Transcription factor EB (TFEB) influences invasion and migration in oral squamous cell carcinomas

Abstract

Objective

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and plays an important role in various cancers. However, the function of TFEB in oral squamous cell carcinomas has not been examined. The aim of this study was to elucidate the role of TFEB in oral squamous cell carcinomas.

Materials and Methods

Expression levels of TFEB were examined in six different human oral squamous carcinoma cells: HSC2, HSC3, HSC4, SAS, OSC20, and SCC25. Knockdown of TFEB using small interfering RNA in HSC2 and HSC4 cells was performed. Cell morphology was observed by immunofluorescence microscopy. Cell proliferation, invasion, and adhesion were analysed.

Results

Expression levels of TFEB were high in HSC2, moderate in HSC4 and SCC25, and low in HSC3 and OSC20 cells. Knockdown of TFEB did not affect proliferation of HSC2 and HSC4 cells, but did induced enlargement of lysosomes and endosomes in HSC4 cells. TFEB silencing reduced invasion and migration of these HSC cell squamous carcinoma cells; however, increased cell adhesion was also observed.

Conclusions

TFEB knockdown reduces invasion and migration of cancer cells, likely through lysosomal regulation. Taken together, TFEB influences cell invasion and migration of oral squamous cell carcinomas.

This article is protected by copyright. All rights reserved.

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Sjögren's Syndrome X-Chromosome Dose Effect: An Epigenetic Perspective

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined.

Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of SS patients.

We identified 58 upregulated X-chromosome genes, including 22 genes previously shown to escape XCI, based on the analysis of SS patient salivary gland GEO2R gene expression datasets. Moreover, we found XIST and its cis regulators RLIM, FTX, and CHIC1, and polycomb repressor genes of the PRC1/2 complexes to be upregulated. Many of the X-chromosome genes implicated in SS pathogenesis can be regulated by transcription factors which we found to be overexpressed and/or differentially methylated in SS patients.

Determination of the mechanisms underlying methylation-dependent gene expression and impaired XCI is needed to further elucidate the etiopathogenesis of SS.

This article is protected by copyright. All rights reserved.

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Is insufficient pulmonary air support the cause of dysphonia in chronic obstructive pulmonary disease?

Publication date: Available online 8 January 2018
Source:Auris Nasus Larynx
Author(s): Megahed M. Hassan, Mona T. Hussein, Ahmed Mamdouh Emam, Usama M. Rashad, Ibrahim Rezk, Al Hussein Awad
ObjectiveOptimal pulmonary air support is essential pre-requisite for efficient phonation. The objective is to correlate pulmonary and vocal functions in chronic obstructive pulmonary disease (COPD) to find out whether the reduced pulmonary function per se could induce dysphonia.MethodsIn this prospective case-control study, sixty subjects with stable COPD underwent evaluation of pulmonary and vocal functions. The pulmonary functions measured include {Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF)}. The vocal functions were {jitter, shimmer, noise-to-harmonic ratio, pitch perturbation quotient, amplitude perturbation quotient, maximum phonation time (MPT), sound pressure level, phonatory efficiency, resistance and power. A control group (n=35) underwent the same measurements. These functions were compared between subjects and controls. Also, correlation of the vocal and pulmonary functions was conducted.ResultsThirty five (58.3%) of COPD subjects have dysphonia. The pulmonary functions were lower in all COPD group than in the control group (P<0.001 for all parameters). Also, the FVC, FEV1, PEF and MMEF % of predicted values were significantly lower in subjects with dysphonia (n=35) than those without dysphonia (n=25) with P values 0.0018, <0.001, 0.0011 and 0.0026 respectively. In addition, the MPT in all subjects showed positive correlations to the 5 pulmonary functions (P=0.004 for FEV1/FVC ratio and P<0.001 for the rest). Also, the phonatory efficiency showed significant positive correlations with the pulmonary functions FVC, FEV1, PEF and MMEF (P=0.001, 0.001, 0.002 and 0.001 respectively). Unlike efficiency, the phonatory resistance revealed significant negative correlations with these pulmonary functions in the same order (P=0.001, 0.003, 0.002, 0.001 respectively).ConclusionDysphonia is a common comorbidity with COPD which attributed to multifactorial etiologies. The lower the pulmonary function in COPD patients is the more likely to have dysphonia. Decreased pulmonary function was associated with reduced MPT and phonatory efficiency but with increased phonatory resistance. The reduced pulmonary functions in COPD can be the underlying cause of the altered vocal function and dysphonia. Great part of this dysphonia is functional, and hence, can be corrected by voice therapy in compensated subjects. Further researches are needed to evaluate the efficacy of voice therapy in these patients.



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Volumetric comparison of maxillofacial soft tissue morphology: CT in the supine position versus three-dimensional optical scanning in the sitting position

Publication date: Available online 8 January 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Yoshihiro Yamaguchi, Kensuke Yamauchi, Hikari Suzuki, Yuko Sai, Shinnosuke Nogami, Tetsu Takahashi
ObjectiveThree-dimensional (3D) surgical simulation has become popular, but the accuracy of such simulation is difficult to assess. Because maxillofacial soft tissue profiles vary with posture, we compared such profiles obtained in the supine and sitting positions.Study DesignIn total, 28 patients with skeletal class III jaw deformities underwent computed tomography (CT) in the supine position and 3D optical scanning in the sitting position. The two sets of 3D data were superimposed, and linear and volumetric differences were calculated. We evaluated the cheeks, the subauricular and infraorbital regions, the nose, the lips, and the chin. Statistical analyses were performed using paired Student's t-tests. Differences with P < 0.05 were considered to be significant.ResultsPatients were divided into three groups based on body mass index (BMI). The facial profiles of the cheeks and subauricular areas differed significantly between the sitting and supine positions. The extent of variation increased with BMI.ConclusionsWhen a patient moves from a sitting to a supine position, maxillofacial soft tissue migrates from the cheeks to the subauricular regions. Thus, simulations for surgery based on supine CT alone do not accurately model the cheeks and subauricular areas.



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Informed refusal in oral and maxillofacial radiology: does it exist?

Publication date: Available online 8 January 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): James R. Geist




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Exogenous Cushing syndrome due to misuse of potent topical steroid

Abstract

We report an infant with exogenous Cushing syndrome after being treated for 2 months with a potent topical corticosteroid via the mother's application of topical clobetasol for diaper rash without a prescription. We emphasize that potent topical steroids should be used with great caution, especially when used under occlusion (e.g., diaper area) and that parents should be warned about potential side effects of these medications, particularly when used in infants.

http://ift.tt/2DbVFTH

Doing the math: A simple approach to topical timolol dosing for infantile hemangiomas

Abstract

Topical timolol maleate has recently gained popularity as a treatment for superficial infantile hemangiomas, but calculating a safe dose of timolol can be time consuming, which may limit the medication's use in fast-paced clinical environments. This report offers a simplified calculation of the maximum daily safe dosage as 1 drop of medication per kilogram of body weight.

http://ift.tt/2D9ZLvj

Mood changes with methotrexate therapy for dermatologic disease

Abstract

Neurotoxicity and cognitive effects of low-dose methotrexate for rheumatologic disease have often been described, but the neuropsychiatric effects of low-dose methotrexate for cutaneous disease have been underreported in the dermatology literature. We describe two children who experienced mood changes with methotrexate treatment for lichen sclerosus with morphea overlap and psoriasis, with rapid resolution of these symptoms after methotrexate cessation. We also detail possible mechanisms underlying psychiatric changes with methotrexate therapy.

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Pityriasis lichenoides: Long-term follow-up study

Abstract

Background/Objectives

Pityriasis lichenoides is an uncommon papulosquamous disorder of unknown etiology. The objective of this study was to review the clinical features and treatment responses of individuals with pityriasis lichenoides seen at a tertiary referral center.

Methods

Seventy-five patients diagnosed with pityriasis lichenoides between 1997 and 2013 were reviewed, and 46 had long-term follow-up via telephone interviews.

Results

Fifty (67%) patients were diagnosed with pityriasis lichenoides chronica, 22 (29%) with pityriasis lichenoides et varioliformis acuta, and 3 (4%) with mixed pityriasis lichenoides chronica and pityriasis lichenoides et varioliformis acuta features. Mean ± standard deviation age at onset was 12 ± 13 years (median 8 years). Disease duration was significantly shorter for patients with pityriasis lichenoides et varioliformis acuta (35 ± 35 months) than for those with pityriasis lichenoides chronica (at least 78 ± 48 months). At long-term follow-up, 23 of 28 (82%) patients with pityriasis lichenoides chronica and 3 of 16 (19%) with pityriasis lichenoides et varioliformis acuta had active disease. None progressed to lymphomatoid papulosis or cutaneous T-cell lymphoma. Ten of 23 active pityriasis lichenoides chronica cases had residual pigmentary change independent of race and lasted at least 35 ± 20 months. The most effective treatments were phototherapy (47% response rate), heliotherapy (33%), topical corticosteroids (27%), and antibiotics (25%).

Conclusion

Pityriasis lichenoides is a predominantly pediatric disorder. The time course of pityriasis lichenoides chronica is significantly longer than that of pityriasis lichenoides et varioliformis acuta. Pityriasis lichenoides chronica may persist with pigmentary alterations in the absence of other signs of active inflammation. Treatment response is often limited, particularly for patients with pityriasis lichenoides chronica.

