond Universal Adhesive (SBU; 3M ESPE); (2) CoJet+silane (SI, ESPE Sil; 3M ESPE)+Adper Scotchbond 1 XT Adhesive (XT; 3M ESPE); (3) CoJet+10-methacryloyloxydecyl dihydrogen phosphate–based silane (MO; Monobond Plus; Ivoclar Vivadent)+XT; (4) CoJet+XT; (5) 30-μm alumina airborne-particle abrasion (AL)+SBU; (6) AL+SI+XT; (7) AL+MO+XT; (8) AL+XT; (9) no pretreatment+SBU; and (10) no pretreatment+XT. All blocks were repaired using the Filtek Supreme XTE (3M ESPE) composite resin. Stick-shaped specimens (0.9×0.9 mm) were obtained and submitted to microtensile bond strength (μTBS) and %NL testing after 24 hours. μTBS data were analyzed with 1-way ANOVA, followed by the Tukey post hoc test, and NL data with nonparametric Kruskal-Wallis and Dunn tests (α=.05).

Results

For μTBS, CoJet, and AL pretreatments showed significantly higher mean μTBS, especially when used together with SBU. No pretreatment+XT yielded the lowest mean μTBS. For NL, marginal sealing improved significantly after the use of SBU regardless of the surface treatment. This improvement was only statistically different after tribochemical silica coating.

Conclusions

Airborne-particle abrasion with alumina particles, silica coated or not, together with the application of SBU resulted in the highest mean μTBS. The lowest %NL was recorded when aged LU blocks were repaired using SBU.

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Effect of different times of nonthermal argon plasma treatment on the microtensile bond strength of self-adhesive resin cement to yttria-stabilized tetragonal zirconia polycrystal ceramic

Publication date: Available online 6 November 2018

Source: The Journal of Prosthetic Dentistry

Author(s): Alexandre Barboza Elias, Renata Antoun Simão, Maíra Prado, Paulo Francisco Cesar, Glauco Botelho dos Santos, Eduardo Moreira da Silva

Abstract

Statement of problem

Nonthermal argon plasma may increase the surface energy of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) dental ceramics. However, studies that evaluated the effect of increased plasma treatment times on the bond strength of resin cements to Y-TZP ceramics are lacking.

Purpose

The purpose of this in vitro study was to evaluate the effect of different nonthermal argon plasma (NTAP) treatment times on the surface energy and bond strength of a self-adhesive resin cement to Y-TZP ceramic.

Material and methods

Forty-eighty Y-TZP plates were divided into 2 groups (n=24): as-sintered (AS) and airborne-particle abrasion (APA) with 50-μm Al₂O₃, which were subdivided into 4 groups (n=6) according to the time of NTAP treatment: 0, 20, 60, and 120 seconds. The surface energy was evaluated with a goniometer. Forty Y-TZP blocks submitted to the same surface treatments (8 groups; n=5) were cemented to composite resin blocks, using a self-adhesive resin cement. After storage in distilled water at 37°C for 24 hours, the Y-TZP-composite resin blocks were cut into beams and submitted to a microtensile bond strength (μTBS) test. Data were analyzed using 2-way ANOVA and the Tukey honestly significant differences test (α=.05).

Results

Treatment with NTAP increased the surface energy for AS and APA groups (P<.05). For both groups, the μTBS was as follows: 0 seconds < 20 seconds < 60 seconds = 120 seconds (P<.05). Only after 120 seconds of NTAP treatment was the μTBS of APA higher than that of AS (P<.05).

Conclusions

Treatment with NTAP improved the surface energy and increased the μTBS of self-adhesive resin cement to Y-TZP ceramic, with higher times of plasma treatment resulting in higher bond strength.

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Computer-based implant planning involving a prefabricated custom tray with alumina landmark structures

Publication date: Available online 5 November 2018

Source: The Journal of Prosthetic Dentistry

Author(s): Jong-Eun Kim, Ji-Hyun Park, Jee-Hwan Kim, June-Sung Shim

Abstract

The purpose of this technical report was to describe a method for the fabrication of a custom tray with landmark structures to coordinate cone beam computed tomography and scan data for use in guided implant surgery in patients with numerous artifact-causing metal prostheses. The fabricated custom tray can be used to coordinate cone beam computed tomography data and scan data from the dentition, as well as to fabricate the prostheses.

