Towards understanding the mechanisms of actions of CEACAM6 in cancer progression

Abstract

Human carcinoembryonic antigen (CEA) is the prototypic member of highly related cell surface glycoproteins that includes Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and others. CEACAM6 (formerly NCA) that belongs to the immunoglobulin superfamily, is a cell adhesion proteins of the CEA family. It is normally expressed on the epithelial surfaces and the surface of myeloid (CD66c). CEACAM6 is a multi-functional glycoprotein that mediates homotypic binding with other CEA family members and heterotypic binding with integrin receptors. It functions by organizing tissue architecture and regulating different signal transduction, while aberrant expression leads to the development of human malignancies. It was firstly discovered in proliferating cells of adenomas and hyperplastic polyps in comparison to benign colonic tissue when over-expressed on the surface of various cell types in model systems. CEACAM6, functions as a pan-inhibitor of cell differentiation and cell polarization, and it also cause distortion of tissue architecture. Moreover, over-expression of CEACAM6 modulates cancer progression through aberrant cell differentiation, anti-apoptosis, cell growth and resistance to therapeutic agents. In addition, CEACAM6 over-expression in multiple malignancies promoting cell invasion and metastasis thereby representing an acquired advantage of tumor cells directly responsible for an invasive phenotype. This review will focus on the findings supporting the mechanism of actions linking the oncogenic potential of CEACAM6 to the onset of cancer progression and pathogenesis specially in breast cancer, and to validate CEACAM6 as a target to pave the way towards the design of efficient therapeutic strategies against BC.

This article is protected by copyright. All rights reserved.

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Does the reduction of inferior turbinate size affect lower airway functions?

Publication date: Available online 6 November 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Ozlem Unsal, Mehtap Ozkahraman, Mufide Arzu Ozkarafakili, Meltem Akpinar, Arzu Yasemin Korkut, Senem Kurt Dizdar, Berna Uslu Coskun
IntroductionAlthough the nose and lungs are separate organs, numerous studies have reported that the entire respiratory system can be considered as a single anatomical and functional unit. The upper and lower airways affect each other either directly or through reflex mechanisms.ObjectiveIn this study, we aimed to evaluate the effects of the radiofrequency ablation of persistent inferior turbinate hypertrophy on nasal and pulmonary function.MethodsTwenty-seven patients with bilateral persistent inferior turbinate hypertrophy without septal deviation were included in this study. All of the patients were evaluated using anterior rhinoscopy, nasal endoscopy, acoustic rhinometry, a visual analogue scale, and flow-sensitive spirometry on the day before and 4 months after the radiofrequency ablation procedure.ResultsThe post-ablation measurements revealed that the inferior turbinate ablation caused an increase in the mean cross-sectional area and volume of the nose, as well as in the forced expiratory volume in 1s, forced vital capacity, and peak expiratory flow of the patients. These differences between the pre- and post-ablation results were statistically significant. The post-ablation visual analogue scale scores were lower when compared with the pre-ablation scores, and this difference was also statistically significant.ConclusionThis study demonstrated that the widening of the nasal passage after the reduction of the inferior turbinate size had a favorable effect on the pulmonary function tests.



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A case of segmental stiff skin syndrome treated with systemic losartan

Abstract

Stiff skin syndrome (SSS) is a rare, autosomal dominant cutaneous disorder with progressive, symmetric, sclerotic skin changes of the shoulders, hips, and thighs. In a recent publication, a distinct segmental variant of SSS was proposed. In this report we discuss the case of a boy with segmental SSS and review the current literature.

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Intralabyrinthine sporadic endolymphatic sac tumour

Publication date: Available online 6 November 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): C. Lucas, J.-C. Leclère, E. Mornet, R. Marianowski
IntroductionEndolymphatic sac tumours are benign, slowly growing tumours that invade the temporal bone, and present clinically in the form of unilateral hearing loss. They can be sporadic or occur in the context of Von Hippel-Lindau disease (VHL).Case summaryThe authors report a case of endolymphatic sac tumour arising in the utricle presenting histological and immunohistochemical features corresponding to endolymphatic sac tumour in a patient without VHL.DiscussionEndolymphatic sac tumours invade the posterior part of the petrous temporal bone. According to two studies concerning patients with Von Hippel-Lindau disease, endolymphatic sac tumours arise from the endolymphatic duct. This case of intralabyrinthine sporadic endolymphatic sac tumour supports this hypothesis for sporadic forms, indicating the need for labyrinthectomy associated with tumour resection to avoid recurrence.



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Therapeutic response to domperidone in gastroparesis: A prospective study using the GCSI-daily diary

Abstract

Common symptoms of gastroparesis include nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. Domperidone is used for treatment of gastroparesis. Daily symptom scoring may help document efficacy.

Aim

To determine the effectiveness of domperidone for gastroparesis symptoms using the gastroparesis cardinal symptom index-daily diary (GCSI-DD) and to determine which symptoms improve and when with domperidone treatment.

Methods

Symptomatic patients with diabetic or idiopathic gastroparesis were enrolled. Gastric emptying was performed using 4 hour scintigraphy. GCSI-DD recorded symptoms at baseline and during six weeks of treatment with domperidone 10 mg TID. GCSI-DD records severity of nausea, early satiety, postprandial fullness, upper abdominal pain, overall gastroparesis symptoms on a scale of 0 (no symptom) to 4 (very severe) and records the number of vomiting episodes per day.

Results

Thirty-four patients with gastroparesis (5 diabetic, 29 idiopathic) participated in this open label study. Treatment duration averaged 36.9 ± 7.6 days. Improvement in overall gastroparesis symptoms occurred on day 3 of treatment and maintained during the treatment. Early satiety, postprandial fullness, and overall symptom severity significantly improved from baseline to the final week of treatment (P < .05 for all), whereas nausea had borderline improvement (P = .055). Side effects included palpitations (5 patients), headache (5), breast tenderness (2), menstrual bleeding (2), dizziness (1), drowsiness (1), chest pain (1), swelling (1), constipation (1).

Conclusions

Domperidone improves symptoms of gastroparesis, reducing overall gastroparesis symptom severity and decreasing early satiety, postprandial fullness, and nausea. GCSI-DD is useful to document efficacy of therapy for gastroparesis.

Therapeutic response to domperidone in gastroparesis: A prospective study using the GCSI-daily diary. The figure shows the mean daily symptom scores during the initial two weeks of treatment as recorded in the GCSI-DD.

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Issue Information - Ed Board

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Quality of life in the GLARIUS trial randomizing bevacizumab/irinotecan versus temozolomide in newly diagnosed, MGMT-nonmethylated glioblastoma

Abstract

Background

The GLARIUS trial which investigated the efficacy of bevacizumab (BEV)/irinotecan (IRI) as compared to standard temozolomide (TMZ) in the first-line therapy of MGMT-nonmethylated glioblastoma showed that progression-free survival was significantly prolonged by BEV/IRI while overall survival was similar in both arms. The present report focusses on quality of life (QoL) and Karnofsky performance score (KPS) during the whole course of the disease.

Patients and methods

Patients (n=170) received standard radiotherapy and were randomized (2:1) for BEV/IRI or standard TMZ. At least every three months KPS was determined and QoL was measured using the EORTC-QLQ C30 and BN20 questionnaires. A generalized estimating equation model (GEE) evaluated differences in the course of QoL and KPS over time. Also, the time to first deterioration and the time to postprogression deterioration was analyzed separately.

Results

In all dimensions of QoL and KPS, GEE analyses and time to first deterioration analyses did not detect significant differences between the treatment arms. At progression, 82% of patients receiving second-line therapy in the standard arm received BEV second-line therapy. For the dimensions motor dysfunction and headaches, time to postprogression deterioration was prolonged in the standard arm receiving crossover second-line BEV in the vast majority of patients at the time of evaluation.

Conclusions

GLARIUS did not find indications for a BEV-induced detrimental effect on QoL in first-line therapy of MGMT-nonmethylated GBM patients. Moreover, GLARIUS provided some indirect corroborative data supporting the notion that BEV may have beneficial effects upon QoL in relapsed GBM.

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Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis

Twenty years ago, Patchell and colleagues¹ demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.

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Functional Outcomes after De-Escalated Chemoradiation for Human Papillomavirus-Positive Oropharyngeal Cancer: Secondary Analysis of a Phase II Trial

Publication date: Available online 6 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): John V. Hegde, Narek Shaverdian, Carol Felix, Pin-Chieh Wang, Darlene Veruttipong, Sophia Hsu, Jonathan Riess, Shyam D. Rao, Megan E. Daly, Allen M. Chen
PurposeTo analyze functional outcomes for patients treated on a phase II trial of de-escalated chemoradiation for human papillomavirus (HPV)-positive oropharyngeal cancer.MethodsEligibility included p16-positive, stage III or IV oropharyngeal squamous cell carcinoma, and Zubrod performance status 0-1. Treatment was induction paclitaxel 175 mg/m² and carboplatin AUC 6 for 2 cycles every 21 days followed by concurrent paclitaxel 30 mg/m² every 7 days with dose-reduced radiation of 54 or 60 Gy. Trends in body weight and body mass index (BMI) were analyzed with gastrostomy tube and narcotic utilization rates. Functional outcomes were assessed using the University of Washington Quality of Life Scale and the Functional Assessment of Cancer Therapy-Head and Neck Scale.ResultsForty-five patients were registered, of whom 40 were evaluable. Only 1 patient had a BMI deemed to be unhealthy at the completion of treatment. For the 15 patients (38%) with a normal BMI (18-25 kg/m²) pre-treatment, recovery back to baseline occurred at approximately 18 months (average BMI 23.2 vs. 22.3 kg/m², respectively, p=0.09). Two patients (5%) had gastrostomy tubes placed during treatment. No patient was enteral feeding tube dependent at 6 months post-treatment. Ninety-five percent tolerated a normal regular diet at last follow-up.ConclusionsDe-escalated chemoradiation may improve functional outcomes as indicated by the relatively low incidence of gastrostomy tube placement and long-term dysphagia. In patients with a normal BMI prior to chemoradiation, BMI recovered to baseline levels.

