Efficacy of chlorhexidine rinses after periodontal or implant surgery: a systematic review

Abstract

Background

Biofilm management and infection control are essential after periodontal and implant surgery. In this context, chlorhexidine (CHX) mouth-rinses are frequently recommended post-surgically. Despite its common use and many studies in this field, a systematic evaluation of the benefits after periodontal or implant surgery is—surprisingly—still missing.

Objectives

To evaluate the benefits of chlorhexidine rinsing after periodontal or implant surgery in terms of plaque and inflammation reduction potential. Furthermore, to screen whether the concentration changes or additives in CHX solutions reduce side effects associated with its use.

Materials and methods

A systematic literature search was performed for clinical trials, which compared CHX rinsing after periodontal or implant surgery with rinsing using placebo, non-staining formulations, or solutions with reduced concentrations of the active compound. Four databases (Medline, PubMed, Embase, Cochrane) were searched up to June 2018. Two reviewers independently identified and screened the literature.

Results

From 691 titles identified, only eleven publications met the inclusion criteria and were finally included. Mainly early publications assessed the benefits of CHX over placebo rinsing, whereas more recent publications focused more on the evaluation of new formulations with regard to effectiveness and side effects. The use of CHX after surgery showed in general significant reduction in plaque (means of 29–86% after 1 week) and bleeding (up to 73%) as compared to placebo. No consensus, however, was found regarding the most beneficial CHX formulation avoiding side effects.

Conclusion

Chlorhexidine rinsing helps to reduce biofilm formation and gingival inflammation after surgery. However, no additional reduction of periodontal probing depth over any given placebo or control solution could be found irrespective of whether CHX was used or not. The use of additives such as antidiscoloration systems (ADS) or herbal extracts may reduce side effects while retaining efficacy.

Clinical relevance

Within the limitations of this review, it can be concluded that CHX may represent a valuable chemo-preventive tool immediately after surgery, during the time period in which oral hygiene capacity is compromised. To reduce the side effects of CHX and maintain comparable clinical effects, rinsing with less concentrated formulations (e.g., 0.12%) showed the most promising results so far.

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Effect of brightness and contrast variation for detectability of root resorption lesions in digital intraoral radiographs

Abstract

Objectives

To evaluate the performance of periapical radiography assessed under different radiographic brightness and contrast variations in the detection of simulated internal (IRR) and external (ERR) root resorption lesions. Additionally, observers' preferences related to image quality for these diagnostic tasks were evaluated.

Methods

Thirty single-root teeth were divided into two groups (n = 15): IRR, in which lesions were simulated using mechanical and biochemical processes; and ERR, in which cavities standardized with drills of different sizes were performed on the root surfaces. Digital radiographs were obtained and subsequently adjusted in 4 additional combinations, resulting in 5 brightness/contrast variations (V1–V5). Five radiologists evaluated the radiographs. The observers' preference on the image quality was also recorded.

Results

For both conditions, there were no differences in the accuracy and specificity between the five brightness/contrast variations (p > 0.05), but the sensitivity for ERR was significantly lower in V4 (+ 15% brightness/−15% contrast) in the large size (p < 0.05). The observers classified V2 (− 15% brightness/+15% contrast) as the "best" image quality for IRR and ERR evaluation.

Conclusions

For IRR and ERR lesions, brightness and contrast variation does not affect the diagnostic performance of digital intraoral radiography within the tested range. The observers prefer images with a reasonable decrease in brightness and increase in contrast.

Clinical relevance

Brightness and contrast enhancement tools are commonly applied in digital radiographic assessment. The use of these tools for detection of root resorptions can be applied according to the observer preference without influence on diagnostic accuracy.

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Kinesio Taping Application in Dysphonic Singers

Kinesio Taping (KT) application in speech therapy has been studied in a few works about dysphonia, facial nerve palsy, sialorrhea, atypical deglutition, postsurgical recovery after thyroidectomy and laryngectomy. The aim of this study was the evaluation of the possible role of KT in supporting speech therapy in singers complaining of dysphonia using singing voice handicap index (SVHI), fundamental frequency (F0), shimmer, jitter and harmonic to noise ratio (mean H/N).

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Comparison of Two Versions of the Acoustic Voice Quality Index for Quantification of Dysphonia Severity

The acoustic voice quality index (AVQI) is a specific acoustic indicator designed to objectively estimate dysphonia severity and measure the values of acoustic parameters based on the diagnostic category. This study compared the performance of two AVQI versions (2.02 and 3.01, v2 and v3) and PraatCPPS using a voice sample of Korean population.

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Identifiers of Language Impairment for Spanish–English Dual Language Learners

Purpose

The purpose of this study was to determine if a standardized assessment developed for Spanish–English dual language learners (SEDLLs) differentiates SEDLLs with language impairment (LI) from children with typical language better than the translated/adapted Spanish and/or English version of a standardized assessment and to determine if adding informal measure/s to the standardized assessment increases the classification accuracy.

Method

Standardized and informal language assessment measures were administered to 30 Mexican American 4- to 5-year-old SEDLLs to determine the predictive value of each measure and the group of measures that best identified children with LI and typical language. Discriminant analyses were performed on the data set.

Results

The Morphosyntax and Semantics subtests of the Bilingual English–Spanish Assessment (Peña, Gutierrez-Clellen, Iglesias, Golstein, & Bedore, 2014) resulted in the largest effect size of the individual assessments with a sensitivity of 93.3% and a specificity of 86.7%. Combining these subtests with mean length of utterance in words from the child's better language sample (English or Spanish) was most accurate in identifying LI and can be used with above 90% confidence.

Conclusion

The Bilingual English–Spanish Assessment Morphosyntax and Semantics subtests were shown to comprise an effective measure for identifying LI; however, including a language sample is suggested to identify LI with greater accuracy.

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Sketch and Speak: An Expository Intervention Using Note-Taking and Oral Practice for Children With Language-Related Learning Disabilities

Purpose

This preliminary study investigated an intervention procedure employing 2 types of note-taking and oral practice to improve expository reporting skills.

Procedure

Forty-four 4th to 6th graders with language-related learning disabilities from 9 schools were assigned to treatment or control conditions that were balanced for grade, oral language, and other features. The treatment condition received 6 30-min individual or pair sessions from the school of speech-language pathologists (SLPs). Treatment involved reducing statements from grade-level science articles into concise ideas, recording the ideas as pictographic and conventional notes, and expanding from the notes into full oral sentences that are then combined into oral reports. Participants were pretested and posttested on taking notes from grade-level history articles and using the notes to give oral reports. Posttesting also included written reports 1 to 3 days following the oral reports.

Results

The treatment group showed significantly greater improvement than the control group on multiple quality features of the notes and oral reports. Quantity, holistic oral quality, and delayed written reports were not significantly better. The SLPs reported high levels of student engagement and learning of skills and content within treatment. They attributed the perceived benefits to the elements of simplicity, visuals, oral practice, repeated opportunities, and visible progress.

Conclusion

This study indicates potential for Sketch and Speak to improve student performance in expository reporting and gives direction for strengthening and further investigating this novel SLP treatment.

Supplemental Material

https://doi.org/10.23641/asha.7268651

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Orthodontics students show off their artistic side

Competitors in the School of Dentistry's annual orthodontics wire sculpture contest have come up with breathtaking creations year after year since the contest's inception in 1966. The intricate, delicately fashioned entries have included everything from a geisha figure to the Eiffel Tower to the Lion King.

The post Orthodontics students show off their artistic side appeared first on UW School of Dentistry.

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Seldinger technique in repair of the parotid duct

Injuries to the parotid ducts are difficult to locate, assess, and repair, and traditionally, solid metal dilators and soft plastic tubes have had only limited success. We describe the Seldinger technique with a central venous catheter, which makes repair easier.

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Qualitative study to identify issues affecting quality of life in adults with craniofacial anomalies

Our objective was to identify key issues that affect the quality of life (QoL) of adult patients with craniofacial anomalies. This was a qualitative prospective study using in-depth, semi-structured interviews. Ten patients who fulfilled the inclusion criteria were recruited during their attendance at the Adult Craniofacial Clinic at the Eastman Dental Hospital, University College London Hospitals NHS Foundation Trust. Interviews ceased when no new themes arose. A framework method of analysis was used to identify themes that related to QoL.