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Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis

Abstract

Background/Objectives

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions, typically to drugs or infection. The incidence and outcomes of these conditions in children are unknown. The objective of this study was to report the overall burden of Stevens-Johnson syndrome and toxic epidermal necrolysis in children in the United States.

Methods

We performed a retrospective cohort analysis of children and adolescents younger than 18 years of age using the 2009 and 2012 Kids' Inpatient Database.

Results

We identified 1486 children and adolescents hospitalized with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis. The national incidence per 100 000 was 6.3 for Stevens-Johnson syndrome, 0.7 for Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome, and 0.5 for toxic epidermal necrolysis. The highest incidence in children was in those aged 11-15 years (38.4 per 100 000). Toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome were associated with longer stay, greater mortality, and higher hospital charges than those with Stevens-Johnson syndrome. Hospital mortality was highest in children with toxic epidermal necrolysis and in children aged 0-5 years.

Conclusions

The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in children is higher than reported in adults, and there are significant age-based variations in incidence and outcomes across the pediatric population. Further study is needed to determine the most effective treatment strategies to reduce costs and improve outcomes in children hospitalized with severe cutaneous reactions.

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Towards an international language for Incontinence-Associated Dermatitis (IAD): design and evaluation of psychometric properties of the Ghent Global IAD Categorisation Tool (GLOBIAD) in 30 countries

Summary

Background

Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different levels of severity. An internationally accepted instrument to assess the severity of IAD in adults with established diagnostic accuracy, agreement, and reliability is needed to support clinical practice and research.

Objectives

To design and psychometrically evaluate the Ghent Global IAD Categorisation Tool (GLOBIAD).

Methods

The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs reflecting different severity levels in a sample of 823 health professionals in 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, inter-rater reliability (multi-rater Fleiss kappa), and intra-rater reliability (Cohen's Kappa) were assessed.

Results

The GLOBIAD consists of two categories according to the presence of persistent redness (Cat.1) and skin loss (Cat.2), both subdivided based on the presence of clinical signs of infection. The agreement for differentiating between Cat.1 and Cat.2 was 0.86 [95% confidence interval (CI) 0.86-0.87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0.55 (95%CI 0.55-0.56). The Fleiss Kappa for differentiating between Cat.1 and Cat.2 was 0.65 (95%CI 0.65-0.65). The overall Fleiss Kappa was 0.41 (95%CI 0.41-0.41). The Cohen's Kappa for differentiating between Cat.1 and Cat.2 was 0.76 (95%CI 0.75-0.77). The overall Cohen's Kappa was 0.61 (95%CI 0.59-0.62).

Conclusions

The development of the GLOBIAD is a major step forward towards a better systematic assessment of IAD in clinical practice and research worldwide. Further validation is however needed.

This article is protected by copyright. All rights reserved.

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Imatinib-induced pseudoporphyria

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Reviewer thank you list

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Editorial Board

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Training Groups

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Viable tumor in salvage neck dissections in head and neck cancer: Relation with initial treatment, change of lymph node size and human papillomavirus

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Karlijn van den Bovenkamp, Bart Dorgelo, Maartje G. Noordhuis, Bernard F.A.M. van der Laan, Bert van der Vegt, Hendrik P. Bijl, Jan L. Roodenburg, Boukje A.C. van Dijk, Sjoukje F. Oosting, Ed M.D. Schuuring, Johannes A. Langendijk, Gyorgy B. Halmos, Boudewijn E.C. Plaat
ObjectivesTo identify predictive factors for the presence of viable tumor and outcome in head and neck cancer patients who undergo therapeutic salvage neck dissections.Materials and MethodsRetrospective analysis of 76 salvage neck dissections after radiotherapy alone (n = 22), radiotherapy in combination with carboplatin/5-fluorouracil (n = 42) or with cetuximab (n = 12).ResultsViable tumor was detected in 41% of all neck dissections. Univariate analysis revealed initial treatment with radiotherapy without systemic therapy (OR 6.93, 95%CI: 2.28–21.07, p < .001), increased lymph node size after initial treatment compared to pretreatment CT scan (OR 20.48, 95%CI: 2.46–170.73, p = .005), more extensive neck dissections (OR 8.40, 95%CI: 2.94–23.98, p < .001), and human papillomavirus negative cancer (OR 4.22, 95%CI: 1.10–16.22, p = .036) as predictors of viable tumor. Patients with decreased or stable, but persistently enlarged lymph node size after chemoradiation had a significantly lower chance of viable tumor (OR 0.15, 95%CI: 0.05–0.41, p < .001). Disease-specific 5-year survival was 34% in case of viable tumor, and 78% when no viable tumor was found (p < .001).ConclusionsViable tumor in salvage neck dissections is associated with reduced survival. Radiotherapy alone, human papillomavirus negative cancer and increase in lymph node size, are associated with viable tumor in salvage neck dissections. In case of decreased or stable lymph node size after chemoradiation, watchful waiting could be considered.



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How do oral and maxillofacial surgeons manage concussion?

Craniofacial trauma results in distracting injuries that are easy to see, and as oral and maxillofacial surgeons (OMFS) we gravitate towards injuries that can be seen and are treatable surgically. However, we do tend not to involve ourselves (and may potentially overlook) injuries that are not obvious either visually or radiographically, and concussion is one such. We reviewed the records of 500 consecutive patients who presented with facial fractures at the Queen Elizabeth Hospital, Birmingham, to identify whether patients had been screened for concussion, and how they had been managed.

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An RNA-seq screen of P. gingivalis LPS treated human gingival fibroblasts

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Yufeng Xie, Mengjun Sun, Yiru Xia, Rong Shu
Backgroundand objective: In gingival tissues, lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) is the most critical stimulator for inducing inflammatory response. Human gingival fibroblasts (HGFs) are the major constituents of gingival connective tissues. The aim of this study was to investigate P. gingivalis LPS induced whole transcriptional profile in HGFs and the potential crosstalk between microRNAs (miRNAs) and inflammatory cytokines.MethodsRNA-seq was performed on HGFs with and without P. gingivalis LPS treatment. The gene expression of selected inflammatory cytokines and miRNAs induced by LPS at different time points was evaluated by quantitative RT-PCR. The protein expression of chemokines was further confirmed by ELISA.ResultsInterestingly, most of the significantly changed genes (198/204) were up-regulated at 4 h after 10 μg/ml LPS stimulation, including inflammatory cytokines and miRNAs. Confirmed by quantitative RT-PCR, the mRNA levels of IL-1β, IL-6 and IL-8 showed single up-regulation peak (4 h/6 h) after 1 μg/ml and 10 μg/ml LPS treatment. Similarly, 1 μg/ml LPS induced single up-regulation peak (8 h) of miRNA-146a, −146b and −155 expression. However, 10 μg/ml LPS induced the increased expression of miRNA-146a and −155 at both early stage (2 h/4 h) and late stage (24 h).ConclusionTaken together, we investigated P. gingivalis LPS induced whole transcriptional profile, and the different behaviors of miRNA expression induced by different doses of LPS in HGFs.



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Ultrastructural damage in Streptococcus mutans incubated with saliva and histatin 5.

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): A.M. Fernández-Presas, Y. Márquez Torres, R. García González, A. Reyes Torres, I. Becker Fauser, H. Rodríguez Barrera, B. Ruíz García, R. Toloza Medina, J. Delgado Domínguez, J.L. Molinarí Soriano
ObjectiveTo study the ultrastructural alterations induced in Streptococcus mutans (ATCC 25175) incubated with saliva, saliva plus histatin 5 and histatin 5.MethodsS. mutans incubated with saliva histatin 5 or a combination of both were morphologically analyzed and counted. The results were expressed as (CFU)ml⁻¹. Ultrastructural damage was evaluated by transmission electron microscopy. Ultrastructural localization of histatin 5 was examined using immunogold labeling. Apoptotic cell death was determined by flow cytometry (TUNEL).ResultsA decrease in the bacteria numbers was observed after incubation with saliva, saliva with histatin 5 or histatin 5 compared to the control group (p<0.0001). Ultrastructural damage in S. mutans incubated with saliva was found in the cell wall. Saliva plus histatin 5 induced a cytoplasmic granular pattern and decreased the distance between the plasma membrane bilayers, also found after incubation with histatin 5, together with pyknotic nucleoids. Histatin 5 was localized on the bacterial cell walls, plasma membranes, cytoplasm and nucleoids. Apoptosis was found in the bacteria incubated with saliva (63.9%), saliva plus histatin 5 (71.4%) and histatin 5 (29.3%). Apoptosis in the control bacteria was 0.2%.ConclusionsAntibacterial activity against S. mutans and the morphological description of damage induced by saliva and histatin 5 was demonstrated. Pyknotic nucleoids observed in S. mutans exposed to saliva, saliva plus histatin 5 and histatin 5 could be an apoptosis-like death mechanism. The knowledge of the damage generated by histatin 5 and its intracellular localization could favor the design of an ideal peptide as a therapeutic agent.