Teaser

For patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma undergoing chemoradiation with induction chemotherapy followed by de-escalated chemoradiation to 54 or 60 Gy with concurrent paclitaxel, functional outcomes, including nutritional status, gastrostomy tube use, dysphagia, and narcotic use, appear similar or favorable to historical controls treated with definitive chemoradiation to 70 Gy. These findings support ongoing efforts to evaluate de-escalated chemoradiation in patients with HPV-associated oropharyngeal carcinoma.


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PARP inhibition combined with thoracic radiation exacerbates esophageal and skin toxicity in C57BL6 mice

Publication date: Available online 6 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Luiza Madia Lourenco, Yanyan Jiang, Neele Drobnitzky, Marcus Green, Fiona Cahill, Agata Patel, Yasmin Shanneik, John Moore, Anderson J. Ryan
PurposePARP inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation. In this study, we examined the normal tissue response in mice treated with PARP inhibitors (BMN673 or AZD2281) in combination with thoracic radiation.Methods and MaterialsAnti-tumor effects of fractionated radiation (5 Gy x 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. Normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated 5 Gy x 4 radiation delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. DNA damage response in the esophagus and skin was assessed by γH2AX immunohistochemistry.ResultsWhilst PARP inhibition enhanced radiation-induced tumor growth inhibition in nude mice, it was also associated with significant body weight loss and increased damage to the esophagus and skin within the field of irradiation in C57BL6 mice. PARP inhibition compromised the repair of radiation-induced DNA damage in the esophagus and skin.ConclusionAlthough PARP inhibition enhanced the anti-tumor response to fractionated radiation, it also enhanced the radiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies utilizing PARP inhibitors and radiotherapy, in particular where the field of radiation includes the esophagus.

Teaser

PARP inhibitors have been demonstrated to potentiate the anti-tumor effect of radiation in preclinical studies. However, their effect on normal tissue response to radiation is unclear. Here we show that PARP inhibitors not only enhance radiation-induced tumor growth inhibition, but also enhance the response of the esophagus and skin to radiation. Therefore, caution may be warranted when combining PARP inhibition with radiotherapy that includes proliferating normal tissues.


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Low-dose hypersensitive response for residual pATM and γH2AX foci in normal fibroblasts of cancer patients

Publication date: Available online 6 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Dorota Słonina, Aleksandra Kowalczyk, Anna Janecka-Widła, Damian Kabat, Wiktor Szatkowski, Beata Biesaga
PurposeIn our previous study, using flow cytometry-based clonogenic survival assay, we demonstrated low-dose hyper-radiosensitivity (HRS) effect in normal fibroblasts of 4 of the 25 cancer patients investigated. In the present study, we define the dose-response relationship for initial and residual pATM and γH2AX foci and temporal response of pATM foci in fibroblasts of the 4 HRS-positive patients and 8 HRS-negative patients and answer the question regarding the role of DNA double strand break (DSB) recognition and repair in the mechanism of HRS.Methods and MaterialsThe cells were irradiated with single doses (0.1 - 4 Gy) of 6MV x-rays. The number of initial and residual pATM and γH2AX foci was assessed 1 hour and 24 hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2 Gy.ResultsHRS response (confirmed by the induced-repair model) was clearly evident for residual pATM and γH2AX foci in fibroblasts of HRS-positive patients, but not in fibroblasts of HRS-negative patients. Significantly less DSB was recognized by pATM early (10 – 30 minutes) after irradiation with 0.2 Gy in HRS-positive compared to HRS-negative fibroblasts.ConclusionsThe present results provide the evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleoshuttling of the pATM protein to be involved in HRS response.

Teaser

We demonstrate, for the first time, low-dose hypersensitive response for both residual pATM and γH2AX foci in normal fibroblasts of 4 HRS-positive patients and its lack in fibroblasts of 8 HRS-negative patients. We also show that in HRS-positive fibroblasts not all DSB are recognized by pATM early after irradiation with low dose. The data provide the evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS.


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Value of elective radiation oncology rotations: how many is too many?

Publication date: Available online 6 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Samuel Jang, Stephen A. Rosenberg, Craig Hullet, Kristin A. Bradley, Randall J. Kimple




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Outcome after Radiotherapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement

Publication date: Available online 6 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James Laird, Jennifer Ma, Karen Chau, Monica Chelius, Weiji Shi, Zhigang Zhang, Benjamin H. Lok, Joachim Yahalom
PurposeLangerhans cell histiocytosis (LCH) is a rare malignant disease characterized by histiocytic proliferation. We intended to characterize the efficacy and safety of radiation therapy (RT) in a contemporary cohort and to explore if there are sites at higher risk for local recurrence.Materials/MethodsBetween 1995 and 2015, we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement (SS/MS) and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiotherapy. Patient demographics, treatment, and local failure were compared by site of lesion.ResultsMedian age at RT was 35 years (range 1.5 – 67). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high-risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (7.5 – 50.4). At a median follow-up of 45 months (6 – 199), local recurrence or progression was noted in 5 of 46 (11%) lesions. There were no local failures of the 31 bone lesions evaluated, while the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% CI 32 – 83%; p = 0.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 (13%) patients, all of whom were adults with multisystem disease.ConclusionRadiotherapy is a safe and effective measure for providing local control of LCH involving the bone. While bone lesions are well controlled with low doses of radiation, disease in other tissues such as the skin and brain may require higher doses of radiation or additional treatment modalities.

Teaser

Langerhans cell histiocytosis is a rare histiocytic malignancy associated with a wide range of clinical presentations and outcomes. We explored treatment patterns and outcomes in a cohort of 39 patients with 46 radiation-treated lesions. We found the rate of local failure was significantly higher in patients with non-bone lesions, especially of the skin and brain, compared to excellent local control in bone lesions with relatively low doses of radiation.


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Abnormal esophageal acid exposure on high-dose proton pump inhibitor therapy is common in systemic sclerosis patients

Abstract

Background

Esophageal dysfunction and gastro-esophageal reflux disease (GERD) are common among patients with systemic sclerosis (SSc). Although high-dose proton pump inhibitors (PPIs) typically normalize esophageal acid exposure, the effectiveness of PPI therapy has not been systematically studied in SSc patients. The aim of this study was to characterize reflux in SSc patients on high-dose PPI using esophageal pH-impedance testing.

Methods

In this case-controlled retrospective analysis, 38 patients fulfilling 2013 American College of Rheumatology SSc criteria who underwent esophageal pH-impedance testing on twice-daily PPI between January 2014 and March 2017 at a tertiary referral center were compared with a control-cohort of 38 non-SSc patients matched for PPI formulation and dose, hiatal hernia size, age, and gender. Patient clinical characteristics, including endoscopy and high-resolution manometry findings, were assessed via chart review.

Key Results

On pH-impedance, SSc patients had higher acid exposure times (AETs) than controls. Sixty-one percent of the SSc patients and 18% of the control patients had a total AET ≥4.5% (P < .001). Systemic sclerosis patients also had significantly longer AETs, longer median bolus clearance, and lower nocturnal impedance values.

Conclusions & Inferences

Abnormal esophageal acid exposure despite high-dose PPI therapy was common among patients with SSc. The lack of increased reflux episodes in the SSc patients, and longer bolus clearance times and lower nocturnal impedance, supports ineffective clearance as the potential mechanism. Systemic sclerosis patients may require adjunctive therapies to PPIs to control acid reflux.

Esophageal dysfunction and reflux are common in patients with systemic sclerosis yet the effectiveness of acid suppression therapy in these patients has not been systematically studied. Our study indicates that systemic sclerosis patients have significant esophageal acid exposure despite high-dose proton pump inhibitor therapy, suggesting ineffective esophageal clearance as a mechanism. Patients with systemic sclerosis may need adjunctive therapies in addition to acid suppression to control their reflux.

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Management of organ motion in scanned ion beam therapy

Scanned ion beam therapy has special demands for treatment of intra-fractionally moving tumors such as lesions in lung or liver. Interplay effects between beam and organ motion can in those settings lead to un...

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Normal lung sparing Tomotherapy technique in stage III lung cancer

Radiation pneumonitis (RP) has been a challenging obstacle in treating stage III lung cancer patients. Beam angle optimization (BAO) technique for Tomotherapy was developed to reduce the normal lung dose for s...

