Dermoid Cyst of the Parotid Gland: A Rare Entity

Abstract

Dermoid cysts of the head and neck are a rare entity. These cysts are benign cystic malformations and histologically composed of tissues originating from ectoderm and mesoderm. Dermoid cysts usually presents as midline neck mass and rarely appear in lateral region. These are extremely rare in parotid gland, however should be considered as a differential in the list of parotid mass. There are a few cases published till date. Superficial parotidectomy is suggested as surgical treatment, however sometimes enucleation is also sufficient. There are only very few case reports published on dermoid cysts in parotid glands. We present a rare case of this entity and the challenges faced in making diagnosis with a short review of the literature.

http://bit.ly/2QRnJpq

A Survival Analysis of Hypopharyngeal Cancer Patients: A Hospital-Cancer registry Based Study

Abstract

To study the survival in patients affected with hypopharyngeal cancer among treatment groups and different stages. Data of hypopharyngeal cancer patients diagnosed from 1st January 2010 to 31st December 2010 was used in the present study. The cases were analyzed for gender, age group distribution, sub-sites at presentation, stage at diagnosis and the type of treatments. Survival from the date of first diagnosis was estimated and hazard ratios were calculated. Survival probability and hazards ratios (HR) were calculated by Kaplan–Meier method and Cox-proportional regression analysis respectively. Censoring of patient who survived longer than 5 years was done. Active follow-up was done for the survival analysis. The study cohort included 217 patients and treatment compliance was observed in 46.9% of cases. The median age at diagnosis was 57 years (range 24–90), 86.2% of cases were locally advanced cases (stage III and IV), pyriform sinus was major sub-site (96%), radiotherapy was main treatment modality alone in 84.8% of cases, median survival was 31 months and 5-year overall survival was 36.9%, and HR for stage IV was 1.9 (P = 0.03, 95% CI − 1.04 to 3.7). In developing setting of North East India, radiotherapy was the main modality of treatment for hypopharyngeal cancer patients, and understanding the clinical parameters and survival of this group of cancers is crucial for its control.

http://bit.ly/2BEiVt4

Feasibility of Parotid Duct Transposition for the Treatment of Dry Eye: A Cadaveric Study

Abstract

Total dry eye is encountered less frequently, but it may lead to blindness. Transposition of parotid duct to the conjunctival cul-de-sac is a method of treatment for advanced cases of xerophthalmia to prevent blindness. Tears and parotid secretions have similar composition; therefore saliva provides an excellent replacement for tears. Limitation of this procedure is that the length of the parotid duct may not be adequate to reach the conjunctival cul-de-sac. This study was conducted in 30 fresh cadavers to assess the length of parotid duct and technical feasibility of parotid duct transposition for the treatment of dry eye. The parotid duct was dissected and resting length of parotid duct was measured on both sides without stretching. The distance between ear lobule to lateral canthus was also measured on both sides in each cadaver. The length of parotid duct ranges from 4.5 to 7 cm with average length was 5.8 cm. The majority of the cadavers had parotid duct length of 6 cm. Length of the right and left parotid duct was found to be equal in all cadavers. Parotid duct reached comfortably in 24 cadavers (80%) while it was short in 6 cadavers (20%) by 1–1.50 cm in length. Parotid duct can be transposed easily to the lower conjunctival cul-de-sac in majority of the cases. If the parotid duct is falling short than a cuff of the buccal mucosa can be taken in order to gain length.

http://bit.ly/2QVkFJ1

Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53 -transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer

Abstract

Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3–48.6) and 43.3% of arm C (95% CI 23.9–65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7–46.3), 16.7% (95% CI 2.9–49.1), and 23.8% (95% CI 9.1–47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.

http://bit.ly/2AiE4Jn

Metaplastic carcinoma of breast

: A series of nine cases from a regional cancer center in Northeast India

p. 69

Srigopal Mohanty, Yumkhaibam Sobita Devi, Daffilyne Lyngdoh Nongrum, Laishram Jaichand Singh, Vimal Sekar, Deep Sikha Das DOI:10.4103/oji.oji_39_18   Background: Metaplastic carcinoma of the breast (MCB) is a rare histological subtype of breast carcinoma containing glandular and nonglandular components with mixed epithelial and mesenchymal differentiations. Aim of the Study: The study aimed to report clinical, radiological and pathological profiles, treatment and outcome of patients diagnosed with MCB from a tertiary care institute along with literature review. Materials and Methods:Diagnosed cases of MCB were obtained from the record over a period of January 2010 to December 2017, and data were recorded in a structured pro forma. Results: A total of 9 (0.9%) cases of MCB were identified out of 1031 breast cancer patients with the median age of presentation of 53 years. The palpable lump was the most common presentation (77.78%). The mean tumor size was 4.9 cm in greatest dimension. Sonographically, most of the lesions were solid (44.44%) followed by cystic (33.33%). Mammographically, microcalcifications were absent in eight cases. Histologically, 55.56% of cases were purely epithelial subtype (3: pure squamous and 2: adenosquamous) and 4 (44.44%) cases were mixed epithelial and mesenchymal subtypes (3: carcinosarcoma and 1: invasive lobular carcinoma with sarcomatous component and osseous metaplasia). All the cases were having triple-negative receptor status. Modified radical mastectomy (MRM) was performed in all cases and 33.33% of cases had axillary node positive. About 77.88% and 88.89% of cases received adjuvant chemotherapy and adjuvant radiotherapy, respectively. At median follow-up of 27 months, local recurrence and distant metastases were seen in 1 and 3 cases, respectively. At present, 33.33%, 22.22%, and 44.45% of patients were died, alive, and lost for follow-up, respectively. Conclusion: MCB is a rare histologic subtype of breast cancer with larger tumor size at presentation and MRM is the preferred surgical procedure over breast conservation surgery. Long-term and regular follow-up is necessary to know the outcome.

http://www.ojionline.org/articles/2018/2/4/images/OncolJIndia_2018_2_4_69_248535_f1.jpg

Anti-cancer and anti-inflammatory activities of aronia (Aronia melanocarpa) leaves

p. 586

Nhuan Do Thi, Eun-Sun Hwang

DOI:10.4103/2221-1691.248095  

Objective: To determine the anti-cancer effect of aronia leaf extract on SK-Hep1 cells using migration, metallo metrix proteinase-2/-9 (MMP-2/-9) and MT-1 MMP expression and to evaluate the anti-inflammatory activities of the leaf extract. Methods: The effect of aronia leaf extract on cancer prevention was investigated. SK-Hep1 human liver cancer cell line was treated with aronia leaf extract at various concentractions. MTT assay was used to measure cancer cell growth inhibition, and wound migration assay was used for metastasis determination. The expression of MMP-2/-9 was measured at the protein level using zymography and the expression of MMP-2/-9 and MT-1 MMP was examined at the gene level by RT-PCR. Raw 264.7 macrophage cells were stimulated with lipopolysaccharides to induce inflammation, and then the inhibition of inflammation was evaluated by treatment of aronia leaf extract. Expressions of interleukin-6, tumor factor-α, and nitric oxide (NO) were also determined. Results: SK-Hep1 cell growth was inhibited in proportion to the concentration of aronia leaf extract. In migration assay, aronia leaf extract showed 61.3%-96.3% wound size inhibtion after treating 50-200 μg/mL of aronia leaf extract for 24 h. At the protein level, the expression of MMP-2 and MMP-9 decreased as the concentration of aronia leaf extract treated with SK-Hep1 cells increased. In addition, the same pattern as in the protein was also observed in the mRNA levels. The expressions of MMP-2 and MMP-9 protein were inhibited by 92.2% and 53.8%, respectively after treatment with 200 μg/mL aronia leaf extract. In addition, Raw 264.7 cells treated with aronia leaf extract did not affect cell survival. There was dose dependent inhibition of interleukine-6, tumor necrosis factor-α and nitric oxide after treating aronia leaf extract in lipopolysaccharides-treated Raw 264.7 cell. Conclusions: The results show that aronia leaf has anticancer and and antimetastatic properties in SK-Hep1 and Raw 264.7 cells.

Effects of phototherapy on outer hair cell function in infants with hyperbilirubinemia

 p. 52
Vikas Mysore Dwarakanath, Pavana Mohan, Sapthami Patel
DOI:10.4103/jisha.JISHA_8_17  
Introduction: Hyperbilirubinemia in newborns has been hypothesized to cause damage to inner ear, thus leading to sensorineural hearing loss. Phototherapy is treatment protocol in most of the hospitals for newborns with high bilirubin levels. The present study aimed to determine the effects of phototherapy on outer hair cell (OHC) function of cochlea. Methods: Twenty-two neonates with hyperbilirubinemia undergoing phototherapy and 22 neonates without any high-risk registers were included in the study. Distortion product otoacoustic emission (DPOAE) was administered before and after phototherapy. Auditory brainstem response (ABR) evaluation was done during the postphototherapy recording. Results: Results showed that DP amplitude and signal-to-noise ratio improved significantly after phototherapy. ABR evaluation revealed; 19 neonates had significantly prolonged wave V latency compared to normal, whereas no peaks were identified among three neonates. Most of the infantile hyperbilirubinemia are found to be harmless until and unless treatment is not initiated at the earliest, but still it is found that short-term increase in bilirubin level can induce temporary changes in OAEs and ABR measures. ABR needs to be repeated over a period of time for these three neonates to rule out auditory dyssynchrony (AD). Conclusion: The results indicate that phototherapy has temporary effects on OHC function and can improve as the bilirubin levels reduce. Follow-up testing over a period of time helps in discriminating the sensory pathology and AD.
http://www.jisha.org/currentissue.asp?sabs=y