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Evaluation of biochemical variables in patients with trigeminal neuralgia

The aim of this study was to evaluate the calcium, sodium, potassium, serum iron, vitamin B12, and albumin concentrations, and alkaline phosphatase (ALP) activity, in samples of serum from patients with primary trigeminal neuralgia (TN), and investigate the associations between them. Results from 73 patients who had been diagnosed with primary TN between December 2015 and 2017 were compared with those of 70 healthy subjects. Calcium (p=0.013), iron (p=0.004), and albumin (p=0.001) concentrations in the primary TN group were significantly lower than those in the control group, whereas the ALP activity was significantly higher in the TN group than in the control group (p=0.007).

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Application of the Communication Complexity Scale in Peer and Adult Assessment Contexts for Preschoolers With Autism Spectrum Disorders

Purpose

The purpose of this study was to measure changes in communication of preschoolers with autism using the Communication Complexity Scale (CCS; Brady et al., 2012) and to examine the utility of the CCS in measuring pretreatment and posttreatment changes within peer and adult assessment contexts.

Method

The CCS was used to code preassessment and postassessment for 23 children with autism randomly assigned to a treatment that incorporated a peer-mediated approach and a speech-generating device and 22 assigned to a business-as-usual condition with untrained peers. Children were assessed in 2 structured 30-min contexts—1 with an adult examiner and 1 with a peer partner coached by an adult.

Results

Children in both groups showed significant changes in communication complexity CCS scores from pretreatment to posttreatment in the adult and peer contexts. At both occasions, CCS scores were higher with adult partners yet showed greater improvements over time with peer partners.

Conclusions

Results showed that the CCS was sensitive to change over time but did not discriminate changes in communication complexity associated with maturation versus treatment. It did show some differences based on interactions with peer versus adult partners. Outcomes provide preliminary support for using this scale to measure communication changes in different contexts.

Supplemental Material

https://doi.org/10.23641/asha.7408856

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The Development of American Sign Language–Based Analogical Reasoning in Signing Deaf Children

Purpose

This article examines whether syntactic and vocabulary abilities in American Sign Language (ASL) facilitate 6 categories of language-based analogical reasoning.

Method

Data for this study were collected from 267 deaf participants, aged 7;6 (years;months) to 18;5. The data were collected from an ongoing study initially funded by the U.S. Institute of Education Sciences in 2010. The participants were given assessments of ASL vocabulary and syntax knowledge and a task of language-based analogies presented in ASL. The data were analyzed using mixed-effects linear modeling to first see how language-based analogical reasoning developed in deaf children and then to see how ASL knowledge influenced this developmental trajectory.

Results

Signing deaf children were shown to demonstrate language-based reasoning abilities in ASL consistent with both chronological age and home language environment. Notably, when ASL vocabulary and syntax abilities were statistically taken into account, these were more important in fostering the development of language-based analogical reasoning abilities than were chronological age and home language. We further showed that ASL vocabulary ability and ASL syntactic knowledge made different contributions to different analogical reasoning subconstructs.

Conclusions

ASL is a viable language that supports the development of language-based analogical reasoning abilities in deaf children.

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Evaluation of the Serum Levels of Galectin‐3 in Patients with Oral Lichen Planus Disease

Abstract

Objectives

Galectin‐3, a member of beta‐galactoside‐binding proteins, can be found in cytoplasm and nucleus as well as extracellularly in various tissues and involved in many physiological and pathological processes. We aimed to measure the serum levels of galectin‐3 in oral lichen planus (OLP) disease and compare the result with that observed in healthy ones.

Materials and Methods

In this cross‐sectional study, the serum levels of galectin‐3 were measured in 56 healthy individuals and 53 pathologically proven OLP patients including those with atrophic/erosive (33 cases) or reticular (20 cases) lesions, using enzyme‐linked immunosorbent assay (ELISA).

Results

Compared with healthy individuals (1.1±0.4 ng/ml), galectin‐3 serum levels in patients with OLP (3.1±1.1 ng/ml) were significantly elevated (p < 0.0001). Serum galectin‐3 levels were elevated significantly in patients with atrophic/erosive lesions compared to those of reticular (3.9±2.1 ng/ml vs. 1.9±1.4 ng/ml, p = 0.001), but it has not associated with age and gender.

Conclusions

The elevation of galectin‐3 in OLP is a future tool to increase the knowledge about the possible etiology of the disease and may be helpful to differentiate atrophic/erosive lesions from reticular ones. To the best of our knowledge, this is the first study evaluated the serum galectin‐3 levels in OLP.

This article is protected by copyright. All rights reserved.

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Three-dimensional analyses of nasolabial forms and upper lip surface symmetry after primary lip repair in patients with complete unilateral cleft lip and palate

Publication date: Available online 5 December 2018

Source: Journal of Cranio-Maxillofacial Surgery

Author(s): Namiko Kimura, Etsuro Nozoe, Takako Okawachi, Kiyohide Ishihata, Takao Fuchigami, Norifumi Nakamura

Summary

Purpose

To analyze three-dimensional (3D) nasolabial forms and upper lip surface symmetry after primary lip repair in children with unilateral cleft lip and palate (UCLP).

Methods

Subjects were 22 Japanese children with complete UCLP who underwent primary lip repair and were followed-up for 4–6 years. The 3D coordinates of facial landmarks and the angle and radius of the approximate nasal alar circle were calculated. Upper lip surface symmetry was analyzed using histogram intersection.

Results

The nasal tip and columella base were slightly dislocated to the cleft side, and the midpoint of Cupid's bow shifted to the non-cleft side. The nasal alar and the top of Cupid's bow were reconstructed at the same height, while the approximate nasal alar circle was smaller on the cleft side. The mean value of similarity for upper lip surface symmetry was 0.82; a subject with a higher value had more symmetrical contour lines in the visualized surface image.

Conclusions

Postoperative nasolabial forms were almost restored to symmetrical levels, while retaining a small nasal alar. Histogram intersection is applicable as a method for the quantitative evaluation of upper lip surface symmetry in UCLP.

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Adaptive change in temporomandibular joint tissue and mandibular morphology following surgically induced anterior disc displacement by bFGF injection in a rabbit model

Publication date: Available online 5 December 2018

Source: Journal of Cranio-Maxillofacial Surgery

Author(s): Momoko Sato, Takamitsu Tsutsui, Akinori Moroi, Kunio Yoshizawa, Yoshihito Aikawa, Hajime Sakamoto, Koichiro Ueki

Summary

Purpose

The purpose of this study was to examine the effect of injecting basic fibroblast growth factor following surgical induced anterior disc displacement in temporomandibular joints (TMJ).

Materials and Methods

Adult male Japanese white rabbits (n=16; 2.0-2.5 kg; 10 weeks old) were assigned to experimental and control groups. In the experimental group, anterior disc displacement was induced in the bilateral TMJ. Recombinant human basic fibroblast growth factor (rh bFGF) 0.1μg/1μL aqueous solution was injected into the left retro-discal connective tissue close to the disc (ADL group), and saline alone was injected into the same site on the right (ADR group). In the control group, a sham operation without disc position change was performed in the bilateral TMJ (CR group and CL group). Four animals from the experimental (ADR and ADL) and control (CR and CL) groups were sacrificed at 1 and 12 weeks postoperatively to evaluate the mandibular morphology and computed tomographic (CT) value of the condylar head, using 3 dimensional computed tomography. Furthermore, cartilage layers and disc tissue were examined histologically.

Results

Regarding CT value at the 0 degree site of the condylar surface, ADR showed the lowest value after 1 week (P=0.0325). However, there were no significant differences among the 4 groups regarding CT values at the other degree sites after 1 and 12 weeks. Regarding mandibular length, ADR showed the lowest value after 12 weeks (P=0.0079). In condylar width, ADR showed the lowest value after 1 week (P=0.0097).

Conclusion

This study suggested that surgically induced anterior disc displacement could affect condylar morphology in the early stage, and could decrease mandibular length in the late stage. However, bFGF injection into the TMJ might prevent the degenerative change derived from anterior disc displacement and inhibition of sequential mandibular growth.

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Computer-assisted surgery in therapeutic strategy distraction osteogenesis of hemifacial microsomia: accuracy and predictability

Publication date: Available online 6 December 2018

Source: Journal of Cranio-Maxillofacial Surgery

Author(s): Andy Tan, Yuanhao Chai, Weijun Mooi, Xiaojun Chen, Haisong Xu, Aung M. Zin, Li Lin, Yan Zhang, Xianxian Yang, Gang Chai

Abstract

Background

Distraction osteogenesis can be used to treat hemifacial microsomia in patients of any age group. Application of three-dimensional (3D) technology in the surgical planning of distraction osteogenesis allows the placement of an intraoral distractor to define the cutting line and help predict the outcome of surgery.