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Multicriteria plan optimization in the hands of physicians: a pilot study in prostate cancer and brain tumors

The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and templa...

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Clinical outcomes of graves’ ophthalmopathy treated with intensity modulated radiation therapy

Radiation for Graves' ophthalmopathy (GO) has traditionally utilized lateral opposing fields (LOF) or three-dimensional conformal radiotherapy (3DCRT) technique. The current study was conducted to report clini...

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First intraindividual comparison of contrast-enhanced MRI, FET- and DOTATOC- PET in patients with intracranial meningiomas

For irradiation treatment planning of meningiomas the use of PET-scans is well established. The most frequently used tracers are either based on amino acids or the somatostatin receptor ligand DOTATOC. Since u...

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Eosinophil Biology in COPD

Chronic obstructive pulmonary disease (COPD) is a lethal disease that is predicted to become the third leading cause of death globally within 3 years. Recent research has highlighted the heterogeneity of the pathologic characteristics of COPD, indicating that disease mechanisms are complex.…

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TAGLN2 is a candidate prognostic biomarker promoting tumorigenesis in human gliomas

Transgelin-2 (TAGLN2) is a member of the calponin family of actin-bundling proteins that is involved in the regulation of cell morphology, motility, and cell transformation. Here, the clinical significance and...

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Eosinophil Biology in COPD

Chronic obstructive pulmonary disease (COPD) is a lethal disease that is predicted to become the third leading cause of death globally within 3 years. Recent research has highlighted the heterogeneity of the pathologic characteristics of COPD, indicating that disease mechanisms are complex.…

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Treatment of Primary Acute Patellar Dislocation: Systematic Review and Quantitative Synthesis of the Literature

Purpose: The aim of this study was to evaluate clinical outcomes, rate of redislocation, and complications after conservative or surgical procedures used to treat primary acute patellar dislocation. Methods: A comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase, and Google Scholar databases using various combinations of the keywords "patella," "dislocation," "treatment," "acute," "primary" was performed. The following data were extracted: demographics, chondral defects and soft tissue lesions, outcome measurements, type of management, recurrence of instability, and complications. Results: A total of 2134 knees in 2086 patients were included, with an average age at dislocation of 20.3 years. The average Kujula score was 75.6 for patients treated conservatively and 88.7 for patients undergoing surgical treatment in the short–medium follow-up (less than 5 years); the average Kujula score was 87.5 for patients treated conservatively and 86.6 for patients undergoing surgical treatment in the long-term follow-up (more than 5 years). The rate of recurrence was significantly lower in the surgical group (25%) than in the conservative group (36.4%). The overall complication rate was 6.5% (29 of 441 knees) in the surgical management group. No complications were reported for patients treated conservatively. Conclusions: Surgical treatment of primary acute patellar dislocation leads to significantly lower rate of redislocation and provides better short–medium clinical outcomes, whereas in the long-term follow-up, results of patients treated conservatively were as good as those of surgical patients. Further randomized controlled trials, describing anatomical abnormalities and soft-tissue integrity that may influence the choice of treatment, are needed. Level of Evidence: Systematic review, level IV.

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Neuroendocrine Dysfunction in a Young Athlete With Concussion: A Case Report

Abstract: An 18-year-old female ringette and basketball player presented to our sport concussion clinic 27 months after concussion with fatigue, headache, exercise intolerance, polyuria, nocturia, and difficulties concentrating. Her history was remarkable for 4 previous concussions. Her neurologic examination was normal. Neuroendocrine screen including thyroid function, morning cortisol, glucose, and insulin-like growth factor-1 (screening test for growth hormone deficiency) were normal. Further testing for growth hormone deficiency with an insulin hypoglycemia test revealed severe growth hormone deficiency. Urine and serum electrolytes were borderline normal, suggesting partial diabetes insipidus. Treatments with growth hormone replacement lead to complete recovery. This case highlights the importance of maintaining a high index of suspicion for neuroendocrine abnormalities in athletes with persistent symptoms after sport concussion. Symptoms can be nonspecific and go undiagnosed for years, but appropriate recognition and treatment can restore function.

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Depression, Anxiety, and Alcohol Use in Elite Rugby League Players Over a Competitive Season

Objective: To assess the prevalence of symptoms of depression, anxiety, and rates of alcohol misuse in elite rugby league players in Australasia. Design: A cross-sectional, epidemiological study with repeated measures. Setting: Surveys were conducted during the 2015 preseason and in-season. Participants: Four hundred four elite rugby league players participated preseason and 278 players in-season. Main Outcome Measures: Symptoms of depression were measured using the Patient Health Questionnaire-9 scale, symptoms of generalized anxiety disorder (GAD) with the GAD-7 scale, and the Alcohol Use Disorders Identification Test Consumption scale was used to assess hazardous alcohol use. Results: The overall prevalence of depression was 12.6% preseason and 10.1% in-season. Generalized anxiety disorder had a prevalence of 14.6% and 10.1% for these 2 periods. Overall, 68.6% of players had hazardous levels of alcohol use preseason, and 62.8% in-season. There was no significant difference for any of the main outcomes between the periods. Players with a history of mental illnesses had 5.62 greater odds (95% confidence interval [CI], 2.62-12.04) of depression than those without during preseason, and 22.08 greater odds (95% CI, 7.77-62.71) in-season. Players reporting ≥3 previous concussions had 2.02 greater odds (95% CI, 1.07-3.82) of depression than those reporting ≤2 in the preseason sample. Conclusions: Rugby league players have a lower prevalence of depression compared with studies of the general population and other athletes, but a higher prevalence of GAD, and high rates of alcohol misuse. Clubs may consider implementing regular screening for these conditions. Further prospective research to determine causality of independent factors is required.

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Rankings of High School Sports Injury Rates Differ Based on Time Loss Assessments

Objective: To examine how injury definition inclusiveness affects the rank order of injury rates in 27 high school (HS) sports. Design: The National Athletic Treatment, Injury and Outcomes Network (NATION) used certified athletic trainers (ATs) to collect injury and athlete-exposure (AE) data in practices and competitions for 27 HS sports during the 2011/2012 to 2013/2014 academic years. Time loss (TL) injuries resulted in ≥24 hours of participation restriction. Nontime loss (NTL) injuries resulted in

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Carbon Monoxide Exposure in Youth Ice Hockey

Objective: To examine the effect of ice resurfacer type on carboxyhemoglobin levels in youth hockey players. We hypothesized that players in arenas with electric resurfacers would have normal, stable carboxyhemoglobin levels during games, whereas those in arenas with internal combustion engine (IC) resurfacers would have an increase in carboxyhemoglobin levels. Design: Prospective cohort study. Setting: Enclosed ice arenas in the northeastern United States. Participants: Convenience sample of players aged 8 to 18 years old in 16 games at different arenas. Eight arenas (37 players) used an IC ice resurfacer and 8 arenas (36 players) an electric resurfacer. Interventions: Carboxyhemoglobin levels (SpCO) were measured using a pulse CO-oximeter before and after the game. Arena air was tested for carbon monoxide (CO) using a metered gas detector. Players completed symptom questionnaires. Main Outcome Measures: The change in SpCO from pregame to postgame was compared between players at arenas with electric versus IC resurfacers. Results: Carbon monoxide was present at 6 of 8 arenas using IC resurfacers, levels ranged from 4 to 42 parts per million. Carbon monoxide was not found at arenas with electric resurfacers. Players at arenas with IC resurfacers had higher median pregame SpCO levels compared with those at electric arenas (4.3% vs 1%, P

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Anterior Knee Impingement in a High-Level Football Punter: A Case Report and Description of the Active–Passive Knee Extension Test

Abstract: A 22-year-old football punter complained of anterior knee pain deep to his patellar tendon that occurred every time the knee of his kicking leg reached full extension during a punt. Arthroscopy confirmed anterior impingement between a fibrous tissue eminence directly anterior to his anterior cruciate ligament (ACL) and the intercondylar roof in full extension. With the eminence removed, full extension no longer caused impingement as demonstrated arthroscopically. He resumed punting at maximal effort 6 weeks postoperatively without pain. We report the active–passive knee extension test, a physical examination maneuver designed to identify patients with anterior knee impingement between tissue anterior to the ACL and the intercondylar roof. This test is a helpful part of the clinical examination in detecting these lesions.

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Disparities in Athletic Trainer Staffing in Secondary School Sport: Implications for Concussion Identification

Objective: First, to assess whether teams at schools with an athletic trainer (AT) on staff had a higher number of diagnosed concussions than teams without medical personnel present. Second, to assess whether the variability in employment of a certified AT by Washington state high schools is patterned by socioeconomic and demographic characteristics. Design: Cross-sectional survey. Setting: Washington state public high schools. Participants: Stratified random sample of football and soccer coaches (n = 270 teams, 144 schools). Independent Variables: Presence of an AT and school characteristics (percentage of students qualifying for free or reduced price lunch, rural location, enrollment). Results: Football and boys' soccer teams at schools with an AT had a significantly greater number of athletes with diagnosed concussions compared to teams at schools without an AT (P

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In Response to: Keep the Physical in Physical Education

No abstract available

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Transcanal endoscopic ear surgery for perilymphatic fistula after electric acoustic stimulation

Transcanal endoscopic ear surgery (TEES) will become a very useful therapeutic option. A perilymphatic fistula (PLF) is defined as sudden sensorineural hearing loss and/or vertigo caused by leakage of the perilymph through a fistula from the oval window and/or round window. We report a case of PLF after electric acoustic stimulation (EAS), a kind of cochlear implant, successfully treated by TEES. A 38-year-old man presented to our hospital with vertigo and hearing loss (HL). His vertigo was induced by Valsalva maneuvers.

