New Method for Sex Prediction Using the Human Non-Adult Auricular Surface of the Ilium in the Collection of Identified Skeletons of the University of Coimbra

Abstract

Sex estimation in non-adult skeletons is crucial in bioarchaeology and forensic anthropology. It was not extensively considered in the past, mainly because it was stated that the dimorphic osteological features were difficult to identify before adulthood. Over the past few years, this statement was disproved, and the study of numerous dimorphic non-adult skeletal traits was approached. This paper presents a new methodology that evaluates the auricular surface of the non-adult ilia. Several morphological and continuous variables were recorded for 34 individuals (21 females and 13 males) aged between 7 and 18 from the Coimbra Identified Skeletons Collection (University of Coimbra, Portugal).

The results show low intra and inter-observer errors for all the variables, which renders the methodology replicable. Two ratios related to the shape of the anterior area of the auricular surface offer the most dimorphic data (proportions of cases correctly assigned: 0.82 and 0.88; sexual allocation probabilities: 0.85 for both variables). A discriminant function and a logistic regression were developed, which correctly classified the 82.35 and the 88.23% of the individuals, respectively. Moreover, two qualitative variables, referred to as the overall morphology and the apex morphology, also show statistically significant differences between males and females (proportions of correct assignation: 0.82 and 0.76; sexual allocation probabilities: 0.79 and 0.76).

These variables can be incorporated in a multifactorial approach together with other indicators already available in the specialised literature in order to help improve the accuracy of the results obtained. This methodological procedure has to be applied with other identified samples, including younger individuals, so as to test whether the trends presented in this context are maintained and are useful in populations from a different geographical provenience.

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Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria

Abstract

Background

Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE-mediated mechanisms also play an important role in CU.

Methods

Reactivity of CU patients' peripheral blood basophils (n=60) to specific anti-FcεRI and IgE-independent fMLP stimulation was determined by basophil activation test in comparison to patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q₂oL.

Results

Stimulating CU patients' basophils via FcεRI, we identified three distinct immunological phenotypes. One subgroup of patients' basophils reacted to FcεRI stimulation, whereas the others had anti-FcεRI non-reactive basophils. Among the latter a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase and also exhibited the strongest disease impact on their quality of life.

Conclusions

CU patients can be categorized into three immunological subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.

This article is protected by copyright. All rights reserved.

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Endoscopic endonasal management of esthesioneuroblastoma: A retrospective multicenter study

The aim of the present study was to illustrate the safety and utility of the endoscopic endonasal approach (EEA) for the treatment of esthesioneuroblastomas (ENB).

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Combined interventional sialendoscopy and intraductal steroid therapy for recurrent sialadenitis in Sjögren's syndrome. Results of a pilot monocentric trial

Abstract

Objectives

To evaluate the effectiveness of interventional sialendoscopy alone or combined with outpatient intraductal steroid irrigations in patients with sialoadenitis due to Sjögren's syndrome (SS).

Design

A pilot therapeutic study.

Setting

ENT Clinics, Universities of Milan and Pavia.

Study Population

We included 22 patients with SS of whom 12 underwent interventional sialendoscopy followed by intraductal steroid irrigations (group A), and 10 interventional sialendoscopy alone (group B).

Outcomes measures

The following outcome measures were considered and recorded before and after the therapeutic intervention: (i) number of episodes of glandular swelling, (ii) cumulative prevalence of patients with glandular swelling assessed by the specific domain the EULAR SS Disease Activity Index (ESSDAI); (iii) severity of pain by means of a 0-10 pain visual analogue scale (VAS), (iv) severity of xerostomia and other disease symptoms assessed by the EULAR SS Patient Reported Index (ESSPRI) and the Xerostomia Inventory questionnaire.

Results

The post-operative reduction in the mean number of episodes of glandular swelling was 87% (95% CI: 77-93) and 75% (95% CI: 47-88%) in the group A and B, respectively. The percentage of patients with glandular swelling, decreased from 41.7% to 0.0% in the group A and from 30.0% to 0.0% in the group B, respectively. Most of the patients experienced a subjective clinical improvement documented by the statistically significant reductions in the post-operative mean pain VAS group A p<0.001; group B p=0.004), Xerostomia Inventory p<0.001 and p=0.003), and ESSPRI scores (p<0.001 and p=0.008). Interventional sialendoscopy followed by outpatient intraductal steroid irrigations was more effective than interventional sialendoscopy alone, when pain VAS, Xerostomia Inventory, and ESSPRI scores before and after treatment, were analysed together using the multivariate Hotelling T² test (p=0.0173).

Conclusions

This pilot study confirms that interventional sialendoscopy with steroid duct irrigation significantly reduces the number of painful episodes of sialadenitis, and improves the subjective sensation of oral dryness and other disease symptoms in patients with SS. The study results also suggest that the improvement is greater when interventional sialendoscopy is combined with a cycle of outpatient steroid ductal irrigations. Larger controlled randomised studies are certainly needed to confirm these preliminary data.

This article is protected by copyright. All rights reserved.

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Endoscopic endonasal management of esthesioneuroblastoma: A retrospective multicenter study

Publication date: Available online 5 June 2017
Source:Auris Nasus Larynx
Author(s): Takayuki Nakagawa, Satoru Kodama, Masayoshi Kobayashi, Tetsuji Sanuki, Shuho Tanaka, Nobuhiro Hanai, Toyoyuki Hanazawa, Hiroko Monobe, Hidenori Yokoi, Motohiko Suzuki, Masaru Yamashita, Koichi Omori
ObjectiveThe aim of the present study was to illustrate the safety and utility of the endoscopic endonasal approach (EEA) for the treatment of esthesioneuroblastomas (ENB).MethodsWe retrospectively reviewed patients with a diagnosis of ENB between March 2008 and February 2016 at 10 tertiary referral hospitals in Japan, and assessed demographic data, stage of disease, surgical approach, outcomes and postoperative complications.ResultsA total of 22 patients (10 males and 12 females; mean age at presentation, 49.0 years) underwent endoscopic endonasal resection of newly diagnosed ENBs. Dulguerov staging at presentation was T1, 6 patients; T2, 9 patients; T3, 5 patients; and T4, 2 patients. As surgical procedures, unilateral resection via EEA was performed in 12 patients aiming preservation of the contralateral olfactory system, and bilateral resection via EEA was done in 10 patients. Post-operative radiotherapy was done in 20 patients. Pathological margin studies revealed margin-free resections in 21 patients (95.5%). The mean period of follow-up was 44 months. Local recurrence was observed in one T2 patient 12 months after bilateral resection. All patients were alive at the last follow-up, and 21 patients showed no evidence of disease. No post-operative complications including bleeding, CSF leak and meningitis were identified. Preservation of olfactory function was achieved in 11 patients (91.7%).ConclusionThe results of the present study indicate the safety and utility of multilayer resection using EEA for treatment of ENBs.



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Long-term outcomes of central neck dissection for cN0 papillary thyroid carcinoma

Objective.The risk-benefit ratio of central neck dissection (CND) in patients affected by papillary thyroid carcinoma (PTC) without clinical or ultrasonographic (US) evidence of neck lymph node metastasis (cN0) is currently debated. The aim of this study was to evaluate long-term outcome of CND on locoregional recurrence, distant metastasis, survival, and postoperative complications in a large series of patients with cN0-PTC.Study Design.Observational retrospective controlled study.

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The effects of fibroblast growth factor-2 delivered via a Gelfoam patch on the regeneration of myringosclerotic traumatic eardrum perforations lying close to the malleus

We evaluated the effects of fibroblast growth factor-2 (FGF-2) delivered via a Gelfoam patch on the regeneration of myringosclerotic traumatic tympanic membrane perforations (TMPs) lying close to the malleus.

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Curcumin Protects Against Acoustic Trauma in the Rat Cochlea

Publication date: Available online 5 June 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Harun Soyalıç, Fikret Gevrek, Serhat Karaman
ObjectivesIn this study we evaluated the therapeutic utility of curcumin in a rodent model of acoustic trauma using histopathology, immunohistochemical, and distortion product otoacoustic emission (DPOAEs) measurements.Methods28 Wistar albino rats were included in the study and randomly assigned to 4 treatment groups. The first group (group 1) served as the control and was exposed to acoustic trauma alone. Group 2 was the curcumin group. Group 3 was the curcumin plus acoustic trauma group. Group 4 was the saline plus acoustic trauma group. Otoacoustic emission measurements were collected at the end of the experiment and all animals were sacrificed. Cochlea were collected and prepared for TUNEL (TdT-mediated deoxyuridinetriphosphate nick end-labelling) staining assay.ResultsGroup 3 maintained baseline DPOAEs values at 3000 Hz, 4000Hz and 8000Hz on the 3rd and 5th day of the experiment. DPOAEs results were correlated with the immunohistochemical and histopathological findings in all groups. In comparison to the histopathologic control group, Group 1 exhibited a statistically significant increase in apoptotic indices in the organ of Corti, inner hair cell, and outer hair cell areas (p<0.05). Relative to the control group, rats in Group 3 showed little increase in inner hair cell and outer hair cell apoptotic indices.ConclusionsOur results support the conclusion that curcumin may protect the cochlear tissues from acoustic trauma in rats. Curcumin injection prior to or after an acoustic trauma reduces cochlear hair cell damage and may protect against hearing loss.