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SUPRAGINGIVAL AND SUBGINGIVAL MICROBIOTA FROM PATIENTS WITH POOR ORAL HYGIENE SUBMITTED TO RADIOTHERAPY FOR HEAD AND NECK CANCER TREATMENT

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Elerson Gaetti-Jardim, Ellen Cristina Gaetti Jardim, Christiane Marie Schweitzer, Júlio Cesar Leite da Silva, Murilo Moura Oliveira, Danilo Chizzolini Masocatto, Cauê Monteiro dos Santos
ObjectiveThis case-control study aimed to evaluate the effects of conventional radiotherapy (RT) on the prevalence and populations of oral microorganisms in head and neck cancer patients who did not receive adequate preventive dental care. It was hypothesized that side effects of radiotherapy could be associated with radiation dose, microbiological aspects, and socioeconomic conditions of the patients.DesignTwenty-eight dentate patients with head and neck cancer submitted to RT were included in the study. Radiation dose received varied from 4320 to 7020 cGy. Patients with the same demographic and health conditions, but no history of cancer or antineoplastic treatment were used as controls. Clinical examinations were carried out before RT, 15–22 days after starting RT, immediately after and 6 months after RT. Supra and subgingival biofilms were collected and cultivated onto selective and non-selective media. Isolates were identified by biochemical and physiological characteristics. Stimulated and unstimulated salivary flow rate and saliva buffer capacity were also determined.ResultsMucositis, dermatitis, xerostomia, dysgeusia, dysphagia and candidiasis were common after starting RT and during the treatment period. Xerostomia was followed by a decrease in salivary pH and buffer capacity, which showed association with the increase of cariogenic cocci and yeast populations, which were also associated with deterioration of hygiene. Candida and family Enterobacteriaceae showed increased prevalence with RT, and were associated with the occurrence of mucositis and xerostomia.ConclusionsModifications in oral biofilms of irradiated patients showed association with xerostomia and hygiene conditions, which reinforces the necessity of improving patient compliance to oral health care programs.



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11q23 deletion syndrome (Jacobsen syndrome) with severe bleeding: a case report

11q23 deletion syndrome, also known as Jacobsen syndrome, is characterized by growth retardation, psychomotor retardation, facial dysmorphism, multiple congenital abnormalities, and thrombocytopenia. In 11q23 ...

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Is insufficient pulmonary air support the cause of dysphonia in chronic obstructive pulmonary disease?

Optimal pulmonary air support is essential pre-requisite for efficient phonation. The objective is to correlate pulmonary and vocal functions in chronic obstructive pulmonary disease (COPD) to find out whether the reduced pulmonary function per se could induce dysphonia.

http://ift.tt/2CTS7Yg

Anesthesia for Same Day Discharge After Craniotomy: Review of a Single Center Experience

Same day discharge or outpatient surgery for intracranial procedures has become possible with the advent of image-guided minimally invasive approaches to surgery and availability of short-acting anesthetic agents. In addition, patient satisfaction and the benefits of avoiding hospital stay have resulted in the evolution of neurosurgical day surgery. We reviewed our experience and the available literature to determine the perioperative factors involved which have promoted and will improve this concept in the future. Craniotomy and biopsy for supratentorial brain tumors and surgical clipping of intact cerebral aneurysms have been successfully performed as day surgeries. Patient perceptions and satisfaction surveys have helped in better understanding and delivery of care and successful outcomes. There are major differences in health care across the globe along with socioeconomic, medicolegal, and ethical disparities, which must be considered before widespread application of this approach. Nevertheless, collaborative effort by surgeons, anesthesiologists, and nurses can help in same day discharge of patients after cranial neurosurgery. Veena Sheshadri, MD, Department of Neuroanesthesia and Neurocritical Care, Gleneagles Global Hospitals, Bengaluru, Karnataka, India. All the authors contributed substantially to the conception and design of the manuscript and to the interpretation of data. S.V., V.L., and M.P.: contributed to the literature search, acquisition, and analysis of data. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Lashmi Venkatraghavan, MD, FRCA, FRCPC, Department of Anesthesia, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada (e-mail: lashmi.venkatraghavan@uhn.on.ca). Received May 29, 2017 Accepted November 28, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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Innate Sex Bias of Staphylococcus aureus Skin Infection Is Driven by {alpha}-Hemolysin [INFECTIOUS DISEASE AND HOST RESPONSE]

Numerous studies have reported sex bias in infectious diseases, with bias direction dependent on pathogen and site of infection. Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs), yet sex bias in susceptibility to S. aureus SSTI has not been described. A search of electronic health records revealed an odds ratio of 2.4 for S. aureus SSTI in males versus females. To investigate the physiological basis of this bias, we compared outcomes between male and female mice in a model of S. aureus dermonecrosis. Consistent with the epidemiological data, female mice were better protected against SSTI, with reduced dermonecrosis followed later by increased bacterial clearance. Protection in females was disrupted by ovariectomy and restored by short-term estrogen administration. Importantly, this sex bias was mediated by a sex-specific response to the S. aureus–secreted virulence factor α-hemolysin (Hla). Infection with wild-type S. aureus suppressed inflammatory cytokine production in the skin of female, but not male, mice when compared with infection with an isogenic hla deletion mutant. This differential response was conserved following injection with Hla alone, demonstrating a direct response to Hla independent of bacterial burden. Additionally, neutrophils, essential for clearing S. aureus, demonstrated sex-specific S. aureus bactericidal capacity ex vivo. This work suggests that sex-specific skin innate responsiveness to Hla and neutrophil bactericidal capacity play important roles in limiting S. aureus SSTI in females. Understanding the molecular mechanisms controlling this sex bias may reveal novel targets to promote host innate defense against S. aureus skin infection.

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Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development [IMMUNE REGULATION]

The surface receptor FcRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type–specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a⁺ NK cells versus CD16a^– NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a^– NK cells compared with CD16a⁺ NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type–specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.

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Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis [INNATE IMMUNITY AND INFLAMMATION]

In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca²⁺-dependent mechanisms causing pathological bone loss. Ca²⁺-dependent CREB/c-fos activation via Ca²⁺-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca²⁺ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca²⁺-activated K⁺ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca²⁺-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-B ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1^–/– and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes (p < 0.05) alongside decreased osteoclast formation (p < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca²⁺ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca²⁺ amplitudes in BMMs by ~50% (p < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1^–/– reduced RANKL+/–TNF-stimulated phosphorylation of CREB and expression of c-fos in BMMs (p < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p < 0.01). These data indicate that KCa3.1 regulates Ca²⁺-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.

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Brucella abortus Triggers a cGAS-Independent STING Pathway To Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation [INFECTIOUS DISEASE AND HOST RESPONSE]

Immunity against microbes depends on recognition of pathogen-associated molecular patterns by innate receptors. Signaling pathways triggered by Brucella abortus DNA involves TLR9, AIM2, and stimulator of IFN genes (STING). In this study, we observed by microarray analysis that several type I IFN–associated genes, such as IFN-β and guanylate-binding proteins (GBPs), are downregulated in STING knockout (KO) macrophages infected with Brucella or transfected with DNA. Additionally, we determined that STING and cyclic GMP–AMP synthase (cGAS) are important to engage the type I IFN pathway, but only STING is required to induce IL-1β secretion, caspase-1 activation, and GBP2 and GBP3 expression. Furthermore, we determined that STING but not cGAS is critical for host protection against Brucella infection in macrophages and in vivo. This study provides evidence of a cGAS-independent mechanism of STING-mediated protection against an intracellular bacterial infection. Additionally, infected IFN regulatory factor-1 and IFNAR KO macrophages had reduced GBP2 and GBP3 expression and these cells were more permissive to Brucella replication compared with wild-type control macrophages. Because GBPs are critical to target vacuolar bacteria, we determined whether GBP2 and GBP^chr3 affect Brucella control in vivo. GBP^chr3 but not GBP2 KO mice were more susceptible to bacterial infection, and small interfering RNA treated–macrophages showed reduction in IL-1β secretion and caspase-1 activation. Finally, we also demonstrated that Brucella DNA colocalizes with AIM2, and AIM2 KO mice are less resistant to B. abortus infection. In conclusion, these findings suggest that the STING-dependent type I IFN pathway is critical for the GBP-mediated release of Brucella DNA into the cytosol and subsequent activation of AIM2.

http://ift.tt/2maVYWK

Cytoplasmic Linker Protein CLIP170 Negatively Regulates TLR4 Signaling by Targeting the TLR Adaptor Protein TIRAP [INNATE IMMUNITY AND INFLAMMATION]

Cytoplasmic linker protein 170 (CLIP170) is a CAP-Gly domain–containing protein that is associated with the plus end of growing microtubules and implicated in various cellular processes, including the regulation of microtubule dynamics, cell migration, and intracellular transport. Our studies revealed a previously unrecognized property and role of CLIP170. We identified CLIP170 as one of the interacting partners of Brucella effector protein TcpB that negatively regulates TLR2 and TLR4 signaling. In this study, we demonstrate that CLIP170 interacts with the TLR2 and TLR4 adaptor protein TIRAP. Furthermore, our studies revealed that CLIP170 induces ubiquitination and subsequent degradation of TIRAP to negatively regulate TLR4-mediated proinflammatory responses. Overexpression of CLIP170 in mouse macrophages suppressed the LPS-induced expression of IL-6 and TNF-α whereas silencing of endogenous CLIP170 potentiated the levels of proinflammatory cytokines. In vivo silencing of CLIP170 in C57BL/6 mice by CLIP170-specific small interfering RNA enhanced LPS-induced IL-6 and TNF-α expression. Furthermore, we found that LPS modulates the expression of CLIP170 in mouse macrophages. Overall, our experimental data suggest that CLIP170 serves as an intrinsic negative regulator of TLR4 signaling that targets TIRAP.