Long-term exposure to traffic noise

Effect of long-term exposure to traffic noise on acceptable noise level measures in traffic police officers p. 47
PG Vipin Ghosh, D Nagashreeya, V Hemavathi
DOI:10.4103/jisha.JISHA_24_18  
Introduction: The acceptable noise level (ANL) measure is a subjective way of identifying how much of noise a person is able to put up with while listening to speech. Individuals with low ANL were observed to be satisfied hearing users than the individuals with high ANL. However, the reason for large individual variations of the measure is still not well understood. Exposure to noise may be one such factor that would affect the ANL which was never explored. Among the individuals who are exposed to noise, majority are exposed to occupational noise. Traffic police is such a working population who is exposed continuously to traffic noise during their duty hours. Hence, the present study was planned to investigate ANL measures in traffic police officers that might further provide insight toward the heterogeneity of the measure. Methods: A total of 38 participants were divided into two groups. Group 1 consisted of 19 traffic police officers with minimum of 5 years of job experience and Group 2 consisted of normal hearing individuals without any noise exposure. All the participants underwent routine audiological evaluations followed by ANL testing. Results: The mean ANL obtained in both the groups was statistically compared. The results revealed that the traffic police officers yielded better ANLs than participants in Group 2. Conclusion: This ability of traffic police officers to put up with more noise while listening to speech may be attributed to their long-standing experience in listening to wanted signals in noise.
http://www.jisha.org/currentissue.asp?sabs=y

“Slime” dermatitis, a fad‐associated chronic hand dermatitis - Kondratuk - - Pediatric Dermatology - Wiley Online Library

"Slime" is the colloquial name for a non‐Newtonian viscoelastic putty‐like substance that is currently a popular plaything among pre‐teens and adolescents. Several ingredients in homemade slime recipes may cause irritant or allergic contact dermatitis. We report two children who developed slime‐associated chronic hand dermatitis, more prominently on their dominant hand. We review the potential for irritant and allergic contact dermatoses as the causes of dermatitis associated with homemade slime.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13729

The impact of pediatric atopic dermatitis on families: A review - Yang - - Pediatric Dermatology - Wiley Online Library

Atopic dermatitis (AD) is an extremely common childhood disease, with considerable impact on the quality of life of affected children and their families. While pruritus is the hallmark symptom of this disease, AD has been well‐documented to impact patients beyond physical symptoms, resulting in behavior problems, mood disorders, and sleep disturbance.

Objective
This literature review outlines how atopic dermatitis impacts the quality of life of families of children affected by AD.

Methods
A total of 3436 articles were identified via an online search of the MEDLINE health literature database and were screened for relevance to quality of life impacts on families with children affected by AD.

Results
Caring for children affected by AD can be an extremely time‐consuming task that can impair personal relationships, decrease psychosocial functioning, and cause sleep loss among family members of affected patients. Additionally, AD may result in work absence or decreased work productivity for caregivers. Special diets, irritant and allergen avoidance strategies, and alternative therapies are commonly used by patients to manage their disease and require large amounts of family involvement.

Conclusions
Atopic dermatitis can greatly decrease quality of life of families of affected children in various domains, including sleep, finances, and relationships. Early intervention and psychotherapy may be needed in some patients to address these quality of life impairments.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13727

Successful treatment of hemorrhagic bullous Henoch‐Schonlein purpura with intravenous immunoglobulins - Mauro - - Pediatric Dermatology - Wiley Online Library

Henoch‐Schonlein purpura (HSP) is the most common systemic vasculitis in childhood. There is no consensus about the management for isolated cutaneous manifestations in HSP. We describe a case of HSP presenting with severe skin lesions that did not respond to standard therapy with corticosteroids. The 11‐year‐old child was treated with intravenous immunoglobulins, which induced rapid and persistent resolution of symptomatology.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13715

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome - Saleem - - Pediatric Dermatology - Wiley Online Library

Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13713

Focal facial dermal dysplasia type 4.Bilateral preauricular scarlike defects surrounded by a hair collar, resembling membranous aplasia cutis congenita.

We present a rare case of focal facial dermal dysplasia type 4 (FFDD4) in an otherwise healthy boy infant, presenting as bilateral preauricular scarlike defects surrounded by a hair collar, resembling membranous aplasia cutis congenita. The presence of a hair collar supports the hypothesis that FFDD is caused by abnormal closure at facial embryonic fusion lines, but unlike midline scalp defects is not associated with neurological compromise. Other types of FFDD occur at different sites and can be associated with cranial dysgraphism. Awareness of this rare condition by dermatologists is imperative to enable prompt recognition and minimize diagnostic delay.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13730

Bullous pemphigoid in adolescence - Patsatsi - - Pediatric Dermatology - Wiley Online Library

Bullous pemphigoid (BP) is the most common autoimmune blistering disease affecting the elderly but is quite rare in childhood. The majority of pediatric cases have been reported during early childhood. Adolescence is divided into three phases: early (10‐13 years), middle (14‐17), and late (18‐21). This review aimed to identify BP cases in adolescence and demonstrate their clinical features and course. Our literature search was performed in Medline with the terms "bullous pemphigoid in childhood and adolescence," "childhood bullous pemphigoid," "juvenile bullous pemphigoid," and "autoimmune blistering and autoimmune bullous diseases in childhood." The data extraction for late adolescence was limited by the fact that this age group is included in adult BP registries. We identified nine cases in early adolescence. Mucosa were affected in 5 of 9 cases. Treatment consisted of systemic prednisone (8/9), in combination with dapsone (2/9), azathioprine (2/9), or erythromycin/nicotinamide (1/9). Relapses were reported in 3 of 9 cases. We identified five cases occuring in middle adolescence. Mucosa were not affected. Treatment consisted of systemic prednisone (5/5), in combination with dapsone (3/5), azathioprine (2/5), doxycycline/nicotinamide (1/5), or mycophenolate mofetil (1/5). Relapses were reported in two of five cases. No case of BP in the late adolescence was included in the results, as only one case met the search criteria, and overlapped with pemphigus vulgaris. With only 14 cases found in our review, BP in adolescence appears even rarer than in earlier childhood. Despite its low prevalence, BP should be included in the differential diagnosis of autoimmune blistering diseases in adolescents.
https://onlinelibrary.wiley.com/doi/10.1111/pde.13717

Quantitative Evaluation of Nasolabial Alterations following Nasoalveolar Molding (NAM) Therapy in Patients with Unilateral Cleft Lip

Facial plast Surg
DOI: 10.1055/s-0038-1675633

The clinical benefit of nasoalveolar molding (NAM) is actively debated between cleft centers without clear consensus. Nasolabial measurements were performed on pediatric patients with unilateral clefts of the lip, with or without cleft palate, at an academic cleft/craniofacial center prior to and following NAM therapy between June 2015 and August 2016. The parameters of interest were: columella height and width, cleft nostril height and width, and lip width. Measurements were performed using photographs taken alongside a reference object. The image output was then scaled to the size of the reference object and the capture angle. Intraclass correlation coefficient was calculated to assess reliability of the photographic measurements. Descriptive statistics (mean, standard deviation [SD]) were calculated to characterize the pre- and post-NAM measurements. Student's t-tests were performed to compare the pre-NAM versus post-NAM measurements. The primary objective was to measure the effect of NAM on the nasal aesthetic units that are known to be anatomically aberrant in the cleft lip patient. Nine patients were included in this study. Average pre-NAM age was 2.5 weeks, and average post-NAM age was 13 weeks. Average columellar height increased from 3.70 mm (SD = 0.14) pre-NAM to 5.85 mm (SD = 1.96) post-NAM (p < 0.01); average columellar width increased from 4.71 mm (SD = 0.49) to 5.93 mm (SD = 0.71) (p < 0.01); average cleft nostril height increased from 3.54 mm (SD = 2.97) to 6.81 mm (SD = 2.98) (p = 0.01); and average cleft nostril width decreased from 15.46 mm (SD = 2.91) to 11.05 mm (SD = 1.01) (p = 0.01). Average lip width decreased from 34.61 mm (SD = 1.73) to 33.87 mm (SD = 3.67); however, this change was not statistically significant (p = 0.16). This study objectively quantifies positive changes in nasal aesthetics associated with NAM therapy, providing further evidence for its utility as a presurgical treatment modality for optimal aesthetic nasal results in the unilateral cleft lip patient. The major limitation of this study was a lack of control group, as our center universally treats complete unilateral cleft lip patients with NAM therapy. However, the authors strongly believe that the positive aesthetic nasal findings would persist if compared with a non-NAM control group.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://bit.ly/2GQ50pQ

Utility of response assessment PET-CT to predict residual disease in neck nodes: A comparison with the Histopathology

To assess the ability of Positron Emission Tomography-Computed Tomography (PET-CT) scans to detect residual disease in neck nodes with the Histopathology (HPR) as the gold standard. To obtain a Standardized Uptake Value max cutoff in these patients to predict residual disease in neck.

http://bit.ly/2QOBzZA

Immature Neutrophils Released in Acute Inflammation Exhibit Efficient Migration despite Incomplete Segmentation of the Nucleus [INNATE IMMUNITY AND INFLAMMATION]

Acute inflammation recruits neutrophils with a band-shaped nucleus to the circulation. This neutrophil population was recently shown to have superior antibacterial capacity. Early recruitment of banded neutrophils to an infection site will likely improve the outcome of the immune response, yet it critically depends on efficient migration. However, the current dogma states that the segmentation of the mature neutrophil nucleus has evolved to favor migration through narrow pores as found between endothelial cells and in the interstitium. Therefore, we hypothesized that banded neutrophils migrate less efficiently than neutrophils with segmented nuclei, whereas recently described neutrophils with hypersegmented nuclei would in turn migrate more efficiently. Acute inflammation was evoked in a human model of experimental endotoxemia to recruit neutrophil subsets with different nuclear segmentation to the circulation. To simulate migration toward an infection site, migration of the subsets was studied in in vitro models of transendothelial migration or interstitial chemokinesis and chemotaxis. In both models, nuclear segmentation did not increase migration speed. In dense collagen matrices, the speed of the hypersegmented neutrophils was even reduced compared with the banded neutrophils. Fluorescence microscopy suggested that the hypersegmented neutrophils displayed reduced rear release and deposited more membrane vesicles. Vice versa, migration through narrow pores did not induce nuclear segmentation in the neutrophils. In conclusion, like neutrophils with a segmented nucleus, the banded subset exhibited efficient migration through narrow pores. These findings suggest that the nucleus does not preclude the banded subset from reaching an infection site.

http://bit.ly/2Q5Ikku

SLAMF7 Is a Critical Negative Regulator of IFN-{alpha}-Mediated CXCL10 Production in Chronic HIV Infection [INNATE IMMUNITY AND INFLAMMATION]