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Clinical role of electrocochleography in children with auditory neuropathy spectrum disorder

Publication date: Available online 5 June 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Tatyana E. Fontenot, Christopher K. Giardina, Holly F. Teagle, Lisa R. Park, Oliver F. Adunka, Craig A. Buchman, Kevin D. Brown, Douglas C. Fitzpatrick
ObjectivesTo assess electrocochleography (ECochG) to tones as an instrument to account for CI speech perception outcomes in children with auditory neuropathy spectrum disorder (ANSD).Materials & methodsChildren (<18 years) receiving CIs for ANSD (n=30) and non-ANSD (n=74) etiologies of hearing loss were evaluated with ECochG using tone bursts (0.25-4 kHz). The total response (TR) is the sum of spectral peaks of responses across frequencies. The compound action potential (CAP) and the auditory nerve neurophonic (ANN) in ECochG waveforms were used to estimate nerve activity and calculate nerve score. Performance on open-set monosyllabic word tests was the outcome measure. Standard statistical methods were applied.ResultsOn average, TR was larger in ANSD than in non-ANSD subjects. Most ANSD (73.3%) and non-ANSD (87.8%) subjects achieved open-set speech perception; TR accounted for 33% and 20% of variability in the outcomes, respectively. In the ANSD group, the PTA accounted for 69.3% of the variability, but there was no relationship with outcomes in the non-ANSD group.In both populations, nerve score was sensitive in identifying subjects at risk for not acquiring open-set speech perception, while the CAP and the ANN were more specific.ConclusionIn both subject groups, the TRs correlated with outcomes but these measures were notably larger in the ANSD group. There was also strong correlation between PTA and speech perception outcome in ANSD group. In both subject populations, weaker evidence of neural activity was related to failure to achieve open-set speech perception.



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Factors influencing hearing outcomes in pediatric patients undergoing ossicular chain reconstruction

Publication date: August 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 99
Author(s): Nandini Govil, Thomas M. Kaffenberger, Amber D. Shaffer, David H. Chi
ObjectiveOssicular chain disruption in children leads to conductive hearing loss. Few studies have focused on factors influencing successful results in pediatric ossicular chain reconstruction (OCR). We aim to determine whether demographic or surgical factors affect hearing outcomes in pediatric OCR.MethodsWe conducted a retrospective chart review of 120 patients undergoing OCR at our institution, a tertiary care hospital, between 2003 and 2014, with median length of follow-up of 2.2 years (range 0.1–9.3 years). Pediatric patients (<18 years old at time of surgical procedure) who had current procedural terminology (CPT) codes of OCR, and available pre- and post-operative audiograms were included in the study. Demographic information, surgical details, and pre- and post-operative pure-tone averages (PTA), speech reception thresholds (SRT), and air-bone gaps (ABG) were recorded from clinic notes, audiograms and operative reports. Differences between PTA, SRT and ABG pre- and post-operatively, as well as demographic and surgical factors, were evaluated using Wilcoxon rank-sum tests. Factors influencing revision were evaluated using Log-rank tests.ResultsA total of 120 patients (123 ears) were included. 35.8% of cases were revised, most commonly due to displaced prostheses. 28.5% of surgeries resulted in normal hearing (PTA ≤25 dB) post-operatively. Post-operative SRT and ABG were significantly better in patients with partial ossicular replacement prosthesis (PORP) compared with those with total ossicular replacement prosthesis (TORP) (p = 0.016, 0.027). Titanium prostheses resulted in better post-operative PTA and larger changes in PTA compared with all other materials (p = 0.034, p = 0.038).ConclusionsIn our experience, children with titanium prostheses had better hearing outcomes than those with other materials, and children with PORP had better hearing outcomes than those with TORP.



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Evaluation of speech in noise abilities in school children

Publication date: August 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 99
Author(s): Nádia Giulian de Carvalho, Carolina Verônica Lino Novelli, Maria Francisca Colella-Santos
This study aimed to analyze the perception of speech in noise in children with poor school performance and to compare them with children with good school performance, considering gender, age and ear side as variables.The intelligibility of speech was evaluated in school children utilizing the Brazilian Hearing in Noise Test (HINT) in the situations of quiet (Q), Left ear competitive noise (NL), Right Ear Competitive Noise (NR), as well as the global average of other hearing situations, denominated Noise Composite (NC). Ninety seven school children between the ages of 8 and 10 were recruited in five schools of São Paulo-Brazil; the control group (CG) consisted of 54 students (23 male/ 31 female) without language and/or speech difficulties and good school performance, and the study group (SG) consisted of 43 students (28 male/ 15 female) identified by their teachers as having poor school performance.The variables gender and ear side did not interfere in speech perception. The age variable influenced only the CG. The SG had worse performance than the CG in the Q, NF and NC conditions. NF was the most difficult for both groups.The perception of speech in noise was the worst in children with poor school performance. The variables gender and ear side did not interfere in speech perception. The age group variable influenced the performance of the group of children with good school performance, demonstrating a better ability in older children. The speech perception in noise ability is more difficult for both groups when the noise affects both ears.



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Comparison between selective and routine intensive care unit admission post-supraglottoplasty

Publication date: Available online 5 June 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Timothy Cooper, Bree Harris, Ahmed Mourad, Daniel Garros, Hamdy El-Hakim
ObjectiveTo compare major post-operative respiratory complications, post-operative disposition and duration of hospital admission before and after adopting a selective intensive care unit (ICU) admission care plan following supraglottoplasty (SGP).MethodsRetrospective case series set in a tertiary pediatric referral center. Eligible patients undergoing SGP between October 2003 and July 2015 were identified through a prospectively kept surgical database. Historical cohorts with routine admission to ICU and selective admission to ICU were identified based on a shift in surgeon practice. The cohorts were compared with respect to demographics, presenting features, endoscopic findings, baseline sleep and swallowing study results, major respiratory complications (including repeat or unplanned ICU admission or intubation) and length of post-operative hospital admission.Results141 eligible patients were identified with 35 children in the routine ICU admission cohort and 106 in the selective ICU admission cohort. There were no significant differences between cohorts regarding major respiratory complications with only one patient in the selective ICU admission cohort requiring an unplanned admission to ICU (P=1.00, Fisher's exact test). This gives a number needed to harm of 78 step-down unit admissions for 1 unplanned ICU admission. The rate of ICU admission was reduced from 71% to 26% with adoption of a selective ICU admission care plan (p<0.01, χ²). Mean duration of post-operative hospitalization was reduced from 5.1 ± 3.5 days to 1.9 ± 2.3 days (P<0.01, Student's t-test).ConclusionsSelective post-operative ICU admission following SGP significantly reduces ICU utilization and may reduce length of hospital stay without compromising safety and care. This has significant cost benefit implications.



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Clinical and bacteriological differences of deep neck infection in pediatric and adult patients: review of 123 cases

Publication date: Available online 5 June 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Yuichi Shimizu, Hiroshi Hidaka, Daiki Ozawa, Risako Kakuta, Kazuhiro Nomura, Hisakazu Yano, Ken-ichi Watanabe, Yukio Katori
ObjectivesDeep neck infections (DNIs) can lead to life-threatening disease. However, the detailed pathophysiology remains unclear due to its rarity and only a few reports have directly compared DNIs in children and adults. This study aimed to reveal the clinical differences between DNIs in children and adults.MethodsWe retrospectively reviewed 123 patients who suffered from DNIs at Tohoku University Hospital from August 2005 to July 2015. We extracted data on patient sex, age, antecedent illness, extension of infections, operative procedures, and bacteriology results. The patients were categorized into pediatric (≤18 years) and adult (>18 years) groups. Fisher's exact test was performed to determine significant differences between the two groups.ResultsFifteen children (6 males and 9 females) and 108 adults (71 males and 37 females) were identified. The most common antecedent illness in pediatric patients was lymphadenitis, which was the least common in adult patients (73% vs 7%, p < 0.0001). The incidence of DNIs extending below the hyoid bone was significantly lower in pediatric patients than in adult patients (20% vs 53%, p < 0.05). Regarding bacterial culture analysis, Staphylococcus species was the most common pathogen in children (60%), whereas only 9% of adults were positive for Staphylococcus (p < 0.001). Streptococcus species were significantly less common in children than in adults (27% vs 56%, p = 0.05). Anaerobes were also significantly less common in children than in adults (13% vs 45%, p < 0.01). Concerning surgical intervention, 53% of pediatric patients underwent external incision compared with 70% of adults. Specifically, tracheostomy was significantly less frequently performed in children than in adults (7% vs 54%, p < 0.01).ConclusionDNIs in children feature different characteristics from those in adults regarding severity, antecedent illness, bacteriology, and clinical management.



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CXCR3.1 and CXCR3.2 Differentially Contribute to Macrophage Polarization in Teleost Fish [IMMUNOGENETICS]

The study of multiple copies of chemokine receptor genes in various teleosts has long appealed to investigators seeking to understand the evolution of the immune system. The CXCR CXCR3 gene has two isoforms, CXCR3.1 and CXCR3.2, which are both expressed in macrophages. The distinct roles of teleost CXCR3s have not been identified previously. In this article, we found that CXCR3.1 and CXCR3.2 differentially contributed to macrophage polarization in the teleosts: ayu (Plecoglossus altivelis), grass carp (Ctenopharyngodon idella), and spotted green pufferfish (Tetraodon nigroviridis). In ayu macrophages, the P. altivelis CXCR3.1 (PaCXCR3.1) gene was constitutively expressed, whereas the P. altivelis CXCR3.2 (PaCXCR3.2) gene was induced postinfection with Escherichia coli. Upon E. coli infection, PaCXCR3.1⁺ and PaCXCR3.2⁺ macrophages showed an M1 and an M2 phenotype, respectively. CXCL9–11-like proteins mediated M1 and M2 polarization by interacting with the PaCXCR3.1 and PaCXCR3.2 proteins on macrophages, respectively. The transcription factors P. altivelis STAT1 and P. altivelis STAT3 were activated in PaCXCR3.1⁺ and PaCXCR3.2⁺ macrophages, respectively. Furthermore, the prognosis of septic ayu adoptively transferred with PaCXCR3.2⁺ macrophages was improved. Our data reveal a previously unknown mechanism for macrophage polarization, suggesting that redundant genes may regulate crucial functions in the teleost immune system.