http://ift.tt/2mbfi6d

Human Naive and Memory T Cells Display Opposite Migratory Responses to Sphingosine-1 Phosphate [CLINICAL AND HUMAN IMMUNOLOGY]

The role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration. This inhibition was also more pronounced for CD4 T cells than for CD8 T cell subsets, and was dependent on S1PR2, as shown using the S1PR2 antagonist JTE-013. S1PR1 was progressively downregulated during T cell differentiation whereas S1PR2 expression remained stable. Our results suggest that the ratio between S1PR1 and S1PR2 governs the migratory behavior of T cell subsets. They also challenge previous models of the role of S1P in lymphocyte recirculation and suggest that S1P promotes retention of memory T cell subsets in secondary lymphoid organs, via S1PR2.

http://ift.tt/2mauOPB

Foxp1 Negatively Regulates T Follicular Helper Cell Differentiation and Germinal Center Responses by Controlling Cell Migration and CTLA-4 [IMMUNE REGULATION]

T follicular helper (Tfh) cells play an essential role in the formation of germinal centers (GC) and generation of high-affinity Abs. The homing of activated CD4⁺ T cells into B cell follicles and the involvement of key costimulatory and coinhibitory molecules are critical in controlling both the initiation and the magnitude of GC responses. Meanwhile, studies have shown that a high number of single clone B cells leads to intraclonal competition, which inhibits the generation of high-affinity Abs. Our previous work has shown that transcription factor Foxp1 is a critical negative regulator of Tfh cell differentiation. In this study, we report that the deletion of Foxp1 leads to a high proportion of activated CD4⁺ T cells homing into B cell follicles with faster kinetics, resulting in earlier GC formation. In addition, we show that Foxp1-deficient Tfh cells restore the generation of high-affinity Abs when cotransferred with high numbers of single clone B cells. We find that Foxp1 regulates the expression levels of cytotoxic T lymphocyte–associated Ag-4 (CTLA-4) in activated CD4⁺ T cells and that Ctla4 is a direct Foxp1 target. Finally, we demonstrate that CTLA-4 expression on conventional CD4⁺ T cells plays a cell-intrinsic role in Tfh cell differentiation in vivo, and CTLA-4 blockade helps abolish the intraclonal competition of B cells in generating high-affinity Abs.

http://ift.tt/2mblNWP

Osteoblasts Are Rapidly Ablated by Virus-Induced Systemic Inflammation following Lymphocytic Choriomeningitis Virus or Pneumonia Virus of Mice Infection in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

A link between inflammatory disease and bone loss is now recognized. However, limited data exist on the impact of virus infection on bone loss and regeneration. Bone loss results from an imbalance in remodeling, the physiological process whereby the skeleton undergoes continual cycles of formation and resorption. The specific molecular and cellular mechanisms linking virus-induced inflammation to bone loss remain unclear. In the current study, we provide evidence that infection of mice with either lymphocytic choriomeningitis virus (LCMV) or pneumonia virus of mice (PVM) resulted in rapid and substantial loss of osteoblasts from the bone surface. Osteoblast ablation was associated with elevated levels of circulating inflammatory cytokines, including TNF-α, IFN-, IL-6, and CCL2. Both LCMV and PVM infections resulted in reduced osteoblast-specific gene expression in bone, loss of osteoblasts, and reduced serum markers of bone formation, including osteocalcin and procollagen type 1 N propeptide. Infection of Rag-1–deficient mice (which lack adaptive immune cells) or specific depletion of CD8⁺ T lymphocytes limited osteoblast loss associated with LCMV infection. By contrast, CD8⁺ T cell depletion had no apparent impact on osteoblast ablation in association with PVM infection. In summary, our data demonstrate dramatic loss of osteoblasts in response to virus infection and associated systemic inflammation. Further, the inflammatory mechanisms mediating viral infection-induced bone loss depend on the specific inflammatory condition.

http://ift.tt/2maVVKy

Time-Restricted Feeding Alters the Innate Immune Response to Bacterial Endotoxin [INNATE IMMUNITY AND INFLAMMATION]

An important entraining signal for the endogenous circadian clock, independent of light, is food intake. The circadian and immune systems are linked; forced desynchrony of the circadian clock via nighttime light exposure or genetic ablation of core clock components impairs immune function. The timing of food intake affects various aspects of the circadian clock, but its effects on immune function are unknown. We tested the hypothesis that temporal desynchrony of food intake alters innate immune responses. Adult male Swiss Webster mice were provided with food during the night, the day, or ad libitum for 4 wk, followed by administration of LPS prior to the onset of either the active phase (zeitgeber time [ZT]12: Experiment 1) or the inactive phase (ZT0: Experiment 2). Three hours after LPS administration, blood was collected, and serum was tested for bacteria-killing capacity against Escherichia coli, as a functional assay of immune function. Additionally, cytokine expression was examined in the serum (protein), spleen, and hypothalamus (mRNA). Day-fed mice suppressed bacteria-killing capacity and serum cytokine responses to LPS during the active phase (ZT12). Night-fed mice increased bactericidal capacity, as well as serum and hypothalamic mRNA responses of certain proinflammatory cytokines during the active phase. Only day-fed mice enhanced serum cytokine responses when LPS challenge occurred during the inactive phase (ZT0); this did not result in enhanced bactericidal capacity. These data suggest that mistimed feeding has functional relevance for immune function and provide further evidence for the integration of the circadian, metabolic, and immune systems.

http://ift.tt/2maVP5E

mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production [INNATE IMMUNITY AND INFLAMMATION]

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE₂, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE₂ levels and is highly expressed at sites of inflammation. PGE₂ is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen–CFA immunization response, lack of mPGES1 impaired the numbers of CD4⁺ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1^–/– CD4⁺ cells showed impaired IL-17A, IFN-, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE₂ by cocultured APCs synergized with that of Ag-experienced CD4⁺ T cells, with mPGES1 competence in the APC compartment enhancing CD4⁺ IL-17A and IFN- responses. However, in contrast with CD4⁺ cells that were Ag primed in vivo, exogenous PGE₂ inhibited proliferation and skewed IL-17A to IFN- production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE₂ production that impacts effector T cell IL-17A and IFN- responses.

http://ift.tt/2m8sIjb

Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria [INNATE IMMUNITY AND INFLAMMATION]

Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP–AMP synthase (cGAS). Activated cGAS synthesizes 2'3'-cGAMP, which we subsequently can detect using liquid chromatography–tandem mass spectrometry. 2'3'-cGAMP acts as a second messenger for STING activation and triggers TBK1/IRF3 activation, resulting in type I IFN production in human cells. This induction of type I IFN was independent of IFI16. Access of DNA to the cytosolic compartment is mediated by hemozoin, because incubation of purified malaria pigment with DNase abrogated IFN-β induction. Collectively, these observations implicate cGAS as an important cytosolic sensor of P. falciparum genomic DNA and reveal the role of the cGAS/STING pathway in the induction of type I IFN in response to malaria parasites.

http://ift.tt/2maVHDc

Induction of Immunosuppressive CD8+CD25+FOXP3+ Regulatory T Cells by Suboptimal Stimulation with Staphylococcal Enterotoxin C1 [INFECTIOUS DISEASE AND HOST RESPONSE]

Superantigens (SAgs) produced by Staphylococcus aureus at high concentrations induce proliferation of T cells bearing specific TCR Vβ sequences and massive cytokinemia that cause toxic shock syndrome. However, the biological relevance of SAgs produced at very low concentrations during asymptomatic colonization or chronic infections is not understood. In this study, we demonstrate that suboptimal stimulation of human PBMCs with a low concentration (1 ng/ml) of staphylococcal enterotoxin C1, at which half-maximal T cell proliferation was observed, induced CD8⁺CD25⁺ T cells expressing markers related to regulatory T cells (Tregs), such as IFN-, IL-10, TGF-β, FOXP3, CD28, CTLA4, TNFR2, CD45RO, and HLA-DR. Importantly, these CD8⁺CD25⁺ T cells suppressed responder cell proliferation mediated in contact-dependent and soluble factor–dependent manners, involving galectin-1 and granzymes, respectively. In contrast, optimal stimulation of human PBMCs with a high concentration (1 μg/ml) of staphylococcal enterotoxin C1, at which maximal T cell proliferation was observed, also induced similar expression of markers related to Tregs, including FOXP3 in CD8⁺CD25⁺ cells, but these T cells were not functionally immunosuppressive. We further demonstrated that SAg-induced TCR Vβ–restricted and MHC class II–restricted expansion of immunosuppressive CD8⁺CD25⁺ T cells is independent of CD4⁺ T cells. Our results suggest that the concentration of SAg strongly affects the functional characteristics of activated T cells, and low concentrations of SAg produced during asymptomatic colonization or chronic S. aureus infection induce immunosuppressive CD8⁺ Tregs, potentially promoting colonization, propagation, and invasion of S. aureus in the host.

http://ift.tt/2CRStyD

In This Issue [IN THIS ISSUE]

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Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-{beta}-Mediated Tumor Immune Evasion [TUMOR IMMUNOLOGY]