Aim

This study compared the results of distraction osteogenesis performed, using computer-assisted surgery, on OMENS-plus-classified M2A, M2B, and M3 type patients. Comparisons were in terms of either accuracy or predictability.

Methods

40 patients were selected to participate in the 8-month study. Preoperative image data from 3D-CT scans of the 40 patients were translated into DICOM format 3D cephalometrics, run using the computer software MIMICS version 18, and based on eight reference anatomical landmark points, five lines of measurement, and the midline of the mandibular plane. The distraction vector for the affected side of mandible was selected and the elongation process simulated repeatedly until satisfactory results were obtained. The surgical guide was created using CAD/CAM-RP technology. The distraction osteogenesis procedure was then performed using the surgical guides. Follow-up for all patients continued until 8 months postoperatively. Accuracy with and without computer-assisted surgery was assessed linearly and volumetrically. Simple mean comparisons and paired t-tests were conducted using IBM SPSS V21.

Results

In those patients who received computer-assisted surgery, distraction in the M2A type mandible showed accuracy of around 97.77% ± 7.92% (p > 0.05) for height and 97.91% ± 10.23% (p > 0.05) for length of the mandible. Meanwhile, the M2B type mandible presented accuracy of around 93.85% ± 8.07% (p > 0.05) for height and 95.85% ± 10.16% (p > 0.05) for length. For the M3 type mandible accuracy was around 98.42% ± 6.58% (p > 0.05) for height and 97.14% ± 11.45% (p > 0.05) for length. These measurements showed no significant differences between preoperative design and real outcome.

Conclusions

Individualized guides improve the accuracy of distraction osteogenesis. They help the surgeon to identify the mandibular defect and ensure the desired outcome after the operation.

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Chondrosarcoma of the jaw bones: a review of 224 cases reported to date and an analysis of prognostic factors

Publication date: Available online 6 December 2018

Source: International Journal of Oral and Maxillofacial Surgery

Author(s): L.L. de Souza, F.S.C. Pontes, F.P. Fonseca, D.S. da Mata Rezende, V.C.S. Vasconcelos, H.A.R. Pontes

Abstract

The objective was to integrate the available published data on chondrosarcoma (CHS) of the jaw bones into a comprehensive analysis of its clinical and histological features, treatment, and prognostic factors. An electronic search was undertaken in October 2017. To be eligible, the publication had to provide sufficient clinical/histological data to confirm the diagnosis. One hundred and ten publications (224 cases of CHS) were identified and included. There was a slightly higher prevalence of CHS in males than in females. Most subjects with CHS were in the second to fifth decades of life. The most common symptom was swelling and the most commonly observed location was the maxilla. Histologically, most tumours were of the conventional type and were low grade tumours. The treatment of choice was tumour resection. Histological grade, treatment with chemotherapy alone, and the presentation of recurrence or metastasis were found to be significant independent prognostic factors: patients who presented high-grade tumours, who received chemotherapy alone as the treatment of choice, and those who presented recurrence or metastasis were more likely to have a worse prognosis. In addition, radical surgery associated with radiotherapy as the treatment protocol showed a better prognosis.

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Comparison of Two Versions of the Acoustic Voice Quality Index for Quantification of Dysphonia Severity

Publication date: Available online 6 December 2018

Source: Journal of Voice

Author(s): Geun-Hyo Kim, Yeon-Woo Lee, In-Ho Bae, Hee-June Park, Byung-Joo Lee, Soon-Bok Kwon

Summary

Objectives

The acoustic voice quality index (AVQI) is a specific acoustic indicator designed to objectively estimate dysphonia severity and measure the values of acoustic parameters based on the diagnostic category. This study compared the performance of two AVQI versions (2.02 and 3.01, v2 and v3) and PraatCPPS using a voice sample of Korean population.

Materials and Methods

Voice samples for sustained vowel and connected speech were elicited from 2257 patients across 14 diagnostic categories. Auditory-perceptual (A-P) assessments of dysphonia severity were compared to acoustic parameters of severity derived from two versions of the AVQI (v2 and v3) as well as the PraatCPPS.

Results

The AVQI-estimated severity (v2 and v3) and PraatCPPS severity for concatenated voice samples strongly correlated with each other and were significantly associated with A-P ratings. The AVQI (v2 and v3) and PraatCPPS showed high reliability in differentiating between pathological voice disorders.

Conclusion

The AVQI (v2 and v3) and PraatCPPS were strongly correlated with the A-P ratings and provided valid estimates of dysphonia severity. However, the associations of the A-P ratings with the AVQIv2 were significantly stronger than those with the AVQIv3 and PraatCPPS, suggesting that the V2 outperformed the V3 and PraatCPPS.

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Gadoterate Meglumine Administration in Multiple Sclerosis has no Effect on the Dentate Nucleus and the Globus Pallidus Signal Intensities

Publication date: Available online 6 December 2018

Source: Academic Radiology

Author(s): Salem Hannoun, Rayane Issa, Nabil K. El Ayoubi, Ribal Haddad, Marwa Baalbaki, Bassem I. Yamout, Samia J. Khoury, Roula Hourani

Rationale and objectives

Previous studies on possible accumulation of gadolinium-based contrast agents (GBCA) in the brain suggest that macrocyclic GBCA are less likely to accumulate than linear GBCA. However, conflicting results have been reported, especially in MS. The aim of this study is to investigate retrospectively the correlation between gadoterate-meglumine (macrocyclic GBCA) use and T1 signal intensity changes (SI) in the dentate nucleus and the GP on unenhanced T1-weighted images in a large cohort of MS patients.

Materials and methods

Unenhanced T1-weighted images of 232 MS patients who previously received multiple intravenous administrations of 0.1 mmol/kg of gadoterate-meglumine were reviewed. The change in T1 SI ratios of dentate nucleus/central pons (DN/CP) and globus pallidus/centrum semiovale (GP/CSO) was calculated between the first and last MRIs and correlated with age, number of injections, time interval between MRIs, disease duration, activity, and therapy.

Results

DN/CP ratio showed no significant changes whereas the GP/CSO ratio showed a significant decrease (p < 0.0001) between the first and last MRIs. Multivariable analyses of both ratios, controlling for age, disease duration, and time interval between MRIs, showed no significant correlation between the number of gadolinium injections and the differences in DN/CP (standardized beta = −0.018, p = 0.811) or GP/CSO SI ratios (standardized beta = −0.049, p = 0.499).

Conclusion

Repeated administration of gadoterate-meglumine in MS patients did not result in increased T1 SI in the DN or the GP. The significant decrease of GP/CSO ratio between the first and last MRIs is not due to gadolinium accumulation but rather to varying MR parameters.

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Radiomics Signature: A Biomarker for the Preoperative Distant Metastatic Prediction of Stage I Nonsmall Cell Lung Cancer

Publication date: Available online 6 December 2018

Source: Academic Radiology

Author(s): Li Fan, MengJie Fang, WenTing Tu, Di Zhang, Yun Wang, Xiuxiu Zhou, Yi Xia, ZhaoBin Li, ShiYuan Liu

Objectives

To evaluate the predictive value of radiomics features on the distant metastasis (DM) of stage I nonsmall cell lung cancer (NSCLC) preoperatively, by comparing with clinical characteristics and CT morphological features, and to screen the important prognostic predictors.

Methods

One hundred ninety-four stage I NSCLC patients were retrospectively enrolled, DM free survival (DMFS) was evaluated. The consensus clustering analysis was used to build the radiomics signatures in the primary cohort and validated in the validation cohort. The univariate survival analysis was performed in clinical characteristics, CT morphological features and radiomics signatures, respectively. Cox model was performed and C-index was calculated.

Results

There were 25 patients (12.9%) with DM. The median DMFS was 15 months. Three hundred thirteen radiomics features were selected, then classified into five groups, two subtypes (I and II) with each group. The RS1 showed the best prognostic ability with C-index of 0.355(95% confidence interval [CI], 0.269–0.442; p < 0.001). The histological type exhibited a good prognostic ability with C-index of 0.123 (95% CI, 0.000–0.305; p < 0.001) for DMFS. Cox model showed RS1(hazard ratio [HR] 18.025, 95% CI 2.366–137.340), pleural indentation sign (HR 2.623, 95% CI 1.070–6.426) and histological type (HR 4.461, 95% CI 1.783–11.162) were the independent prognostic factors (p < 0.05).