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Harmed by Sunscreen? What Parents Need to Know

Photoallergic reactions to suncreens can come out of the blue. A dermatologist at the Cleveland Clinic offers advice on how to avoid them.
WebMD Health News

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Identifying Preclinical Psoriatic Arthritis in Hope of Prevention

Dr Kevin Deane explains how this new research may provide a window of opportunity for preventing psoriatic arthritis.
Medscape Rheumatology

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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects [INNATE IMMUNITY AND INFLAMMATION]

During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH_i), we propose a direct mechanistic link between complement activation and neutrophil pH_i. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pH_i by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pH_i of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pH_i. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pH_i balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

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RIG-I-like Receptor Triggering by Dengue Virus Drives Dendritic Cell Immune Activation and TH1 Differentiation [INFECTIOUS DISEASE AND HOST RESPONSE]

Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses. DENV infection induced DC maturation and secretion of IL-1β, IL-6, and TNF. Inhibition of DENV RNA replication abrogated these responses. Notably, silencing of RNA sensors RIG-I or MDA5 abrogated DC maturation, as well as cytokine responses by DENV-infected DCs. DC maturation was induced by type I IFN responses because inhibition of IFN-α/β receptor signaling abrogated DENV-induced DC maturation. Moreover, DENV infection of DCs resulted in CCL2, CCL3, and CCL4 expression, which was abrogated after RIG-I and MDA5 silencing. DCs play an essential role in T_H cell differentiation, and we show that RIG-I and MDA5 triggering by DENV leads to T_H1 polarization, which is characterized by high levels of IFN-. Notably, cytokines IL-6, TNF, and IFN- and chemokines CCL2, CCL3, and CCL4 have been associated with disease severity, endothelial dysfunction, and vasodilation. Therefore, we identified RIG-I and MDA5 as critical players in innate and adaptive immune responses against DENV, and targeting these receptors has the potential to decrease hemorrhagic fever in patients.

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New Insights into the Role of IL-1{beta} in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis [BRIEF REVIEWS]

Multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic T_H cells that elicit demyelination and axonal damage. How T_H cells acquire pathogenicity and communicate with myeloid cells and cells of the CNS remain unclear. IL-1β is recognized to play an important role in experimental autoimmune encephalomyelitis (EAE) and perhaps MS. Clinical EAE is significantly attenuated in IL-1R–deficient and IL-1β–deficient mice, and IL-1β is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. In this article, we focus on new reports that elucidate the cellular sources of IL-1β and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1β during EAE, with this cytokine inducing response in both hematopoietic and nonhematopoietic cells. These findings from the EAE model should inspire efforts toward investigating the therapeutic potential of IL-1 blockade in MS.

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A Schistosoma japonicum Infection Promotes the Expansion of Myeloid-Derived Suppressor Cells by Activating the JAK/STAT3 Pathway [INFECTIOUS DISEASE AND HOST RESPONSE]

Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, play an important part in suppression of host immune responses during many pathologic conditions, including cancer and infectious diseases. Thus, understanding the functional diversity of these cells as well as the underlying mechanisms is crucial for the development of disease control strategies. The role of MDSCs during Schistosoma japonicum infection, however, is not clear, and there is a lack of systematic study so far. In this study, we provide strong evidence that the soluble egg Ag (SEA) and schistosome worm Ag (SWA) of S. japonicum enhance the accumulation of MDSCs. Ag-induced MDSCs have more potent suppressive effects on T cell responses than do control MDSCs in both in vivo S. japonicum infection and in vitro SEA- and SWA-treated mouse bone marrow cells experiments. Interestingly, the enhanced suppressive activity of MDSCs by Ag administration was coupled with a dramatic induction of the NADPH oxidase subunits gp91^phox and p47^phox and was dependent on the production of reactive oxygen species. Moreover, mechanistic studies revealed that the Ag effects are mediated by JAK/STAT3 signaling. Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the Ag effects on the MDSCs. In summary, this study sheds new light on the immune modulatory role of SEA and SWA and demonstrates that the expansion of MDSCs may be an important element of a cellular network regulating immune responses during S. japonicum infection.

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Cutting Edge: Differential Fine-Tuning of IL-2- and IL-15-Dependent Functions by Targeting Their Common IL-2/15R{beta}/{gamma}c Receptor [CUTTING EDGE]

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15– and IL-2–dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2–dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.

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A Time- and Compartment-Specific Activation of Lung Macrophages in Hypoxic Pulmonary Hypertension [INNATE IMMUNITY AND INFLAMMATION]

Studies in various animal models suggest an important role for pulmonary macrophages in the pathogenesis of pulmonary hypertension (PH). Yet, the molecular mechanisms characterizing the functional macrophage phenotype relative to time and pulmonary localization and compartmentalization remain largely unknown. In this study, we used a hypoxic murine model of PH in combination with FACS to quantify and isolate lung macrophages from two compartments over time and characterize their programing via RNA sequencing approaches. In response to hypoxia, we found an early increase in macrophage number that was restricted to the interstitial/perivascular compartment, without recruitment of macrophages to the alveolar compartment or changes in the number of resident alveolar macrophages. Principal component analysis demonstrated significant differences in overall gene expression between alveolar and interstitial macrophages (IMs) at baseline and after 4 and 14 d hypoxic exposure. Alveolar macrophages at both day 4 and 14 and IMs at day 4 shared a conserved hypoxia program characterized by mitochondrial dysfunction, proinflammatory gene activation, and mTORC1 signaling, whereas IMs at day 14 demonstrated a unique anti-inflammatory/proreparative programming state. We conclude that the pathogenesis of vascular remodeling in hypoxic PH involves an early compartment-independent activation of lung macrophages toward a conserved hypoxia program, with the development of compartment-specific programs later in the course of the disease. Thus, harnessing time- and compartment-specific differences in lung macrophage polarization needs to be considered in the therapeutic targeting of macrophages in hypoxic PH and potentially other inflammatory lung diseases.

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Cutting Edge: ERK1 Mediates the Autocrine Positive Feedback Loop of TGF-{beta} and Furin in Glioma-Initiating Cells [CUTTING EDGE]

Glioblastoma is the most common and aggressive intrinsic brain tumor in adults. Self-renewing, highly tumorigenic glioma-initiating cells (GIC) have been linked to glioma invasive properties, immunomodulation, and increased angiogenesis, leading to resistance to therapy. TGF-β signaling has been associated with the tumorigenic activity of GIC. TGF-β is synthesized as a precursor molecule and proteolytically processed to the mature form by members of the family of the proprotein convertases subtilisin/kexin. In this study we report that furin is unique among the proprotein convertases subtilisin/kexin in being highly expressed in human GIC. Furin cleaves and promotes activation of pro–TGF-β1 and pro–TGF-β2, and TGF-β2 in turn increases furin levels. Notably, TGF-β2 controls furin activity in an ALK-5–dependent manner involving the ERK/MAPK pathway. We thus uncover a role of ERK1 in the regulation of furin activity by supporting a self-sustaining loop for high TGF-β activity in GIC.

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In This Issue [IN THIS ISSUE]

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Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants [CUTTING EDGE]

Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. RTEs are functionally distinct from their more mature but still naive T cell counterparts, because they exhibit dampened proliferation and reduced cytokine production upon activation. In this article, we show that, compared with more mature but still naive T cells, RTEs are impaired in their ability to perform aerobic glycolysis following activation. Impaired metabolism underlies the reduced IFN- production observed in activated RTEs. This failure to undergo Ag-induced aerobic glycolysis is caused by reduced mTORC1 activity and diminished Myc induction in RTEs. Critically, exogenous IL-2 restores Myc expression in RTEs, driving aerobic glycolysis and IFN- production to the level of mature T cells. These results reveal a previously unknown metabolic component to postthymic T cell maturation.

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B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.

http://ift.tt/2sxaDOk

Alternative Start Sites Downstream of Non-Sense Mutations Drive Antigen Presentation and Tolerance Induction to C-Terminal Epitopes [ANTIGEN RECOGNITION AND RESPONSES]

CTL responses to the transgene product remain an active area of concern for the gene therapy field. A patient's underlying genetic mutation may influence the qualitative nature of these potentially destructive T cell responses. Individuals with a mutation that introduces a premature termination codon (PTC) that prevents synthesis of the full-length peptide are considered more likely to mount a transgene-specific T cell response because of a lack of immune tolerance to C-terminal epitopes as a consequence of absent endogenous Ag presentation. In this article, we demonstrate that a human ornithine transcarbamylase gene containing various PTC-inducing non-sense mutations is able to generate and present epitopes downstream of the termination codon. Generation of these epitopes occurs primarily from alternative translation start sites downstream of the stop codon. Furthermore, we show that expression of these genes from adeno-associated virus vectors in C57BL/6 mice is able to induce peripheral tolerance to epitopes downstream of the PTC. These results suggest that, despite the lack of full-length endogenous protein, patients with PTC-inducing non-sense mutations may still present T cell epitopes downstream of the premature termination site that may render the subject tolerant to wild-type transgene products.

http://ift.tt/2rXKkDY

Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response [INFECTIOUS DISEASE AND HOST RESPONSE]

Sepsis is characterized by a disproportionate host response to infection that often culminates in multiple organ failure. Current concepts invoke a deregulated immune reaction involving features of hyperinflammation, as well as protracted immune suppression. However, owing to the scarcity of human data, the precise origin of a long-term suppression of adaptive immunity remains doubtful. We report on an explorative clinical study of chronic critical illness (CCI) patients aimed at assessing the long-term consequences of sepsis on T cell function. Blood was drawn from 12 male CCI patients (median age 67 y, range 48–79 y) receiving continuous mechanical ventilation and renal replacement therapy in a long-term care hospital who had been treated in an external acute care hospital for severe sepsis. T cells were purified and subjected to flow cytometric immune-phenotyping and functional assays. We found that T cells from CCI patients featured higher basal levels of activation and stronger expression of the inhibitory surface receptor programmed cell death 1 compared with controls. However, T cells from CCI patients exhibited no suppressed TCR response at the level of proximal TCR signaling (activation/phosphorylation of PLC, Erk, Akt, LAT), activation marker upregulation (CD69, CD25, CD154, NUR77), IL-2 production, or clonal expansion. Rather, our data illustrate an augmented response in T cells from CCI patients in response to TCR/coreceptor (CD3/CD28) challenge. Thus, the present findings reveal that CCI sepsis patients feature signs of immune suppression but that their T cells exhibit a primed, rather than a suppressed, phenotype in their TCR response, arguing against a generalized T cell paralysis as a major cause of protracted immune suppression from sepsis.