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4⁺ T cells that sequester Pam₃Cys₄ (CD4⁺ T^Pam3) become primed for T_h1 differentiation. CD4⁺ T^Pam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β–OVA–expressing thymomas, produce high amounts of IFN- and sensitize tumors to PD-1/programmed cell death ligand 1 blockade–induced rejection. In contrast, naive OT2 cells without Pam₃Cys₄ cargo are prone to TGF-β–dependent inducible regulatory Foxp3⁺ CD4⁺ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4⁺ T^Pam3 cells are resistant to TGF-β–mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88–dependent PI3K signaling pathway. These data show that CD4⁺ T^Pam3 cells are capable of T_h1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy.

http://ift.tt/2CPGxO7

Inhibitors of the PD-1 Pathway in Tumor Therapy [TRANSLATING IMMUNOLOGY]

The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy–related adverse events, and development of safe and effective combination therapies.

http://ift.tt/2m8EhXL

Role of CD44 in Regulating TLR2 Activation of Human Macrophages and Downstream Expression of Proinflammatory Cytokines [INNATE IMMUNITY AND INFLAMMATION]

Osteoarthritis (OA) is a low-grade chronic inflammatory joint disease. Innate immunity contributes to OA progression, mediated by TLR2 and TLR4. We evaluated the role of cluster determinant 44 (CD44), a transmembrane glycoprotein, in regulating TLR2-linked macrophage activation and resultant proinflammatory responses. TLR2 stimulation was performed on differentiated THP-1 macrophages in the presence or absence of a CD44-specific Ab or hyaluronan (HA). NF-B nuclear translocation, IL-1 β and TNF-α gene expression, and protein concentrations were determined. Anti-CD44 Ab and HA treatments reduced NF-B translocation, IL-1β and TNF-α expression, and production (p < 0.001). Inhibition of proinflammatory response in macrophages by HA was mediated by CD44. Protein phosphatase 2A mediated the reduction in NF-B translocation by HA. CD44 knockdown reduced NF-B nuclear translocation and downstream IL-1β and TNF-α protein production following TLR2 receptor stimulation (p < 0.001). CD44^+/+ murine bone marrow–derived macrophages produced higher TNF-α compared with CD44^–/– macrophages following TLR2 stimulation (p < 0.01). HA dose-dependently inhibited TLR2-induced TNF-α production by murine bone marrow–derived macrophages (p < 0.001). OA synovial fluids (SF) stimulated TLR2 and TLR4 receptors and induced NF-B translocation in THP-1 macrophages. Anti-CD44 Ab treatment significantly reduced macrophage activation by OA SF (p < 0.01). CD44 regulated TLR2 responses in human macrophages, whereby a reduction in CD44 levels or engagement of CD44 by its ligand (HA) or a CD44-specific Ab reduced NF-B translocation and downstream proinflammatory cytokine production. A CD44-specific Ab reduced macrophage activation by OA SF, and CD44 is a potentially novel target in OA treatment.

http://ift.tt/2CStFqo

A Believers Overview of Cancer Immunosurveillance and Immunotherapy [BRIEF REVIEWS]

The field of tumor immunology has grown around the idea that one of the important roles of the immune system is to eliminate cancer. This idea was difficult to reconcile with the accepted notion that the immune system evolved to distinguish self from nonself and therefore tumors derived from self-tissues would not be recognized. Lack of appropriate animal models prevented experimental testing of cancer immunosurveillance. This changed with the realization that the immune system evolved to recognize danger and with the advent of mouse models deficient in one or more immune function, which showed predicted increases in susceptibility to cancer. Simultaneously, technical advances that enabled the study of the human immune system provided data for the existence of tumor-specific T cells and Abs and led to molecular identification of tumor Ags, fully validating the cancer immunosurveillance hypothesis. Immunotherapy designed to strengthen cancer immunosurveillance has achieved unprecedented clinical successes.

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Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species [INFECTIOUS DISEASE AND HOST RESPONSE]

In Legionella pneumophila infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on L. pneumophila infection in vitro and in vivo. Metformin treatment suppressed growth of L. pneumophila in a time- and concentration-dependent fashion in bone marrow–derived macrophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in L. pneumophila–infected bone marrow–derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase–derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine L. pneumophila pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macrophages, which may contribute to improved survival in L. pneumophila pneumonia.

http://ift.tt/2CRnoLv

Hitting the Target: How T Cells Detect and Eliminate Tumors [BRIEF REVIEWS]

The successes of antitumor immuno-based therapies and the application of next-generation sequencing to mutation profiling have produced insights into the specific targets of antitumor T cells. Mutated proteins have tremendous potential as targets for interventions using autologous T cells or engineered cell therapies and may serve as important correlates of efficacy for immunoregulatory interventions including immune checkpoint blockade. As mutated self, tumors present an exceptional case for host immunity, which has primarily evolved in response to foreign pathogens. Tumor Ags' resemblance to self may limit immune recognition, but key features appear to be the same between antipathogen and antitumor responses. Determining which targets will make efficacious Ags and which responses might be elicited therapeutically are key questions for the field. Here we discuss current knowledge on antitumor specificity, the mutations that provide immunogenic targets, and how cross-reactivity and immunodominance may contribute to variation in immune responses among tumor types.

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A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes [INNATE IMMUNITY AND INFLAMMATION]

Normal cartilage cells are susceptible to lysis by NK cells. This phenomenon may play a role in immune cartilage destruction; however, the mechanisms of chondrocyte recognition by NK cells remain poorly understood. Therefore, the aim of this study was to reveal a possible role of NKR-P1A/lectin-like transcript 1 (LLT1) interaction in NK cell–mediated cytotoxicity against normal human articular chondrocytes. Chondrocytes were isolated from articular cartilage obtained during talonavicular joint surgery. PBMC or polyclonal NK cells isolated from normal donors served as effector cells. Cell-mediated cytotoxicity against chondrocytes was evaluated by means of 18-h ⁵¹Cr-release assay. Specific mRNA expression was evaluated by classical and quantitative RT-PCR, and proteins were detected by Western blot analysis. We found that lysis of articular chondrocytes by PBMC or polyclonal NK cells was potentiated by stimulation with IL-2. Stimulation of effector cells with IL-2 downregulated mRNA expression of inhibitory NKR-P1A NK cell receptor, and blocking of NKR-P1A with specific mAbs resulted in increased chondrocyte killing. Chondrocytes constitutively expressed LLT1, a ligand of NKR-P1A. LLT1 expression by chondrocytes could be upregulated by IL-1α and TNF. Chondrocyte treatment with IL-1α resulted in their increased resistance to killing by natural cytotoxic cells. This could be reversed by blocking of NKR-P1A. These results show that susceptibility of normal articular chondrocytes to lysis by NK cells is modulated by NKR-P1A/LLT1 interactions. Thus, NKR-P1A/LLT1 interaction might provide some novel target for therapeutic interventions in the course of pathological cartilage injury.

http://ift.tt/2CR72ma

Metabolic Barriers to T Cell Function in Tumors [BRIEF REVIEWS]

The metabolic programs that drive T cell functions are exquisitely sensitive to cell intrinsic and extrinsic factors, allowing T cells to respond in a fine-tuned manner to a variety of immune challenges and conditions. However, many of the factors essential for effector T cell function are perturbed in the tumor microenvironment, where oncogenic mutations drive unrestrained cancer cell growth that leads to excess nutrient consumption, excess waste excretion, and insufficient oxygen delivery. This imposes metabolic constraints on infiltrating cells that result in dysfunction and loss of potential antitumor activity in both naturally occurring as well as tailored T cells introduced as part of immunotherapy. In this review, we highlight the metabolic properties that characterize tumor-infiltrating T cells, the barriers within the metabolic landscape of the tumor microenvironment, and the opportunities and challenges they present in development of new cancer therapeutics.

http://ift.tt/2CTIM2E

CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon [MUCOSAL IMMUNOLOGY]

CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate–induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.

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Tissue-Resident Cytolytic Innate Lymphocytes in Cancer [BRIEF REVIEWS]

Innate lymphoid cells (ILCs) are critical components of tissues in the body, providing a first line of defense against challenges to host integrity. In contrast to strictly cytokine-producing helper ILCs, resident innate lymphocyte populations with cytolytic potential have been identified in multiple tissues in both mouse and human. These cells express the transcription factor Tbet, NK cell receptors, granzymes, perforin, and death receptors, and can directly kill tumor cells. Signals in the tumor microenvironment may promote this response, including the cytokine IL-15 and stress-associated ligands for activating NK receptors. Although there is evidence that these cells are tissue and tumor resident, their lineage remains unclear. Whether they are derived from the NK or helper ILC lineages or represent a third differentiation pathway remains to be determined. A better understanding of their lineage will help clarify their regulation and function in the context of antitumor immunity.

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The Cancer Immunotherapy Revolution: Mechanistic Insights [EDITORIAL]

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Unlocking the Complexities of Tumor-Associated Regulatory T Cells [BRIEF REVIEWS]

Regulatory T (Treg) cells are found at elevated densities in many human cancers and are thought to be a major barrier to the generation of robust antitumor T cell responses. In this review, we discuss recent advances in the understanding of tumor-associated Treg cell diversity and function. Emerging evidence indicates that the transcriptional program of Treg cells infiltrating human cancers may represent a composite program blending a tissue-associated expression signature with an additional tumor-specific signature common to Treg cells from multiple cancer types. Studies in mouse models have defined unique molecular pathways required for Treg cell function in the tumor context that can be manipulated to selectively dampen intratumoral Treg cell activity. Finally, an expanding body of work has revealed diverse functions for Treg cells in nonlymphoid tissues that are unrelated to immune suppression, suggesting a need to explore functions of intratumoral Treg cells beyond the regulation of antitumor immunity.