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“Flip-over flap” in two-stage cleft palate repair

Publication date: Available online 6 November 2018

Source: Journal of Cranio-Maxillofacial Surgery

Author(s): Maurice Y. Mommaerts, Karsten KH. Gundlach, Ana Tache

Summary

Purpose

This study served to evaluate a two-stage concept in cleft palate repair, including key use of a triangular hinge ("flip-over") flap, in order to prevent palatal fistulae. It uses data from a prospective registry established in 1991.

Materials and Methods

The concept entails Furlow soft palate repair (at 1 year of age) and hard palate closure (at 4 years) by a three-pronged approach [paring of the edges with or without postero-lateral relaxing incisions, peninsula (Veau) flap(s)], plus a triangular hinge flap. The latter is elevated from the oral layer of the already-repaired soft palate, stays based anteriorly, and is flipped over to close the posterior nasal layer defect. The case series is compared with data from the literature.

Results

The palatal fistula rate for Veau II to IV types (two-stage surgeries) was 4.3%. The overall fistula rate in the cleft population (Veau I-IV) was 2.9%. Meta-analyses describe 4.9 and 8.6% on average. There was no difference between sample A in which the flip-over flaps were used only when modified Veau flaps were indicated (until 2006) and sample B in which it was used regardless of the technique of hard palate closure applied (2006-2018). The fistula rate decreased to zero after 2010, which may reflect also an influence of other factors such as the interpositioning of a collagen membrane and also of improved surgical judgment.

Conclusions

Using a flip-over flap in two-stage cleft palate repair may contribute to prevent fistula formation at the hard/soft palate junction.

Level of Evidence

III.

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IgE blockade during food allergen ingestion enhances the induction of inhibitory IgG antibodies

Publication date: Available online 4 November 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Amanda J. Stranks, Samantha C. Minnicozzi, Samuel J. Miller, Oliver T. Burton, Stephanie L. Logsdon, Jonathan M. Spergel, Kari C. Nadeau, Jacqueline A. Pongracic, Dale T. Umetsu, Rima Rachid, Andrew J. MacGinnitie, Lynda Schneider, Hans C. Oettgen

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Thirdhand smoke component can exacerbate a mouse asthma model through mast cells

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Mang Yu, Kaori Mukai, Mindy Tsai, Stephen J. Galli

Background

Thirdhand smoke (THS) represents the accumulation of secondhand smoke on indoor surfaces and in dust, which, over time, can become more toxic than secondhand smoke. Although it is well known that children of smokers are at increased risk for asthma or asthma exacerbation if the disease is already present, how exposure to THS can influence the development or exacerbation of asthma remains unknown.

Objective

We investigated whether epicutaneous exposure to an important component of THS, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), can influence asthma pathology in a mouse model elicited by means of repeated intranasal challenge with cockroach antigen (CRA).

Methods

Wild-type mice, α7 nicotinic acetylcholine receptor (nAChR)– or mast cell (MC)–deficient mice, and mice with MCs that lacked α7 nAChRs or were the host's sole source of α7 nAChRs were subjected to epicutaneous NNK exposure, intranasal CRA challenge, or both, and the severity of features of asthma pathology, including airway hyperreactivity, airway inflammation, and airway remodeling, was assessed.

Results

We found that α7 nAChRs were required to observe adverse effects of epicutaneous NNK exposure on multiple features of CRA-induced asthma pathology. Moreover, MC expression of α7 nAChRs contributed significantly to the ability of epicutaneous NNK exposure to exacerbate airway hyperreactivity to methacholine, airway inflammation, and airway remodeling in this model.

Conclusion

Our results show that skin exposure to NNK, a component of THS, can exacerbate multiple features of a CRA-induced model of asthma in mice and define MCs as key contributors to these adverse effects of NNK.