http://ift.tt/2sx5plF

Disease-Specific Effects of Matrix and Growth Factors on Adhesion and Migration of Rheumatoid Synovial Fibroblasts [AUTOIMMUNITY]

In rheumatoid arthritis (RA), cartilage and bone matrix are degraded, and extracellular matrix (ECM) proteins, acting as cellular activators, are liberated. Similar to ECM proteins, matrix-bound chemokines, cytokines, and growth factors (GFs) influence functional properties of key cells in RA, especially synovial fibroblasts. The role of these molecules on attachment, migration, and proinflammatory and prodestructive activation of RASFs was analyzed. Adhesion/migration of RASFs were examined under GF-enriched (GF⁺) or –reduced (GF^–) conditions with or without addition of matrix-associated GFs, TGF-β, and platelet-derived GF to GF^– or culture supernatants. Fibroblast adhesion and alterations in proinflammatory/prodestructive properties (e.g., IL-6/matrix metalloproteinase 3-release) in response to matrix-associated molecules were compared. Effects of GF⁺, GF^–, and other ECM components on human RASF-mediated cartilage invasion were examined in the SCID mouse model. RASF adhesion under GF^– conditions was significantly lower compared with GF⁺ conditions (6.8- versus 8.3-fold). This effect was specific for RA because control cells showed opposite effects (e.g., osteoarthritis synovial fibroblasts [SF]; GF^– versus GF⁺: 10.7- versus 8-fold). Addition of TGF-β to GF^– increased RASF attachment (12.7-fold) compared with other matrices and components. RASF adhesion to GF⁺ matrix resulted in the strongest IL-6 and matrix metalloproteinase-3 release, and was even more pronounced compared with supplementation of single GFs. In vivo, GF^– matrix decreased RASF-mediated cartilage invasion compared with GF⁺ matrix. ECM components and especially GFs when bound within ECM actively enhance RASF attraction and cartilage adhesion. This observation was specific for RASFs as a reverse behavior was observed for controls.

http://ift.tt/2swXDrQ

Endothelial CD2AP Binds the Receptor ICAM-1 To Control Mechanosignaling, Leukocyte Adhesion, and the Route of Leukocyte Diapedesis In Vitro [INNATE IMMUNITY AND INFLAMMATION]

Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to the tissue across the endothelial cell monolayer that lines blood vessels. Leukocyte adhesion, crawling, and transmigration are regulated by clustering of the endothelial mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins are known to promote ICAM-1 function, the molecular mechanisms that limit ICAM-1–mediated adhesion to prevent excessive leukocyte transmigration remain unknown. We identify the endothelial actin-binding protein CD2-associated protein (CD2AP) as a novel interaction partner of ICAM-1. Loss of CD2AP stimulates the dynamics of ICAM-1 clustering, which facilitates the formation of ICAM-1 complexes on the endothelial cell surface. Consequently, neutrophil adhesion is increased, but crawling is decreased. In turn, this promotes the neutrophil preference for the transcellular over the paracellular transmigration route. Mechanistically, CD2AP is required for mechanosensitive ICAM-1 downstream signaling toward activation of the PI3K, and recruitment of F-actin and of the actin-branching protein cortactin. Moreover, CD2AP is necessary for ICAM-1–induced Rac1 recruitment and activation. Mechanical force applied on ICAM-1 impairs CD2AP binding to ICAM-1, suggesting that a tension-induced negative feedback loop promotes ICAM-1–mediated neutrophil crawling and paracellular transmigration. To our knowledge, these data show for the first time that the mechanoreceptor ICAM-1 is negatively regulated by an actin-binding adaptor protein, i.e., CD2AP, to allow a balanced and spatiotemporal control of its adhesive function. CD2AP is important in kidney dysfunction that is accompanied by inflammation. Our findings provide a mechanistic basis for the role of CD2AP in inflamed vessels, identifying this adaptor protein as a potential therapeutic target.

http://ift.tt/2sxbTkE

Fc{gamma}RIIIa Signaling Modulates Endosomal TLR Responses in Human CD4+ T Cells [AUTOIMMUNITY]

Recognition of Ab-opsonized pathogens by immune cells triggers both TLR and Fc receptor signaling. Fc receptors endocytose modified nucleic acids bound to Abs and deliver them to endosomes, where they are recognized by nucleic acid–sensing TLRs (NA-TLRs). We show that in CD4⁺ T cells, NA-TLRs, TLR3, TLR8, and TLR9 are upregulated by FcRIIIa-pSyk cosignaling and localize with FcRIIIa on the cell surface. TLR9 accumulates on the cell surface, where it recognizes CpG oligonucleotide 2006. Subcellular location of NA-TLRs is a key determinant in discriminating self versus viral nucleic acid. Hydroxychloroquine used for treating systemic lupus erythematosus and a Syk inhibitor blocked NA-TLR localization with FcRIIIa. Engaging TLR9 with CpG oligonucleotide contributes to the development of IL17A⁺ and IL-21⁺ populations. RNA-sequencing analysis showed upregulation of proinflammatory cytokines, NF-B signaling, and heat shock protein pathway RNA transcripts. These data suggest a role for FcRIIIa-pSyk cosignaling in modulating NA-TLR responses in human CD4⁺ T cells by affecting the amounts and cellular distribution. These events are important for understanding of autoimmune pathology.

http://ift.tt/2rXp414

Transcriptional Heterogeneity of Mast Cells and Basophils upon Activation [SYSTEMS IMMUNOLOGY]

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow–derived mast cells and bone marrow–derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow–derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow–derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33–activated transcriptome was enriched in genes commonly altered by NF-B in response to TNF, by IL-6 via STAT3, and in response to IFN-. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33–stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.

http://ift.tt/2sx4OjX

Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System [AUTOIMMUNITY]

Multiple sclerosis (MS) is a disease that is characterized by immune-mediated destruction of CNS myelin. Current MS therapies aim to block peripheral immune cells from entering the CNS. Although these treatments limit new inflammatory activity in the CNS, no treatment effectively prevents long-term disease progression and disability accumulation in MS patients. One explanation for this paradox is that current therapies are ineffective at targeting immune responses already present in the CNS. To this end, we sought to understand the metabolic properties of T cells that mediate ongoing inflammation in the demyelinating CNS. Using experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a well-studied model of MS, we showed that the CD4⁺ and CD8⁺ T cells that invade the EAE CNS are highly glycolytic. Elevated glycolytic rates in T cells isolated from the EAE CNS correlate with upregulated expression of glycolytic machinery and is essential for inflammatory responses to myelin. Surprisingly, we found that an inhibitor of GAPDH, 3-bromopyruvic acid (3-BrPa), blocks IFN-, but not IL-17A, production in immune cells isolated from the EAE CNS. Indeed, in vitro studies confirmed that the production of IFN- by differentiated Th1 cells is more sensitive to 3-BrPa than is the production of IL-17A by Th17 cells. Finally, in transfer models of EAE, 3-BrPa robustly attenuates the encephalitogenic potential of EAE-driving immune cells. To our knowledge, these data are among the first to demonstrate the metabolic properties of T cells in the demyelinating CNS in vivo.

http://ift.tt/2sx2mK4

CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses [IMMUNOTHERAPY AND VACCINES]

DNA vaccines are attractive immunogens for priming humoral and cellular immune responses to the encoded Ag. However, their ability to induce Ag-specific CD8⁺ T cell responses requires improvement. Among the strategies for improving DNA vaccine immunogenicity are booster vaccinations, alternate vaccine formulations, electroporation, and genetic adjuvants, but few, such as extracellular vesicles (EVs), target natural Ag delivery systems. By focusing on CD63, a tetraspanin protein expressed on various cellular membranes, including EVs, we examined whether a DNA vaccine encoding an Ag fused to CD63 delivered into EVs would improve vaccine immunogenicity. In vitro transfection with plasmid DNA encoding an OVA Ag fused to CD63 (pCD63-OVA) produced OVA-carrying EVs. Immunizations with the purified OVA-carrying EVs primed naive mice to induce OVA-specific CD4⁺ and CD8⁺ T cells, whereas immunization with EVs purified from cells transfected with control plasmids encoding OVA protein alone or a calnexin-OVA fusion protein delivered into the endoplasmic reticulum failed to do so. Vaccinating mice with pCD63-OVA induced potent Ag-specific T cell responses, particularly those from CD8⁺ T cells. CD63 delivery into EVs led to better CD8⁺ T cell responses than calnexin delivery into the endoplasmic reticulum. When we used a mouse tumor implantation model to evaluate pCD63-OVA as a therapeutic vaccine, the EV-delivered DNA vaccination significantly inhibited tumor growth compared with the control DNA vaccinations. These results indicate that EV Ag delivery via DNA vaccination offers a new strategy for eliciting strong CD8⁺ T cell responses to the encoded Ag, making it a potentially useful cancer vaccine.

http://ift.tt/2rXvmxU

Early Emergence of CD19-Negative Human Antibody-Secreting Cells at the Plasmablast to Plasma Cell Transition [CLINICAL AND HUMAN IMMUNOLOGY]

Long-lived human plasma cells (PCs) play central roles in immunity and autoimmunity and are enriched among the subpopulation of CD19^neg human PCs. However, whether human CD19^neg PCs are necessarily aged cells that have gradually lost CD19 expression is not known. Assessing peripheral blood samples at steady-state and during the acute response to influenza vaccination in healthy donors, we identify the presence of phenotypic CD19^neg plasmablasts, the proliferative precursor state to mature PCs, and demonstrate by ELISPOT that these are Ab-secreting cells (ASCs). During the acute response to influenza vaccination, CD19^pos, CD19^low, and CD19^neg ASCs secrete vaccine-specific Abs and show linked IGHV repertoires. To address precursor/product relationships, we use in vitro models that mimic T-dependent and T-independent differentiation, finding that the CD19^neg state can be established at the plasmablast to PC transition, that CD19^neg PCs increase as a percentage of surviving PCs in vitro, and that CD19^neg and CD19^pos PCs can be maintained independently. These data provide proof-of-principle for the view that newly generated ASCs can acquire a mature PC phenotype that is accompanied by loss of CD19 expression at an early stage of differentiation and that aging is not an obligate requirement for a CD19^neg state to be established.