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Utility of multi-detector CT scans after colorectal endoscopic submucosal dissection: a prospective study

Several reports have described the major adverse events after endoscopic submucosal dissection (ESD), such as perforation or bleeding. However, few studies have discussed the occurrence of post-ESD electrocoagulation syndrome (PEECS) after colorectal ESD. Additionally, the occurrence of fever without abdominal pain in patients requires postoperative management similar to that required for PEECS. Therefore, we have defined post-ESD inflammatory syndrome (PEIS) as composed of both PEECS and fever without abdominal pain.

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Width and depth of resection for small colorectal polyps: hot versus cold snare polypectomy

Curability is associated with resection width and depth in polypectomy. We evaluated the resection width and depth achieved with hot snare polypectomy (HSP) and cold snare polypectomy (CSP) for small colorectal polyps.

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Per-oral endoscopic myotomy in patients with or without prior Heller myotomy: comparing long-term outcomes in a large U.S. single-center cohort (with videos)

Heller myotomy (HM) is one of the most effective treatments for esophageal achalasia. However, failures do exist and the success rate tends to decrease with time. The efficacy of rescue treatments for patients with failed Heller is limited. A few small-scale studies have reported outcomes of per-oral endoscopic myotomy (POEM) in these patients. We conducted this study to systematically assess feasibility, safety, and efficacy of POEM on post-Heller patients.

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Impact of experience on self-assessment accuracy of clinical colonoscopy competence

Self-assessment is important for life-long learning and a recommended assessment method for endoscopy skills. Prior literature has not investigated self-assessment accuracy of colonoscopic competence in the clinical setting. This study aimed to determine the self-assessment accuracy of novice, intermediate, and experienced endoscopists.

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Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology, and overall survival in patients with unresectable pancreatic cancer

Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study was to evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer.

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Upper GI involvement in children with familial adenomatous polyposis syndrome: single-center experience and meta-analysis of the literature

Familial adenomatous polyposis (FAP) is a hereditary syndrome that can affect the entire GI tract. Current screening recommendations include esophagogastroduodenoscopy (EGD) starting at age 25 to 30 years or earlier in symptomatic patients. However, there are few reports describing upper GI tract involvement in children with FAP which support the notion of early screening. The aim of our study is to understand the prevalence and severity of upper GI involvement in children with FAP.

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Short- and long-term changes of the pharyngeal airway after surgical mandibular advancement in Class II patients—a three-dimensional retrospective study

To evaluate the short- and long-term impact of mandibular-only advancement on pharyngeal airway space (PAS) changes by using cone-beam computed tomography (CBCT) and a new segmentation software. Furthermore, to determine whether a correlation exists between forward movement and PAS gain.

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How a diverse research ecosystem has generated new rehabilitation technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. ...

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Wireless intraoral tongue control of an assistive robotic arm for individuals with tetraplegia

For an individual with tetraplegia assistive robotic arms provide a potentially invaluable opportunity for rehabilitation. However, there is a lack of available control methods to allow these individuals to fu...

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Salivary Aerobics

I read with interest the paper by Meng et al, 'Sialoendoscopy combined with an internal stent and postoperative massage as a comprehensive treatment of delayed I131-induced parotitis.'1

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Study of anatomical variations of the zygomaticofacial foramen and calculation of reliable reference points for operation

Dissection on to the facial aspect of the zygoma is common in procedures of the midface for trauma, craniofacial deformity, and cosmesis. These procedures carry the risk of injury to the neurovascular structures that exit from the zygomaticofacial foramen (ZFF). The purpose of this study was to map the ZFF, and to establish reliable reference points from which to identify it before and during operation. We also aimed to compare the anatomy of the ZFF between sexes and among geographical populations.

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Restructuring the Vocal Fatigue Index Using Mokken Scaling: Insights Into the Complex Nature of Vocal Fatigue

Vocal fatigue is a frequent symptom and a debilitating condition affecting individuals with voice disorders. In spite of the various attempts to define and quantify vocal fatigue, this complex trait has not been well understood. Mokken scaling was performed on the Vocal Fatigue Index (VFI) to develop a hierarchical understanding of the latent trait of vocal fatigue. Two hundred nine patients with voice disorders completed the VFI and provided the item responses necessary to complete the Mokken scaling.

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Clinical Features of Psychogenic Voice Disorder and the Efficiency of Voice Therapy and Psychological Evaluation

The aim of this study was to define the clinical features of psychogenic voice disorder (PVD) and explore the treatment efficiency of voice therapy and psychological evaluation.

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Observer Agreement for Measurements in Videolaryngostroboscopy

This study evaluated the levels of intraobserver and interobserver agreement for measurements of visuoperceptual variables in videolaryngostroboscopic examinations and compared the observers' behavior during independent versus consensus panel rating.

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The Effect of Hydration on Voice Quality in Adults: A Systematic Review

We aimed to critically appraise scientific, peer-reviewed articles, published in the past 10 years on the effects of hydration on voice quality in adults.

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Differences between Subjective and Objective Assessment of Speech Deficiency in Parkinson Disease

This study aims to establish the frequency at which patients with Parkinson disease subjectively assess the intensity of their speech disorders, factors that the patients believe determine the severity of their vocal impairment, and how their subjective self-assessment of vocal impairment by means of the Voice Handicap Index compares with the objective evaluation of the performance of the articulatory organs by means of Frenchay Dysarthria Assessment.

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The Effects of Amplification on Vocal Dose in Teachers with Dysphonia

The purpose of this study was to determine if voice amplification influenced vocal dose in female teachers with dysphonia.

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Reply to: “Reliability and Validity of Speech Evaluation in Adductor Spasmodic Dysphonia; Common Mistake and Statistical Issues” by Saori Yanagida

We thank Dr. Sabour for his interest in our article "Reliability and validity of speech evaluation in adductor spasmodic dysphonia."1 In this research, Pearson correlation coefficient was obtained for the purpose of evaluating the intra- and interrater or intra- and intermeasurer reliabilities for perceptual evaluation and acoustic measures. As Dr. Sabour pointed out, calculation of the intraclass correlation coefficient (ICC) showed there was almost no difference between that value and Pearson correlation coefficient (Tables 1, 2).

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Abnormal Cortical Neural Synchrony During Working Memory in Schizophrenia

Working memory (WM) encompasses the encoding, maintenance, and retrieval of mental representations that guide behavior (Baddeley, 2012; Miyake and Shah, 1999). Recent experimental studies have demonstrated that people with schizophrenia (PSZ) have WM storage capacity deficits which is not simply explained by instability in WM mental representation (Gold et al., 2010) or attentional deficits (Erickson et al., 2015), suggesting that problems in multiple neural processes might contribute to limited WM capacity in PSZ.

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RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming

The restless legs syndrome (RLS) is a sensory-motor disorder characterized by uncomfortable sensations, especially in the legs, combined with an urge to move. The symptoms are most pronounced at rest in the evening and at night (Allen et al., 2014b; Allen, 2015). In spite of the circadian variation of those sensory and motor symptoms, diurnal changes of potentially associated cognitive functions as well as the underlying neurophysiological and neuroanatomical processes have not yet been investigated.

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Bilateral loss of cortical SEPs predict severe MRI lesions in neonatal hypoxic ischemic encephalopathy treated with hypothermia

Hypoxic-ischemic encephalopathy (HIE) in term neonates is a significant cause of infant mortality and morbidity. As a routine, early assessment of neonatal encephalopathy is based on clinical observation (graded by Sarnat and Sarnat, 1976), MRI and EEG recordings of brain electrical activity while the acquisition of somatosensory evoked potentials (SEPs) in the neonatal period is often hampered by logistic reasons. After moderate whole-body hypothermia (therapeutic hypothermia- TH) proved its efficacy and safety in reducing death and cerebral palsy and improving neurological outcome (Azzopardi et al, 2009), clinicians and researchers needed to test its influence on the most widely used prognostic tools.

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Robotic-assisted DIEP flap harvest: a feasibility study on cadaveric model

The DIEP flap has reduced the incidence of abdominal wall complications compared to the TRAM flap [1]. However, this risk still remains [1-2] because the anterior sheath of the rectus muscle needs to be incised longitudinally to dissect the deep inferior epigastric vessels. We believe that robotic dissection of the deep inferior epigastric vessels may reduce donor site morbidity by preserving the anterior sheath of the rectus muscle as much as possible. The aim of this study was to assess the technical feasibility of DIEP flap harvest with robotically assisted dissection of the deep inferior epigastric vessels.