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Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell–specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell–intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.

http://ift.tt/2CPziWp

Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment [BRIEF REVIEWS]

Myeloid-derived suppressor cells (MDSC) are a diverse population of immature myeloid cells that have potent immune-suppressive activity. Studies in both mice and humans have demonstrated that MDSC accumulate in most individuals with cancer, where they promote tumor progression, inhibit antitumor immunity, and are an obstacle to many cancer immunotherapies. As a result, there has been intense interest in understanding the mechanisms and in situ conditions that regulate and sustain MDSC, and the mechanisms MDSC use to promote tumor progression. This article reviews the characterization of MDSC and how they are distinguished from neutrophils, describes the suppressive mechanisms used by MDSC to mediate their effects, and explains the role of proinflammatory mediators and the tumor microenvironment in driving MDSC accumulation, suppressive potency, and survival.

http://ift.tt/2maI7zB

Alternative Splicing Transcripts of Zebrafish LGP2 Gene Differentially Contribute to IFN Antiviral Response [INNATE IMMUNITY AND INFLAMMATION]

In mammals, RIG-I like receptors (RLRs) RIG-I and melanoma differentiation–associated gene 5 (MDA5) sense cytosolic viral RNA, leading to IFN antiviral response; however, LGP2 exhibits controversial functions. The same happens to fish LGP2. In this study we report that three zebrafish LGP2 splicing transcripts, a full-length LGP2, and two truncating variants, LGP2v1 and LGP2v2, play distinct roles during IFN antiviral response. Overexpression of the full-length LGP2 not only potentiates IFN response through the RLR pathway, in the absence or presence of poly(I:C) at limited concentrations, but also inhibits IFN response by relative high concentrations of poly(I:C) through functional attenuation of signaling factors involved in the RLR pathway; however, LGP2v1 and LGP2v2 only retain the inhibitory role. Consistently, LGP2 but not LGP2v1 and LGP2v2 confers protection on fish cells against spring viremia of carp virus (SVCV) infection and at limited expression levels, LGP2 exerts more significant protection than either RIG-I or MDA5. Further data suggest that in the early phase of SVCV infection, LGP2 functions as a positive regulator but along with SVCV replicating in cells up to a certain titer, which leads to a far more robust expression of IFN, LGP2 switches to a negative role. These in vitro results suggest an ingenious mechanism where the three zebrafish LGP2 splicing transcripts work cooperatively to shape IFN antiviral responses.

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Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity [BRIEF REVIEWS]

Limited representation of intratumoral immune cells is a major barrier to tumor control. However, simply enhancing immune responses in tumor-draining lymph nodes or through adoptive transfer may not overcome the limited ability of tumor vasculature to support effector infiltration. An alternative is to promote a sustained immune response intratumorally. This idea has gained traction with the observation that many tumors are associated with tertiary lymphoid structures (TLS), which organizationally resemble lymph nodes. These peri- and intratumoral structures are usually, but not always, associated with positive prognoses in patients. Preclinical and clinical data support a role for TLS in modulating immunity in the tumor microenvironment. However, there appear to be varied functions of TLS, potentially based on their structure or location in relation to the tumor or the origin or location of the tumor itself. Understanding more about TLS development, composition, and function may offer new therapeutic opportunities to modulate antitumor immunity.

http://ift.tt/2CVaJam

Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity [INNATE IMMUNITY AND INFLAMMATION]

Necroptosis is a form of cell death associated with inflammation; however, the biological consequences of chronic necroptosis are unknown. Necroptosis is mediated by RIPK1, RIPK3, and MLKL kinases but in hematopoietic cells RIPK1 has anti-inflammatory roles and functions to prevent necroptosis. Here we interrogate the consequences of chronic necroptosis on immune homeostasis by deleting Ripk1 in mouse dendritic cells. We demonstrate that deregulated necroptosis results in systemic inflammation, tissue fibrosis, and autoimmunity. We show that inflammation and autoimmunity are prevented upon expression of kinase inactive RIPK1 or deletion of RIPK3 or MLKL. We provide evidence that the inflammation is not driven by microbial ligands, but depends on the release of danger-associated molecular patterns and MyD88-dependent signaling. Importantly, although the inflammation is independent of type I IFN and the nucleic acid sensing TLRs, blocking these pathways rescues the autoimmunity. These mouse genetic studies reveal that chronic necroptosis may underlie human fibrotic and autoimmune disorders.

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Dendritic Cell-Based Cancer Vaccines [BRIEF REVIEWS]

Dendritic cells (DC) are specialized immune cells that play a critical role in promoting an immune response against Ags, which can include foreign pathogenic Ags and self-tumor Ags. DC are capable of boosting a memory T cell response but most importantly they are effective initiators of naive T cell responses. Many years of studies have focused on the use of DC vaccines against cancer to initiate and shape an antitumor-specific immune response and/or boost existing spontaneous antitumor T cell responses. In this study we give a brief overview of DC biology, function, and cellular subsets, and review the current status of the field of DC as cancer vaccines.

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Ex-situ Organ Preservation: The Temperature Paradigm

No abstract available

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Liver Simulated Allocation Modeling: Were the Predictions Accurate for Share 35?

AbstractBackgroundThe liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes.MethodsLSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data.ResultsCandidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease.ConclusionsAlthough the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Background The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes. Methods LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data. Results Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease. Conclusions Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation. Corresponding Author: W. Ray Kim, MD, Division of Gastroenterology and Hepatology, Stanford University, Alway Building, Room M211, 300 Pasteur Drive, Stanford, CA 94305, Phone: 650-725-6511; fax: 650-732-5488; wrkim@stanford.edu Authorship: Aparna Goel was responsible for research design, data analysis, interpretation of data, writing of the paper and critical revision of the manuscript. W. Ray Kim was responsible for research design, interpretation of the data, and critical revision of the manuscript for important intellectual content. Joshua Pyke was responsible for research design, data analysis, interpretation of the data and critical revision of the manuscript for important intellectual content and statistical analysis. David P. Schladt was responsible for research design and critical revision of the manuscript for important intellectual content. Bertram L. Kasiske was responsible for research design and critical revision of the manuscript for important intellectual content. Jon J. Snyder was responsible for data analysis and critical revision of the manuscript for important intellectual content and statistical analysis. John R. Lake was responsible for research design and critical revision of the manuscript for important intellectual content. Ajay K. Israni was responsible for research design and critical revision of the manuscript for important intellectual content. Disclosure: The authors have no conflicts of interest to disclose. Funding: This work was conducted under the support of the Minneapolis Medical Research Foundation, contractor for SRTR, as a deliverable under contract no. HHSH250201500009C (US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation). As a US Government-sponsored work, there are no restrictions on its use. The views expressed herein are those of the authors and not necessarily those of the US Government. WRK was partially supported by DK 34238/9 and AKI was partially supported by R01 HS 24527. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Effects of Short-Term Subnormothermic Perfusion after Cold Preservation on Liver Grafts from Donors after Cardiac Death: An Ex Vivo Rat Model

AbstractBackgroundWe previously reported that short oxygenated warm perfusion before cold storage (CS) had improved the graft viability of rat livers from donors after cardiac death (DCD). In this study, we investigated the effectiveness of short-term oxygenated subnormothermic perfusion for different durations after CS in a rat DCD model.MethodsWe used an isolated perfused rat liver system. In Study 1: the grafts were retrieved from Wistar rats 30min after cardiac arrest (thoracotomy), preserved in CS for 6h, and perfused with oxygenated subnormothermic (20-25°C) Krebs-Henseleit buffer for different durations (0, 15, 30, 60, and 90min groups; n=5 in each). In Study 2: in addition to subnormothermic ex vivo liver perfusion (SELP), after 15min incubation at room temperature, the grafts were reperfused under normothermic condition for 60min as a model of liver transplantation (0, 30, 60, and 90min groups; n=5 in each).ResultsIn Study 1, portal flow, bile production and tissue adenosine triphosphate (ATP) increased with perfusion duration. In Study 2, SELP significantly improved portal flow volume (P

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Benign prostatic hyperplasia surgical scoring (BPHSS): an novel scoring system for the perioperative outcomes of holmium laser enucleation of the prostate

Abstract

To develop a standardized scoring system, the BPH surgical scoring (BPHSS) system, to quantify the ability to predict the perioperative outcomes resulting from an enlarged prostate. There are two parts included in this study: the retrospective observational study (875 patients treated with holmium laser enucleation of the prostate, HoLEP) and the prospective observational study (111 patient underwent HoLEP). All the outcome data included the following: the basic patient preoperative characteristics, operation time (OT), pre- and post- surgery hemoglobin decrease, Na⁺ variation, hospital stay duration, duration of bladder irrigation, catheterization time, and hospitalization time. The BPHSS, consisting of prostatic volume (PV), prostate-specific antigen (PSA), bladder stones, intravesical prostatic protrusion (IPP), and metabolic syndrome (MetS), was observed regarding the perioperative outcomes. In the retrospective study, patients in high BPHSS group (6–8 points) showed significant increase in the OT (74.61, 95%CI = 16.98–327.84, P < 0.001), hemochrome reduction (416.50, 95%CI = 35.48–4889.88, P < 0.001), hospital stay (1.80, 95%CI = 1.35–2.41, P < 0.001), and bladder irrigation duration (4.04, 95%CI = 1.35–12.10, P = 0.013) compared with the low BPHSS group (0–2 points). In the prospective study, there also existed significant differences between the three scoring grades (P < 0.01) in OT, hemochrome decrease, and the hospital stay. The BPHSS is suitable to predict the perioperative outcomes in patients undergoing HoLEP. It may help urologist to prepare more before surgery to treat the enlarged prostates. Further studies are needed to validate this scoring system in BPH patients in multiple centers.