http://ift.tt/2rXCA4F

Recruitment of Human C1 Esterase Inhibitor Controls Complement Activation on Blood Stage Plasmodium falciparum Merozoites [INFECTIOUS DISEASE AND HOST RESPONSE]

The complement system is a front-line defense system that opsonizes and lyses invading pathogens. To survive, microbes exposed to serum must evade the complement response. To achieve this, many pathogens recruit soluble human complement regulators to their surfaces and hijack their regulatory function for protection from complement activation. C1 esterase inhibitor (C1-INH) is a soluble regulator of complement activation that negatively regulates the classical and lectin pathways of complement to protect human tissue from aberrant activation. In this article, we show that Plasmodium falciparum merozoites, the invasive form of blood stage malaria parasites, actively recruit C1-INH to their surfaces when exposed to human serum. We identified PfMSP3.1, a member of the merozoite surface protein 3 family of merozoite surface proteins, as the direct interaction partner. When bound to the merozoite surface, C1-INH retains its ability to complex with and inhibit C1s, MASP1, and MASP2, the activating proteases of the complement cascade. P. falciparum merozoites that lack PfMSP3.1 showed a marked reduction in C1-INH recruitment and increased C3b deposition on their surfaces. However, these PfMSP3.1 merozoites exhibit enhanced invasion of RBCs in the presence of active complement. This study characterizes an immune-evasion strategy used by malaria parasites and highlights the complex relationship between merozoites and the complement system.

http://ift.tt/2rXvltQ

Low skeletal muscle mass is a predictive factor for chemotherapy dose-limiting toxicity in patients with locally advanced head and neck cancer

Publication date: August 2017
Source:Oral Oncology, Volume 71
Author(s): Anne W. Wendrich, Justin E. Swartz, Sandra I. Bril, Inge Wegner, Alexander de Graeff, Ernst J. Smid, Remco de Bree, Ajit J. Pothen
ObjectivesLow skeletal muscle mass (SMM) or sarcopenia is emerging as an adverse prognostic factor for chemotherapy dose-limiting toxicity (CLDT) and survival in cancer patients. Our aim was to determine the impact of low SMM on CDLT in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with primary radiochemotherapy (RCT).Patients and methodsConsecutive patients diagnosed with LA-HNSCC and treated with primary RCT between 2007 and 2011 in our center were included. Clinical variables were retrospectively retrieved and SMM was measured at the level of the third cervical vertebra using pre-treatment head and neck CT-scans. After determining a cut-off value for low SMM, multivariate analysis was performed to identify prognostic factors for CDLT.ResultsOf 112 patients included, 30.4% experienced CDLT. The optimal cut-off value for low SMM as a predictor of CDLT was ≤43.2cm²/m². Using this cut-off, 54.5% patients had low SMM. Patients with low SMM experienced CDLT more frequently than patients with normal SMM (44.3% vs. 13.7%, p<0.001) and received a higher dose of chemotherapy/kg lean body mass (estimated from SMM, p=0.044). At multivariate analysis, low SMM was independently inversely associated with CDLT (OR 0.93, 95%CI: 0.88–0.98). Patients experiencing CDLT had a lower overall survival than patients who did not (mean 36.6vs. 54.2months, p=0.038).ConclusionLow SMM is an independent risk factor for CDLT in LA-HNSCC patients treated with primary RCT. Pre-therapeutic estimation of SMM using routine CT-scans of the head and neck region may identify patients at risk of CDLT.



http://ift.tt/2rMe5a3

Characterization, treatment and outcomes of salivary ductal carcinoma using the National Cancer Database

Publication date: August 2017
Source:Oral Oncology, Volume 71
Author(s): Virginia Osborn, Babak Givi, Anna Lee, Niki Sheth, Dylan Roden, David Schwartz, David Schreiber
ObjectivesTo analyze clinical, treatment and outcome data for patients with salivary ductal carcinoma in a large population-based sample.Materials and methodsThe National Cancer Database was queried to identify patients diagnosed with salivary ductal carcinoma between 2004 and 2013. Kaplan Meier and Cox regression analysis were used to assess overall survival (OS) and identify impact of specific variables on OS.ResultsA total of 495 patients were identified. The most common site of tumor origin was the parotid (80%). 130 patients (26.3%) presented with early stage (I-II) disease, 257 patients (51.9%) with locoregionally advanced pathologic stage (III-IVB) disease and 41 patients (8.3%) with metastatic disease. The 5year OS for these patients was 79.5%, 40.4% and 0% respectively. At presentation, 46.6% had node positive disease. Surgery was performed in 100% of patients with early stage disease, 98.4% with advanced disease and 90.2% with metastatic disease. Radiation therapy, generally postoperative radiation, was given to 58.5% of patients with stage I-II disease, 71.6% with stage III-IVB disease and 53.7% with metastatic disease. Chemotherapy was utilized in 5.4% of patients with stage I-II disease, 35% with stage III-IVB and 70.7% with metastatic disease. On multivariable analysis, there were no significant differences in OS based on receipt of adjuvant radiotherapy, chemotherapy, or chemoradiotherapy.ConclusionSalivary ductal carcinoma represents an uncommon and aggressive subset of salivary tumors for which current adjuvant treatments do not have a detectable impact on overall survival.



http://ift.tt/2sJWvAK

CBT-101 Study for Advanced Solid Tumors and c-Met Dysregulation

Conditions:   Solid Tumor;   Advanced Cancer;   Renal Cancer;   Gastric Cancer;   Gastroesophageal Junction Adenocarcinoma
Intervention:   Drug: CBT-101 Oral Capsules
Sponsor:   CBT Pharmaceuticals, Inc.
Not yet recruiting - verified June 2017

http://ift.tt/2qXvvw4

Expiratory Muscle Strength Training in Improving Bulbar Function and Quality of Life in Patients With Head and Neck Cancer

Condition:   Malignant Head and Neck Neoplasm
Interventions:   Other: Best Practice;   Other: Educational Intervention;   Other: Exercise Intervention;   Other: Expiratory Muscle Strength Training;   Other: Quality-of-Life Assessment;   Other: Questionnaire Administration
Sponsor:   Ohio State University Comprehensive Cancer Center
Recruiting - verified May 2017

http://ift.tt/2rsD29U

Evaluation of Pathway Modulation by Raf, MEK, & Kinase Inhibitors

Conditions:   Metastatic Cancer;   Melanoma;   Colon Cancer;   Differentiated Thyroid Cancer;   Hepatocellular Carcinoma;   Renal Cell Carcinoma;   Metastatic Melanoma;   HCC;   Metastatic Colon Cancer
Intervention:   Other: Solar Simulator
Sponsor:   University of Arizona
Recruiting - verified June 2017

http://ift.tt/2qXBFMV

Ultrasound Elastography in Imaging Patients With Thyroid Nodules

Conditions:   Malignant Thyroid Gland Neoplasm;   Thyroid Gland Nodule
Intervention:   Procedure: Shear Wave Elastography
Sponsor:   Stanford University
Not yet recruiting - verified May 2017

http://ift.tt/2rsNON5

The Effects on Major Organ Complications on Esophagectomy of New Anesthetic ERAS Strategy: a Prospective Investigation

Conditions:   Esophageal Cancer;   Complication, Postoperative;   Anesthesia
Intervention:   Procedure: Fluid therapy optimization
Sponsor:   National Taiwan University Hospital
Not yet recruiting - verified May 2017

http://ift.tt/2rsUURQ

Coconut Oil: Managing Radiation-Induced Xerostomia

Condition:   Xerostomia
Intervention:   Other: Coconut Oil
Sponsor:   Ottawa Hospital Research Institute
Not yet recruiting - verified June 2017

http://ift.tt/2qXuN24

Concentration-dependent effects of PM 2.5 mass on expressions of adhesion molecules and inflammatory cytokines in nasal mucosa of rats with allergic rhinitis

Abstract

Allergic rhinitis (AR) represents a clinical health issue affecting approximately 500 million people worldwide. This study aimed to explore the effects of airborne fine particulate matter (PM_2.5) on the nasal mucosa of rats with AR. Seventy-five healthy male SD rats were included and randomly divided into the normal, model, low-concentration, middle-concentration, and high-concentration groups (15 rats each group). AR rat models were established using sensitized mixture and were stimulated using different concentrations of PM_2.5. Sneeze and nose-scratching events were observed. Automatic hematology analyzer was utilized to count white blood cells (WBCs). The serum IgE, ICAM-1, and VCAM-1 expressions, eosinophil (EOS) infiltration, and IFN-γ, IL-4, IL-5, IL-33, and TSLP expressions were detected by ELISA, HE staining, and qRT-PCR. Greater numbers of WBCs, increased IgE level, elevated levels of ICAM-1, VCAM-1, EOS, IFN-γ, IL-4, IL-5, IL-33, and TSLP in the model, low-concentration, middle-concentration, and high-concentration groups than the normal group. The same trend also exhibited in rats of the middle-concentration and high-concentration groups than that of the model and low-concentration groups. Comparisons between normal rats and AR rats indicated that AR rats exhibit remarkably higher cytokine expression levels of IFN-γ, IL-4, IL-5, TSLP, and IL-33. The study revealed that as stimulation is triggered by PM_2.5, AR rats result in increased levels of adhesion molecules and inflammatory cytokine expressions in a concentration-dependent manner. Analyses of PM_2.5 as well as, its effects on AR are crucial in the continued drive for both prevention and management of the disease.

http://ift.tt/2rWAIcE

Idiopathic hypogonadotropic hypogonadism reversal after testosterone replacement in a 34-year-old male