Conclusion

Radiomics provided a new modality for the distant metastatic prediction of stage I NSCLC. Patients with type II of RS1, pleural indentation sign and nonadenocarcinoma indicated the high probability of postsurgical DM.

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Curating the PGY1 Year for Interventional Radiology Residency

Publication date: Available online 6 December 2018

Source: Academic Radiology

Author(s): M. Victoria Marx

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Characterization of Metastatic Sternal Lesions on Dynamic Contrast-Enhanced Breast MRI in Women with Invasive Breast Cancer

Publication date: Available online 5 December 2018

Source: Academic Radiology

Author(s): Amie Y. Lee, Ryan Navarro, Lindsay P. Busby, Heather I. Greenwood, Matthew D. Bucknor, Kimberly M. Ray, Bonnie N. Joe

Rationale and Objectives

Detecting sternal lesions is not the purpose of breast MRI, but diagnosing metastasis has major clinical implications. Our purpose was to determine the breast MRI features of sternal metastases detected on PET-CT and bone-scan.

Materials and Methods

Between 01/2010-09/2018, 379 patients with breast cancer had sternal findings on PET-CT or bone-scan, 21 of which underwent breast MRI within 100 days. Sternal lesions were considered metastatic if (1) biopsy demonstrated metastasis, (2) the lesion had similar appearance to synchronous sites of biopsy-proven osseous metastases, or (3) there were numerous suspicious lesions in which widespread osseous metastasis was presumed. Four radiologists reviewed the MR images to determine if metastases were retrospectively detectable. MRI reports were reviewed to determine if lesions were prospectively described. MRI features of metastatic sternal lesions were compared to benign controls.

Results

Fourteen sternal metastases met inclusion criteria. Lesions were retrospectively detectable on breast MRI by all radiologists in 86% (12/14) of cases, but prospectively reported in 57%. Of the 12 MRI-detectable metastases, mean maximum dimension was 33 mm, 7 had >1 lesion, all were T1-hypointense, 11 were T2-hyperintense, 11 were noncircumscribed, 6 extended beyond cortex, 11 enhanced heterogeneously, and 11 demonstrated washout. Heterogeneous enhancement (p = 0.002), noncircumscribed margins (p < 0.001), multiplicity (p = 0.005), and size >1 cm (p < 0.001) were more frequent with metastatic compared to benign sternal lesions.

Conclusion

Most sternal metastases (86%) were retrospectively detectable on breast MRI, but only 57% were prospectively reported, emphasizing the importance evaluating the sternum on breast MRI. Certain MRI features may raise suspicion for metastasis.

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Time and pattern of the fusion of the spheno-occipital synchondrosis in patients with skeletal Class I and Class III malocclusion.

Time and pattern of the fusion of the spheno-occipital synchondrosis in patients with skeletal Class I and Class III malocclusion.

Angle Orthod. 2018 Dec 05;:

Authors: Yang JH, Cha BK, Choi DS, Park JH, Jang I

Abstract
OBJECTIVES:: To investigate the time and pattern of fusion of the spheno-occipital synchondrosis in patients with skeletal Class I and Class III malocclusion using cone-beam computed tomography (CBCT).
MATERIALS AND METHODS:: A total of 262 CBCT images were collected: 140 skeletal Class I (0° < ANB < 4°; 71 males, 69 females) and 122 skeletal Class III (ANB ≤ 0°; 61 males and 61 females). The fusion stages were identified using CBCT images of a six-stage system defined by the appearance of osseous cores and ossifying vestige in the synchondrosis. The age distributions of each stage and the pattern of fusion were evaluated.
RESULTS:: The stages of fusion progressed with increasing age ( P < .05, r = .824), and the age distributions in the female groups were generally 1 to 3 years younger than those in the male groups. However, no significant differences were observed between the skeletal Class I and Class III groups regarding the time of ossification of the synchondrosis. The osseous cores appeared most frequently in the supero-center part, followed by the mid-center part of the synchondrosis.
CONCLUSIONS:: The time and pattern of fusion of the spheno-occipital synchondrosis are not apparently different between patients with Class I malocclusion and those with Class III malocclusion. The osseous cores appear frequently in the supero-center and mid-center of the synchondrosis with various patterns before the end of the pubertal growth spurt period.

PMID: 30516418 [PubMed - as supplied by publisher]

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Finite element analysis of stresses on adjacent teeth during the traction of palatally impacted canines.

Finite element analysis of stresses on adjacent teeth during the traction of palatally impacted canines.

Angle Orthod. 2018 Dec 05;:

Authors: Zeno KG, El-Mohtar SJ, Mustapha S, Ghafari JG

Abstract
OBJECTIVE:: To evaluate stresses on maxillary teeth during alignment of a palatally impacted canine (PIC) under different loading conditions with forces applied in vertical and buccal directions.
MATERIALS AND METHODS:: A three-dimensional finite element model of the maxilla was developed from a cone beam computed tomographic scan of a patient with a left PIC. Traction was simulated under different setups: (1) palatal spring extending from a transpalatal bar (TPB) anchored on the first molars (M1) and alternatively combined with different archwires (0.016 × 0.022-inch; 0.018 × 0.025-inch) with and without engaging second molars and (2) a buccal force against 0.018-inch, 0.016 × 0.022-inch, and 0.018 × 0.025-inch archwires with and without engaging the left lateral incisor (I2).
RESULTS:: Without fixed appliances, stresses were assumed by M1; with fixed appliances, stresses were distributed on all teeth, decreasing mesially toward the midline. Direct buccal pull exerted most stress on neighboring I2 (19-20% with different wire sizes) and first premolar (12-17%), decreasing distally, along a similar pattern with different archwire sizes. When I2 was bypassed, stresses on adjacent teeth increased only by 3-6%. Higher stresses occurred with the lighter round wire.
CONCLUSIONS:: This first research on stresses on adjacent teeth during PIC traction provided needed quantitative data on the pattern of stress generation, suggesting the following clinical implications: use of distal-vertical pull from posterior anchorage (TPB) as initial movement and when using a buccal force, bypassing the lateral incisor and using heavier wires that would minimize side effects.

PMID: 30516417 [PubMed - as supplied by publisher]

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A prospective, split-mouth, clinical study of orthodontic titanium miniscrews with machined and acid-etched surfaces.

A prospective, split-mouth, clinical study of orthodontic titanium miniscrews with machined and acid-etched surfaces.

Angle Orthod. 2018 Dec 05;:

Authors: Park HJ, Choi SH, Choi YJ, Park YB, Kim KM, Yu HS

Abstract
OBJECTIVES:: To determine whether the success rate and primary stability of surface-treated miniscrews differ from those of nontreated miniscrews.
MATERIALS AND METHODS:: Patients who required one or more miniscrews for the same reason in each quadrant were recruited into a single-blinded, split-mouth, randomized, controlled trial with a 1:1 allocation ratio. Self-drilling miniscrews with two surface types were used: those with no surface treatment, and those with an acid-etched surface treatment. The cumulative success rate and primary stability of each type of miniscrew were examined, and factors potentially affecting the success and failure of miniscrews were investigated.
RESULTS:: Forty patients were included in the study, with a total of 98 orthodontic miniscrews. The overall success rate was 88.8%, and the respective success rates for acid-etched and machined surface miniscrews were 91.8% and 85.7%. The respective mean insertion torques were 13.62 ± 5.95 N·cm and 13.38 ± 4 N·cm, and periotest values measured immediately after insertion were -0.50 ± 2.77 for acid-etched miniscrews and -0.28 ± 3.36 for machined surface miniscrews. There was no significant difference in the mean insertion torques and periotest values according to surface treatment and jaw.
CONCLUSIONS:: Neither the success rate nor the primary stability of acid-etched surface miniscrews and machined surface miniscrews differed significantly. There is a high possibility that miniscrews will fall out in patients who have an open bite or those who require total distalization.

PMID: 30516419 [PubMed - as supplied by publisher]

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Effect of automated messaging on oral hygiene in adolescent orthodontic patients: A randomized controlled trial.

Effect of automated messaging on oral hygiene in adolescent orthodontic patients: A randomized controlled trial.