Current advances in combined antiretroviral therapy have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. In this study, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation. We observed increased frequencies of SLAMF7⁺ PBMCs in HIV⁺ individuals in a clinical phenotype-dependent manner, with discordant and long-term nonprogressor patients showing elevated SLAMF7 levels, and elite controllers showing levels comparable to healthy controls. We also noted that SLAMF7 was sensitive to IFN- stimulation, a factor elevated during HIV infection. Further studies revealed SLAMF7 to be a potent inhibitor of the monocyte-derived proinflammatory chemokine CXCL10 (IP-10) and other CXCR3 ligands, except in a subset of HIV⁺ patients termed SLAMF7 silent (SF7S). Studies utilizing small molecule inhibitors revealed that the mechanism of CXCL10 inhibition is independent of known SLAMF7 binding partners. Furthermore, we determined that SLAMF7 activation on monocytes is able to decrease their susceptibility to HIV-1 infection in vitro via downregulation of CCR5 and upregulation of the CCL3L1 chemokine. Finally, we discovered that neutrophils do not express SLAMF7, are CXCL10⁺ at baseline, are able to secrete CXCL10 in response to IFN- and LPS, and are nonresponsive to SLAMF7 signaling. These findings implicate the SLAMF7 receptor as an important regulator of IFN-–driven innate immune responses during HIV infection.

http://bit.ly/2VaM9sr

Chrysalis: A New Method for High-Throughput Histo-Cytometry Analysis of Images and Movies [NOVEL IMMUNOLOGICAL METHODS]

Advances in imaging have led to the development of powerful multispectral, quantitative imaging techniques, like histo-cytometry. The utility of this approach is limited, however, by the need for time consuming manual image analysis. We therefore developed the software Chrysalis and a group of Imaris Xtensions to automate this process. The resulting automation allowed for high-throughput histo-cytometry analysis of three-dimensional confocal microscopy and two-photon time-lapse images of T cell–dendritic cell interactions in mouse spleens. It was also applied to epi-fluorescence images to quantify T cell localization within splenic tissue by using a "signal absorption" strategy that avoids computationally intensive distance measurements. In summary, this image processing and analysis software makes histo-cytometry more useful for immunology applications by automating image analysis.

http://bit.ly/2rUY0gQ

Improved Multiplex Immunohistochemistry for Immune Microenvironment Evaluation of Mouse Formalin-Fixed, Paraffin-Embedded Tissues [NOVEL IMMUNOLOGICAL METHODS]

Immune profiling of tissue through multiplex immunohistochemistry is important for the investigation of immune cell dynamics, and it can contribute to disease prognosis and evaluation of treatment response in cancer patients. However, protocols for mouse formalin-fixed, paraffin-embedded tissue have been less successful. Given that formalin fixation and paraffin embedding remains the most common preparation method for processing mouse tissue, this has limited the options to study the immune system and the impact of novel therapeutics in preclinical models. In an attempt to address this, we developed an improved immunohistochemistry protocol with a more effective Ag-retrieval buffer. We also validated 22 Abs specific for mouse immune cell markers to distinguish B cells, T cells, NK cells, macrophages, dendritic cells, and neutrophils. In addition, we designed and tested novel strategies to identify immune cells for which unique Abs are currently not available. Last, in the 4T1 model of breast cancer, we demonstrate the utility of our protocol and Ab panels in the quantitation and spatial distribution of immune cells.

http://bit.ly/2LCNbJp

The Noncoding RNA nc886 Regulates PKR Signaling and Cytokine Production in Human Cells [IMMUNE REGULATION]

Protein kinase RNA-activated (PKR) is a cytoplasmic receptor for dsRNA, and as such is involved in detection of viral infection. On binding dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates its substrate, eukaryotic translation initiation factor 2 subunit α (eIF2α), causing inhibition of mRNA translation and shutdown of viral protein production. However, active PKR has also been found to be involved in the NF-B signaling pathway by inducing phosphorylation of IBα. PKR is regulated by the noncoding RNA nc886, which has altered expression in cancer. We have found that expression of nc886 is highly upregulated during activation of human CD4⁺ T cells. As has been described in other cell types, nc886 bound to PKR in human T cell lysates, preventing PKR phosphorylation by polyinosinic:polycytidylic acid or HIV trans-activation response element RNA in lysates of T cell lines or primary human CD4⁺ T cells. Using clonal human T cell lines, we found that nc886 expression was strictly required for IFN- and IL-2 expression and secretion after T cell activation but did not affect proliferation or activation-induced cell death. In stimulated human PBMCs, nc886 expression strongly correlated with IFN- expression. Although nc886 inhibited PKR activation by dsRNA, it was required for PKR phosphorylation during T cell stimulation, with subsequent NF-B signaling and CREB phosphorylation. nc886 also regulated PKR phosphorylation during human monocyte-derived macrophage activation. We have therefore identified nc886 as a noncoding RNA marker of T cell activation and regulator of PKR-dependent signaling.

http://bit.ly/2rVuQhJ

Cesarean Section Induces Microbiota-Regulated Immune Disturbances in C57BL/6 Mice [IMMUNE SYSTEM DEVELOPMENT]

Epidemiological studies have shown that children born by cesarean section (CS) are at higher risk of developing chronic inflammatory diseases, and it has been suggested that a skewed gut microbial colonization process early in life and altered priming of the immune system are causative. The aim of this study was to clarify whether impaired regulatory immunity in CS-delivered C57BL/6 mice is dependent on gut microbiota (GM) disturbances. The GM of conventionally bred mice born by CS differed clearly from mice born by vaginal delivery. The proportion of regulatory T cells was reduced in mice born by CS, whereas the invariant NKT (iNKT) cell subset was increased compared with vaginal delivery mice. In addition, regulatory markers (Foxp3, Il10, Ctla4) and macrophage markers (Cd11c, Egr2, Nos2) were downregulated, whereas iNKT markers (Il4, Il15) were upregulated in ileum of CS-delivered mice. The GM of CS-delivered mice was sufficient to transfer the shifts in immunity associated with delivery mode when inoculated into germ-free mice. Feeding a prebiotic diet reestablished gene expression of intestinal immune markers and iNKT cells in CS mice but was not sufficient to restore the level of regulatory T cells. The results support that CS delivery is associated with microbiota-mediated shifts in regulatory immunity and, therefore, provide a basis for future microbiota-directed therapeutics to infants born by CS.

http://bit.ly/2LCN8xd

Composition and Clinical Impact of the Immunologic Tumor Microenvironment in Oral Squamous Cell Carcinoma [TUMOR IMMUNOLOGY]

Immunotherapy shows promising results and revolutionizes treatment of oral squamous cell carcinoma (OSCC). The immunologic microenvironment might have prognostic/predictive implications. Morphologic immunologic parameters (inflammatory infiltrate, stromal content, and budding activity [BA] [potentially indicating epithelial–mesenchymal transition]) were evaluated in 66 human primary therapy-naive OSCCs. Intraepithelial/stromal tumor-infiltrating lymphocytes (TILs; CD3⁺/CD4⁺/CD8⁺/CD4⁺FOXP3⁺/IL-17A⁺) were quantified, and ratios were calculated. HLA class I in tumor cells was evaluated immunohistochemically. mRNA in situ hybridization to detect IFN- was performed. Analysis was performed within invasive front (IF) and tumor center (TCe). Decreased HLA expression was associated with low TIL density, pronounced stromal content, and high BA; IFN- in TILs was correlated with high-density TILs; and IFN- in tumor cells was correlated with absence of BA (p < 0.05). Heterogeneity of parameters (TCe/IF) was rare. Low density of stromal CD4⁺FOXP3⁺ TILs within TCe and IF was identified as an independent prognostic factor for poor overall, disease-specific, and disease-free survival (p ≤ 0.011). Refining prognostication in OSCC with high-density CD4⁺FOXP3⁺ infiltrate within TCe and/or IF, high FOXP3:CD4 ratio was significantly correlated with favorable outcome in this subgroup. Furthermore, high-stromal CD8:CD4 ratio was found to be an independent favorable prognostic factor. In summary, immunologic parameters were closely intertwined. Morphologic correlates of epithelial–mesenchymal transition were associated with downregulation of HLA and decreased inflammation. Heterogeneity was infrequent. Low-density stromal CD4⁺FOXP3⁺ infiltrate within TCe and IF was an independent poor prognostic factor. Stratification of cases with high-density CD4⁺FOXP3⁺ TILs by FOXP3:CD4 ratio enables refinement of prognostication of this subgroup. CD8:CD4 ratio was identified as an independent prognostic factor.

http://bit.ly/2rUXYWg

Computational Analysis Supports IL-17A as a Central Driver of Neutrophil Extracellular Trap-Mediated Injury in Liver Ischemia Reperfusion [SYSTEMS IMMUNOLOGY]

Hepatic ischemia reperfusion (I/R) is a clinically relevant model of acute sterile inflammation leading to a reverberating, self-sustaining inflammatory response with resultant necrosis. We hypothesized that computerized dynamic network analysis (DyNA) of 20 inflammatory mediators could help dissect the sequence of post-I/R mediator interactions that induce injury. Although the majority of measured inflammatory mediators become elevated in the first 24 h, we predicted that only a few would be secreted early in the process and serve as organizational centers of downstream intermediator complexity. In support of this hypothesis, DyNA inferred a central organizing role for IL-17A during the first 3 h of reperfusion. After that, DyNA revealed connections among almost all the inflammatory mediators, representing an ongoing cytokine storm. Blocking IL-17A immediately after reperfusion disassembled the inflammatory networks and protected the liver from injury. Disassembly of the networks was not achieved if IL-17A blockage was delayed two or more hours postreperfusion. Network disassembly was accompanied by decrease in neutrophil infiltration and neutrophil extracellular trap (NET) formation. By contrast, administration of recombinant IL-17A increased neutrophil infiltration, NET formation, and liver necrosis. The administration of DNase, a NET inhibitor, significantly reduced hepatic damage despite prior administration of IL-17A, and DNase also disassembled the inflammatory networks. In vitro, IL-17A was a potent promoter of NET formation. Therefore, computational analysis identified IL-17A's early, central organizing role in the rapid evolution of a network of inflammatory mediators that induce neutrophil infiltration and NET formation responsible for hepatic damage after liver I/R.