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Diagnosis and Treatment of Gorham-Stout Disease in Maxillofacial Regions

Purpose: This study was aimed to investigate the clinical features, imaging examination, and treatment of the patients with Gorham-Stout disease (GSD) in maxillofacial region, so as to improve the understanding of GSD. Methods: The medical records of the patients with GSD who were referred to Shanghai Ninth People's Hospital from January 2010 to May 2016 were reviewed. Their ages, lesion location, imaging results, laboratory examination results, treatment, and therapeutic effects were analyzed. Results: A total of 4 cases were included (males 2, females 2). The average onset age was 40 years. GSD attacked the mandible in 2 cases; mandible and temporal bone in 1 case; and mandible, temporal bone, and zygoma in 1 case. All cases were examined by computed tomography (CT), which showed bone resorption and atrophy of soft tissue in involved region. Four patients were given alendronate for treatment. All of them had no significant signs of progress after treatment. Conclusions: GSD can affect one single bone or multiple bones in maxillofacial region. The diagnosis mainly depends on the imaging examinations. Enhanced CT or magnetic resonance imaging is advocated for differential diagnosis of this disease. Alendronate was used with apparent good effect in these patients. Address correspondence and reprint requests to Dr. Baoli Wang, MD, Attending physician, Department of Oral & Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P. R. China; E-mail: baoliwang123456@163.com Received 10 July, 2017 Accepted 1 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Unit Advancement Flap for Lower Lip Reconstruction

Background: Lower lip reconstruction requires consideration of esthetic and functional outcome in selecting a surgical procedure, and reconstruction with local tissue is useful. The authors reconstructed full-thickness defects with a unit advancement flap. Methods: Reconstruction was performed using this method in 4 patients with lower lip squamous cell carcinoma in whom tumor resection with preservation of the mouth angle was possible. The lower lip resection width was 30 to 45 mm, accounting for 50% to 68% of the entire width of the lower lip. The flap was prepared by lateral extension from above the mental unit and matched with the potential wrinkle line of the lower lip in order to design a unit morphology surrounded by the anterior margin of the depressor labii inferioris muscle. It was elevated as a full-thickness flap composed of the orbicularis oris muscle, skin, and mucosa of the residual lower lip from the bilateral sides, and advanced to the defect. Flap transfer was adjusted by small triangular resection of the skin on the lateral side of the mental unit. Results: The postoperative scar was inconspicuous in all patients and there was no impairment of the mouth opening–closing or articulation functions. Conclusions: This was a relatively simple surgical procedure. A blood supply of the flap was stable, and continuity of the orbicularis oris muscle was reconstructed by transferred the residual lower lip advancement flap from the bilateral sides. The postoperative mouth opening–closing function was sufficient, and dentures could be placed from an early phase in elderly patients. The postoperative scar was consistent with the lip unit morphology, being esthetically superior. This procedure may be applicable for reconstruction of defects approximately 1/3 to 2/3 the width of the lower lip where the mouth angle is preserved. Address correspondence and reprint requests to Akihiro Ogino, MD, PhD, Department of Plastic and Reconstructive Surgery, Toho University Omori Medical Center, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan; E-mail: akihiro.ogino@med.toho-u.ac.jp Received 25 August, 2017 Accepted 23 September, 2017 This article is presented at the 59th Annual Meeting of the Japanese Society of Plastic and Reconstructive Surgery. The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Purpose of Zygoma Reduction: Not Just for a Smaller Cheek Bone

No abstract available

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Treatment of Severe Maxillary Hypoplasia With Combined Orthodontics and Distraction Osteogenesis

Distraction osteogenesis (DO) is a technique that allows the generation of new bone in a gap between 2 vascularized bone surfaces in response to the application of graduated tensile stress across the bone gap. Distraction osteogenesis has become a routine treatment of choice to correct skeletal deformities and severe bone defects in the craniofacial complex over the past decade. Distraction osteogenesis has been successfully chosen in lengthening the maxilla and the mandible; in the maxilla and recently in the mandible, the jawbones have been distracted and widened transversely to relieve severe anterior dental crowding and transverse discrepancies between the dental arches. Distraction osteogenesis for maxillary advancement started in 1993 and is now widely used, especially in patients with skeletal Class III malocclusion caused by maxillary hypoplasia. The aim of this study was to present the efficiency of combined orthodontic and DO in the severe maxillary hypoplasia. A 35-year-old Italian man presented to our clinical practice with the chief complaint of esthetic and functionally problems because of skeletal Class III malocclusion with anterior crossbite. Considering that the severity of the skeletal discrepancy is remarkable but compensated by the DO potential, the combined orthodontic and DO treatment was considered adequate, like less invasive and equally effective. It was obtained a good alignment with the upper and lower arch dental alveolar maxillary advancement that allowed to correct the sagittal relationships. The patient was satisfied for the treatment results and had considerable improvement in his self-esteem. Address correspondence and reprint requests to Alessandra Lucchese, DDS, MS, Via Olgettina, 48, 20132 Milan, Italy; E-mail: lcclsn@unife.it Received 13 August, 2017 Accepted 28 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Effect of Surgery First Orthognathic Approach on the Temporomandibular Joint: A Clinical Evaluation

Introduction: Correction of severe malocclusions with skeletal discrepancies requires orthodontic treatment in combination with orthognathic surgery. Even though conventional orthognathic surgery (COS) is a common and well-accepted approach its influence on the signs and symptoms of temporomandibular disorders (TMDs) is still debated. Recently with the introduction of surgery first approach, a different timing for the management of dentoskeletal imbalances has been proposed. The present study is aimed at assessing the relationship between surgery first approach and temporomandibular joint (TMJ) disorders. Methods: The study sample consisted of 24 patients who were selected to be treated with surgery first approach. Clinical follow-ups after surgery were performed every week for the first month, at 3 months, 6 months, and at 1 year. A radiological follow-up was performed at 1 week and at 1 year after the operation with a panorex and a latero-lateral teleradiograph. To assess the effect of surgery first approach on the TMDs signs and symptoms, a clinical assessment was performed 4 days before surgery (T1), 6 months after surgery (T2), and 1 year postoperatively (T3). Results: The results of the authors' study show that pain assessment revealed a general improvement of this symptom in correspondence to TMJ and masticatory muscles except in the masseter and neck region. Also joint noises, TMJ functioning, migraine, and headache underwent a considerable improvement. Conclusion: Surgery first approach is an innovative orthognathic procedure and, by undergoing surgery first approach, patients with pre-existing TMJ dysfunction may experience a significant improvement or even resolution of the TMDs signs and symptoms. Address correspondence and reprint requests to Dr Paolo De Angelis, DDS, Department of Oral and Maxillo-Facial Surgery, Catholic University of the Sacred Heart Medical School, Corso Vittorio Emanuele 28, 63100 Ascoli Piceno, Italy; E-mail: dr.paolodeangelis@gmail.com Received 10 July, 2017 Accepted 30 September, 2017 The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Comparison of Tongue-in-Groove and Columellar Strut on Rotation and Projection in Droopy Nasal Tip: Contribution of a Cap Graft

Underrotation of the nasal tip with narrow nasolabial angle is a common nasal deformity that leads to a long nose appearance, named drooping nose. In these patients, there are various techniques described to correct droopy tip and to achieve a desirable nasal tip rotation such as lateral crural steal, lateral crural overlay, tongue-ingroove, columellar strut graft, tip rotation sutures, cephalic trimming, and others. In this study, the effects of tongue-in-groove (TIG) and columellar strut graft (CS) and the contribution of cap graft on nasal tip rotation and projection were evaluated. Twenty-eight consecutive patients who underwent open approach rhinoplasty by the same senior author (ULD) between January 2015 and December 2016 with the diagnosis of septonasal deformity and droopy nasal tip were included. In 9 of these patients nasal tip was constructed with strut graft, in 6 patients with both strut and cap grafts, in 6 patients with TIG technique and in 7 patients with both TIG and cap graft. Standardized right lateral images were taken preoperatively and 6 months postoperatively to use for further assessments. The nasal tip rotation was evaluated by measuring nasolabial angle (NLA) and the nasal projection (NP) was evaluated by using the Goode method. Finally, the postoperative values of NLA and NP at the 6th month were compared with preoperative recorded values in between groups. Each group showed increase at nasal projection; however, significance was present only in CS graft and TIG groups (P=0.011 and P=0.027 relatively). Each 4 groups showed significant increase in nasal tip rotation. In addition, the comparison of percent changes between preoperative and postoperative NP and NLA revealed no difference (P=0.56 and P=0.431 relatively). In conclusion, the authors argued that TIG and CS graft techniques are both reliable methods to correct droopy nasal tip and using additional cap graft over dome area when required is safe and useful. Address correspondence and reprint requests to Uygar Levent Demir, MD, Associate Professor, Department of Otolaryngology, Uludag University Medical School, 16059 Gorukle, Nilufer—Bursa, Turkey, 16059; E-mail: uygardemir@hotmail.com Received 20 July, 2017 Accepted 1 October, 2017 This study was approved by the ethical committee of Medical School. The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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External Validation of University of Wisconsin's Clinical Criteria for Obtaining Maxillofacial Computed Tomography in Trauma