A 34-year-old male presented to the endocrinology clinic with the complaint of the absence of facial, axillary and pubic hairs. Further history revealed absent ejaculations and decreased early morning erections. The patient had no history of headaches, visual problems or anosmia. On physical examination, there were sparse facial, axillary and pubic hairs, bilateral gynaecomastia, stretch penile length of 5 cm and bilateral testicular volume of 10 mL. Laboratory investigations showed low luteinising hormone, follicular stimulating hormone and testosterone with normal prolactin and thyroid profile. MRI of the pituitary gland showed no evidence of pituitary microadenoma or macroadenoma. The patient was started on testosterone injections. After 9 months of testosterone replacement, the patient's testicular size increased to 20 mL bilaterally and his penile length increased to the mean adult size for his age with normal testosterone and luteinising hormone. He was, thus, advised to discontinue testosterone therapy.

http://ift.tt/2rCN46y

Congenital hypofibrinogenaemia: a presymptomatic detection of an extremely rare bleeding disorder in preterm twins

Twenty-eight-week-old preterm monochorionic–diamniotic twins were admitted to the neonatal intensive care unit secondary to low birth weight and mild respiratory distress syndrome. A low fibrinogen level of less than 0.5 g/L was detected following an abnormal full blood count. They required fibrinogen transfusions until 32 weeks corrected gestation to maintain adequate fibrinogen levels. Parental screening revealed that their mother had a previously undiagnosed hypofibrinogenaemia. Of note, her only symptom was menorrhagia. This may have implications on further pregnancies as it can be associated with spontaneous miscarriage and post-partum haemorrhage. Congenital hypofibrinogenaemia is a rare disorder and there are no reported cases from Ireland. A higher degree of suspicion for screening is required to detect new cases and demonstrates the benefits of checking parental levels in such situations.

http://ift.tt/2sIyBWf

Postmenopausal pregnancy? Evaluation of elevated hCG in a 59-year-old woman

Slightly elevated serum human chorionic gonadotropin (hCG) can be a normal finding in postmenopausal women. We report a case of a 59-year-old woman with a history of abnormal uterine bleeding who presented with a concern for pregnancy after developing nausea and vomiting a few weeks after unprotected intercourse. Although pregnancy was extremely unlikely, hCG was obtained in order to reassure the patient since she reported that her mother conceived at the age of 60. Serum hCG was positive, prompting concern for malignancy versus pregnancy. Stable serum hCG levels, elevated follicle-stimulating hormone and negative transvaginal ultrasound ruled out both malignancy and pregnancy. Positive serum pregnancy test and hCG elevation was attributed to normal postmenopausal state.

http://ift.tt/2rKAbcG

Triple synchronous primary malignancies: a rare occurrence

Triple synchronous primary malignant neoplasms are rare. The exact aetiology is unknown; however, risk factors include older age, family history, genetic aberrations, prolonged exposure to carcinogens and smoking. We describe a previously healthy 48-year-old woman who presented with abdominal pain and a palpable abdominal mass. Imaging revealed a complex cystic, solid pelvic mass and another mass in the right upper quadrant. She received an extensive abdominal surgery including exploratory laparotomy, pelvic mass resection, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, omentectomy and right adrenalectomy. During surgery, a mass in the distal sigmoid colon was noted and subsequent sigmoidectomy was performed. The surgical specimen revealed three different primary tumours with three different histologies, a granulosa cell tumour of the ovary, adrenocortical carcinoma and adenocarcinoma of the colon. She received six cycles of adjuvant chemotherapy for colon cancer with 5-fluorourocil, leucovorin and oxaliplatin and is currently living with no recurrence.

http://ift.tt/2sJ0Sf0

Modafinil in schizophrenia: is the risk worth taking?

Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients.

http://ift.tt/2rKAaFE

Bilateral isolated submandibular gland mumps

Isolated submandibular swellings pose a diagnostic challenge to the practising otolaryngologist. We report an unusual case of mumps isolated to bilateral submandibular glands. We discuss the case and the literature surrounding this condition and remind clinicians that mumps should be considered as a diagnosis in the presence of submandibular gland swelling in the absence of typical parotid swelling associated with mumps. Early consideration of this differential diagnosis, serological testing and a multidisciplinary approach may help to clinch the diagnosis earlier and prevent spread of the virus.

http://ift.tt/2sIIUcB

A clinical review of inhalation anesthesia with sevoflurane: from early research to emerging topics

Abstract

A large number of studies during the past two decades have demonstrated the efficacy and safety of sevoflurane across patient populations. Clinical researchers have also investigated the effects of sevoflurane, its hemodynamic characteristics, its potential protective effects on several organ systems, and the incidence of delirium and cognitive deficiency. This review examines the clinical profiles of sevoflurane and other anesthetic agents, and focuses upon emerging topics such as organ protection, postoperative cognitive deficiency and delirium, and novel ways to improve postanesthesia outcomes.

http://ift.tt/2rWce2X

Vaginal birth after two previous caesarean deliveries in a patient with uterus didelphys and an interuterine septal defect

Uterus didelphys is a congenital abnormality characterised by double uteri, double cervices and a double or single vagina that affects 0.3% to 11% of the general female population. A 23-year-old woman, gravida 3 para 3003, with uterus didelphys, acquired an iatrogenic interuterine septal defect during an otherwise routine primary caesarean delivery for fetal malpresentation. The defect was repaired but noted to have dehisced during her second pregnancy. A repeat caesarean section was performed due to fetal malpresentation after an unsuccessful external cephalic version. The dehisced defect was left unrepaired. During her third pregnancy, the placenta implanted in the right uterus, but the fetus migrated to the left uterus at approximately 28 weeks gestation. The umbilical cord traversed the interuterine septal defect. With the fetus in the vertex presentation at term gestation, the patient underwent a vaginal birth after two previous caesarean deliveries without any major perinatal complications.

http://ift.tt/2qXLLxe

Plain language summaries

Linked Comment: Cranenburgh et al. Br J Dermatol 2017; 176:1508–1515

Linked Comment: Teasdale et al. Br J Dermatol 2017; 176:1500–1507

Linked Comment: Kobashi et al. Br J Dermatol 2017; 176:1525–1532

Linked Comment: Linden et al. Br J Dermatol 2017; 176:1465–1474

Linked Comment: Koppes et al. Br J Dermatol 2017; 176:1533–1540

Linked Comment: Polesie et al. Br J Dermatol 2017; 176:1492–1499

Linked Comment: Yenamandra et al. Br J Dermatol 2017; 176:1624–1632

Linked Comment: Weiss et al. Br J Dermatol 2017; 176:1456–1464

Linked Comment: Kibsgaard et al. Br J Dermatol 2017; 176:1486–1491

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Daylight photodynamic therapy: where and when is it possible?

Linked Article: O'Mahoney et al. Br J Dermatol 2017; 176:1607–1616.

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‘Whoever has will be given more’ (Matthew 13:12): authorship of systematic reviews and clinical trials in the biological age

Linked Article: Gómez-García et al. Br J Dermatol 2017; 176:1633–1644.

Tauber and Paul. Br J Dermatol 2017; 176:1669–1671.

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Image Gallery: Kaposiform haemangioendothelioma

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Field treatment of actinic keratosis on the scalp

Linked Article: Weiss et al. Br J Dermatol 2017; 176:1456–1464.

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Methotrexate increases the risk of melanoma: or does it?

Linked Article: Polesie et al. Br J Dermatol 2017; 176:1492–1499.

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Psoriasis and the interleukin-10 family: evidence for a protective genetic effect, but not an easy target as a drug

Linked Article: Galimova et al. Br J Dermatol 2017; 176:1577–1587.

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Corrigendum

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Parents managing childhood long-term conditions: longitudinal research is needed on online forums as sources of peer-to-peer information

Linked Article: Teasdale et al. Br J Dermatol 2017; 176:1500–1507.

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The gathering storm: hydroxychloroquine retinopathy screening in the U.K.

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Neutrophilic eccrine hidradenitis can be induced by BRAF inhibitors

Linked Article: Herms et al. Br J Dermatol 2017; 176:1645–1648.

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Image Gallery: Rhinosporidiosis

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Image Gallery: Cutaneous lesions in the external auditory canal causing hearing loss

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Image Gallery: Treatment of refractory alopecia universalis with oral tofacitinib citrate and adjunct intralesional triamcinolone injections

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Biomarkers in contact dermatitis

Linked Article: Koppes et al. Br J Dermatol 2017; 176:1533–1540.

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Erratum

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Patients' reports as indicators of quality of care

Linked Article: van Cranenburgh et al. Br J Dermatol 2017; 176:1508–1515.

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A new clinical diagnostic matrix for epidermolysis bullosa

Linked Article: Yenamandra et al. Br J Dermatol 2017; 176:1624–1632.

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Minocycline as an alternative to doxycycline in the treatment of rosacea

Linked Article: van der Linden et al. Br J Dermatol 2017; 176:1465–1474.

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Image Gallery: Microcystic adnexal carcinoma (syringomatous carcinoma and sclerosing sweat duct carcinoma) as an extensive sclerotic erythematous plaque with telangiectasia over the face

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Omalizumab effectively protects against early- and late allergic responses in asthma after 4 weeks

Abstract

Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. Since new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR). Ten patients (IgE >300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at week 1, 2, 4 and 8. EAR was significantly reduced after 4 weeks (ΔFEV1 28 vs. 11%; p<0.001), eNO (86 vs. 53ppb; p<0.05) and basophil activation after 2 weeks (CD63 expression 79 vs. 32%, p<0.05) and LAR already after 1 week (ΔFEV1 26 vs. 13%, p<0.05). These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy.

This article is protected by copyright. All rights reserved.

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The robotic ENT microsurgery system: A novel robotic platform for microvascular surgery

Objective

Assess the feasibility of a novel robotic platform for use in microvascular surgery.

Study Design

Prospective feasibility study.

Setting

Robotics laboratory.

Methods

The Robotic ENT (Ear, Nose, and Throat) Microsurgery System (REMS) (Galen Robotics, Inc., Sunnyvale, CA) is a robotic arm that stabilizes a surgeon's instrument, allowing precise, tremor-free movement. Six microvascular naïve medical students and one microvascular expert performed microvascular anastomosis of a chicken ischiatic artery, with and without the REMS. Trials were blindly graded by seven microvascular surgeons using a microvascular tremor scale (MTS) based on instrument tip movement as a function of vessel width. Time to completion (TTC) was measured, and an exit survey assessed participants' experience. The interrater reliability of the MTS was calculated.