http://bit.ly/2LCei7g

Salmonella enterica Serovar Typhimurium Travels to Mesenteric Lymph Nodes Both with Host Cells and Autonomously [MUCOSAL IMMUNOLOGY]

Salmonella infection is a globally important cause of gastroenteritis and systemic disease and is a useful tool to study immune responses in the intestine. Although mechanisms leading to immune responses against Salmonella have been extensively studied, questions remain about how bacteria travel from the intestinal mucosa to the mesenteric lymph nodes (MLN), a key site for Ag presentation. In this study, we used a mouse model of infection with Salmonella enterica serovar Typhimurium (STM) to identify changes in intestinal immune cells induced during early infection. We then used fluorescently labeled STM to identify interactions with immune cells from the site of infection through migration in lymph to the MLN. We show that viable STM can be carried in the lymph by any subset of migrating dendritic cells but not by macrophages. Moreover, approximately half of the STM in lymph are not associated with cells at all and travel autonomously. Within the MLN, STM associates with dendritic cells and B cells but predominantly with MLN-resident macrophages. In conclusion, we describe the routes used by STM to spread systemically in the period immediately postinfection. This deeper understanding of the infection process could open new avenues for controlling it.

http://bit.ly/2rVqCGN

Different Isoforms of the Neuronal Guidance Molecule Slit2 Directly Cause Chemoattraction or Chemorepulsion of Human Neutrophils [INNATE IMMUNITY AND INFLAMMATION]

The movement of neutrophils between blood and tissues appears to be regulated by chemoattractants and chemorepellents. Compared with neutrophil chemoattractants, relatively little is known about neutrophil chemorepellents. Slit proteins are endogenously cleaved into a variety of N- and C-terminal fragments, and these fragments are neuronal chemorepellents and inhibit chemoattraction of many cell types, including neutrophils. In this report, we show that the ~140-kDa N-terminal Slit2 fragment (Slit2-N) is a chemoattractant and the ~110-kDa N-terminal Slit2 fragment (Slit2-S) is a chemorepellent for human neutrophils. The effects of both Slit2 fragments were blocked by Abs to the Slit2 receptor Roundabout homolog 1 or the Slit2 coreceptor Syndecan-4. Slit2-N did not appear to activate Ras but increased phosphatidylinositol 3,4,5-triphosphate levels. Slit2-N–induced chemoattraction was unaffected by Ras inhibitors, reversed by PI3K inhibitors, and blocked by Cdc42 and Rac inhibitors. In contrast, Slit2-S activated Ras but did not increase phosphatidylinositol 3,4,5-triphosphate levels. Slit2-S–induced chemorepulsion was blocked by Ras and Rac inhibitors, not affected by PI3K inhibitors, and reversed by Cdc42 inhibitors. Slit2-N, but not Slit2-S, increased neutrophil adhesion, myosin L chain 2 phosphorylation, and polarized actin formation and single pseudopods at the leading edge of cells. Slit2-S induced multiple pseudopods. These data suggest that Slit2 isoforms use similar receptors but different intracellular signaling pathways and have different effects on the cytoskeleton and pseudopods to induce neutrophil chemoattraction or chemorepulsion.

http://bit.ly/2LAkVXQ

Perivascular Adventitial Fibroblast Specialization Accompanies T Cell Retention in the Inflamed Human Dermis [CLINICAL AND HUMAN IMMUNOLOGY]

Perivascular accumulation of lymphocytes can be a prominent histopathologic feature of various human inflammatory skin diseases. Select examples include systemic sclerosis, spongiotic dermatitis, and cutaneous lupus. Although a large body of work has described various aspects of the endothelial and vascular smooth muscle layers in these diseases, the outer adventitial compartment is poorly explored. The goal of the current study was to characterize perivascular adventitial fibroblast states in inflammatory human skin diseases and relate these states to perivascular lymphocyte accumulation. In normal skin, adventitial fibroblasts are distinguished by CD90 expression, and dense perivascular lymphocytic infiltrates are uncommon. In systemic sclerosis, this compartment expands, but lymphocyte infiltrates remain sparse. In contrast, perivascular adventitial fibroblast expression of VCAM1 is upregulated in spongiotic dermatitis and lupus and is associated with a dense perivascular T cell infiltrate. VCAM1 expression marks transitioned fibroblasts that show some resemblance to the reticular stromal cells in secondary lymphoid organs. Expanded adventitial compartments with perivascular infiltrates similar to the human settings were not seen in the inflamed murine dermis. This species difference may hinder the dissection of aspects of perivascular adventitial pathology. The altered perivascular adventitial compartment and its associated reticular network form a niche for lymphocytes and appear to be fundamental in the development of an inflammatory pattern.

http://bit.ly/2LyDlrS

CCR2 Signaling Selectively Regulates IFN-{alpha}: Role of {beta}-Arrestin 2 in IFNAR1 Internalization [IMMUNE REGULATION]

An integral component of the antiviral response, type I IFNs require regulation to modulate immune activation. We identify β-arrestin 2 as a key modulator of type I IFN in primary human macrophages, an essential component of the innate immune response. β-Arrestin 2 was selectively activated by CCL2/CCR2 signaling, which induced a decrease in IFN-α, but not IFN-β expression. Small interfering RNA knockdown of β-arrestin 2 demonstrated its role in IFNAR1 internalization, as well as STAT1 and IRF3 activation. As a result, cytokine responses were not propagated following HIV infection and TLR3 activation. However, remnants of IFN signaling remained intact, despite β-arrestin 2 activation, as IFN-β, IFN-, IFN-1, IRF7, TRAIL, and MxA expression were sustained. Similar effects of β-arrestin 2 on IFN signaling occurred in hepatocytes, suggesting that arrestins may broadly modulate IFN responses in multiple cell types. In summary, we identify a novel role of β-arrestin 2 as an integral regulator of type I IFN through its internalization of IFNAR1 and a subsequent selective loss of downstream IFN signaling.

http://bit.ly/2rWTT3Y

Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity [IMMUNE REGULATION]

The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell–dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138⁺Blimp1⁺ splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.

http://bit.ly/2LB3Rkx

Neutrophil and Granulocytic Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression Significantly Contributes to Immune Dysregulation in Common Variable Immunodeficiency Disorders [IMMUNE REGULATION]

Common variable immunodeficiency disorders (CVID) represent a group of primary immunodeficiency diseases characterized by hypogammaglobulinemia and impaired specific Ab response, resulting in recurrent infections due to dysfunctional immune response. The specific mechanisms mediating immune deficiency in CVID remain to be determined. Previous studies indicated that immune dysregulation in CVID patients is associated with chronic microbial translocation, systemic immune activation, and altered homeostasis of lymphocytic and myeloid lineages. A detailed phenotypic, functional characterization of plasma markers and immune cell populations was performed in 46 CVID patients and 44 healthy donors. CVID patients displayed significantly elevated plasma levels of a marker of neutrophil activation neutrophil gelatinase–associated lipocalin. Neutrophils from CVID patients exhibited elevated surface levels of CD11b and PD-L1 and decreased levels of CD62L, CD16, and CD80, consistent with a phenotype of activated neutrophils with suppressive properties. Neutrophils from CVID patients actively suppressed T cell activation and release of IFN- via the production of reactive oxygen species. Furthermore, CVID was associated with an increased frequency of low-density neutrophils (LDNs)/granulocytic myeloid-derived suppressor cells. LDN/granulocytic myeloid-derived suppressor cell frequency in CVID patients correlated with reduced T cell responsiveness. Exogenous stimulation of whole blood with bacterial LPS emulated some but not all of the phenotypic changes observed on neutrophils from CVID patients and induced neutrophil population with LDN phenotype. The presented data demonstrate that neutrophils in the blood of CVID patients acquire an activated phenotype and exert potent T cell suppressive activity. Specific targeting of myeloid cell–derived suppressor activity represents a novel potential therapeutic strategy for CVID.

http://bit.ly/2rVKA48

ROR{gamma}t Represses IL-10 Production in Th17 Cells To Maintain Their Pathogenicity in Inducing Intestinal Inflammation [IMMUNE REGULATION]

The role of retinoid-related orphan receptor t (RORt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORt-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORt inhibitor–treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1^–/– T cells produced significantly fewer IL-10 when treated with RORt inhibitor compared with wild-type T cells. Furthermore, RORt inhibitor–treated Prdm1^–/– Th17 cells induce more severe colitis compared with RORt inhibitor–treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.

http://bit.ly/2LB3NRP

Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7 [IMMUNE REGULATION]

Viral infection activates the transcription factor IFN regulatory factor 7 (IRF7), which plays a critical role in the induction of IFNs and innate antiviral immune response. How virus-induced IFN signaling is controlled in fish is not fully understood. In this study, we demonstrate that N-myc downstream-regulated gene 1a (NDRG1a) in zebrafish plays a role as a negative regulator for virus-triggered IFN induction. First, the activation of the IFN promoter stimulated by the polyinosinic-polycytidylic acid or spring viremia of carp virus was decreased by the overexpression of NDRG1a. Second, NDRG1a interacted with IRF7 and blocked the IFN transcription activated by IRF7. Furthermore, NDRG1a was phosphorylated by TANK-binding kinase 1 (TBK1) and promoted the K48-linked ubiquitination and degradation of IRF7. Finally, the overexpression of NDRG1a blunted the transcription of several IFN-stimulated genes, resulting in the host cells becoming susceptible to spring viremia of carp virus infection. Our findings suggest that fish NDRG1a negatively regulates the cellular antiviral response by targeting IRF7 for ubiquitination and degradation, providing insights into the novel role of NDRG1a on the innate antiviral immune response in fish.