Objectives: Patients sustaining multisystem trauma are at risk for oral and maxillofacial fractures. Although the University of Wisconsin established criteria to help guide the clinician in obtaining additional cross-sectional imaging to evaluate possible facial fractures, it has not been externally validated. Our aim was to evaluate whether the University of Wisconsin's Criteria is generalizable to external institutions through validation and to report modern practice patterns at a level 1 trauma center. Methods: A retrospective case study was performed of all patients who had computed tomography of the facial bones (CT face) at a tertiary, academic, Level 1 trauma center over the 6-month period ending on June 30, 2015. The electronic medical record was reviewed for the 5 University of Wisconsin criteria (bony step off or instability, periorbital ecchymosis, malocclusion, tooth absence, and glasgow coma scale). Final interpretation of CT face findings by board-certified radiologists (facial fractures, intracranial hemorrhage, and cervical spine injury) were also captured. Our modeling was similar to that described by the reference study, the internal validation study. Sensitivity, specificity, negative, and positive predictive values with 95% confidence intervals were evaluated. A P 

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Clinical Findings of a Cantilever Iliac Bone Graft for Secondary Correction of Cleft Lip–Nose Deformities

The authors performed a cantilever iliac bone graft for the secondary correction of severe cleft lip–nose deformities after the completion of growth. For the purpose of clarifying effects of the cantilever iliac bone grafts and the adverse events with regard to their time course changes after this procedure, the authors retrospectively surveyed long-term morphologic changes in 65 cleft lip, alveolus, and palate patients in whom cleft lip–nose deformities were treated with a cantilever iliac bone graft (age at surgery: 14–45 years old). All postsurgical documents of facial photographs and radiologic images were reviewed to evaluate the effects and adverse events. The main adverse events were deviations of the apex of the nose, excess resorption of the grafted iliac bone, protruding deformations of the grafted iliac bone at the root of the nose, and fracture of the grafted iliac bone. Additional surgery was necessary in 10.7% of patients. Postsurgical changes in facial profiles became favorable, measured on lateral view of cephalometric radiography, achieving morphologic improvements. A cantilever iliac bone graft was effective for improving nasal deformities in cleft lip, alveolus, and palate patients, although the counter measures should be taken to these adverse events. Address correspondence and reprint requests to Kazuto Hoshi, MD, PhD, Department of Oral-Maxillofacial Surgery, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; E-mail: hoshi-ora@h.u-tokyo.ac.jp Received 8 May, 2017 Accepted 7 August, 2017 This study was performed after approval by the Ethics Committee of the Faculty of Medicine, the University of Tokyo (No 2945-5). The authors report no conflicts of interest. © 2018 by Mutaz B. Habal, MD.

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Revision Sinus Surgery Sets the Stage for a Successful Outcome

Revision endoscopic sinus surgery presents challenges not often seen in primary surgeries. Rhinologists at Memorial Hermann-Texas Medical Center and McGovern... Read the full article...

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Under Pressure: On Call During Hurricane Harvey

By Wednesday, Ronda Alexander, MD, knew the storm was going to hit Houston. It would turn out to be the... Read the full article...

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Dissolvable Steroid Implant May Improve Sinus Surgery Outcomes

When dissolvable, slow-release steroid implants are placed in the newly created opening of the frontal sinuses of sinus surgery patients,... Read the full article...

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How do oral and maxillofacial surgeons manage concussion?

Publication date: Available online 8 January 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): D. Hammond, R. Welbury, G. Sammons, E. Toman, M. Harland, S. Rice
Craniofacial trauma results in distracting injuries that are easy to see, and as oral and maxillofacial surgeons (OMFS) we gravitate towards injuries that can be seen and are treatable surgically. However, we do tend not to involve ourselves (and may potentially overlook) injuries that are not obvious either visually or radiographically, and concussion is one such. We reviewed the records of 500 consecutive patients who presented with facial fractures at the Queen Elizabeth Hospital, Birmingham, to identify whether patients had been screened for concussion, and how they had been managed. Of the 500 cases 186 (37%) had concussion, and 174 (35%) had a more severe traumatic brain injury. The maxillofacial team documented loss of consciousness in 314 (63%) and pupillary reactions in 215 (43%). Ninety-three (19%) were referred for a neurosurgical opinion, although most of these were patients who presented with a Glasgow coma scale (GCS) of ≤13. Only 37 patients (7%) were referred to the traumatic brain injury clinic. Recent reports have indicated that 15% of all patients diagnosed with concussion have symptoms that persist for longer than two weeks. These can have far-reaching effects on recovery, and have an appreciable effect on the psychosocial aspects of the patients' lives. As we have found, over one third of patients with craniofacial trauma are concussed. We think, therefore, that all patients who have been referred to OMFS with craniofacial trauma should be screened for concussion on admission, and at the OMFS follow up clinic. In addition, there should be an agreement between consultants that such patients should be referred to the traumatic brain injury clinic for follow up.



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Alveolar corticotomies for accelerated orthodontics: A systematic review

Publication date: Available online 8 January 2018
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Ariane Paredes de Sousa Gil, Orion Luiz Haas, I. Méndez-Majón, J. Masiá-Gridilla, A. Valls-Ontañón, F. Hernández-Alfaro, R. Guijarro-Martínez
IntroductionIt has been suggested that alveolar corticotomies may accelerate tooth movement, broaden the scope of malocclusion types that can be treated orthodontically, decrease the need for extractions, and support long-term stability. Several techniques have been proposed, although the indications, ideal design and technical characteristics, potential complications, and objective clinician and patient satisfaction remain unclear. This systematic review aimed to provide scientific support to validate alveolar corticotomies as a reliable approach to accelerated orthodontics.Material & MethodsA literature search was conducted using MEDLINE (via PubMed), Cochrane, and EMBASE electronic databases until December, 2016. Articles written in any language other than English, Spanish, French, German, and Portuguese were excluded. Randomized controlled trials, controlled clinical trials, and case series involving healthy adult patients, with a sample size of at least 5 patients, and using alveolar corticotomy techniques were included. Two reviewers extracted the data independently.ResultsThree randomized clinical trials, 2 prospective randomized clinical trials, 6 case series and 1 randomized controlled split-mouth study were included. No clinical trials were retrieved. Mean total treatment time in corticotomy-facilitated orthodontic cases was 8.85 months (range, 4-20 months); control groups treatment duration was 16.4 months (range, 7.8-28.3 months). Complications such as pain, swelling, and dentin hypersensitivity were reported. Few studies mentioned patient/clinician satisfaction. The faster and less invasive procedures appeared to be well tolerated. However, the methodological quality of the selected studies was low, with only low to moderate scientific evidence.ConclusionsCorticotomy-facilitated orthodontics resulted in decreased treatment time. Few complications and low morbidity were found. More solid evidence-based research is required to support these results.



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A worldwide comparison of the management of surgical treatment of advanced oral cancer

Publication date: Available online 8 January 2018
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Katinka Kansy, Andreas Albert Mueller, Thomas Mücke, Friederike Koersgen, Klaus Dietrich Wolff, Hans-Florian Zeilhofer, Frank Hölzle, Winnie Pradel, Matthias Schneider, Andreas Kolk, Ralf Smeets, Julio Acero, Piet Haers, G.E. Ghali, Jürgen Hoffmann
IntroductionMicrovascular surgery following tumor resection has become an important field of oral and maxillofacial surgery (OMFS). Following the results from management of T1/T2 floor-of-mouth and tongue squamous cell carcinoma (SCC) in German-speaking countries, Europe, and worldwide, this paper presents specific concepts for the management of resection and reconstruction of T3/T4 SCC of the maxillary and mandibular alveolar process and tongue.MethodsThe DÖSAK questionnaire was distributed in three different phases to a growing number of maxillofacial units worldwide. Within this survey, clinical patient settings were presented to participants and center-specific treatment strategies were evaluated.ResultsA total of 188 OMFS units from 36 different countries documented their treatment strategies for T3/T4 maxillary and mandibular alveolar process and tongue SCC. The extent of surgical resections and subsequent reconstructions is more consistent than with T1/T2 tumors, although the controversy surrounding continuity resections and mandible-sparing procedures remains. For continuity resection of the mandible the fibula free flap is the most frequently used bone replacement, whereas maxilla reconstruction concepts are less consistent, ranging from locoregional coverage concepts and different microvascular reconstruction options to treatment via obturator prosthesis.ConclusionResults from treatment strategies for T3/T4 tumors underline the limited evidence for the appropriate amount of resection and subsequent reconstruction process, especially in cases involving the mandible. Prospective randomized trials will be necessary in the long term to establish valid treatment guidelines.



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