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Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Karla E. Cervantes-Luevano, Nicoletta Caronni, Maria C. Castiello, Elena Fontana, Giulia M. Piperno, Asma Naseem, Paolo Uva, Marita Bosticardo, Genni E. Marcovecchio, Luigi D. Notarangelo, Maria P. Cicalese, Alessandro Aiuti, Anna Villa, Federica Benvenuti

Background

Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined.

Objective

Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS.

Methods

We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens.

Results

Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase.

Conclusions

These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.

Graphical abstract

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Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Laurène Pfajfer, Nina K. Mair, Raúl Jiménez-Heredia, Ferah Genel, Nesrin Gulez, Ömür Ardeniz, Birgit Hoeger, Sevgi Köstel Bal, Christoph Madritsch, Artem Kalinichenko, Rico Chandra Ardy, Bengü Gerçeker, Javier Rey-Barroso, Hanna Ijspeert, Stuart G. Tangye, Ingrid Simonitsch-Klupp, Johannes B. Huppa, Mirjam van der Burg, Loïc Dupré, Kaan Boztug

Background

The actin-interacting protein WD repeat–containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells.

Objective

Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects.

Methods

Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes.

Results

Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation.

Conclusion

Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses.

Graphical abstract

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CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Otavio Cabral-Marques, Tabata Takahashi França, Ashraf Al-Sbiei, Lena Friederike Schimke, Taj Ali Khan, Claudia Feriotti, Tania Alves da Costa, Osvaldo Reis Junior, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Claudia Valente, Regina Sumiko Watanabe Di Gesu, Asif Iqbal, Gabriela Riemekasten, Gustavo Pessini Amarante-Mendes, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Paulo Vitor Soeiro Pereira, Maria J. Fernandez-Cabezudo

Background

Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches.

Objectives

We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function.

Methods

We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function.

Results

Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients.

Conclusion

Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.

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Protein corona–mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Limei Shen, Stefan Tenzer, Wiebke Storck, Dominika Hobernik, Verena Katherina Raker, Karl Fischer, Sandra Decker, Andrzej Dzionek, Susanne Krauthäuser, Mustafa Diken, Alexej Nikolaev, Joachim Maxeiner, Petra Schuster, Cinja Kappel, Admar Verschoor, Hansjörg Schild, Stephan Grabbe, Matthias Bros

Background

Nanoparticle (NP)–based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen-presenting cells. Their cellular distribution and serum protein interaction ("protein corona") after systemic administration and their effect on the functional properties of NPs is poorly understood.

Objectives

We analyzed the relevance of the protein corona on cell type–selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy.

Methods

The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxis and allergic asthma were assessed.

Results

DEX-NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG_2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG_2a production. Treatment of OVA-sensitized mice with the DEX-NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition.

Conclusions

Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses.

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Basophils from allergic patients are neither hyperresponsive to activation signals nor hyporesponsive to inhibition signals

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Lydie Cassard, Katia Sperber, Tan-Phuc Buivan, Aurélie Cotillard, Raphaëlle Bourdet-Sicard, Matthew L. Albert, Estelle Mottez, Jérôme Laurent, Marie-Thérèse Guinnepain, Marc Daëron

Background

Basophil activation contributes to inflammatory reactions, especially in allergy. It is controlled, both positively and negatively, by several mechanisms. High-affinity IgE receptors (FcεRI) generate a mixture of activation and inhibition signals when aggregated, the ratio of which depends on the concentration of allergen recognized by receptor-bound IgE. Low-affinity IgG receptors (FcγRIIA/B) generate inhibition signals when coengaged with FcεRI by allergen-antibody immune complexes. Commensal and probiotic bacteria, such as Lactobacillus paracasei, generate inhibition signals through still unclear mechanisms.

Objective

We sought to investigate whether mechanisms that control, both positively and negatively, basophil activation, which were unraveled and studied in basophils from healthy donors, are functional in allergic patients.