http://bit.ly/2rXx1l0

Structural Insights into the Preferential Binding of PGRP-SAs from Bumblebees and Honeybees to Dap-Type Peptidoglycans Rather than Lys-Type Peptidoglycans [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The peptidoglycan recognition protein SAs (PGRP-SAs) from Bombus ignitus (Bi-PGRP-SA), Apis mellifera (Am-PGRP-SA), and Megachile rotundata PGRP-SA (Mr-PGRP-SA) exhibit an intrinsic ability to preferentially bind to Dap-type peptidoglycan (PGN) from Bacillus subtilis rather than Lys-type PGN from Micrococcus luteus. This ability is more analogous to the binding exhibited by PGRP-LCx and PGRP-SD than to that exhibited by PGRP-SA in Drosophila. Moreover, Bi-PGRP-SA and Am-PGRP-SA share greater sequence identity with Drosophila PGRP-LCx than with PGRP-SD and retain several conserved contact residues, including His³⁷/His³⁸, His⁶⁰/His⁶¹, Trp⁶⁶/Trp⁶⁷, Ala¹⁵⁰/Ala¹⁵¹, and Thr¹⁵¹/Thr¹⁵². However, the corresponding contact residue Arg⁸⁵ is not a major anchor residue in bees (e.g., bumblebees, honeybees, and leaf-cutting bees), and an in silico analysis indicated that the residues Thr¹⁵¹/Thr¹⁵² and Ser¹⁵³/Ser¹⁵⁴ of Bi-PGRP-SA and Am-PGRP-SA are deduced to be anchor residues. In addition, the nonconserved residues Asp⁶⁷ in Bi-PGRP-SA and Mr-PGRP-SA and His⁶⁸ in Am-PGRP-SA are deduced to be involved in the binding to Dap-type PGNs in bumblebees, honeybees, and leaf-cutting bees. We conclude that the structures and specificities of PGRP-SAs in bees are more analogous to those of PGRP-LCx than to those of Drosophila PGRP-SA. This phenomenon might be explained by the fact that the evolutionary clade of Hymenoptera is more ancient than that of Diptera.

http://bit.ly/2LB3Kp7

CD62L Is a Functional and Phenotypic Marker for Circulating Innate Lymphoid Cell Precursors [INNATE IMMUNITY AND INFLAMMATION]

Innate lymphoid cells (ILCs) guard epithelial tissue integrity during homeostasis, but can be potent immune effector cells during inflammation. Precursors to all ILC subsets (ILC precursors [ILCP]) have been identified in human peripheral blood (PB). We found that during homeostasis, ILCP in PB of mouse and human expressed homing receptors for secondary lymphoid organs, mainly CD62L. These ILCP entered mouse lymph nodes in a CD62L-dependent way and relied on S1P receptors for their exit. Importantly, CD62L expression was absent on human ILCs expressing NKp44 in tonsils and PB of Crohn disease patients, and relatively fewer CD62L⁺ ILCP were present in PB of Crohn disease patients. These data are in agreement with selective expression of CD62L on nonactivated ILCP. As such, we conclude that CD62L not only serves as a functional marker of ILCP, but has potential to be used in the clinic as a diagnostic marker in inflammatory disorders.

http://bit.ly/2rUhKBh

Characterization of Mauritian Cynomolgus Macaque Fc{gamma}R Alleles Using Long-Read Sequencing [IMMUNOGENETICS]

The FcRs are immune cell surface proteins that bind IgG and facilitate cytokine production, phagocytosis, and Ab-dependent, cell-mediated cytotoxicity. FcRs play a critical role in immunity; variation in these genes is implicated in autoimmunity and other diseases. Cynomolgus macaques are an excellent animal model for many human diseases, and Mauritian cynomolgus macaques (MCMs) are particularly useful because of their restricted genetic diversity. Previous studies of MCM immune gene diversity have focused on the MHC and killer cell Ig-like receptor. In this study, we characterize FcR diversity in 48 MCMs using PacBio long-read sequencing to identify novel alleles of each of the four expressed MCM FcR genes. We also developed a high-throughput FcR genotyping assay, which we used to determine allele frequencies and identify FcR haplotypes in more than 500 additional MCMs. We found three alleles for FcR1A, seven each for FcR2A and FcR2B, and four for FcR3A; these segregate into eight haplotypes. We also assessed whether different FcR alleles confer different Ab-binding affinities by surface plasmon resonance and found minimal difference in binding affinities across alleles for a panel of wild type and Fc-engineered human IgG. This work suggests that although MCMs may not fully represent the diversity of FcR responses in humans, they may offer highly reproducible results for mAb therapy and toxicity studies.

http://bit.ly/2LCMQq7

Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment [INFECTIOUS DISEASE AND HOST RESPONSE]

Virus–bacteria coinfections are associated with more severe exacerbations and increased risk of hospital readmission in patients with chronic obstructive pulmonary disease (COPD). The airway epithelium responds to such infections by releasing proinflammatory and antimicrobial cytokines, including IL-17C. However, the regulation and role of IL-17C is not well understood. In this study, we examine the mechanisms regulating IL-17C production and its potential role in COPD exacerbations. Human bronchial epithelial cells (HBE) obtained from normal, nontransplanted lungs or from brushings of nonsmokers, healthy smokers, or COPD patients were exposed to bacteria and/or human rhinovirus (HRV). RNA and protein were collected for analysis, and signaling pathways were assessed with pharmacological agonists, inhibitors, or small interfering RNAs. HBE were also stimulated with IL-17C to assess function. HRV–bacterial coinfections synergistically induced IL-17C expression. This induction was dependent on HRV replication and required NF-B–mediated signaling. Synergy was lost in the presence of an inhibitor of the p38 MAP kinase pathway. HBE exposed to IL-17C show increased gene expression of CXCL1, CXCL2, NFKBIZ, and TFRC, and release CXCL1 protein, a neutrophil chemoattractant. Knockdown of IL-17C significantly reduced induction of CXCL1 in response to HRV–bacterial coinfection as well as neutrophil chemotaxis. HBE from healthy smokers release less IL-17C than cells from nonsmokers, but cells from COPD patients release significantly more IL-17C compared with either nonsmokers or healthy smokers. These data suggest that IL-17C may contribute to microbial-induced COPD exacerbations by promoting neutrophil recruitment.

http://bit.ly/2rXKJ7c

LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Both common and rare genetic variants of laccase domain-containing 1 (LACC1, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of Citrobacter rodentium, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and C. rodentium colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A–producing CD4⁺ T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying LACC1 variants.

http://bit.ly/2LCMOyv

The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury [INNATE IMMUNITY AND INFLAMMATION]

Uncontrolled inflammatory response during sepsis predominantly contributes to the development of multiorgan failure and lethality. However, the cellular and molecular mechanisms for excessive production and release of proinflammatory cytokines are not clearly defined. In this study, we show the crucial role of the GTPase Ras-related protein in brain (Rab)1a in regulating the nucleotide binding domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and lung inflammatory injury. Expression of dominant negative Rab1 N124I plasmid in bone marrow–derived macrophages prevented the release of IL-1β and IL-18, NLRP3 inflammasome activation, production of pro–IL-1β and pro–IL-18, and attenuated TLR4 surface expression and NF-B activation induced by bacterial LPS and ATP compared with control cells. In alveolar macrophage–depleted mice challenged with cecal ligation and puncture, pulmonary transplantation of Rab1a-inactivated macrophages by expression of Rab1 N124I plasmid dramatically reduced the release of IL-1β and IL-18, neutrophil count in bronchoalveolar lavage fluid, and inflammatory lung injury. Rab1a activity was elevated in alveolar macrophages from septic patients and positively associated with severity of sepsis and respiratory dysfunction. Thus, inhibition of Rab1a activity in macrophages resulting in the suppression of NLRP3 inflammasome activation may be a promising target for the treatment of patients with sepsis.

http://bit.ly/2s4UXTD

Gastric duplication cyst in an adult with autoimmune hemolytic anemia: a case report and review of the literature

Gastric duplication cysts are uncommon congenital anomalies found primarily in children and rarely seen in the adult population. Accurate diagnosis of cysts before resection is difficult even using the most ad...

http://bit.ly/2BF9jhQ

Spatiotemporal activation of the C/EBP{beta}/{delta}-secretase axis regulates the pathogenesis of Alzheimer’s disease [Neuroscience]

Alzheimer's disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the...

http://bit.ly/2QUEakX

Unraveling the blue paradox: Incomplete analysis yields incorrect conclusions about Phoenix Islands Protected Area closure [Social Sciences]

In PNAS, McDermott et al. (1) analyze a 2014–2016 central Pacific fishing surge, focusing on the Phoenix Islands Protected Area (PIPA) inside the Kiribati exclusive economic zone (EEZ). The authors incorrectly attribute the surge to the anticipated industrial fishing closure of PIPA and describe the phenomenon as a blue paradox...

http://bit.ly/2QPr20i

Reply to Zahednasab et al.: HHV-6 and marmoset EAE [Biological Sciences]

We thank Zahednasab et al. (1) for their enthusiastic support of our paper (2) and insightful comments. We wholeheartedly agree that additional studies are needed to more fully elucidate mechanisms underlying the association of HHV-6 and other viruses with neuroinflammatory pathologies like multiple sclerosis (MS). The authors correctly note that...

http://bit.ly/2QSgmy9

Role of HHV-6 subtypes in accelerating EAE progression [Biological Sciences]

We enthusiastically read the article in PNAS by Leibovitch et al. (1), in which they show that intranasal inoculations with human herpesvirus (HHV)-6A and HHV-6B accelerate the onset and severity of experimental autoimmune encephalomyelitis (EAE). They performed an outstanding job in utilizing marmosets to mimic the multiple sclerosis (MS)-like symptoms...

http://bit.ly/2BJJQUa

Reply to Hanich et al.: Alternate explanations for the blue paradox do not withstand statistical scrutiny [Social Sciences]

A primary goal of McDermott et al. (1) was to stimulate discussion of the "blue paradox" among proponents of marine reserves. We welcome the chance to engage with conservation experts and are grateful for the commentary provided by Hanich et al. (2). However, we are unconvinced by their arguments. Hanich...

http://bit.ly/2BGgtm0

Acknowledgment of Reviewers, 2018 [Reviewer Acknowledgment]

The PNAS editors would like to thank all the individuals who dedicated their considerable time and expertise to the journal by serving as reviewers in 2018. Their generous contribution is deeply appreciated. A Lars Aagaard Stuart A. Aaronson Pierre Abad Alejandro Aballay Snezhana I. Abarzhi Maria Abascal Adam R. Abate...

http://bit.ly/2QQEIbj

SOG1 activator and MYB3R repressors regulate a complex DNA damage network in Arabidopsis [Plant Biology]