Angle Orthod. 2018 Dec 05;:

Authors: Ross MC, Campbell PM, Tadlock LP, Taylor RW, Buschang PH

Abstract
OBJECTIVE:: To determine whether automated text messages sent daily to adolescent orthodontic patients improves oral hygiene more than weekly reminders.
MATERIALS AND METHODS:: A blinded, prospective, randomized controlled trial was designed to evaluate the effects of automated messages on oral hygiene. Subjects were recruited from patients undergoing orthodontic treatment at the Texas A&M University College of Dentistry, Department of Orthodontics. They were being treated with a variety of fixed full appliances in both arches. Subjects were randomly assigned to either a once-a-week text message group or a daily text message group. There were 52 females and 27 males who were 12 to 17 years of age. Oral hygiene was measured at the beginning of the study and again 8.6 ± 0.9 weeks later.
RESULTS:: The daily reminder group (N = 42) had significantly greater improvements in oral hygiene compliance than the weekly reminder group (N = 37). The daily score decreases were 48%, 21% and 19% for the bleeding index (BI), plaque index (PI), and gingival index (GI), respectively. The weekly score decreases were 27%, 14% and 13% for the BI, PI, and GI. There were no sex differences in hygiene changes during the study. The 42% of patients who completed the survey at the end of the study wanted more frequent messages and reported that messages related to decreasing treatment time were the most effective, while those related to oral hygiene were the least effective.
CONCLUSIONS:: Daily text messages are more effective at improving oral hygiene than weekly text messages.

PMID: 30516416 [PubMed - as supplied by publisher]

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Differences in heritability of craniofacial skeletal and dental characteristics between hypo- and hyper-divergent patterns using Falconer's method and principal component analysis.

Differences in heritability of craniofacial skeletal and dental characteristics between hypo- and hyper-divergent patterns using Falconer's method and principal component analysis.

Angle Orthod. 2018 Dec 05;:

Authors: Kim DK, Sung J, Song YM, Kim EM, Kim YH, Baek SH

Abstract
OBJECTIVES:: To investigate the difference in heritability of craniofacial skeletal and dental characteristics between hypodivergent and hyperdivergent patterns.
MATERIALS AND METHODS:: 53 Korean adult monozygotic (MZ) and dizygotic (DZ) twins and their siblings were divided into a hypodivergent group (Group 1, SN-MP < 35°, 17 MZ pairs; 11 DZ and sibling [DS] pairs of the same gender) and hyper-divergent group (Group 2, SN-MP > 35°, 16 MZ pairs; 9 DS pairs of the same gender). A total of 56 cephalometric variables were measured using lateral cephalographs. Craniofacial structures were divided into anteroposterior, vertical, dental, mandible, and cranial base characteristics. Falconer's method was used to calculate heritability (h2 > 0.8, high). After principal component analysis (PCA), the mean h2 value of each component was calculated.
RESULTS:: Group 1 exhibited high heritability values in shape and position of the mandible, vertical angular/ratio variables, cranial base shape, and maxillary incisor inclination. Group 2 showed high heritability values in anteroposterior position of the maxilla, intermaxillary relationship, vertical angular variables, cranial base length, and mandibular incisor inclination. Occlusal plane inclination showed high heritability in both groups. Although vertical structure presented a high overall mean h2 value in Group 1, there were no structures that exhibited a high overall mean h2 value in Group 2. PCA derived 10 components with 91.2% and 92.7% of cumulative explanation in Groups 1 and 2, respectively.
CONCLUSIONS:: It is necessary to estimate or predict growth according to vertical pattern for providing differential diagnosis and orthodontic/orthopedic treatment planning.

PMID: 30516415 [PubMed - as supplied by publisher]

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A randomized clinical trial to evaluate the plaque removal efficacy of an oscillating-rotating toothbrush versus a sonic toothbrush in orthodontic patients using digital imaging analysis of the anterior dentition.

A randomized clinical trial to evaluate the plaque removal efficacy of an oscillating-rotating toothbrush versus a sonic toothbrush in orthodontic patients using digital imaging analysis of the anterior dentition.

Angle Orthod. 2018 Dec 05;:

Authors: Erbe C, Jacobs C, Klukowska M, Timm H, Grender J, Wehrbein H

Abstract
OBJECTIVE:: To compare the plaque removal efficacy of an oscillating-rotating electric toothbrush with an orthodontic brush head versus a sonic toothbrush in adolescent patients with fixed orthodontic appliances.
MATERIALS AND METHODS:: This was a randomized, examiner-blind, replicate single-use, two-treatment, four-period, crossover study with a washout period between visits of approximately 24 hours. Forty-four adolescent patients with fixed orthodontic appliances in both arches were randomized based on a computer-generated randomization schedule to one of four toothbrush treatment sequences. The primary outcome was plaque score change from baseline, measured using digital plaque imaging analysis.
RESULTS:: Baseline plaque levels for both brush treatments were high, covering more than 50% of the tooth area. Effective plaque removal was observed with both brush treatments ( P < .001); however, the reduction in plaque with the oscillating-rotating toothbrush was statistically significantly greater ( P = .017) compared with the sonic toothbrush.
CONCLUSIONS:: The study provides evidence for more effective plaque-removing efficacy of the oscillating-rotating toothbrush versus the sonic toothbrush among orthodontic patients.

PMID: 30516414 [PubMed - as supplied by publisher]

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A randomized controlled trial of a power brush/irrigator/mouthrinse routine on plaque and gingivitis reduction in orthodontic patients.

A randomized controlled trial of a power brush/irrigator/mouthrinse routine on plaque and gingivitis reduction in orthodontic patients.

Angle Orthod. 2018 Dec 05;:

Authors: Erbe C, Klukowska M, Timm HC, Barker ML, van der Wielen J, Wehrbein H

Abstract
OBJECTIVES:: To assess plaque and gingivitis reduction in orthodontic patients after 4 weeks' use of an oscillating-rotating power brush, irrigator, and mouthrinse.
MATERIALS AND METHODS:: This was a randomized, examiner-blind, clinical trial comparing plaque and gingivitis outcomes for an experimental power brush/irrigator/mouthrinse oral hygiene routine vs a dental prophylaxis followed by regular manual brushing (positive control). Fifty-one participants with fixed orthodontic appliances in the upper and lower jaw and a minimum of 15 gingival bleeding sites were randomly assigned to experimental or positive control treatment. Both groups were instructed to use their products at least twice daily. At baseline, week 1, and week 4, plaque was evaluated using digital plaque imaging analysis and a conventional subjective index. Gingival inflammation and bleeding were also measured. Analysis of covariance was used to compare groups.
RESULTS:: Fifty-one participants (mean age = 13.9 years) were randomized; 50 (25 per group) completed the study. At baseline, group means were not statistically different ( P > .1) for gingival inflammation or bleeding. At week 4, the experimental and control groups had a 10.0% to 32.7% and 5.9% to 6.7% reduction vs baseline, respectively, in plaque (across both methods); 12.6% and 8.3% reduction, respectively, in gingival inflammation; and 50.6% and 37.8% reduction, respectively, in bleeding. At week 4, group differences favoring the experimental group were statistically significant ( P < .05) for gingival inflammation, gingival bleeding, and plaque (by conventional and digital imaging indexes).
CONCLUSIONS:: Use of a power brush/irrigator/mouthrinse resulted in statistically significantly greater plaque and gingivitis reductions than prophylaxis followed by manual brushing in patients with fixed appliances over 4 weeks.

PMID: 30516413 [PubMed - as supplied by publisher]

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Cardiac Denervation for Arrhythmia Treatment with Transesophageal Ultrasonic Strategy in Canine Models

Publication date: Available online 6 December 2018

Source: Ultrasound in Medicine & Biology

Author(s): Yuanqing Yao, Jun Qian, Shunkang Rong, Yuwen Huang, Bo Xiong, Gang Yang, Dengqing Zhang, Shimin Deng, Jie Tan, Que Zhu, Changming Deng, Dichuan Liu, Haitao Ran, Zhigang Wang, Jing Huang

Abstract

Stellate ganglion (SG) modification has been investigated for arrhythmia treatment. In this study, transesophageal SG imaging and intervention were explored using a homemade 30F integrated focused ultrasonic catheter in healthy mongrel canines in vivo. Anatomic details of SGs were ultrasonically imaged and evaluated. SG had a heterogeneous echoic structure and characteristic profiles sketched by hyper-echoic outlines in an ultrasonogram. Left SGs in the experimental group were successfully ablated through the esophagus under ultrasonic guidance provided by the catheter itself. Two weeks after the ablation, the QT and QTc of the experimental group decreased compared with those of the sham group and at baseline (both p values < 0.001). Histologic examination revealed that left SGs were destroyed. No major complications were observed. This approach may be further explored as a method for ganglia remodeling evaluation and as a strategy of ganglia modification for arrhythmia and for other diseases.