Methods

FcεRI and FcγRIIA/B expression, FcεRI-dependent activation, FcεRI-dependent inhibition, and FcγRIIB-dependent inhibition were examined in blood basophils incubated overnight with or without L paracasei and challenged under 10 experimental conditions. Basophils from healthy donors were compared with basophils from patients who consulted an allergology outpatient clinic over a period of 3 months with respiratory allergy, anaphylaxis antecedents, chronic urticaria, and/or atopic dermatitis.

Results

Patients' basophils expressed neither more FcεRI nor less FcγRIIB than basophils from healthy donors. They were neither hyperreactive to positive regulation nor hyporeactive to negative regulation, irrespective of the receptors or mechanisms involved and the allergic manifestations of the patients.

Conclusion

Regulatory mechanisms that control basophil activation are fully functional in allergic patients. Intrinsic defects in these mechanisms do not explain allergic manifestations. Based on these mechanisms, immune checkpoint modifiers can be developed as novel therapeutic tools for allergy.

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Intestinal IFN-γ–producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Johanna Sophie Alfen, Paola Larghi, Federica Facciotti, Nicola Gagliani, Roberto Bosotti, Moira Paroni, Stefano Maglie, Paola Gruarin, Chiara Maria Vasco, Valeria Ranzani, Cristina Frusteri, Andrea Iseppon, Monica Moro, Maria Cristina Crosti, Stefano Gatti, Massimiliano Pagani, Flavio Caprioli, Sergio Abrignani, Richard A. Flavell, Jens Geginat

Background

IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T_R1) cells but is also produced by CD25⁺ regulatory T (Treg) cells.

Objective

We aimed to identify and characterize human intestinal T_R1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs).

Methods

CD4⁺ T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4⁺ T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1β and IL-23 responsiveness was assessed.

Results

Intestinal T_R1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5⁺PD-1⁺ T_R1 cells expressed IFN-γ and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-γ⁺ T_R1 cells, but not IL-7 receptor–positive T_H cells or CD25⁺ Treg cells, showed lower IL-10 expression in patients with IBDs. T_R1 cells were responsive to IL-23, and IFN-γ⁺ T_R1 cells downregulated IL-10 with IL-1β and IL-23. Conversely, CD25⁺ Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression.

Conclusions

We provide the first ex vivo characterization of human intestinal T_R1 cells. Selective downregulation of IL-10 by IFN-γ⁺ T_R1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs.

Graphical abstract

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An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Lisha Zha, Fabiana M.S. Leoratti, Lichun He, Mona O. Mohsen, Mark Cragg, Federico Storni, Monique Vogel, Martin F. Bachmann

Background

Induction of allergen-specific IgG antibodies is a critical parameter for successful allergen-specific immunotherapy. IgG antibodies can inhibit IgE-mediated mast cell activation through direct allergen neutralization or through the inhibitory receptor FcγRIIb. The affinity of IgE antibodies to the allergen has been shown to be critical for cellular activation.

Objective

Here we addressed the question of affinity thresholds of allergen-specific IgG antibodies for inhibition of mast cell activation using 2 different mAbs against the major cat allergen Fel d 1 both in vitro and in vivo in mice.

Methods

Sequences of the 2 high-affinity mAbs were back-mutated to germline, resulting in low-affinity (10⁻⁷ mol/L) antibodies of the exact same specificity.

Results

Using these newly generated recombinant antibodies, we demonstrate that low-affinity antibodies are still able to inhibit mast cell activation through FcγRIIb but do not neutralize the allergen.

Conclusion

Antibody affinity dictates the mechanism of mast cell inhibition, and IgG antibodies triggering the inhibitory FcγRIIb pathway can show a broader cross-reactivity pattern than previously thought. This indicates that allergen-specific immunotherapy generates a larger protective umbrella of inhibitory IgG antibodies than previously appreciated.

Graphical abstract

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Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell cytokine production in vivo

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Shinji Toki, Kasia Goleniewska, Sara Reiss, Jian Zhang, Melissa H. Bloodworth, Matthew T. Stier, Weisong Zhou, Dawn C. Newcomb, Lorraine B. Ware, Gregg D. Stanwood, Aurelio Galli, Kelli L. Boyd, Kevin D. Niswender, R. Stokes Peebles

Background

IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and T_H2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells.