To combat DNA damage, organisms mount a DNA damage response (DDR) that results in cell cycle regulation, DNA repair and, in severe cases, cell death. Underscoring the importance of gene regulation in this response, studies in Arabidopsis have demonstrated that all of the aforementioned processes rely on SUPPRESSOR OF GAMMA...

http://bit.ly/2BDs4lu

Fluctuating selection on migrant adaptive sodium transporter alleles in coastal Arabidopsis thaliana [Plant Biology]

Stressors such as soil salinity and dehydration are major constraints on plant growth, causing worldwide crop losses. Compounding these insults, increasing climate volatility requires adaptation to fluctuating conditions. Salinity stress responses are relatively well understood in Arabidopsis thaliana, making this system suited for the rapid molecular dissection of evolutionary mechanisms....

http://bit.ly/2QPxjt5

Correction Rivas-Carrillo et al., Whole-genome comparison of endogenous retrovirus segregation across wild and domestic host species populations [Correction]

EVOLUTION Correction for "Whole-genome comparison of endogenous retrovirus segregation across wild and domestic host species populations," by Salvador Daniel Rivas-Carrillo, Mats E. Pettersson, Carl-Johan Rubin, and Patric Jern, which was first published October 8, 2018; 10.1073/pnas.1815056115 (Proc Natl Acad Sci USA 115:11012–11017). The authors wish to note: "It has come...

http://bit.ly/2SkOmj9

Correction for Mann, Inner Workings: Hunting for microbial life throughout the solar system [Correction]

INNER WORKINGS Correction for "Inner Workings: Hunting for microbial life throughout the solar system," by Adam Mann, which was first published November 6, 2018; 10.1073/pnas.1816535115 (Proc Natl Acad Sci USA 115:11348–11350). The editors note that on page 11350, left column, last paragraph, line 6, "being developed by" should instead appear...

http://bit.ly/2AgB1kO

Ventral striatum’s role in learning from gains and losses [Neuroscience]

Adaptive behavior requires animals to learn from experience. Ideally, learning should both promote choices that lead to rewards and reduce choices that lead to losses. Because the ventral striatum (VS) contains neurons that respond to aversive stimuli and aversive stimuli can drive dopamine release in the VS, it is possible...

http://bit.ly/2BHV23H

Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy [Immunology and Inflammation]

Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and...

http://bit.ly/2BF0a8L

Climate network percolation reveals the expansion and weakening of the tropical component under global warming [Earth, Atmospheric, and Planetary Sciences]

Global climate warming poses a significant challenge to humanity; it is associated with, e.g., rising sea level and declining Arctic sea ice. Increasing extreme events are also considered to be a result of climate warming, and they may have widespread and diverse effects on health, agriculture, economics, and political conflicts....

http://bit.ly/2BIu9wD

Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors [Genetics]

Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key...

http://bit.ly/2BLeBIn

Robust forecast aggregation [Economic Sciences]

Bayesian experts who are exposed to different evidence often make contradictory probabilistic forecasts. An aggregator, ignorant of the underlying model, uses this to calculate his or her own forecast. We use the notions of scoring rules and regret to propose a natural way to evaluate an aggregation scheme. We focus...

http://bit.ly/2QPxzbx

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue [Medical Sciences]

Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue...

http://bit.ly/2BF5Q2F

Right temporal alpha oscillations as a neural mechanism for inhibiting obvious associations [Psychological and Cognitive Sciences]

Creative cognition requires mental exploration of remotely connected concepts while suppressing dominant ones. Across four experiments using different samples of participants, we provide evidence that right temporal alpha oscillations play a crucial role in inhibiting habitual thinking modes, thereby paving the way for accessing more remote ideas. In the first...

http://bit.ly/2BMh3ym

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex [Developmental Biology]

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone...

http://bit.ly/2BJQlGP

High-capacity preconscious processing in concurrent groupings of colored dots [Psychological and Cognitive Sciences]

Grouping is a perceptual process in which a subset of stimulus components (a group) is selected for a subsequent—typically implicit—perceptual computation. Grouping is a critical precursor to segmenting objects from the background and ultimately to object recognition. Here, we study grouping by color. We present subjects with 300-ms exposures of...

http://bit.ly/2QPxxAr

Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks [Genetics]

Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles of NRs as direct regulators of the circadian circuitry. Here we show that the nuclear receptor HNF4A strongly transrepresses the transcriptional...

http://bit.ly/2BRNtYD

Milestone Clinical Events in Patients From North America With Epidermolysis Bullosa

This cohort study uses data from the Epidermolysis Bullosa Clinical Characterization and Outcomes Database to analyze the timing of clinical diagnosis and major clinical events in patients with epidermolysis bullosa from North America.

http://bit.ly/2QUqgzh

Consanguinity and Double Recessive Gene Pathology

This case report describes a 1-year-old child of consanguineous birth with double recessive gene pathology, both cutis laxa (PYCR1) and nephrotic syndrome (PLCE1).

http://bit.ly/2BGpkUD

Association Between Health Maintenance Practices and Skin Cancer Risk as a Source of Detection Bias

This cohort study assesses a possible association between health care screening practices and skin cancer risk using data from the Nurses' Health Study and Health Professionals Follow-up Study.

http://bit.ly/2QUq5UD

Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma

This study of 3 families, 1 from a clinical setting and 2 obtained from the GenoMEL Consortium, evaluated the association of the POT1 germline missense variant p.I78T with familial melanoma.

http://bit.ly/2BJzyUj

Diffusion-Weighted Magnetic Resonance Imaging in the Detection of Residual and Recurrent Cholesteatoma in Children: A Systematic Review and Meta-Analysis

Publication date: Available online 26 December 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Khalil Bazzi, Eugene Wong, Nicholas Jufas, Nirmal Patel

Abstract

Objective

To examine the performance of diffusion-weighted magnetic resonance imaging (DW-MRI) in the detection of residual and recurrent cholesteatoma in children.

Methods

A systematic review and meta-analysis was conducted as per PRISMA guidelines using the following databases from their date of inception: MEDLINE, PubMed, Embase, Cochrane Library, Web of Science. Bivariate meta-analysis using a random effects model was used to calculate summarized pooled estimates of sensitivity, specificity, and diagnostic odds ratios, using second-look surgery as the gold standard comparison.

Results

A total of ten articles (141 cases) were included for qualitative and quantitative analysis. Pooled sensitivity and specificity of non-echo planar imaging (non-EPI) DW-MRI were 89.4% (95%CI 51.9%-98.5%) and 92.9% (95%CI 81.4%-97.5%) respectively. DW-MRI appears limited in its ability to detect lesions less than 3mm in size.

Conclusion

Non-EPI DW-MRI is highly specific but carries uncertain sensitivity in the detection of residual and recurrent cholesteatoma in children. Further research is warranted to determine the specific role of DW-MRI in this patient group, namely when and how often children should be referred for imaging and in which cases the method can be used to completely replace second-look surgery.

http://bit.ly/2VaZPne

Deep interarytenoid notch in young children managed with systematic thickener wean and injection laryngoplasty

Publication date: Available online 26 December 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Usmaan Basharat, Scott Schraff, Lindsay M. Stevens, Pamela Y. Clarke, Paul Kang, Jim Woodward, Shauna R. Schroeder, Aparna Rao, Nathan Page, Dana I. Williams

Abstract

Objectives

Deep interarytenoid notch (DIN) is a congenital variation of the larynx often associated with dysphagia and aspiration (DA) in young children. Feeding therapy with thickeners and surgical management with injection larygoplasty (IL) are used with various efficacies. Thickeners address the functional domain and IL addresses the anatomical domain of treatment. Our objective was to evaluate DIN patients managed with both interventions.

Methods

We conducted a retrospective pilot descriptive study of DIN patients with DA aged 1-3 years receiving thickeners and IL. Patients received a systematic weekly reduction of thickeners, referred to as the Thickener Weaning Protocol (TWP), based on clinical signs and symptoms of DA. The outcomes were assessed by the rate of thickener level reduction and DA-related sign/symptom frequency achieved at 6 months post-treatment.

Results

Thirteen patients with DIN associated DA were analyzed. The TWP was initiated within 2 months in 77% of patients, and within 4 months in 100% of patients. Thickener scores improved from an average of 5.76 (3/4 honey) to 2.15 (thin) (p = 0.001). DA-related signs/symptoms frequency improved from an average of 3.3 to 0.84 (p = 0.05).

Conclusions

These findings suggest that treatment of DIN associated DA with a combination of thickeners and IL results in significant clinical improvements in young children.

http://bit.ly/2Q3mRsx

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter, open‐label, single‐arm, phase 1/2 study on 10 Japanese patients

Abstract

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m² of body surface area). The primary end‐points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19‐positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.

http://bit.ly/2ET9IBc

Epidemiology, risk factors, and outcomes of adult cutaneous non‐tuberculous mycobacterial infection over a 10‐year period in Singapore

Abstract

Background

Unfamiliarity with the presentation, diagnostic process, and treatment of cutaneous non‐tuberculous mycobacterium (NTM) infection leads to poorer outcomes. We describe our experience with managing cutaneous NTM infection in a regional hospital in Singapore from 2005 to 2014.

Methods

Adult patients with cutaneous NTM infections were identified through positive skin tissue cultures in this retrospective case series. We excluded patients younger than 21 years of age, patients whose care was transferred to another hospital, and patients with catheter‐related infections. Data including demographic variables, as well as disease and treatment outcomes, were collected. We compared the data between patients with and without risk factors for immunosuppression to look for any significant difference.

Results

Fifty‐eight cases were reviewed. Mycobacterium abscessus was the commonest organism isolated (51.7%), and abscesses or inflamed cysts were the most common presentation. Nineteen specimens (57.6%) showed suppurative or necrotizing granulomatous dermatitis on biopsy and acid‐fast bacilli were identified in 2 of 21 histologic specimens (9.5%) stained for mycobacterium. Treatment included systemic antibiotics, surgery, or both. In total, 33 cases had clinical resolution while 25 cases were lost to follow‐up. Our study was limited by the under‐reporting of cases, bias due to data from a single center, and high dropout rates, thereby precluding a detailed assessment of treatment outcomes.