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Utilizing Contrast-Enhanced Ultrasound Imaging for Evaluating Fatty Liver Disease Progression in Pre-clinical Mouse Models

Publication date: Available online 6 December 2018

Source: Ultrasound in Medicine & Biology

Author(s): Harshul Pandit, Joseph P. Tinney, Yan Li, Guozhen Cui, Suping Li, Bradley B. Keller, Robert C.G. Martin

Abstract

We developed a protocol to investigate and optimize the application of contrast-enhanced ultrasound (CEUS) to non-invasive diagnosis of progressing fatty liver disease in mouse models. Eighteen 4-wk-old male C57 L/J mice were randomly assigned to one of the three groups and placed on a control diet, high-fat diet or non-alcoholic steatohepatitis diet for the next 10 wk. After 14 wk, B-mode imaging and CEUS imaging using a VisualSonics Vevo2100 system were performed. CEUS imaging and data analysis using three different parameters—peak enhancement, wash-in rate and wash-in perfusion index—revealed a significant decrease in representative blood flow in the high-fat diet group versus controls and a further significant decrease in the non-alcoholic steatohepatitis group (p < 0.001; n = 6/group). In conclusion, compared with B-mode imaging, non-targeted CEUS imaging was more sensitive in diagnosing early-stage fatty infiltration-mediated vascularity changes in liver parenchyma and provided a more accurate steatohepatitis diagnosis in mouse models.

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Identification and prospective stability of eNose derived inflammatory phenotypes in severe asthma

Publication date: Available online 6 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): P. Brinkman, A.H. Wagener, P.P. Hekking, A.T. Bansal, A.H. Maitland-van der Zee, Y. Wang, H. Weda, H.H. Knobel, T.J. Vink, N.J. Rattray, A. D'Amico, G. Pennazza, M. Santonico, D. Lefaudeux, B. De Meulder, C. Auffray, P.S. Bakke, M. Caruso, P. Chanez, K.F. Chung

Abstract

Background

Severe asthma is a heterogeneous condition as shown by independent cluster analyses based on demographic, clinical and inflammatory characteristics. A next step is to identify molecular driven phenotypes using 'omics'-technologies. Molecular fingerprints of exhaled breath are associated with inflammation and may qualify as non-invasive assessment of severe asthma phenotypes.

Objectives

We aimed: 1) to identify severe asthma phenotypes by exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses); 2) to assess stability of eNose derived phenotypes in relation to within-patient clinical and inflammatory changes.

Methods

In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adult severe asthma subjects from the U-BIOPRED cohort. Exhaled metabolites were centrally analyzed by an assembly of eNoses. Unsupervised Ward clustering enhanced by Similarity Profile Analysis (SPA) together with K-Means clustering was performed. For internal validation Partitioning Around Medoids (PAM) and topological data analysis (TDA) were applied. Samples at 12-18 months of prospective follow-up were used to assess longitudinal within-patient stability.

Results

Data were available for 78 subjects (age 55 [IQR: 45-64] years, 41% male). Three eNose-driven clusters (n=26/33/19) were revealed, showing differences in circulating eosinophil- (p=0.045) and neutrophil percentages (p=0.017) and ratio of patients using oral corticosteroids (p=0.035). Longitudinal within-patient cluster stability was associated to changes in sputum eosinophils (p=0.045).

Conclusions

We have identified and followed-up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid usage. This suggests that breath analysis might contribute to the management of severe asthma.

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Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Matthew C. Altman, Elizabeth Whalen, Alkis Togias, George T. O'Connor, Leonard B. Bacharier, Gordon R. Bloomberg, Meyer Kattan, Robert A. Wood, Scott Presnell, Petra LeBeau, Katy Jaffee, Cynthia M. Visness, William W. Busse, James E. Gern

Background

Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and T_H2-type inflammation; however, the early-life immune events that lead to T_H2 skewing and disease development are unknown.

Objective

We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma.

Methods

In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years.

Results

PBMCs from the cases showed higher levels of expression of natural killer (NK) cell–related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell–like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key T_H2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell–like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell–like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma.

Conclusion

These findings provide important mechanistic insight into an early-life immune pathway involved in T_H2 polarization, leading to the development of allergic asthma.

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Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Charlotte Schwab, Annemarie Gabrysch, Peter Olbrich, Virginia Patiño, Klaus Warnatz, Daniel Wolff, Akihiro Hoshino, Masao Kobayashi, Kohsuke Imai, Masatoshi Takagi, Ingunn Dybedal, Jamanda A. Haddock, David M. Sansom, Jose M. Lucena, Maximilian Seidl, Annette Schmitt-Graeff, Veronika Reiser, Florian Emmerich, Natalie Frede, Alla Bulashevska

Background

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects.

Objective

We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers.

Methods

Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.

Results

We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression.

Conclusions

Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

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Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) controls immune synapse stability in human T cells

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Willemijn J.M. Janssen, Valeria Grobarova, Jardin Leleux, Lieneke Jongeneel, Marielle van Gijn, Joris M. van Montfrans, Marianne Boes

Background

Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) is a cytosolic adaptor protein involved with T-cell activation, differentiation, and migration. On cognate T-cell contact, PSTPIP1 is recruited to surface-expressed CD2, where it regulates F-actin remodeling. An immune synapse (IS) is thereby rapidly formed, consisting of T-cell receptor clusters surrounded by a ring of adhesion molecules, including CD2.

Objective

From genetic screening of patients with primary immunodeficiencies, we identified 2 mutations in PSTPIP1, R228C and T274M, which we further characterized in the primary patients' T cells.

Methods

F-actin dynamics were assessed in primary T cells from the patients and control subjects by using fluorescence-activated cell sorting. HEK293T and Jurkat cells were transfected with R228C, T274M, and wild-type PSTPIP1 to visualize F-actin in IS formation. CD2-PSTPIP1 association was quantified through immunoprecipitation assays.

Results

The patients presented with immunodeficiency without signs of autoinflammation. The patient with the R228C mutation had expansion of mostly naive phenotype T cells and few memory T cells; the patient with the T274M mutation had 75% reduction in CD4 T cells that were predominantly of the memory subset. We observed F-actin polymerization defects in T cells from both patients with PSTPIP1, most notably the patient with the T274M mutation. Capping of CD2-containing membrane microdomains was disrupted. Analysis of IS formation using Jurkat T-cell transfectants revealed a reduction in F-actin accumulation at the IS, again especially in cells from the patient with the T274M PSTPIP1 mutation. T cells from the patient with the T274M mutation migrated spontaneously at increased speed, as assessed in a 3-dimensional collagen matrix, whereas T-cell receptor cross-linking induced a significantly diminished calcium flux.

Conclusions

We propose that PSTPIP1 T-cell differentiation defects are caused by defective control of F-actin polymerization. A preactivated polymerized F-actin status, as seen in T cells from patients with the PSTPIP1 T274M mutation, appears particularly damaging. PSTPIP1 controls IS formation and cell adhesion through its function as an orchestrator of the F-actin cytoskeleton.

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Correction

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s):

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Solute carrier family 9, subfamily A, member 3 (SLC9A3)/sodium-hydrogen exchanger member 3 (NHE3) dysregulation and dilated intercellular spaces in patients with eosinophilic esophagitis

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Chang Zeng, Simone Vanoni, David Wu, Julie M. Caldwell, Justin C. Wheeler, Kavisha Arora, Taeko K. Noah, Lisa Waggoner, John A. Besse, Amnah N. Yamani, Jazib Uddin, Mark Rochman, Ting Wen, Mirna Chehade, Margaret H. Collins, Vincent A. Mukkada, Philip E. Putnam, Anjaparavanda P. Naren, Marc E. Rothenberg, Simon P. Hogan

Background

Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored.

Objective

We sought to investigate the involvement of solute carrier family 9, subfamily A, member 3 (SLC9A3) in esophageal epithelial intracellular pH (pH_i) and DIS formation and the histopathologic features of EoE.

Methods

We examined expression of esophageal epithelial gene networks associated with regulation of pH_i in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were used to evaluate the expression and function of SLC9A3.

Results

We identified altered expression of gene networks associated with regulation of pH_i and acid-protective mechanisms in esophageal biopsy specimens from pediatric patients with EoE (healthy subjects, n = 6; patients with EoE, n = 10). The most dysregulated gene central to regulating pH_i was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with EoE, and expression positively correlated with disease severity (eosinophils/high-power field) and DIS (healthy subjects, n = 10; patients with EoE, n = 10). Analyses of esophageal epithelial cells revealed IL-13–induced, signal transducer and activator of transcription 6–dependent SLC9A3 expression and Na⁺-dependent proton secretion and that SLC9A3 activity correlated positively with DIS formation. Finally, we showed that IL-13–mediated, Na⁺-dependent proton secretion was the primary intracellular acid-protective mechanism within the esophageal epithelium and that blockade of SLC9A3 transport abrogated IL-13–induced DIS formation.