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Prospective Randomized Trial Evaluating Ketamine for Adult Bronchoscopy

Background and Objectives: Ketamine has been used in pediatric flexible fiberoptic bronchoscopy (FFB). Its efficacy and safety for sedation of adults undergoing FFB has not been thoroughly investigated, and, consequently, it is not used by most interventional bronchoscopists. We aimed to evaluate the safety and efficacy of sedation for FFB under ketamine-propofol-midazolam (KPM) compared with the fentanyl-propofol-midazolam (FPM) regimen. Materials and Methods: This was a prospective randomized trial of adult patients (n=80) undergoing FFB, randomized to receive sedation with either KPM (n=39) or FPM (n=41). Vital signs including transcutaneous carbon dioxide tension (TcPCO2) were continuously monitored. Sedation-related complications and interventions to maintain respiratory and hemodynamic stability were compared. Both operator and patient were blinded to the sedation regimen used. The operator's and patient's satisfaction from sedation were assessed following recovery. Results: Maximal intraprocedural TcPCO2 values and minimal oxygen saturation did not differ significantly between the KPM and FPM groups (63.2±11.4 mm Hg vs. 61.1±7.2 mm Hg) and (77.1%±12.5% vs. 81.8%±12.0%), respectively. No significant differences were noted between the KPM and FPM groups with respect to sedation-related respiratory or hemodynamic complications. The operator's and patient's satisfaction from sedation was similar between the groups. Conclusions: Ketamine is as safe and effective as fentanyl for adult analgesia and sedation during FFB. In light of this observation and the fact that ketamine does not cause hemodynamic suppression, like most sedative agents, and is a potent bronchodilator, should encourage its more widespread use for adult sedation during FFB.

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Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)–mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R–associated kinase 1 (IRAK1) ubiquitination. β-TrCP–IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys¹³⁴ and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-B and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein–protein interactions between β-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of β-TrCP–IRAK1 interactions. This GC-mediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand–induced K48-linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys¹³⁴ prevent TLR9 ligand–induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand–mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.

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Filamin A Regulates Neutrophil Adhesion, Production of Reactive Oxygen Species, and Neutrophil Extracellular Trap Release [INNATE IMMUNITY AND INFLAMMATION]

Neutrophils are of fundamental importance in the early immune response and use various mechanisms to neutralize invading pathogens. They kill endocytosed pathogens by releasing reactive oxygen species in the phagosome and release neutrophil extracellular traps (NETs) into their surroundings to immobilize and kill invading micro-organisms. Filamin A (FlnA) is an important actin cross-linking protein that is required for cellular processes involving actin rearrangements, such cell migration. It has also been shown to negatively regulate integrin activation and adhesion. However, its role in the regulation of β₂ integrin–dependent adhesion, as well as in other cellular functions in neutrophils, is poorly understood. Using a transgenic mouse model in which FlnA is selectively depleted in myeloid cells, such as neutrophils, we show that FlnA negatively regulates β₂ integrin adhesion to complement component iC3b and ICAM-1 in shear-free, but not shear-flow, conditions. FlnA deletion does not affect phagocytosis of Escherichia coli or Staphylococcus aureus or their intracellular killing. However, FlnA negatively regulates production of reactive oxygen species upon cell activation. Conversely, neutrophil activation through TLR4, as well as through activation by the Gram-negative bacteria E. coli, results in reduced NET production in FlnA-depleted neutrophils. Thus, FlnA is a negative regulator of β₂ integrin–dependent cell adhesion and reactive oxygen species production but is required for NET production in primary murine neutrophils.

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Endoplasmic Reticulum Transmembrane Proteins ZDHHC1 and STING Both Act as Direct Adaptors for IRF3 Activation in Teleost [INNATE IMMUNITY AND INFLAMMATION]

IFN regulatory factor (IRF)3 is a central regulator for IFN-β expression in different types of pathogenic infections. Mammals have various pathogenic sensors that are involved in monitoring pathogen intrusions. These sensors can trigger IRF3-mediated antiviral responses through different pathways. Endoplasmic reticulum–associated proteins stimulator of IFN gene (STING) and zinc finger DHHC-type containing 1 (ZDHHC1) are critical mediators of IRF3 activation in response to viral DNA infections. In this study, grass carp STING and ZDHHC1 were found to have some similar molecular features and subcellular localization, and both were upregulated upon stimulation with polyinosinic:polycytidylic acid, B-DNA, or Z-DNA. Based on these results, we suggest that grass carp STING and ZDHHC1 might possess some properties similar to their mammalian counterparts. Overexpression of ZDHHC1 and STING in Ctenopharyngodon idella kidney cells upregulated IFN expression, whereas knockdown of IRF3 inhibited IFN activation. In addition, coimmunoprecipitation and GST pull-down assays demonstrated that STING and ZDHHC1 can interact separately with IRF3 and promote the dimerization and nuclear translocation of IRF3. Furthermore, we also found that small interfering RNA–mediated knockdown of STING could inhibit the expression of IFN and ZDHHC1 in fish cells. Similarly, knockdown of STING resulted in inhibition of the IFN promoter. In contrast, ZDHHC1 knockdown also inhibited IFN expression but had no apparent effect on STING, which indicates that STING is necessary for IFN activation through ZDHHC1. In conclusion, STING and ZDHHC1 in fish can respond to viral DNA or RNA molecules in cytoplasm, as well as activate IRF3 and, eventually, trigger IFN expression.

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ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

The nucleotide-binding oligomerization domain–like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a molecular platform that induces caspase-1 activation and subsequent IL-1β maturation, and is implicated in inflammatory diseases; however, little is known about the negative regulation of NLRP3 inflammasome activation. In this article, we identified an E3 ligase, Ariadne homolog 2 (ARIH2), as a posttranslational negative regulator of NLRP3 inflammasome activity in macrophages. ARIH2 interacted with NLRP3 via its NACHT domain (aa 220–575) in the NLRP3 inflammasome complex. In particular, we found that while using mutants of ARIH2 and ubiquitin, the really interesting new gene 2 domain of ARIH2 was required for NLRP3 ubiquitination linked through K48 and K63. Deletion of endogenous ARIH2 using CRISPR/Cas9 genome editing inhibited NLRP3 ubiquitination and promoted NLRP3 inflammasome activation, resulting in apoptosis-associated speck-like protein containing a caspase recruitment domain oligomerization, pro–IL-1β processing, and IL-1β production. Conversely, ARIH2 overexpression promoted NLRP3 ubiquitination and inhibited NLRP3 inflammasome activation. Our findings reveal a novel mechanism of ubiquitination-dependent negative regulation of the NLRP3 inflammasome by ARIH2 and highlight ARIH2 as a potential therapeutic target for inflammatory diseases.

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Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock [INNATE IMMUNITY AND INFLAMMATION]

Critically ill patients typically present with hyperglycemia. Treatment with conventional insulin therapy (targeting 144–180 mg/dl) improves patient survival; however, intensive insulin therapy (IIT) targeting normal blood glucose levels (81–108 mg/dl) increases the incidence of moderate and severe hypoglycemia, and increases mortality. Septic patients are especially prone to IIT-induced hypoglycemia, but the mechanism remains unknown. Here, we show that codelivery of insulin with otherwise sublethal doses of LPS induced hypoglycemic shock in mice within 1–2 h. LPS impaired clearance of insulin, which amplified insulin receptor signaling. These effects were mediated by caspase-11, TLR4, and complement, each of which trigger eicosanoid production that potentiates insulin signaling. Finally, in an animal model of sepsis, we observed that Salmonella typhimurium–infected mice exhibited simultaneous impaired insulin clearance coexisting with insulin resistance. Our results raise the possibility that septic patients have impaired insulin clearance, which could increase their susceptibility to hypoglycemia during IIT, contraindicating its use.

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Macrophage-Specific Expression of IL-37 in Hyperlipidemic Mice Attenuates Atherosclerosis [INNATE IMMUNITY AND INFLAMMATION]

Atherosclerosis, the progressive buildup of plaque within arterial blood vessels, can lead to fatal downstream events, such as heart attack or stroke. A key event contributing to the development of atherosclerosis is the infiltration of monocytes and its associated inflammation, as well as the formation of lipid-laden macrophage foam cells within the vessel wall. IL-37 is recognized as an important anti-inflammatory cytokine expressed especially by immune cells. This study was undertaken to elucidate the role of macrophage-expressed IL-37 in reducing the production and effects of proinflammatory cytokines, preventing foam cell formation, and reducing the development of atherosclerosis. Expression of human IL-37 was achieved with a macrophage-specific overexpression system, using the CD68 promoter in mouse primary bone marrow–derived macrophages via retroviral transduction. Macrophage IL-37 expression in vitro resulted in decreased mRNA (e.g., IL-1B, IL-6, and IL-12) and secreted protein production (e.g., IL-6, M-CSF, and ICAM-1) of key inflammatory mediators. IL-37 expression also inhibited macrophage proliferation, apoptosis, and transmigration, as well as reduced lipid uptake, compared with controls in vitro. The in vivo effects of macrophage-expressed IL-37 were investigated through bone marrow transplantation of transduced hematopoietic stem cells into irradiated atherosclerosis-prone Ldlr^–/– mice. After 10 wk on a high-fat/high-cholesterol diet, mice with IL-37–expressing macrophages showed reduced disease pathogenesis, which was demonstrated by significantly less arterial plaque development and systemic inflammation compared with control mice. The athero-protective effect of macrophage-expressed IL-37 has implications for development of future therapies to treat atherosclerosis, as well as other chronic inflammatory diseases.