Results

For microvascular-naïve participants, the mean MTS score for REMS-assisted trials was 0.72 (95% confidence interval [CI] 0.64–1.07) and 2.40 (95% CI 2.12–2.69) for freehand (P < 0.001). The mean TTC was 1,265 seconds for REMS-assisted trials and 1,320 seconds for freehand (P > 0.05). For the microvascular expert, the mean REMS-assisted MTS score was 0.71 (95% CI 0.15–1.27) and 0.86 (95% CI 0.35–1.37) for freehand (P > 0.05). TTC was 353 seconds for the REMS-assisted trial and 299 seconds for freehand. All participants thought the REMS was more accurate and improved instrument handling and stability. The intraclass correlation coefficient for MTS ratings was 0.914 (95% CI 0.823–0.968) for consistency and 0.901 (95% CI 0.795–0.963) for absolute value.

Conclusion

The REMS is a feasible adjunct for microvascular surgery and a potential teaching tool capable of reducing tremor in novice users. Furthermore, the MTS is a feasible grading system for assessing microvascular tremor.

Level of Evidence

NA. Laryngoscope, 2017

http://ift.tt/2qWRDa4

NR4A1 is an endogenous inhibitor of vocal fold fibrosis

Objectives/Hypothesis

NR4A1 was recently identified as an endogenous inhibitor of transforming growth factor (TGF)-β–induced fibrosis, and the role of this nuclear receptor has not been elucidated in tissue health or the response to injury in the vocal folds. Given the clinical implications of vocal fold fibrosis, we investigated NR4A1 expression during vocal fold wound healing in vivo and the regulatory roles of NR4A1 on vocal fold fibroblasts (VFFs) in vitro with the ultimate goal of developing targeted therapies for this challenging patient population.

Study Design

In vivo and in vitro.

Methods

In vivo, the temporal pattern of NR4A1 mRNA expression was quantified following rat vocal fold injury. In vitro, the role of NR4A1 on TGF-β1–mediated transcription of genes underlying fibrosis as well as myofibroblast differentiation and collagen gel contraction was quantified in our human VFF line. Small interfering RNA was employed to alter NR4A1 expression to further elucidate this complex system.

Results

Nr4a1 mRNA increased 1 day after injury and peaked at 7 days. Knockdown of NR4A1 resulted in upregulation of COL1A1 and TGF-β1, with TGF-β1 stimulation (both P < .001) in VFFs. NR4A1 knockdown also resulted in increased α-smooth muscle actin–positive cells (P = .013) and contraction (P = .002) in response to TGF-β1.

Conclusions

NR4A1 has not been described in vocal fold health or disease. Upregulation of TGF-β following vocal fold injury was concurrent with increased NR4A1 expression. These data provide a foundation for the development of therapeutic strategies given persistent TGF-β signaling in vocal fold fibrosis.

Level of Evidence

N/A Laryngoscope, 2017

http://ift.tt/2rs6cFU

Postoperative anticoagulation after free flap reconstruction for head and neck cancer: A systematic review

Objective

Postoperative use of anticoagulation after free tissue transfer in head and neck ablative procedures is common practice, but a clear protocol has not been well established. The outcome measures including total flap failure, thrombosis, and hematoma formation for different anticoagulation regimens in free tissue transfer in the head and neck were reviewed.

Data Sources

PubMed, Ovid, and Cochrane databases were examined for patients who underwent free tissue transfer following head and neck ablative procedures.

Review Methods

Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting anticoagulation regimens following free tissue transfer in head and neck ablative procedures. Outcomes included total flap failure, thrombosis, and hematoma formation. Two independent reviewers assessed the quality of the articles by using the Methodological Index for Non-Randomized Studies.

Results

A total of 368 articles were identified. An additional 36 articles were identified through screening of reference lists. Twenty-one of these studies met final inclusion criteria for qualitative analysis. Outcome data on total flap failure, thrombosis, and hematoma formation were extracted and analyzed for comparison against all anticoagulation regimens. Total flap failure, thrombosis, and hematoma formation rates were 4.4%, 4.5%, and 2.2%, respectively. Individual study rates ranged from 0.0% to 10.7%, 0.0% to 10.4%, and 0.6% to 7.2%, respectively.

Conclusions

There is not adequate evidence to develop a standardized anticoagulation protocol for head and neck free flap procedures. Comparable flap complications were reported between all the employed anticoagulation methods studied, though significant variability in study design among articles existed. Prospective, randomized studies are warranted to determine the optimal postoperative anticoagulation regimen following free tissue transfer of the head and neck. Laryngoscope, 2017

http://ift.tt/2qWRCTy

Serial office-based steroid injections for treatment of idiopathic subglottic stenosis

Objectives/Hypothesis

Current treatment options for idiopathic subglottic stenosis include endoscopic interventions, resection, and tracheotomy. Recently, serial office-based steroid injections were proposed as an alternative that may stabilize or induce regression of airway stenosis without the need for repeated operations. Procedure completion rate, pain, complications, effect on stenosis, time since the last operation, and limitations have not been described.

Study Design

Retrospective case series.

Methods

Retrospective series of 19 patients undergoing serial office-based steroid injection for idiopathic subglottic stenosis. Outcome measures included completion rate, procedure-related pain scores, complications, percentage of airway stenosis, and time since the last operative intervention.

Results

Procedure completion rate was 98.8%. Average pain score during the procedure was 2.3 ± 1.7 on a 10-point scale. There were no immediate complications. One patient underwent awake tracheotomy 8 days after her second injection and was later decannulated. Average stenosis decreased from 35% ± 15% to 25% ± 15% (n = 16; P = .086) over the first of three injections and 40% ± 15% to 25% ± 10% to 20% ± 10% (n = 8; P = .002) for those patients completing two sets of three injections. Fourteen of 17 patients undergoing at least three injections have not returned to the operating room since the first injection.

Conclusions

Office-based steroid injection represents a promising new treatment pathway for a disease that requires long-term management, offering a purely pharmacologic approach to a disorder that has traditionally been approached from a mechanical perspective. It is safe, well tolerated, and effective. Furthermore, it may help patients and physicians avoid repeated trips to the operating room and the associated risks.

Level of Evidence

4 Laryngoscope, 2017

http://ift.tt/2rs6blk

Simultaneous versus sequential bilateral cochlear implants in adults: Cost analysis in a US setting

Objectives/Hypothesis

From a purely surgical efficiency point of view, simultaneous cochlear implantation (SimCI) is more cost-effective than sequential cochlear implantation (SeqCI) when total direct costs are considered (implant and hospital costs). However, in a setting where only SeqCI is practiced and a proportion of initially unilaterally implanted patients do not progress to a second implant, this may not be the case, especially when audiological costs are factored in. We present a cost analysis of such a scenario as would occur in our institution.

Study Design

Retrospective review and cost analysis.

Methods

Between 2005 and 2015, 370 patients fulfilled the audiological criteria for bilateral implantation. Of those, 267 (72.1%) underwent unilateral cochlear implantation only, 101 (27.3%) progressed to SeqCI, and two underwent SimCI. The total hospital, surgical, and implant costs, and initial implant stimulation series audiological costs between August 2015 and August 2016 (29 adult patients) were used in this analysis.

Results

The total hospital, surgical, and implant costs for this period was $2,731,360.42. Based on previous local trends, if a projected eight (27.3%) of these patients decide to progress to SeqCI, this will cost an additional $750,811.04, resulting in an overall total of $3,482,171.46 for these 29 patients. Had all 29 undergone SimCI, the total projected cost would have been $3,332,991.75, representing a total potential saving of $149,179.67 (4.3%).

Conclusions

In institutions where only SeqCI is allowed in adults, overall patient management may cost marginally more than if SimCI were practiced. This will be of interest to CI programs and health insurance companies.

Level of Evidence

4. Laryngoscope, 2017

http://ift.tt/2qWMmiw

Evaluating speech perception of the MAXUM middle ear implant versus speech perception under inserts

Objectives/Hypothesis

To evaluate the speech perception of the Ototronix MAXUM middle ear implant relative to the cochlear potential for speech perception of patients.

Study Design

Clinical study chart review.

Methods

We performed an evaluation of data from a prospective clinical study of 10 MAXUM patients. Primary outcome measures included comparison of word recognition (WR) scores with MAXUM (WR_MAXUM) versus word recognition under inserts (WR_inserts), and the functional gain improvement for pure-tone average (PTA) (0.5, 1, and 2 kHz) and high-frequency pure-tone average (2, 3, and 4 kHz).

Results

Ten ears in 10 adult patients (six female; average age 68.7 years) were included. The average speech perception gap (difference between WR_inserts and WR_MAXUM) with MAXUM was −9.2% (range, −26% to 4%). A negative number indicates that WR_MAXUM was higher than the WR_inserts. The average PTA with MAXUM was 23.1 dB (range, 18.7–30 dB), a 38.0-dB gain over the preoperative unaided condition (range, 20–53.3 dB). The average high-frequency pure-tone average with MAXUM was 34.4 dB (range, 26–43.3 dB), a 42.8-dB gain over the preoperative unaided condition (range, 32.3–58.7 dB).

Conclusions

These data demonstrate that a significant, very strong correlation was observed between WR_inserts and WR_MAXUM scores (r = 0.86, P = .001), and a patient's WR_inserts score may be used to reasonably predict the word recognition outcomes with MAXUM.

Level of Evidence

4 Laryngoscope, 2017

http://ift.tt/2rs0QL4

Geographic region: Does it matter in cutaneous melanoma of the head and neck?

Objectives/Hypothesis

The head and neck are two of the most common locations for cutaneous melanoma. We present the first population-based analysis of geographic differences in anatomic subsite, clinicopathologic and demographical traits, histopathologic subtype, treatment modality, and disease-specific survival (DSS) of cutaneous head and neck melanoma (CHNM).

Study Design

Retrospective database analysis.