Conclusions

A high index of suspicion is required to diagnose cutaneous NTM infection. Education of both patients and physicians will help to raise the level of awareness and reduce treatment delays.

http://bit.ly/2EJaccl

Global perspectives for the management of onychomycosis

Abstract

Onychomycosis is a fungal nail infection caused by dermatophytes, nondermatophyte molds, and yeasts. This difficult‐to‐treat chronic infection has a tendency to relapse despite treatment. This paper aims to offer a global perspective on onychomycosis management from expert physicians from around the world. Overall, the majority of experts surveyed used systemic, topical, and combination treatments approved in their countries and monitored patients based on the product insert or government recommendations. Although the basics of treating onychomycosis were similar between countries, slight differences in onychomycosis management between countries were found. These differences were mainly due to different approaches to adjunctive therapy, rating the severity of disease and use of prophylaxis treatment. A global perspective on the treatment of onychomycosis provides a framework of success for the committed clinician with appreciation of how onychomycosis is managed worldwide.

http://bit.ly/2EQ5b2v

Updates in management of acute invasive fungal rhinosinusitis

Purpose of review Acute invasive fungal rhinosinusitis (AIFRS) is a rare and often fatal disease, that remains incompletely understood. Case series and literature reviews constitute most of the literature on AIFRS, and act as the standards by which we treat these extremely complex patients. This review discusses management of AIFRS, with focuses on optimal diagnostic and therapeutic strategies. Recent findings Mortality rates remain high, around 50% overall, though some recent studies have shown higher survival rates with early diagnosis and complete surgical resection. Some recent publications on AIFRS have focused on the utility of frozen section analysis both to diagnose and potentially guide the completeness of endoscopic surgical debridement. It was also recently shown that complete endoscopic resection of disease leads to higher survival than when disease was incompletely resected. Additionally, a new antifungal agent was recently approved by the FDA, which has a more favorable pharmacologic and side effect profile, though more studies are necessary to determine its utility. Summary Early diagnosis requires identification of sinusitis symptoms in immunocompromised patients, followed by intranasal biopsy and frozen section analysis. Early surgical debridement and antifungal therapy then remain the cornerstones of AIFRS management. Video abstract See Video, Supplemental Digital Content 1, http://bit.ly/2BKeblx. Correspondence to John R. Craig, MD, Department of Otolaryngology–Head and Neck Surgery, Henry Ford Health System, 2799 W. Grand Blvd, Detroit, MI 48202, USA. Tel: +1 313 971 9320; fax: +1 313 916 7263; e-mail: JCraig1@hfhs.org. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://bit.ly/2QPN9Uo). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2BGEFVj

Analysis of neuromonitoring signal loss during retroauricular versus conventional thyroidectomy

Objective

Loss of signal (LOS) during intraoperative neuromonitoring (IONM) of robotic or endoscopic thyroidectomy via a retroauricular approach (RAT) and during conventional open thyroidectomy (COT) was investigated to compare the risk of recurrent laryngeal nerve (RLN) injury between the two groups.

Study Design

Original article.

Methods

This is a retrospective case series study performed between May 2014 and September 2016. IONM using the NIM 3.0 system (Medtronic Xomed, Inc., Jacksonville, FL) was used for this study. Pre‐ and postoperative vocal cord functions were assessed using a flexible laryngoscope. LOS types noted intraoperatively and their associations with postoperative vocal cord palsy (VCP) were evaluated. LOS rate and temporary and permanent VCP rates were compared between the two groups. The surgical events associated with LOS were also documented and analyzed in this study.

Results

In total, 153 patients were recruited, and 111 patients were enrolled in the RAT group; the remaining 42 patients were enrolled in the COT group. No statistically significant differences in intraoperative LOS (P = 0.812) and postoperative VCP rates (early, permanent; P = 0.259 and P = 0.577, respectively) between the two groups were observed. IONM accuracy of predicting postoperative VCP was 99.1% in our case series.

Conclusion

On the basis of IONM findings, the risks of injury to RLN were similar between the two groups. Comparison of LOS was an objective method for verifying the novel RAT approach. We applied our IONM protocol and troubleshooting algorithm during RAT with acceptable accuracy, but the international standardized method of IONM is applicable and recommended for reducing false results using vagal nerve stimulation.

Level of Evidence

3b. Laryngoscope, 2018

http://bit.ly/2ENJJtX

Prevention of tracheal stenosis with pirfenidone after tracheotomy: An experimental study

Objectives

In this study, pirfenidone's role about reducing tracheal stenosis by suppressing fibrosis and inflammation was examined.

Methods

Tracheotomy was performed on 14 rats, and their cannulas were fixed to tracheotomy area by stoma suture. Two working groups were established. Rats in the first group were given 15 mg/kg/day (1 mL pirfenidone solution) pirfenidone intraperitoneally for 10 days. In the second group as a control group, 1 mL saline solution was applied intraperitoneally. Ten days later, rats were decanulated and kept alive for 3 more weeks.

Anesthetized rats were sacrificed on day 30. All rat tracheas were resected between the first and seventh rings. Epithelial damage, inflammation, and fibrosis were determined histopathologically; diameters of intratracheal lumen and their mucosal thickness parameters were determined histomorphometrically; and TGFβ‐1 (the growth factor beta), TNFα (tumor necrosis factor alpha), and IL‐1β (Interleukin‐1 beta) values were determined immunohistochemically.

Results

According to the parameters of the control group, fibrosis; diameters of intratracheal lumen; and values of TGFβ‐1, TNFα, and IL‐1β were found to be statistically significant.

Conclusion

In our study, it was found that pirfenidone reduces fibrosis and narrowing of intratracheal lumen diameter significantly.

Level of Evidence

NA. Laryngoscope, 2018

http://bit.ly/2EOwhXK

Factors associated with epiglottic petiole prolapse repositioning success

Objective

Epiglottic petiole prolapse is an overlooked entity that could lead to supraglottic airway obstruction for patients with complex airway history. Classical symptoms include exercise intolerance, obstructive sleep apnea, and difficulty with decannulation. The goal of this project was to evaluate the factors associated with epiglottic petiole repositioning success.

Methods

Retrospective case series of patients with a complex history of airway reconstruction evaluated by the aerodigestive team at a tertiary pediatric hospital from May 2003 to August 2017. All patients underwent repositioning for petiole prolapse.

Results

We had a total of 59 patients (14 females, 23.7%) with complex airway anomalies with petiole prolapse noted during a microlaryngoscopy and bronchoscopy. Mean age was 12.9 ± 6.1 year old (range 1.3–35.9). Patients had a history of 2.2 (1–5) open airway surgeries, and 51 of 58 (87.9%) of them had a prior complete laryngofissure. Laryngotracheoplasty and petiole repositioning were performed as a double‐stage surgery for 54 of 58 (91.5%) patients. Epiglottic petiole prolapse was persistent in 20 patients (33.9%) and became symptomatic for 14 of them (23.7%). The main preventive factor of petiole prolapse recurrence was pre‐epiglottic fat debulking at the time of the repositioning, with an odds ratio of 0.06 (95% confidence interval 0.007–0.6, P = 0.01). Stent placement, longer duration of stent placement, and double‐stage procedure also increased the likelihood of success (all P < 0.05).

Conclusion

Patients with petiole prolapse have a history of complete laryngofissure and multiple open airway surgeries. Pre‐epiglottic fat debulking and longer stent placement at the time of the repositioning surgery appear to significantly increase the long‐term success rate.

Level of Evidence

4. Laryngoscope, 2018

http://bit.ly/2EJ6RKl

Laryngeal reconstruction for recurrent desmoid tumor using three‐dimensional modeling: A unique approach for a rare tumor

Desmoid tumors are exceedingly rare within the larynx and cause significant morbidity due to their locally aggressive and infiltrative nature. Surgery is the mainstay of treatment with previous reports describing total and near‐total laryngectomy for cure. We present a case of recurrent glottic desmoid tumor managed with hemilaryngectomy and reconstructed with temporoparietal free tissue, rib, and buccal grafts. Three‐dimensional modeling was utilized to optimize aerodigestive function after laryngeal reconstruction. Laryngoscope, 2018

http://bit.ly/2ESO6VA

Diode laser thermal effect on the paranasal sinus osteoma

http://bit.ly/2EMkF6E

Pharyngobasilar fascia as a landmark in endoscopic skull base surgery: The triangulation technique

http://bit.ly/2EQazm6

Over‐the‐Counter Tinnitus “Cures”: Marketers’ Promises Do Not Ring True

Objectives

The Clinical Practice Guideline of the American Academy of Otolaryngology–Head & Neck Surgery (2014) stated that clinicians should not recommend dietary supplements for the treatment of tinnitus. The aim of this study is to characterize over‐the‐counter tinnitus remedies (OTCTR) on the U.S. market, describe the ingredients and prices, and characterize the methods of promoting these products.

Methods

OTCTR were identified via Web search and visits to retail establishments. Information was collected regarding OTCTR chemical composition, product labeling, advertisements and marketing, price, and customers reviews.

Results

A wide array of unproven OTCTR exist on today's market. All make unfounded claims of relief from ear ringing. Most of the products considered in this study consist of mixtures of inexpensive and common vitamins, minerals, and/or herbs sold at a premium compared to similar preparations not expressly advertised for tinnitus. Certain brands, most notably Arches Tinnitus Formula (Arches Natural Products Inc., Salt Lake City, UT) and Lipo‐Flavonoid (Clarion Brands Inc., Solon, OH), target otolaryngologists by advertising in specialty journals and prominently featuring supposed endorsement by "Ear‐Nose‐and‐Throat Doctors" in their marketing.

Conclusion

It is important for otolaryngologists who are caring for tinnitus sufferers to be aware that a robust and diverse market exists for unproven OTC tinnitus remedies. It is troubling that heavily advertised brands profess support by otolaryngologists. Responsible specialty organizations in the field should consider opposing such commercially motivated representations. Otolaryngology journals may wish to adopt a policy along the lines of The Journal of the American Medical Association publications to decline advertisements of dietary supplements that make unproven therapeutic claims.