Objective

We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation.

Methods

BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge.

Results

GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge.

Conclusion

These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.

Graphical abstract

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IL-25 enhances TH17 cell–mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Hajime Suto, Aya Nambu, Hideaki Morita, Sachiko Yamaguchi, Takafumi Numata, Takamichi Yoshizaki, Eri Shimura, Ken Arae, Yousuke Asada, Kenichiro Motomura, Mari Kaneko, Takaya Abe, Akira Matsuda, Yoichiro Iwakura, Ko Okumura, Hirohisa Saito, Kenji Matsumoto, Katsuko Sudo, Susumu Nakae

Background

In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce T_H2 cytokine production by various cell types, including T_H2 cells, T_H9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in T_H2-type immune responses. Because both T_H2-type and T_H17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing T_H2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate–induced CHS is poorly understood.

Objective

We investigated the contribution of IL-25 to CHS using Il25^−/− mice.

Methods

CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific T_H cell differentiation, and detection of IL-1β–producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively.

Results

In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific T_H cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell– and non–immune cell–derived IL-25 was important for hapten-specific T_H17 cell–mediated rather than T_H2 cell–mediated inflammation in the elicitation phase of CHS by enhancing T_H17-related, but not T_H2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific T_H17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS.

Conclusion

Our results identify a novel IL-25 inflammatory pathway involved in induction of T_H17 cell–mediated, but not T_H2 cell–mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.

Graphical abstract

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Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Michael J. McGeachie, George L. Clemmer, Boris Hayete, Heming Xing, Karl Runge, Ann Chen Wu, Xiaofeng Jiang, Quan Lu, Bruce Church, Iya Khalil, Kelan Tantisira, Scott Weiss

Background

Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids, presents a serious challenge in asthma management, particularly for steroid-resistant patients with little or no response to treatment.

Objective

We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children.

Methods

We selected 104 inhaled corticosteroid–treated asthmatic non-Hispanic white children and determined a steroid responsiveness endophenotype (SRE) using observations of 6 clinical measures over 4 years. We modeled each subject's cellular steroid response using data from a previously published study of immortalized lymphoblastoid cell lines under dexamethasone (DEX) and sham treatment. We integrated SRE with immortalized lymphoblastoid cell line DEX responses and genotypes to build a genome-scale network using the Reverse Engineering, Forward Simulation modeling framework, identifying 7 genes modulating SRE.

Results

Three of these genes were functionally validated by using a stable nuclear factor κ-light-chain-enhancer of activated B cells luciferase reporter in A549 human lung epithelial cells, IL-1β cytokine stimulation, and DEX treatment. By using small interfering RNA transfection, knockdown of family with sequence similarity 129 member A (FAM129A) produced a reduction in steroid treatment response (P < .001).

Conclusion

With this systems-based approach, we have shown that FAM129A is associated with variation in clinical asthma steroid responsiveness and that FAM129A modulates steroid responsiveness in lung epithelial cells.

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A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Ronald A. Panganiban, Maoyun Sun, Amber Dahlin, Hae-Ryung Park, Mengyuan Kan, Blanca E. Himes, Jennifer A. Mitchel, Carlos Iribarren, Eric Jorgenson, Scott H. Randell, Elliot Israel, Kelan Tantisira, Stephanie Shore, Jin-Ah Park, Scott T. Weiss, Ann Chen Wu, Quan Lu

Background

Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive.

Objectives

We sought to identify and characterize functional variants in the 17q21 locus.

Methods

We used the Exome Aggregation Consortium browser to identify coding (amino acid–changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants.

Results

Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10⁻⁶) and EVE (odds ratio, 0.85; joint P_EVE = 1.31 × 10⁻¹³). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein.