Methods

The Surveillance, Epidemiology, and End Results database was queried for cases of CHNM reported between 2000 and 2013. Patients were grouped into East, Midwest, South, and West regions of the United States. Overall incidence, demographic traits, primary tumor site, clinicopathologic traits, histopathologic subtype, treatment modality, and DSS were compared among regions.

Results

There were 49,365 patients with CHNM identified. The West (4.60) and the South (4.42) had significantly higher incidence (per 100,000) than the East (3.84) and Midwest (3.65) (P < .05). DSS was significantly different among regions (P < .0066). The East (5 years: 89.4%, 10 years: 84.1%) had the highest DSS rate, and the South (5 years: 87.0%, 10 years: 81.8%) had the lowest DSS rate. The Midwest (5 years: 88.4%, 10 years: 84.3%) and West (5 years: 88.3%, 10 years: 83.5%) had intermediate DSS. On multivariate analysis, the South had an elevated hazard ratio (1.17, 95% confidence interval: 1.05-1.30) when compared to the West.

Conclusions

Geographic region may play a significant role in CHNM. Incidence is higher in the South and the West. Incidence, histologic subtype, treatment modality, and DSS vary among regions. DSS is lower in the South than the West, even after accounting for other major prognostic factors.

Level of Evidence

4. Laryngoscope, 2017

http://ift.tt/2rClp5Y

Clinical grading of Reinke's edema

Objective

Reinke's edema (RE) is a pathologically benign structural change of the vocal folds with a wide spectrum of clinical severity. We aim to propose and validate a clinical grading system based on size of the lesion to facilitate effective universal communication of disease severity.

Study Design

Retrospective review.

Methods

Patients diagnosed with RE exclusive of other glottic pathology between December 2010 and December 2014 were included. Sixty laryngoscopy photographs were extracted from recorded archived laryngeal videostroboscopy exams, blinded and graded by four laryngologists with experience diagnosing RE.

Results

A high degree of agreement among all four raters was demonstrated by high interclass correlation coefficients with a 95% confidence interval. Similarly, high intra-rater reliability was seen across all raters. Forty-nine (33%) lesions were grade 1. Thirty-five lesions (29.17%) were grade 2; 18 (15%) lesions were grade 3; and nine (7.5%) lesions were grade 4. Contralateral vocal fold was not graded in cases of grade 4.

Conclusion

This clinical grading for RE is a reliable tool for conveying severity of disease. High inter- and intra-rater reliability strongly suggest that RE similarly can be graded by different raters, and that a single rater is expected to grade RE similarly at different times.

Level of Evidence

4. Laryngoscope, 2017

http://ift.tt/2qWZZOX

Systemic therapy for head and neck squamous cell carcinoma: Historical perspectives and recent breakthroughs

Objectives

Despite dramatic developments in drugs established for other malignancies, historically there have been few novel systemic agents available for the management of head and neck squamous cell carcinoma (HNSCC). However, the last decade has observed increased interest in targeted therapies for HNSCC. In 2006, cetuximab became the first major drug for HNSCC to gain Food and Drug Administration (FDA) approval in 3 decades. Recently, both pembrolizumab and nivolumab gained FDA approval for treatment of recurrent or metastatic HNSCC, and trials for other indications in HNSCC are actively underway. As older agents including cisplatin and 5-fluorouracil continue to play a significant role in the management of advanced HNSCC, an understanding of their legacy is paramount. This historical review is not meant to exhaustively catalog every finding relating to HNSCC systemic therapy, but rather is meant to highlight important advances.

Data Sources

Case series and clinical trials available in the literature.

Review Methods

Historically significant series and trials evaluating HNSCC systemic therapy were evaluated.

Results

Standard regimens employed today are largely comprised of drugs discovered over 4 decades ago, although a number of recent phase III clinical trials have shown great promise, leading to the adoption of several new chemotherapeutic agents and treatment strategies.

Conclusions

These findings reinforce the importance of supporting further HNSCC drug discovery as modern treatment strategies using systemic therapy have resulted in measurable improvements in oncologic outcomes. Laryngoscope, 2017

http://ift.tt/2rsaRrw

Strategies for advancing laryngeal tissue engineering

http://ift.tt/2qX18Gj

In reference to laboratory assessment of sudden sensorineural hearing loss: A case-control study

http://ift.tt/2rspR8Q

Morphometric evaluation of facial and vestibulocochlear nerves using magnetic resonance imaging: comparison of Menière’s disease ears with normal hearing ears

Abstract

Loss of neural structures (such as hair cells or neurones within the spiral ganglion) has been proposed to be involved in Menière's disease (MD) (Spoendlin et al. Acta oto-laryngologica Supplementum 499:1–21, 1; Merchant et al. Eur Arch Oto-Rhino-Laryngol Off J Eur Feder Oto-Rhino-Laryngol Soc (EUFOS) Affil German Soc Oto-Rhino-Laryngol Head Neck Surg 252(2):63–75, 2; Tsuji et al. Ann Otol Rhinol Laryngol Suppl 81:26–31, 3; Kariya, Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 28(8):1063–1068, 4; Megerian Laryngoscope 115(9):1525–1535, 5) but this has yet to be confirmed. Therefore, the aim of this study was to investigate morphometric changes of VIIth and VIIIth cranial nerve in MD. MD is characterized by episodic vertigo, tinnitus, fluctuating hearing loss, and aural fullness. The exact pathophysiological mechanisms involved such as viral infections, autoimmune processes, genetic predisposition, cellular apoptosis, and oxidative stress are still not clear. Using a T2-weighted 3D-GE "constructive interference in steady state" (CISS) 3T magnetic resonance imaging (MRI) sequence, we evaluated the properties of the VIIth and VIIIth cranial nerves as they passed from the cerebellopontine angle to the inner ear modiolus. 21 patients with MD were examined along with 39 normal controls. Bidirectional nerve diameters and cross-sectional areas (CSA) were measured in a transverse plane. The comparison of study and control group showed statistically significant (P < 0.000595 after Bonferroni correction) differences between the CSA measurements. The facial, cochlear, superior vestibular, and inferior vestibular nerves (FN, CN, SVN, IVN) of MD patients were significantly larger than those of the control group, both on the MD-affected side and on the healthy side. Thus for example, the cochlear nerve CSA measurements were 0.69 ± 0.14 mm² (P < 0.0001) in the affected ears of the unilateral MD group, 0.70 ± 0.12 mm² (P < 0.0001) in the affected ears of the cohort including the bilateral MD group, 0.71 ± 0.13 mm² (P < 0.0001) in the non-affected ears of the MD patients, as compared to 0.46 ± 0.14 mm² in the control group. The perpendicular nerve diameters were found to vary according to site of measurement and type of measurement used. For example a statistically significant enlargement of the short diameter measurements of the SVN at the level of the meatus was found, but not of long diameter measurements at the same site. Although cellular death would theoretically be expected to lead to a decreased nerve thickness, our data showed a swelling of cranial nerves VII and VIII within the study group compared to our normal hearing control group. The similar reaction of the facial nerve supports mediator-based theories of MD pathophysiology.

http://ift.tt/2qWVd43

Long persistence of TNF-α antagonist induced autoantibodies under subsequent treatment with Ustekinumab but no adverse effects: a case study of 14 psoriasis patients

Abstract

Induction of antinuclear antibodies (ANA) is a well-documented side effect of treatment with the TNF-α antagonists Infliximab, Adalimumab, and Etanercept. In this context, occasional organ-specific and systemic autoimmune phenomena, and an association of autoantibodies with treatment response and anti-drug antibody formation were reported. In genuine autoimmune disease, the detection of autoantibodies can predate clinical manifestations by almost 6 years. However, little is known about the post-treatment dynamics of TNF-antagonist induced ANA, and, in particular, on their effects on the response to, and their dynamics under subsequent biologic treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2rBEMvU

Underreported use of palliative care and patient reported outcome measures to address reduced Quality of Life in calciphylaxis patients: A systematic review

Abstract

Calciphylaxis is associated with significant morbidity and mortality. Palliative care (PC) is a subspecialty that treats the pain and stress of serious illness. We performed a systematic review to assess whether quality of life (QoL) indices and the role of palliative care have been studied in calciphylaxis patients. We hypothesize PC services are underutilized to address reduced QoL in calciphylaxis. Several databases were searched from inception to October 2016 according to modified PRISMA criteria. We searched for papers about calciphylaxis that mentioned the symptoms and supportive needs of patients, QoL or outcome measures to report symptom severity, and the involvement of PC. Twelve papers met inclusion criteria. Reported patient symptoms included pain, skin lesion resolution, and pruritus, with the first being the most frequently reported. Four papers measured pain using a previously verified patient reported outcome measure, including the Visual Analogue Scale (VAS pain). One paper used a verified QoL measure, the Dermatology Quality of Life Index (DQLI). No tool was used consistently. Eight papers reported the use of hospice or PC in the treatment of calciphylaxis. No outcome measure was used to prompt PC involvement. Overall, QoL indices, patient reported outcome measures, and PC are underreported in the treatment of calciphylaxis. Because dermatologists are frequently involved in calciphylaxis patient care, and symptoms can present significant challenges to clinical practice, we aim to raise clinician awareness of PC as a resource to assist in symptom management and adaptive coping strategies for patients from the onset of disease.

This article is protected by copyright. All rights reserved.

http://ift.tt/2qSHdx3

Smad7 positively regulates keratinocyte proliferation in psoriasis

Abstract

Background

Transforming growth factor (TGF)-β1 exerts inhibitory effects on keratinocyte proliferation.

Objectives

To examine whether Smad7, a known inhibitor of TGF-β1 signalling, is involved in the psoriasis-associated keratinocyte hyper-proliferation.

Methods

Smad7 was evaluated in skin sections of psoriatic patients and healthy controls and in mice with Aldara-induced skin pathology by real-time PCR and immunohistochemistry. To assess whether Smad7 positively regulates the in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K) 6 and K16, cell cycle-associated factors, cell cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS.

Results

Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in S-phase of cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through S phase, and hyper-phosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness.

Conclusions

Our data show that Smad7 is over-expressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.

This article is protected by copyright. All rights reserved.

http://ift.tt/2rBVtHH