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Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model [INNATE IMMUNITY AND INFLAMMATION]

Innate defense regulator (IDR) peptide-1002 is a synthetic host defense peptide derivative with strong anti-inflammatory properties. Extending previous data, IDR-1002 suppressed in vitro inflammatory responses in RAW 264.7 murine monocyte/macrophage cells challenged with the TLR4 agonist LPS and TLR2 agonists lipoteichoic acid and zymosan. To investigate the anti-inflammatory mechanisms of IDR-1002 in vivo, the PMA-induced mouse ear inflammation model was used. Topical IDR-1002 treatment successfully dampened PMA-induced ear edema, proinflammatory cytokine production, reactive oxygen and nitrogen species release, and neutrophil recruitment in the ears of CD1 mice. Advanced RNA transcriptomic analysis on the mouse ear transcriptome revealed that IDR-1002 reduced sterile inflammation by suppressing the expression of transmembrane G protein–coupled receptors (class A/1 rhodopsin-like), including receptors for chemokines, PGs, histamine, platelet activating factor, and anaphylatoxin. IDR-1002 also dampened the IFN- response and repressed the IFN regulatory factor 8–regulated network that controls central inflammatory pathways. This study demonstrates that IDR-1002 exhibits strong in vitro and in vivo anti-inflammatory activities, informs the underlying anti-inflammatory mechanisms, and reveals its potential as a novel therapeutic for inflammatory diseases.

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Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation [IMMUNE SYSTEM DEVELOPMENT]

The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII)^lo to mature MHCII^hi mTECs has recently been extended to include a third stage, namely the post-Aire MHCII^lo subset as identified by lineage-tracing models. However, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire MHCII^lo stage has been lacking. In this study, we introduce the lectin Tetragonolobus purpureas agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPA^loMHCII^lo -> TPA^loMHCII^hi -> TPA^hiMHCII^hi -> TPA^hiMHCII^lo. Surprisingly, in the steady-state postnatal thymus TPA^loMHCII^lo pre-Aire rather than terminally differentiated post-Aire TPA^hiMHCII^lo mTECs were marked for apoptosis at an exceptionally high rate of ~70%. Hence, only the minor cycling fraction of the MHCII^lo subset (<20%) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA also further subdivided human mTECs, although with different subset distribution. Our revised road map emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death, namely cornification rather than apoptosis. The high rate of apoptosis in pre-Aire MHCII^lo mTECs points to a "quality control" step during early mTEC differentiation.

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The NF-{kappa}B-Responsive Long Noncoding RNA FIRRE Regulates Posttranscriptional Regulation of Inflammatory Gene Expression through Interacting with hnRNPU [INNATE IMMUNITY AND INFLAMMATION]

Long noncoding RNAs, a newly identified class of noncoding RNAs, are important regulators of gene expression in innate immunity. We report in this study that the transcription of FIRRE, a conserved long noncoding RNA between humans and mice, is controlled by NF-B signaling in macrophages and intestinal epithelial cells. Functionally, FIRRE appears to positively regulate the expression of several inflammatory genes in macrophages or intestinal epithelial cells in response to LPS stimulation via posttranscriptional mechanisms. Specifically, FIRRE physically interacts with heterogeneous nuclear ribonucleoproteins U, regulating the stability of mRNAs of selected inflammatory genes through targeting the AU-rich elements of their mRNAs in cells following LPS stimulation. Therefore, our data indicate a new regulatory role for NF-B–responsive FIRRE in the posttranscriptional regulation of inflammatory genes in the innate immune system.

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Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-{kappa}B Signaling following Brain Injury [INNATE IMMUNITY AND INFLAMMATION]

Traumatic and nontraumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity, and free-radical release, contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we used Nlrx1^–/– mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). In this article, we show that Nlrx1^–/– mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-B signaling cascade is significantly upregulated in Nlrx1^–/– animals. This upregulation is associated with increased microglia and macrophage populations in the cortical lesion. Using a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-B signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host–pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

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Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis [IMMUNE SYSTEM DEVELOPMENT]

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34⁺ hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo-p-dioxin–elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.

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Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice [IMMUNE SYSTEM DEVELOPMENT]

Short-chain fatty acids (SCFAs), the end products of dietary fiber, influence the immune system. Moreover, during pregnancy the maternal microbiome has a great impact on the development of the offspring's immune system. However, the exact mechanisms by which maternal SCFAs during pregnancy and lactation influence the immune system of offspring are not fully understood. We investigated the molecular mechanisms underlying regulatory T cell (T_reg) differentiation in offspring regulated by a maternal high fiber diet (HFD). Plasma levels of SCFAs in offspring from HFD-fed mice were higher than in those from no fiber diet–fed mice. Consequently, the offspring from HFD-fed mice had higher frequencies of thymic T_reg (tT_reg) and peripheral T_regs. We found that the offspring of HFD-fed mice exhibited higher autoimmune regulator (Aire) expression, a transcription factor expressed in the thymic microenvironment, suggesting SCFAs promote tT_reg differentiation through increased Aire expression. Notably, the receptor for butyrate, G protein–coupled receptor 41 (GPR41), is highly expressed in the thymic microenvironment and Aire expression is not increased by stimulation with butyrate in GPR41-deficient mice. Our studies highlight the significance of SCFAs produced by a maternal HFD for T_reg differentiation in the thymus of offspring. Given that Aire expression is associated with the induction of tT_regs, the maternal microbiome influences T_reg differentiation in the thymus of offspring through GPR41-mediated Aire expression.

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Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli [INNATE IMMUNITY AND INFLAMMATION]

Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. In this article, we demonstrate that Rab27a and Rab27b double-knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by wild-type (WT) hematopoietic cells or administration of exosomes produced by GM-CSF–expanded bone marrow cells. In addition, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT, but not miR-155^–/–, cells, suggesting that uptake of miR-155–containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased after treatment with WT, but not miR-155^–/–, exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.

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STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr-/- Mice [IMMUNE REGULATION]

The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4^–/–Ldlr^–/– mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4^–/–Ldlr^–/– mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr^–/– controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8⁺ regulatory T cells (Tregs) in spleens and aortas of Stat4^–/–Ldlr^–/– mice compared with Ldlr^–/– mice. Similarly, STAT4 deficiency supported CD8⁺ Treg differentiation in vitro. STAT4-deficient CD8⁺ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8⁺ Treg functions in vivo. Furthermore, adoptive transfer of Stat4^–/–Ldlr^–/– CD8⁺ Tregs versus Ldlr^–/– CD8⁺ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr^–/– recipients. STAT4 expression in macrophages (Ms) also affected the Tfh/CD8⁺ Treg axis, because conditioned media from Stat4^–/–Ldlr^–/– Ms supported CD8⁺ Treg differentiation, but not Tfh cell differentiation, in a TGF-β–dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr^–/– mice via STAT4-dependent Ms, as well as cell-intrinsic suppression of CD8⁺ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.

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Nonclassical Monocytes Mediate Secondary Injury, Neurocognitive Outcome, and Neutrophil Infiltration after Traumatic Brain Injury [INNATE IMMUNITY AND INFLAMMATION]

Traumatic brain injury (TBI) results in rapid recruitment of leukocytes into the injured brain. Monocytes constitute a significant proportion of the initial infiltrate and have the potential to propagate secondary brain injury or generate an environment of repair and regeneration. Monocytes are a diverse population of cells (classical, intermediate, and nonclassical) with distinct functions, however, the recruitment order of these subpopulations to the injured brain largely remains unknown. Thus, we examined which monocyte subpopulations are required for the generation of early inflammatory infiltrate within the injured brain, and whether their depletion attenuates secondary injury or neurocognitive outcome. Global monocyte depletion correlated with significant improvements in brain edema, motor coordination, and working memory, and abrogated neutrophil infiltration into the injured brain. However, targeted depletion of classical monocytes alone had no effect on neutrophil recruitment to the site of injury, implicating the nonclassical monocyte in this process. In contrast, mice that have markedly reduced numbers of nonclassical monocytes (CX3CR1^–/–) exhibited a significant reduction in neutrophil infiltration into the brain after TBI as compared with control mice. Our data suggest a critical role for nonclassical monocytes in the pathology of TBI in mice, including important clinical outcomes associated with mortality in this injury process.