Conclusions

Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

Graphical abstract

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Airway pathological heterogeneity in asthma: Visualization of disease microclusters using topological data analysis

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Salman Siddiqui, Aarti Shikotra, Matthew Richardson, Emma Doran, David Choy, Alex Bell, Cary D. Austin, Jeffrey Eastham-Anderson, Beverley Hargadon, Joseph R. Arron, Andrew Wardlaw, Christopher E. Brightling, Liam G. Heaney, Peter Bradding

Background

Asthma is a complex chronic disease underpinned by pathological changes within the airway wall. How variations in structural airway pathology and cellular inflammation contribute to the expression and severity of asthma are poorly understood.

Objectives

Therefore we evaluated pathological heterogeneity using topological data analysis (TDA) with the aim of visualizing disease clusters and microclusters.

Methods

A discovery population of 202 adult patients (142 asthmatic patients and 60 healthy subjects) and an external replication population (59 patients with severe asthma) were evaluated. Pathology and gene expression were examined in bronchial biopsy samples. TDA was applied by using pathological variables alone to create pathology-driven visual networks.

Results

In the discovery cohort TDA identified 4 groups/networks with multiple microclusters/regions of interest that were masked by group-level statistics. Specifically, TDA group 1 consisted of a high proportion of healthy subjects, with a microcluster representing a topological continuum connecting healthy subjects to patients with mild-to-moderate asthma. Three additional TDA groups with moderate-to-severe asthma (Airway Smooth Muscle^High, Reticular Basement Membrane^High, and Remodeling^Low groups) were identified and contained numerous microclusters with varying pathological and clinical features. Mutually exclusive T_H2 and T_H17 tissue gene expression signatures were identified in all pathological groups. Discovery and external replication applied to the severe asthma subgroup identified only highly similar "pathological data shapes" through analyses of persistent homology.

Conclusions

We have identified and replicated novel pathological phenotypes of asthma using TDA. Our methodology is applicable to other complex chronic diseases.

Graphical abstract

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Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Christian Rosas-Salazar, Meghan H. Shilts, Andrey Tovchigrechko, Seth Schobel, James D. Chappell, Emma K. Larkin, Tebeb Gebretsadik, Rebecca A. Halpin, Karen E. Nelson, Martin L. Moore, Larry J. Anderson, R. Stokes Peebles, Suman R. Das, Tina V. Hartert

Background

Early life acute respiratory infection (ARI) with respiratory syncytial virus (RSV) has been strongly associated with the development of childhood wheezing illnesses, but the pathways underlying this association are poorly understood.

Objective

To examine the role of the nasopharyngeal microbiome in the development of childhood wheezing illnesses following RSV ARI in infancy.

Methods

We conducted a nested cohort study of 118 previously healthy, term infants with confirmed RSV ARI by RT-PCR. We used next-generation sequencing of the V4 region of the 16S ribosomal RNA gene to characterize the nasopharyngeal microbiome during RSV ARI. Our main outcome of interest was 2-year subsequent wheeze.

Results

Of the 118 infants, 113 (95.8%) had 2-year outcome data. Of these, 46 (40.7%) had parental report of subsequent wheeze. There was no association between the overall taxonomic composition, diversity, and richness of the nasopharyngeal microbiome during RSV ARI with the development of subsequent wheeze. However, the nasopharyngeal detection and abundance of Lactobacillus was consistently higher in infants who did not develop this outcome. Lactobacillus also ranked first among the different genera in a model distinguishing infants with and without subsequent wheeze.

Conclusions

The nasopharyngeal detection and increased abundance of Lactobacillus during RSV ARI in infancy are associated with a reduced risk of childhood wheezing illnesses at age 2 years.

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News Beyond Our Pages

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Marc E. Rothenberg, Jean Bousquet

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The Editors' Choice

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Zuhair K. Ballas, Associate Editors of the JACI

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New aspects of neuroinflammation and neuroimmune crosstalk in the airways

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Christina Nassenstein, Gabriela Krasteva-Christ, Harald Renz

Neuroimmune interaction has long been discussed in the pathogenesis of allergic airway diseases, such as allergic asthma. Mediators released during inflammation can alter the function of both sensory and parasympathetic neurons innervating the airways. Evidence has been provided that the inflammatory response can be altered by various mediators that are released by sensory and parasympathetic neurons and vice versa. Our aim is to demonstrate recent developments in the reciprocal neuroimmune interaction and to include, if available, data from in vivo and clinical studies.