Conclusions

SLC9A3 plays a functional role in DIS formation, and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in patients with EoE.

Graphical abstract

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A burning need to redefine airways disease: Biomass smoke exposure identified as a unique risk factor for ACO in low- and middle- income countries

Publication date: Available online 5 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Amir A. Zeki, Cameron H. Flayer, Angela Haczku

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Brief Overview of This Month's JACI

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s):

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Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Hector Rodriguez Cetina Biefer, Timm Heinbokel, Hirofumi Uehara, Virginia Camacho, Koichiro Minami, Yeqi Nian, Suresh Koduru, Rachid El Fatimy, Ionita Ghiran, Alexander J. Trachtenberg, Miguel A. de la Fuente, Haruhito Azuma, Omid Akbari, Stefan G. Tullius, Anju Vasudevan, Abdallah Elkhal

Background

Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD⁺) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown.

Objective

The objective of this study is to further dissect the mechanism of actions of NAD⁺ and determine the effect of APCs on NAD⁺-mediated T-cell activation.

Methods

Isolated dendritic cells and bone marrow–derived mast cells (MCs) were used to characterize the mechanisms of action of NAD⁺ on CD4⁺ T-cell fate in vitro. Furthermore, NAD⁺-mediated CD4⁺ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC^−/−, MHC class II^−/−, Wiskott-Aldrich syndrome protein (WASP)^−/−, 5C.C7 recombination-activating gene 2 (Rag2)^−/−, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD⁺ on the systemic immune response in the context of Listeria monocytogenes infection.

Results

Our in vivo and in vitro findings indicate that after NAD⁺ administration, MCs exclusively promote CD4⁺ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4⁺ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD⁺ resulted in decreased MHC II expression on CD11c⁺ cells, MC-mediated CD4⁺ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes.

Conclusions

Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD⁺ in the context of primary immunodeficiencies and antimicrobial resistance.

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A computerized decision support tool to implement asthma guidelines for children and adolescents

Publication date: Available online 5 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Carolyn M. Kercsmar, Christine A. Sorkness, Agustin Calatroni, Peter J. Gergen, Gordon R. Bloomberg, Rebecca S. Gruchalla, Meyer Kattan, Andrew H. Liu, George T. O'Connor, Jacqueline A. Pongracic, Stanley J. Szefler, Stephen J. Teach, Jeremy J. Wildfire, Robert A. Wood, Edward M. Zoratti, William W. Busse, NIAID-sponsored Inner-City Asthma Consortium

Abstract

Background

Multi-center randomized controlled trials (RCTs) for asthma management that incorporate usual care regimens could benefit from standardized application of evidence-based guidelines.

Objective

To evaluate performance of a computerized decision support tool, Asthma Control Evaluation and Treatment (ACET) Program, to standardize usual care regimens for asthma management in RCTs.

Methods

Children and adolescents with persistent, uncontrolled asthma, living in urban census tracts were recruited into 3 multi-center RCTs (each with a usual care arm) between 2004 and 2014. A computerized decision support tool scored asthma control and assigned an appropriate treatment step based on published guidelines. Control level determinants (symptoms, rescue medication use, pulmonary function measure, adherence estimates) were collected at visits and entered into the ACET Program. Changes in control level and treatment steps were examined during the trials.

Results

At screening, over half the participants were rated as not or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all three trials. Between 51% and 70% were well-controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last post-treatment visit. Night symptoms were the most common control level determinant; there were few (<1%) instances of complete overlap of factors. FEV₁ was the driver of control level assignment in 30% of determinations.

Conclusion

The ACET decision support tool facilitated standardized asthma assessment and treatment in multicenter RCTs and was associated with attaining and maintaining good asthma control in most participants.

Graphical abstract

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Regulation of type 2 innate lymphoid cell–dependent airway hyperreactivity by butyrate

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Christina Li-Ping Thio, Po-Yu Chi, Alan Chuan-Ying Lai, Ya-Jen Chang

Background

Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant T_H2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the T_H2 cytokines IL-5 and IL-13, which promote acute asthma exacerbation. Short-chain fatty acids (SCFAs) have been shown to attenuate T cell–mediated allergic airway inflammation. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.

Objective

We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.

Methods

We assessed the role of SCFAs in regulating survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in the ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.

Results

We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.

Conclusion

Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma.

Graphical abstract

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Causes of variability in latent phenotypes of childhood wheeze

Publication date: Available online 5 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Ceyda Oksel, Raquel Granell, Osama Mahmoud, Adnan Custovic, A. John Henderson, Syed Hasan Arshad, Silvia Colicino, Paul Cullinan, John Curtin, Graham Devereux, John Holloway, Clare S. Murray, Graham Roberts, Angela Simpson, Steve Turner, Andrew Bush, Peter Ghazal, Jonathan Grigg, Clare M. Lloyd, Benjamin Marsland

Abstract

Background

Latent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.

Objective

To investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.

Methods

We used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size, data collection age and intervals on the results, and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23-24 years.

Results

A relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (e.g. number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157 and 166). The proportion of asthmatics at age 23-24 years differed between phenotypes, while lung function was lower among persistent wheezers.

Conclusions

Sample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by LCA in longitudinal data.

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Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)–LRR oligomerization interface

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Fiona Moghaddas, Ping Zeng, Yuxia Zhang, Heike Schützle, Sebastian Brenner, Sigrun R. Hofmann, Reinhard Berner, Yuanbo Zhao, Bingtai Lu, Xiaoyun Chen, Li Zhang, Suyun Cheng, Stefan Winkler, Kai Lehmberg, Scott W. Canna, Peter E. Czabotar, Ian P. Wicks, Dominic De Nardo, Christian M. Hedrich, Huasong Zeng

Background

Monogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4).

Objective

Here we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. Methods: We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by using flow cytometry and ELISA, respectively.

Results

The p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1–dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4–mediated cytokine release but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex.

Conclusion

This is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex.

Graphical abstract

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Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Jennifer M. Felton, Christopher D. Lucas, David A. Dorward, Rodger Duffin, Tiina Kipari, Sonja Vermeren, Calum T. Robb, Kenneth G. MacLeod, Bryan Serrels, Jürgen Schwarze, Christopher Haslett, Ian Dransfield, Adriano G. Rossi

Background

Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored.

Objectives

In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation.

Methods

Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo.

Results

Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells.

Conclusions

We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.

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Role of Der p 1-specific B cells in immune tolerance during 2-year house dust mite-specific immunotherapy

Publication date: Available online 5 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Tadech Boonpiyathad, Willem van de Veen, Oliver Wirz, Milena Sokolowska, Beate Rückert, Ge Tan, Atik Sangasapaviliya, Panitan Pradubpongsa, Rattanaporn Fuengthong, Pattarawat Thantiworasit, Sunee Sirivichayakul, Kiat Ruxrungtham, Cezmi A. Akdis, Mübeccel Akdis

Abstract

Background

Long-term follow-up of allergen-specific B cells in terms of immunoglobulin isotype expression, plasmablasts differentiation and regulatory B cell (Breg) development during allergen-specific immunotherapy (AIT) has not been reported.

Objective

Allergen-specific B cell responses during 2-years house dust mite (HDM) AIT were compared between responder and non-responder patients.

Methods

B cells specific for the Der p 1 were detected using fluorochrome-labeled allergen method. Frequency of IgA-, IgG1- and IgG4-switched Der p 1-specific B cells, plasmablasts and IL-10 and IL-1RA-producing Breg cells were investigated and correlated to clinical response to AIT.

Results

Sixteen of 25 patients completed the 2-year study. Eleven responder patients showed a successful response to AIT as measured by decreased symptom medication score from 13.23 ± 0.28 to 2.45 ± 0.24, P = 0.001 and decreased skin prick test reactivity to HDM from 7.0 ± 1.3 mm to 2.7 ± 0.5 mm, P = 0.001. IgG4⁺ and IgA⁺ Der p 1-specific B cells showed a significant increase after AIT, with a significantly higher frequency in responders compared to non-responder patients in IgG4⁺ but not in IgA⁺ fraction. The frequency of plasmablasts, IL-10 and/or IL-1RA-producing Breg cells was higher among responders compared to non-responders after 2 years. Increased frequency of Der p 1-specific IgG4⁺ B cells, plasmablasts, IL-10⁺ and dual positive IL-10⁺IL-1RA⁺ Breg cells significantly correlated with improved clinical symptoms over the course of AIT.