Level of Evidence

5. Laryngoscope, 2018

http://bit.ly/2EQ0QeC

The Impact of Nasalance on Cepstral Peak Prominence and Harmonics‐to‐Noise Ratio

Objectives/Hypothesis

Cepstral peak prominence (CPP) has been reported as a reliable measure of dysphonia and a preferred alternative to harmonics‐to‐noise ratio (HNR). However, CPP has been observed to be sensitive to articulatory variation and vocal intensity. The aim of this study was to examine the impact of nasalance on CPP and HNR of voice signals. It was hypothesized that increased nasalance would be associated with decreased CPP.

Study Design

Within‐subject correlation design.

Methods

Thirty vocally healthy female participants were recorded reading and producing a vowel in alternation with a nasal consonant while wearing a nasometer for calculation of nasalance. Recorded vowel, nasalized, and nasal segments of speech were used to calculate CPP using Analysis of Dysphonia in Speech and Voice software, and HNR and vocal intensity using Praat software.

Results

Significant main effects of conditions were observed for CPP. CPP values decreased significantly when phonation changed from vowel to nasalized vowel and to nasal. There was correlation between CPP and nasalance and between CPP and intensity. HNR was slightly higher in the nasal condition than in vowel. There was a weak correlation between HNR and nasalance. No correlation was found between HNR and intensity.

Conclusions

CPP is sensitive to changes in vocal tract configuration caused by nasalization as well as intensity, whereas HNR is not. Therefore, CPP may reflect the periodicity in source signal or the filtering effects of vocal tract. Further research is needed to clarify the application and interpretation of CPP in clinical practice.

Level of Evidence

4 Laryngoscope, 2018

http://bit.ly/2EPZXn9

CT Navigation and sialendoscopy‐assisted transfacial removal of a parotid stone: A technical note

http://bit.ly/2EMkEQ8

Perioperative Analgesia for Patients Undergoing Septoplasty and Rhinoplasty: An Evidence‐Based Review

Objectives/Hypothesis

Opioid misuse and diversion is a pressing topic in today's healthcare environment. The objective of this study was to conduct a review of non‐opioid perioperative analgesic regimens following septoplasty, rhinoplasty, and septorhinoplasty.

Study Design

Evidence‐based systematic review.

Methods

PubMed, MEDLINE, Cochrane Library, and Embase databases were reviewed for articles related to perioperative analgesic use in septoplasty, rhinoplasty, and septorhinoplasty. Quality of studies were assessed via the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria, Jadad scores, and the Cochrane bias tool. Patient demographic data and clinical outcomes, including medication type, dose, administration time, pain scores, and adverse events, were obtained from included studies. Summary tables detailing the benefits and harms of each investigated regimen are included.

Results

Thirty‐seven studies met inclusion criteria for this evidence‐based review. The quality of the studies was determined to be of moderate quality based off of GRADE standardized criteria with a mean Jadad score of 3.1. A preponderance of evidence showed reduced perioperative pain scores and rescue analgesic requirements, supporting the use of local anesthetics for analgesic control. Nonsteroidal anti‐inflammatory drugs (NSAIDs) demonstrated similar decreased visual analog scores and postoperative analgesic demand; however, increased adverse events in this class warrant caution.

Conclusions

Contemporary literature supports the use of NSAIDs, gabapentin, local anesthetics, and α‐agonists as effective perioperative analgesic opioid alternatives for septoplasty and septorhinoplasty. Local anesthetic use is a cost‐effective option resulting in decreased postoperative pain scores and rescue analgesic requirements. Further large‐scale, multi‐institutional, controlled studies are needed to provide definitive recommendations.

Level of Evidence

NA Laryngoscope, 2018

http://bit.ly/2EOwfiA

The Effect of Octanoic Acid on Essential Voice Tremor: A Double‐Blind, Placebo‐Controlled Study

Objectives/Hypothesis

The purpose of this study was to determine the effects of octanoic acid on acoustic, perceptual, and functional aspects of essential voice tremor (EVT).

Study Design

Prospective, double‐blind, placebo‐controlled, crossover study.

Methods

Sixteen participants with a diagnosis of EVT were randomized to a 3‐week dosing condition of octanoic acid or placebo, followed by a 2‐week washout period and crossover to the other condition for an additional 3 weeks. Baseline and post‐testing sessions were completed before and at the completion of each condition. Primary outcome measures were the magnitude of amplitude and frequency tremor, measured from the acoustic signal. Secondary outcomes were auditory‐perceptual ratings of tremor severity and self‐ratings of voice handicap.

Results

Magnitude of amplitude and frequency tremor were significantly lower after 3 weeks of octanoic acid dosing as compared to the placebo condition. Auditory‐perceptual ratings of tremor severity did not show significant differences between conditions. A trend toward better voice was seen for the sustained vowel ratings, but not the sentence‐level ratings. No significant differences between conditions were seen on self‐reported voice disability as assessed on the Voice Handicap Index‐10.

Conclusions

The results of this controlled investigation support the potential utility of octanoic acid for reducing the magnitude of tremor in people with EVT. Further research is needed to determine whether different dosing or treatment combinations can improve functional communication in EVT.

Level of Evidence

1 Laryngoscope, 2018

http://bit.ly/2EKi4u6

Solar urticaria – An Australian case series of 83 patients

Abstract

Solar urticaria (SU) is a rare form of urticaria with a pathogenesis that is poorly understood. It affects all skin types, can be difficult to diagnose, and is challenging to manage effectively. We conducted a retrospective review of patients with SU in our institution. A total of 83 patients (56 females) were identified as having SU. The mean age was 32 years (7–74) at first development of symptoms/signs of SU. Pruritus was the most common symptom reported (79%). Of the 60 patients who underwent monochromator testing at least once, 35 had SU confirmed with most reacting to visible light and UVA, or to UVA alone. Antihistamines and sun avoidance remain the mainstay treatment for SU but other treatments, including omalizumab, are of potential interest in treating patients with recalcitrant SU. The characterisation of this large case series of patients may help dermatologists recognise and manage this rare disorder appropriately.

http://bit.ly/2EPeKi4

In Response to Afreen Et Al

No abstract available

http://bit.ly/2QOF6HB

In Response

No abstract available

http://bit.ly/2BEacqW

Economic Savings From Changing Anesthetic Agent Purchasing Must Include Costs Associated With Expected Changes in Case Times Known From Meta-analyses of Randomized Clinical Trials

No abstract available

http://bit.ly/2QOB7dU

In Response

No abstract available

http://bit.ly/2BF2ltd

Screening Ability of STOP-Bang Questionnaire for Obstructive Sleep Apnea

No abstract available

http://bit.ly/2QPNx5b

In-Flight Medical Emergencies: A Practical Guide to Preparedness and Response

No abstract available

http://bit.ly/2BEPjfc

Chronic Atypical Antipsychotic Use Is Associated With Reduced Need for Postoperative Nausea and Vomiting Rescue in the Postanesthesia Care Unit: A Propensity-Matched Retrospective Observational Study

BACKGROUND: Atypical antipsychotics are efficacious for chemoprophylaxis against chemotherapy-induced nausea and vomiting, but perioperative investigations have been scant. We sought to examine the association between chronic atypical antipsychotic therapy and the likelihood of postoperative nausea and vomiting. METHODS: In this single-center, propensity-matched, retrospective, observational study, elective noncardiac surgical cases from January 2014 to December 2017 were examined with regard to the primary outcome of rescue antiemetic administration in the postanesthesia care unit as a measure of postoperative nausea and vomiting. Chronic administration of olanzapine, aripiprazole, and risperidone was the exposure of interest. Other independent variables included outpatient antiemetics, modified Apfel score, age, American Society of Anesthesiologists physical status score, case length, and exposures to emetogenic and chemoprophylactic agents. Logistic regression was performed using case-level data. Conditional logistic regression was performed after 1:2 propensity matching, sampling without replacement. Monte Carlo simulation was performed to compute the mean patient-level treatment effect on the treated. RESULTS: Of 13,660 cases, 154 cases with patients receiving atypical antipsychotics were matched against 308 cases without, representing 115 and 273 unique patients, respectively. In a well-balanced cohort, the mean patient-level odds of being administered rescue antiemetic was lower for patients chronically taking the 3 atypical antipsychotics under consideration as compared to those not on atypical antipsychotics, with an odds ratio of 0.29 (95% CI, 0.11–0.75; P = .015). CONCLUSIONS: Chronic atypical antipsychotic therapy is associated with reduced risk of postanesthesia care unit antiemetic administration. These findings support the need for prospective studies to establish the safety and efficacy of postoperative nausea and vomiting chemoprophylaxis with these agents. Accepted for publication November 15, 2018. Funding: V.N.O'.-S. is partially supported by a Synergy Grant from the Woodruff Health Sciences Center. Otherwise, this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The Emory University Department of Anesthesiology generously supported the time of the authors in producing this work. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/KegmMq). Reprints will not be available from the authors. Address correspondence to Vikas N. O'Reilly-Shah, MD, PhD, Department of Anesthesiology, Emory University and Children's Healthcare of Atlanta, 3B S, 1364 Clifton Rd, NE, Atlanta, GA 30322. Address e-mail to voreill@emory.edu. © 2018 International Anesthesia Research Society

http://bit.ly/2QPGf1f

Daily Caffeine Consumption Does Not Influence Acupuncture Analgesia in Healthy Individuals: A Preliminary Study

Animal studies suggest that caffeine may interfere with acupuncture analgesia. This study investigated the modulation effect of daily caffeine intake on acupuncture analgesia in 27 healthy subjects using a crossover design. We found that real acupuncture increased pain thresholds compared to sham acupuncture. Further, there was no association between caffeine intake measurements of daily caffeine use, duration of caffeine consumption, or their interaction and preacupuncture and postacupuncture pain threshold changes. Our findings suggest that daily caffeine intake may not influence acupuncture analgesia in the cohort of healthy subjects who participated in study. Accepted for publication November 12, 2018. Funding: J.K. is supported by R01 AT008563, R21 AT008707, and R61/R33 AT009310 from the National Institutes of Health/National Center for Complementary and Integrative Health. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/KegmMq). Reprints will not be available from the authors. Address correspondence to Jian Kong, MD, MS, MPH, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Bldg 120, Room 101 C, Charlestown, MA 02129. Address e-mail to jkong2@mgh.harvard.edu. © 2018 International Anesthesia Research Society

http://bit.ly/2BF2j4z