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Immune checkpoint blockade therapy

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Thomas Wieder, Thomas Eigentler, Ellen Brenner, Martin Röcken

Immune checkpoints are accessory molecules that either promote or inhibit T-cell activation. Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non–small-cell lung cancer, renal cell cancers, hypermutated gastrointestinal cancers, and others. Immune responses, whether directed against infections or against tumors, are divided into 2 phases: an initiation phase and an activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, because persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T lymphocytes (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy also awakes self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients in need from a therapy that was developed by academic research, which impairs further academic treatment development and financially charges the public health system.

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Translational review: Neuroimmune mechanisms in cough and emerging therapeutic targets

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s): Alice E. McGovern, Kirsty R. Short, Aung Aung Kywe Moe, Stuart B. Mazzone

Cough is an essential defensive behavior for maintaining airway patency and to protect the lungs from potentially harmful agents. However, inflammatory pathologies can sensitize and activate the neural pathways regulating cough, leading to excessive and nonproductive coughing that serves little protective utility. Problematic cough continues to be one of the most common reasons for seeking medical advice, yet for many patients, it can be refractory to disease-specific treatments and currently available antitussive therapies. The effect of inflammation on cough neural processing occurs not only at the level of the bronchopulmonary sensory nerve terminals but also within the nervous system at multiple peripheral and central sites. Sensory nerves also actively regulate inflammation, and it is therefore a complex interplay between the immune and nervous systems that contributes to chronic cough and the associated sensory hypersensitivities. In this review we provide a brief overview of cough neurobiology in health and disease and then explore the peripheral and central nervous system sites at which neuroimmune interactions can occur. We present advancements in the development of effective antitussive therapies and suggest novel targets for future consideration.

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Itch: From mechanism to (novel) therapeutic approaches

Publication date: November 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 5

Author(s):

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The relationship between 3D dentofacial photogrammetry measurements and traditional cephalometric measurements.

The relationship between 3D dentofacial photogrammetry measurements and traditional cephalometric measurements.

Angle Orthod. 2018 Nov 05;:

Authors: Castillo JC, Gianneschi G, Azer D, Manosudprasit A, Haghi A, Bansal N, Allareddy V, Masoud MI

Abstract
OBJECTIVES:: To determine the relationship between traditional cephalometric measurements and corresponding nonradiographic three-dimensional (3D) photogrammetry measurements.
MATERIALS AND METHODS:: This was a cross-sectional study of 20 orthodontic patients (10 male and 10 female) who received lateral cephalometric radiographs and 3D dentofacial photogrammetric records with each subject serving as his or her own control for a total sample size of 40 images (20 per method). A 3D analysis that resembled a traditional cephalometric analysis was established using the eyes and natural head orientation as substitutes for the cranial base. Pearson correlation coefficients and multivariable linear regression plots were calculated to evaluate the relationship between the photogrammetry measurements and the cephalometric measurements.
RESULTS:: The ANB angle, mandibular plane angle, lower anterior face height, upper incisor angle to SN, upper incisor angle to NA, and all measurements of lower incisor position and inclination had strong positive Pearson correlation coefficients with the corresponding 3D photogrammetry measurements ( P < .004). Statistically significant regression plots demonstrated that cephalometric relationships between the jaws and incisor orientation can be predicted from corresponding 3D photogrammetry measurements.
CONCLUSIONS:: 3D photogrammetry measurements relating the jaws to each other and incisor orientation has a strong positive correlation with corresponding traditional cephalometric measurements and can serve as cephalometric predictors. Capturing the eyes using 3D photogrammetry can obviate the need to expose the cranial base and allow limiting the radiographic field to the area of interest.

PMID: 30394787 [PubMed - as supplied by publisher]

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Acoustic Comparison of Lower and Higher Belt Ranges in Professional Broadway Actresses

Publication date: Available online 5 November 2018

Source: Journal of Voice

Author(s): Amanda Flynn, Jared Trudeau, Aaron M. Johnson

Abstract

Purpose

Current research on the female belt voice has generally been limited to the range of C5, which is not representative of the current requirements on Broadway. Additionally, much belt research uses voice teachers or college students. The goal of this study was to acoustically examine both higher and lower belt ranges in 10 women who have performed belt roles on Broadway during the last decade.