Conclusion

Allergen-specific B cells in therapy responder patients in AIT are characterized with increased IgA- and IgG4-expressing Der p 1-specific B cells, plasmablasts and IL-10⁺ and/or IL-1RA⁺ Breg cells.

Graphical abstract

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Predictive markers for humoral influenza vaccine response in patients with common variable immunodeficiency

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Ann Gardulf, Hassan Abolhassani, Rolf Gustafson, Lars E. Eriksson, Lennart Hammarström

Background

A subgroup of patients with common variable immunodeficiencies (CVIDs) responds to vaccination. The aim of this study was to try to identify predictive markers for those with a humoral immune response after influenza vaccination.

Methods

Forty-eight patients with CVID (29 female and 19 male patients; mean age, 57.7 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix (GlaxoSmithKline, Wavre, Belgium) and boosted after 1 month. Blood samples were collected before each vaccination and 2 months later. Patients with a 4-fold titer increase in results on the hemagglutinin inhibition test (≥1:40) were considered responders and compared with nonresponders for clinical, immunologic, and genetic markers.

Results

Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a EUROclass SmB⁻Tr^norm21^norm profile (P = .03) with a post–germinal center B-cell pattern (P = .04) in blood, experienced enteropathies (P = .04) compared with nonresponders. On the other hand, bronchiectasis was found exclusively among nonresponders (n = 7), as was autoimmune cytopenia (n = 5). Nonresponders with a EUROclass SmB⁻Tr^norm21^low profile (P = .02) had a significantly greater prevalence of progressive antibody deficiency (P = .048) and, at diagnosis, a higher mean serum IgM level (P = .03), lower mean serum IgG₁ level (P = .007), expansion of absolute counts of cytotoxic CD8⁺ T cells (P = .033), and increased proportion of memory CD8⁺ T cells (P = .044) in blood. CVID-associated HLA markers were not detected in responders (P = .03).

Conclusion

About one fifth of the patients with CVIDs achieved protective antibody levels after A(H1N1) vaccination and selected clinical, and immunologic markers were identified that might predict a positive outcome of influenza vaccination. Patients with CVID should be offered vaccination also against seasonal influenza because of the potential severity of the infection and risk for bacterial complications.

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Cover 1

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s):

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In lasting tribute: William T. Shearer, August 23, 1937–October 9, 2018

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): I. Celine Hanson, Javier Chinen, Lynn Des Prez, Carla M. Davis, Jordan S. Orange

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Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Francesca R. Santoni de Sio, Laura Passerini, Silvia Restelli, Maria Maddalena Valente, Aleksandar Pramov, Maria Elena Maccari, Francesca Sanvito, Maria Grazia Roncarolo, Matthew Porteus, Rosa Bacchetta

Background

Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed.

Objective

We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology.

Methods

We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice).

Results

Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a T_H2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels.

Conclusions

These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome.

Graphical abstract

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Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Stefanie Haeberle, Xiaoying Wei, Katja Bieber, Stephanie Goletz, Ralf J. Ludwig, Enno Schmidt, Alexander H. Enk, Eva N. Hadaschik

Background

Autoimmune bullous diseases/dermatoses (AIBDs) are severe autoantibody-mediated skin diseases. The pathogenic relevance of autoreactive CD4⁺ T cells for the induction of autoantibody production remains to be fully evaluated. Scurfy mice lack functional regulatory T (Treg) cells, experience spontaneous activation of autoreactive CD4⁺ T cells, and display severe erosive skin lesions suggestive of AIBDs.

Objective

We sought to determine whether AIBDs develop in Treg cell–deficient scurfy mice.

Methods

Histology, indirect immunofluorescence (IF) microscopy, direct IF, and ELISA were used to prove the presence of AIBDs in scurfy mice. Monoclonal autoantibodies from sera of scurfy mice were screened by using indirect IF on murine skin, and immunoprecipitation and mass spectrometry were used for target antigen identification, followed by confirmation in modified human embryonic kidney cells and murine keratinocytes. Pathogenicity was determined by injecting the autoantibody into neonatal mice and transferring scurfy CD4⁺ T cells into nu/nu mice.

Results

Autoantibodies against different known autoantigens of AIBDs spontaneously develop in scurfy mice. Histology reveals subepidermal blisters, and direct IF of skin of scurfy mice shows a predominant linear staining pattern. The mAb 20B12 shows a linear staining pattern in indirect IF, recognizes the murine hemidesmosomal protein bullous pemphigoid antigen 230 (BP230) as the target antigen, and cross-reacts with human BP230. Purified mAb 20B12 induces subepidermal blisters in neonatal mice. Transfer of scurfy CD4⁺ T cells is sufficient to induce antibodies with reactivity to AIBD autoantigens and subepidermal blisters in the skin of recipient T cell–deficient nu/nu mice.

Conclusion

We show that the absence of Treg cells leads to AIBDs by pathogenic autoantibodies targeting BP230.

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Autophagy and Its Role in Protein Secretion: Implications for Cancer Therapy

Autophagy is a protein and organelle degradation pathway important for the maintenance of cytoplasmic homeostasis and for providing nutrients for survival in response to stress conditions. Recently, autophagy has been shown to be important for the secretion of diverse proteins involved in inflammation, intercellular signaling, and cancer progression. The role of autophagy in cancer depends on the stage of tumorigenesis, serving a tumor-suppressor role before transformation and a tumor-survival function once a tumor is established. We review recent evidence demonstrating the complexity of autophagy regulation during cancer, considering the interaction of autophagy with protein secretion pathways. Autophagy manipulation during cancer treatment is likely to affect protein secretion andinter-cellular signaling either to the neighboring cancer cells or to the antitumoral immune response. This will be an important consideration during cancer therapy since several clinical trials are trying to manipulate autophagy in combination with chemotherapy for the treatment of diverse types of cancers.

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QuickNAT: A fully convolutional network for quick and accurate segmentation of neuroanatomy

Publication date: 1 February 2019

Source: NeuroImage, Volume 186

Author(s): Abhijit Guha Roy, Sailesh Conjeti, Nassir Navab, Christian Wachinger, Alzheimer's Disease Neuroimaging Initiative

Abstract

Whole brain segmentation from structural magnetic resonance imaging (MRI) is a prerequisite for most morphological analyses, but is computationally intense and can therefore delay the availability of image markers after scan acquisition. We introduce QuickNAT, a fully convolutional, densely connected neural network that segments a MRI brain scan in 20 s. To enable training of the complex network with millions of learnable parameters using limited annotated data, we propose to first pre-train on auxiliary labels created from existing segmentation software. Subsequently, the pre-trained model is fine-tuned on manual labels to rectify errors in auxiliary labels. With this learning strategy, we are able to use large neuroimaging repositories without manual annotations for training. In an extensive set of evaluations on eight datasets that cover a wide age range, pathology, and different scanners, we demonstrate that QuickNAT achieves superior segmentation accuracy and reliability in comparison to state-of-the-art methods, while being orders of magnitude faster. The speed up facilitates processing of large data repositories and supports translation of imaging biomarkers by making them available within seconds for fast clinical decision making.

Graphical abstract

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Spatially informed voxelwise modeling for naturalistic fMRI experiments

Publication date: 1 February 2019

Source: NeuroImage, Volume 186

Author(s): Emin Çelik, Salman Ul Hassan Dar, Özgür Yılmaz, Ümit Keleş, Tolga Çukur

Abstract

Voxelwise modeling (VM) is a powerful framework to predict single voxel responses evoked by a rich set of stimulus features present in complex natural stimuli. However, because VM disregards correlations across neighboring voxels, its sensitivity in detecting functional selectivity can be diminished in the presence of high levels of measurement noise. Here, we introduce spatially-informed voxelwise modeling (SPIN-VM) to take advantage of response correlations in spatial neighborhoods of voxels. To optimally utilize shared information, SPIN-VM performs regularization across spatial neighborhoods in addition to model features, while still generating single-voxel response predictions. We demonstrated the performance of SPIN-VM on a rich dataset from a natural vision experiment. Compared to VM, SPIN-VM yields higher prediction accuracies and better capture locally congruent information representations across cortex. These results suggest that SPIN-VM offers improved performance in predicting single-voxel responses and recovering coherent information representations.

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