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Reactive Oxygen Species Regulate the Inflammatory Function of NKT Cells through Promyelocytic Leukemia Zinc Finger [IMMUNE REGULATION]

Reactive oxygen species (ROS) are byproducts of aerobic metabolism and contribute to both physiological and pathological conditions as second messengers. ROS are essential for activation of T cells, but how ROS influence NKT cells is unknown. In the present study, we investigated the role of ROS in NKT cell function. We found that NKT cells, but not CD4 or CD8 T cells, have dramatically high ROS in the spleen and liver of mice but not in the thymus or adipose tissues. Accordingly, ROS-high NKT cells exhibited increased susceptibility and apoptotic cell death with oxidative stress. High ROS in the peripheral NKT cells were primarily produced by NADPH oxidases and not mitochondria. We observed that sorted ROS-high NKT cells were enriched in NKT1 and NKT17 cells, whereas NKT2 cells were dominant in ROS-low cells. Furthermore, treatment of NKT cells with antioxidants led to reduced frequencies of IFN-– and IL-17–expressing cells, indicating that ROS play a role in regulating the inflammatory function of NKT cells. The transcription factor promyelocytic leukemia zinc finger (PLZF) seemed to control the ROS levels. NKT cells from adipose tissues that do not express PLZF and those from PLZF haplodeficient mice have low ROS. Conversely, ROS were highly elevated in CD4 T cells from mice ectopically expressing PLZF. Thus, our findings demonstrate that PLZF controls ROS levels, which in turn governs the inflammatory function of NKT cells.

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T cells are involve in the induction of macrophage phenotypes in oral leukoplakia and squamous cell carcinoma – a preliminary report

Abstract

Background

The prognosis of human malignancies has been shown to depend on immunological parameters, such as macrophage polarisation (M1 and M2). In the present study, we identify the phenotype of macrophages, and investigate an involvement of infiltrated T cells that participate in the polarization of macrophages, in oral leukoplakia (OLK), and oral squamous cell carcinoma (OSCC).

Methods

Immunohistochemical method was used to examine the number of CD68⁺, CD163⁺ (M2), iNOS⁺ (M1) macrophages, and CD4⁺, CD8⁺, CCR4⁺ (Th2), CCR5⁺ (Th1) cells in 102 cases of OSCC: without metastases – OSCC M(-) (n=54), and with metastases – OSCC M(+) (n=48), 23 cases of OLK, and 18 control cases.

Results

The mean number of CD68⁺, CD163⁺, iNOS⁺, CD4⁺, CCR4⁺, CCR5⁺ cells was significantly increased in OSCC M(+) group compared with OLK, OSCC M(-) and control group. We found positive correlations between the number of CD4⁺ T cells and CD163⁺ and iNOS⁺ macrophages as well as CCR4⁺ and CCR5⁺ cells in both OSCC groups. The mean number of CD8⁺ cells was significantly increased in OSCC M(-) and OLK compared with OSCC M(+) and control group. In OSCC M(+) and OSCC M(-) groups a negative correlation between the number of CD8⁺ cells and CD163⁺ and iNOS⁺ macrophages was found.

Conclusions

The number and co-localization of lymphocytes and macrophages in OLK and OSCC, may indicate that infiltrating cells influence the early and subsequent stage of oral carcinogenesis.

This article is protected by copyright. All rights reserved.

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Antiangiogenic therapy in breast cancer

Summary

Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2)-negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer.

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Application of the 2016 diagnostic approach for autoimmune encephalitis from Lancet Neurology to Chinese patients

A unified clinical approach to diagnose autoimmune encephalitis was published in Lancet Neurology in 2016. Purpose of our study is to examine the feasibility and reasonability of the 2016 "A clinical approach to ...

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Extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a BRAF V600E and PD-L1 positive metastatic lung adenocarcinoma

Abstract

Background

The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression.

Case presentation

We present a case of 74-year-old female, former smoker with metastatic lung adenocarcinoma. The BRAF V600E mutation among other abnormalities was identified by comprehensive genomic profiling. The patient had an excellent 2-year response to the combination of pemetrexed and sorafenib. The patient was then treated with dabrafenib due to the presence of the BRAF V600E mutation and intolerance to cytotoxic chemotherapy. Not only the patient had an 18-month durable response to dabrafenib, she experienced outstanding quality of life with no serious adverse effects. At the time of symptomatic progression, the patient was then treated with two cycles of pembrolizumab based on her positive PD-L1 staining (90%). She had early response and came off pembrolizumab due to side effects. Seven months after initiation of pembrolizumab, the patient is off all the therapy and is currently asymptomatic. The patient is surviving with metastatic disease for over 7 years as of to date.

Conclusions

By appropriately sequencing the three main modalities of systemic therapies, we are able to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. We argue that it is reasonable to first use a BRAF inhibitor before considering immunotherapy for NSCLCs positive for both BRAF V600E and PD-L1.

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Practice and Safety of Allergen Specific Immunotherapy for Allergic Rhinitis in the UK National Health Service: A report of ‘real world’ clinical practice

Abstract

Allergen specific immunotherapy (SIT) alleviates symptoms, improves health-related quality of life and alters the natural course of the disease in patients suffering from allergic rhinitis. It is currently delivered in the UK National Health Service (NHS) via 2 modalities namely subcutaneous injection immunotherapy (SCIT) and sublingual immunotherapy (SLIT). The latter has a superior safety profile – anaphylaxis is a rare occurrence. Most vaccines currently employed for SIT in the UK NHS are unlicensed and available on a named-patient basis and prescribed in secondary care by a specialist.

This article is protected by copyright. All rights reserved.

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Intensive Treatment for Persisting Rhotic Distortions: A Case Series

Purpose

The study explored changes in accuracy of American English rhotics as a result of an intensive 1-week therapy program for adolescents and young adults with residual speech sound errors that had not resolved with previous therapy.

Method

Four case reports are presented of individuals aged 13, 17, 21, and 22 years with residual /ɹ/ distortions. Each participant attended a 1-week intensive program consisting of pretreatment assessments, 14 hr of therapy, and posttreatment assessment. Treatment sessions included structured motor-based practice, ultrasound visual feedback of the tongue, and auditory speech perception training. To assess generalization, untreated words and sentences with rhotics were recorded before and after therapy; these were rated by listeners who were blind to when the recordings were taken.

Results

All participants showed measurable and statistically significant improvement in speech sound accuracy. Averaged across the 4 participants, rhotic accuracy at the word level improved from 35% to 83%. At the sentence level, rhotic accuracy increased from 11% pretreatment to 66% posttreatment in 1 week.

Conclusion

The promise of an intensive treatment program that includes motor-based practice, biofeedback, and auditory perception training is illustrated by the case presentations in which substantial improvements in speech sound accuracy were observed.

Supplemental Materials

http://ift.tt/2iA3f0l

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_AJSLP-16-0232/2662764/Intensive-Treatment-for-Persisting-Rhotic

The Impact of Expiratory Muscle Strength Training on Speech Breathing in Individuals With Parkinson's Disease: A Preliminary Study

Purpose

The purpose of this study was to examine the impact of expiratory muscle strength training on speech breathing and functional speech outcomes in individuals with Parkinson's disease (PD).

Method

Twelve individuals with PD were seen once a week for 8 weeks: 4 pretraining (baseline) sessions followed by a 4-week training period. Posttraining data were collected at the end of the 4th week of training. Maximum expiratory pressure, an indicator of expiratory muscle strength, and lung volume at speech initiation were the primary outcome measures. Secondary outcomes included lung volume at speech termination, lung volume excursion, utterance length, and vocal intensity. Data were collected during a spontaneous speech sample. Individual effect sizes > 1 were considered significant.

Results

Maximum expiratory pressure increased in a majority of participants after training. Training resulted in 2 main respiratory patterns: increasing or decreasing lung volume initiation. Lung volume termination and excursion, utterance length, and vocal loudness were not consistently altered by training.

Conclusions

Preliminary evidence suggests that the direct physiologic intervention of the respiratory system via expiratory muscle strength training improves speech breathing in individuals with PD, with participants using more typical lung volumes for speech following treatment.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_AJSLP-16-0132/2662761/The-Impact-of-Expiratory-Muscle-Strength-Training

The Effect of Hand Gesture Cues Within the Treatment of /r/ for a College-Aged Adult With Persisting Childhood Apraxia of Speech

Purpose

Despite the widespread use of hand movements as visual and kinesthetic cues to facilitate accurate speech produced by individuals with speech sound disorders (SSDs), no experimental investigation of gestural cues that mimic that spatiotemporal parameters of speech sounds (e.g., holding fingers and thumb together and "popping" them to cue /p/) currently exists. The purpose of this study was to examine the effectiveness of manual mimicry cues within a multisensory intervention of persisting childhood apraxia of speech (CAS).

Method

A single-subject ABAB withdrawal design was implemented to assess the accuracy of vowel + /r/ combinations produced by a 21-year-old woman with persisting CAS. The effect of manual mimicry gestures paired with multisensory therapy consisting of verbal instructions and visual modeling was assessed via clinician and naïve listener ratings of target sound accuracy.

Results

According to the perceptual ratings of the treating clinician and 28 naïve listeners, the participant demonstrated improved speech sound accuracy as a function of the manual mimicry/multisensory therapy.

Conclusions

These data offer preliminary support for the incorporation of gestural cues in therapy for CAS and other SSDs. The need for continued research on the interaction of speech and manual movements for individuals with SSDs is discussed.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_AJSLP-15-0172/2662760/The-Effect-of-Hand-Gesture-Cues-Within-the

South Asian Adults' Performance on Executive Function Tests

Purpose

This study compared the performance of South Asian and White adults on the Behavioural Assessment of the Dysexecutive Syndrome (BADS; Wilson, Alderman, Burgess, Emslie, & Evans, 1996) and the Functional Assessment of Verbal Reasoning and Executive Strategies (FAVRES; MacDonald, 2005), tests that can be used by speech-language pathologists to assess executive function (EF).