Method

We analyzed the long-term average spectrum of the middle stable portion of three belted pitches, one from a lower, more traditional belt song and two from a higher, more contemporary belt song. The dB levels of the first three peaks in the long-term average spectrum corresponding to the first three harmonics were extracted and compared across tasks. Age, professional roles played on Broadway, and self-perceived belt strategy were obtained via interview to find potential unifying factors in resonance strategies.

Results

Overall, the dB level of the peaks closest to the second and third harmonics were higher than the peak close to the fundamental frequency. The difference between peaks was statistically greater in the lower belt compared to both higher belt tasks, indicating these singers relied more on a single harmonic in the lower belt range than the higher belt range. In the higher belt range, there was less variability between peaks. No patterns emerged between resonance strategies and demographic information.

Conclusions

Elite female belters use varying resonance strategies to create commercially viable belt sounds in different belt ranges.

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An assessment and comparison of nasolabial aesthetics in bilateral clefts using the anatomical subunit-based scale: a nasoalveolar moulding versus non-nasoalveolar moulding study

Publication date: Available online 6 November 2018

Source: International Journal of Oral and Maxillofacial Surgery

Author(s): K. Bonanthaya, T. Nayak, S. Bitra, M. Rachwalski, P.N. Shetty

Abstract

Nasoalveolar moulding is a presurgical orthopaedic technique used to improve the outcomes of bilateral clefts. However, the lack of a validated scale tailored to bilateral clefts makes it difficult to quantify the merits of nasoalveolar moulding and compare it to other techniques. In this study, a recently published anatomical subunit scale was used to evaluate and compare the early effects of nasoalveolar moulding. Two groups of similarly treated bilateral cleft patients were included: one in which patients underwent presurgical nasoalveolar moulding and one in which they did not. The nasolabial aesthetics were evaluated on two-dimensional photographs at 6 months post cheiloplasty. Cupid's bow, vermilion symmetry, vermilion notching, premaxillary show at rest, scar aesthetics, columella height, columella height, and bialar width were all significantly better in the nasoalveolar moulding group. Using the new scale, it was found that nasolabial aesthetics at 6 months post cheiloplasty were significantly better in patients who had undergone nasoalveolar moulding in infancy.

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Experimental peri-implant mucositis around titanium and zirconia implants in comparison to a natural tooth: part 1—host-derived immunological parameters

Publication date: Available online 5 November 2018

Source: International Journal of Oral and Maxillofacial Surgery

Author(s): Kim Clever, Karl Andreas Schlegel, Heinz Kniha, Georg Conrads, Lothar Rink, Ali Modabber, Frank Hölzle, Kristian Kniha

Abstract

The purpose of this study was to assess host-derived parameters around dental zirconia and titanium implants and natural teeth during the occurrence of mucositis. After 4 weeks of perfect oral hygiene, 16 clinically profiled patients were asked to refrain from oral hygiene for 2 weeks, resulting in experimental plaque accumulation. This was followed by 4 weeks of perfect oral hygiene to reverse the inflammation. Immunological samples were analyzed for interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), and interleukin 1β (IL-1β). Immunological parameters were measured each week, starting at week 4 (session 2) and ending at week 10 (session 8). There were significant differences in IL-6 between the groups (zirconia vs. tooth and titanium vs. tooth), with unfavourable values for the tooth unit (P < 0.05). After reinstitution of oral hygiene, there was a significant increase in TNF-α values for the tooth but not for the zirconia and titanium implants. There were significant differences in IL-1β between the groups (zirconia vs. titanium and titanium vs. tooth), with higher IL-1β levels around titanium implants (P < 0.05). The soft tissue around titanium implants developed a stronger inflammatory response to experimental plaque accumulation in terms of IL-1β values, whereas the teeth presented an increase in IL-6 and TNF-α values.

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