Method

Twenty South Asian and 20 White participants were administered the BADS and FAVRES. Raw scores were converted to profile scores on the BADS and to standard scores on the FAVRES. Analysis of covariance statistics were calculated to compare EF test performance.

Results

South Asian and White participants did not demonstrate significant performance differences on the BADS. On the FAVRES, Whites had significantly higher accuracy scores on 2 of the 4 subtests and significantly higher rationale scores on 3 subtests. South Asian adults who completed all of their formal education in India had lower accuracy and rationale scores on 2 of the 4 subtests versus South Asian adults who completed at least some of their formal education in North America. No significant differences occurred on the Time scores for any subtest or on the overall Reasoning score.

Conclusions

Performance differences on EF tests may exist between South Asian and White adults. Further research is necessary to determine the impact of cultural and linguistic differences on EF test performance in South Asian adults.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_AJSLP-16-0173/2662762/South-Asian-Adults-Performance-on-Executive

Long intergenic non-protein-coding RNA 1567 (LINC01567) acts as a “sponge” against microRNA-93 in regulating the proliferation and tumorigenesis of human colon cancer stem cells

Abstract

Background

Cancer stem cells (CSCs) are considered to be the major factor in tumor initiation, progression, metastasis, recurrence and chemoresistance. Maintaining the stemness and promoting differentiation of these cells involve various factors. Recently, long non-coding RNAs (lncRNAs) have been identified as new regulatory factors in human cancer cells. However, the function of lncRNAs in colon CSCs is still unknown.

Methods

Primary colon cancer cells were maintained in serum-free medium to form spheres and CD133⁺/CD166⁺/CD44⁺ spheroid cells were selected using FACS technique. Then we detected growth curve, colony formation, invasion and migration ability, and tumorigenicity of CD133⁺/CD166⁺/CD44⁺ cells. LOCCS-siRNA and pcDNA-LOCCS plasmid vectors were constructed and transfected to evaluate impact of the lncRNA. We also performed dual luciferase reporter assay to verify the interaction of LOCCS and miR-93.

Results

The research explored lncRNA expression and the regulatory role of novel lncRNAs in colon CSCs. Using the stem cell markers CD133, CD166 and CD44, we found a subpopulation of highly tumorigenic human colon cancer cells. They displayed some characteristics of stem cells, including the ability to proliferate and form colonies, to resist chemotherapeutic drugs, and to produce xenografts in nude mice. We also found an lncRNA, LOCCS, with obviously upregulated expression in colon CSCs. Knockdown of LOCCS reduced cell proliferation, invasion, migration, and generation of tumor xenografts. Furthermore, microRNA-93 (miR-93) and Musashi-1 mediated the tumor suppression of LOCCS knockdown.

Conclusions

There was reciprocal repression between LOCCS and miR-93. Research on mechanisms suggested direct binding, as a predicted miR-93 binding site was identified in LOCCS. This comprehensive analysis of LOCCS in colon CSCs provides insight for elucidating important roles of the lncRNA–microRNA functional network in human colon cancer.

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Physical activity-based interventions using electronic feedback may be ineffective for reducing pain and disability in patients with chronic musculoskeletal pain: a systematic review with meta-analysis

Publication date: Available online 6 November 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Crystian B. Oliveira, Márcia R. Franco, Chris G. Maher, Paulo H. Ferreira, Priscila K. Morelhão, Tatiana M. Damato, Cynthia Gobbi, Rafael Z. Pinto
ObjectiveTo investigate the effectiveness of physical activity-based interventions using electronic feedback to reduce pain and disability compared to minimal or no interventions in patients with chronic musculoskeletal pain.DesignSystematic review with meta-analysisData SourcesThe following electronic databases were searched: EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, SPORTDiscus, Web of Science, Physiotherapy Evidence Database (PEDro), and main clinical trial registers.Study SelectionRandomized controlled trials (RCTs) investigating the effect of physical activity interventions using electronic feedback (eg. physical activity monitors) on pain and disability compared to minimal or no intervention in adults with chronic musculoskeletal pain were considered eligible.Data ExtractionPooled effects were calculated using the standardized mean difference (SMD) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the overall quality of evidence.Data SynthesisFour published RCTs and four registered unpublished RCTs were included. For short-term follow-up, pooled estimations showed no significant differences between physical activity-based interventions compared to minimal intervention on pain intensity (two trials; n= 116; SMD=-0.50; 95% CI -1.91 to 0.91) and disability (two trials, n= 116; SMD=-0.81 95% CI -2.34 to 0.73). Similarly, non-significant results were found for the intermediate-term. According to GRADE, the overall quality of evidence was considered to be of low quality.ConclusionOur findings suggest that physical activity-based interventions using with electronic feedback may be ineffective for reducing pain and disability compared to minimal intervention for patients with chronic musculoskeletal pain. Clinicians should be cautious when implementing this intervention in patients with chronic musculoskeletal pain.



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Psychometric evaluation of the Brachial Assessment Tool Part 1: Reproducibility

Publication date: Available online 6 November 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Bridget Hill Grad, Gavin Williams, John Olver, Scott Ferris, Andrea Bialocerkowski
ObjectiveTo evaluate reproducibility (reliability and agreement) of the Brachial Assessment Tool (BrAT) a new patient-reported outcome measure for adults with traumatic Brachial Plexus Injury (BPI)DesignProspective repeated measure designSettingOutpatient clinicsParticipantsAdults with confirmed traumatic BPIIntervention43 people (age range 19-82) with BPI completed the 31-item 4-response BrAT twice, 2 weeks apart. Results for the 3 subscales and summed score were compared at time 1 and time 2 to determine reliability including systematic differences using paired t tests; test retest using Intraclass Correlation Coefficient (ICC 1,1) and internal consistency using Cronbach alpha. Agreement parameters included standard error of measurement, minimal detectable change and limits of agreement.Main outcome measureThe BrATResultsTest retest reliability was excellent (ICC [1,1] = 0.90 – 0.97). Internal consistency was high (Cronbach alpha 0.90 - 0.98). Measurement error was relatively low (SEM range 3.1 - 8.8). A change of >4 for subscale 1, >6 for subscale 2, >4 for subscale 3 and >10 for the summed score is indicative of change over and above measurement error. Limits of agreement ranged from ± 4.4 (subscale 3) to 11.61 (summed score).ConclusionThese findings support the use of the BrAT as a reproducible patient reported outcome measure for adults with traumatic BPI with evidence of appropriate reliability and agreement for both individual and group comparisons. Further psychometric testing is required to establish the construct validity and responsiveness of the BrAT.



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Robotic-assisted DIEP flap harvest: a feasibility study on cadaveric model

Publication date: Available online 6 November 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Samuel Struk, Benjamin Sarfati, Nicolas Leymarie, Antoine Missistrano, Heba Alkhashnam, Françoise Rimareix, Frédéric Kolb, Jean-François Honart




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Academic Vocabulary Learning in First Through Third Grade in Low-Income Schools: Effects of Automated Supplemental Instruction

Purpose

This study investigated cumulative effects of language learning, specifically whether prior vocabulary knowledge or special education status moderated the effects of academic vocabulary instruction in high-poverty schools.

Method

Effects of a supplemental intervention targeting academic vocabulary in first through third grades were evaluated with 241 students (6–9 years old) from low-income families, 48% of whom were retained for the 3-year study duration. Students were randomly assigned to vocabulary instruction or comparison groups.

Results

Curriculum-based measures of word recognition, receptive identification, expressive labeling, and decontextualized definitions showed large effects for multiple levels of word learning. Hierarchical linear modeling revealed that students with higher initial Peabody Picture Vocabulary Test–Fourth Edition scores (Dunn & Dunn, 2007) demonstrated greater word learning, whereas students with special needs demonstrated less growth in vocabulary.

Conclusion

This model of vocabulary instruction can be applied efficiently in high-poverty schools through an automated, easily implemented adjunct to reading instruction in the early grades and holds promise for reducing gaps in vocabulary development.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_JSLHR-L-17-0100/2662757/Academic-Vocabulary-Learning-in-First-Through

Development of Pointing Gestures in Children With Typical and Delayed Language Acquisition

Purpose

This longitudinal study compared the development of hand and index-finger pointing in children with typical language development (TD) and children with language delay (LD). First, we examined whether the number and the form of pointing gestures during the second year of life are potential indicators of later LD. Second, we analyzed the influence of caregivers' gestural and verbal input on children's communicative development.

Method

Thirty children with TD and 10 children with LD were observed together with their primary caregivers in a seminatural setting in 5 sessions between the ages of 12 and 21 months. Language skills were assessed at 24 months.

Results

Compared with children with TD, children with LD used fewer index-finger points at 12 and 14 months but more pointing gestures in total at 21 months. There were no significant differences in verbal or gestural input between caregivers of children with or without LD.

Conclusions

Using more index-finger points at the beginning of the second year of life is associated with TD, whereas using more pointing gestures at the end of the second year of life is associated with delayed acquisition. Neither the verbal nor gestural input of caregivers accounted for differences in children's skills.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_JSLHR-L-16-0129/2662755/Development-of-Pointing-Gestures-in-Children-With