Superoxide dismutase from Helicobacter pylori suppresses the production of pro-inflammatory cytokines during in vivo infection

Abstract

Background

Helicobacter pylori has undergone considerable adaptation to allow chronic persistence within the gastric environment. While H. pylori-associated diseases are driven by an excessive inflammation, severe gastritis is detrimental to colonization by this pathogen. Hence, H. pylori has developed strategies to minimize the severity of gastritis it triggers in its host. Superoxide dismutase (SOD) is well known for its role in protecting against oxidative attack; less recognized is its ability to inhibit immunity, shown for SOD from mammalian sources and those of some bacterial species. This study examined whether H. pylori SOD (HpSOD) has the ability to inhibit the host immune response to these bacteria.

Materials and Methods

The ability of recombinant HpSOD to modify the response to LPS was measured using mouse macrophages. A monoclonal antibody against HpSOD was generated and injected into H. pylori-infected mice.

Results

Addition of HpSOD to cultures of mouse macrophages significantly inhibited the pro-inflammatory cytokine response to LPS stimulation. A monoclonal antibody was generated that was specific for SOD from H. pylori. When injected into mice infected with H. pylori for 3 months, this antibody was readily detected in both sera and gastric tissues 5 days later. While treatment with anti-HpSOD had no effect on H. pylori colonization at this time point, it significantly increased the levels of a range of pro-inflammatory cytokines in the gastric tissues. This did not occur with antibodies against other antioxidant enzymes.

Conclusions

SOD from H. pylori can inhibit the production of pro-inflammatory cytokine during in vivo infection.

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Letter to the Editor concerning “Can standard anterior Smith–Robinson supramanubrial approach be utilized for approach down to T2 or T3?” by Singhatanadgige W, Zebala LP, Luksanapruksa P, Riew KD [Eur Spine J (2017) 26:2357–2362]

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Histological Assessment of the Liver Explant in Transplanted HCV-Patients Achieving Sustained Virologic Response with Direct-Acting Antiviral Agents

Abstract

Aims

The use of direct-acting anti-viral agents (DAAs) has resulted in extremely high sustained virologic response (SVR) rates in patients being treated while on liver transplantation (LT) waiting lists. The aim of this study was to evaluate the histological findings of HCV patients who achieved SVR after receiving DAA treatment (SVR(+)) prior to LT and comparing them to HCV patients who had not achieved SVR (SVR(-)).

Methods and Results

Fifty-eight adult HCV patients who underwent LT at our institution from 2014-2016 were included in the study. Two pathologists, blinded to SVR status, simultaneously evaluated the histological sections. Assessment included the Histology Activity Index (HAI/modified Knodell score), fibrosis stage (Ishak score), and Laennec cirrhosis stage. The study group comprised of 25 SVR(+) patients (56% male, mean age=63.8), while the control group was composed of 33 SVR(-) patients (69% male, mean age=61.7). There was no significant difference in HAI between groups (p=0.414). Patients who achieved SVR also did not show less portal inflammation (p=0.787), interface hepatitis (p=0.999), confluent necrosis (p=0.627), or spotty necrosis (p=0.093) compared to the control group. There was a trend towards higher degree of inflammation in patients who achieved SVR shorter than 24 weeks (p=0.07). The degree of focal lytic necrosis/apoptosis and portal inflammation was more prominent in SVR(+) patients with shorter interval time.

Conclusions

Our study is the first to report the persistent inflammation in HCV patients who received DAAs prior to LT. This supports the notion that inflammation is immunologically driven and inflammation persists despite the absence of virus.

This article is protected by copyright. All rights reserved.

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Boosting Bifunctional Oxygen Electrocatalysis with 3D Graphene Aerogel-Supported Ni/MnO Particles

Abstract

Electrocatalysts for oxygen-reduction and oxygen-evolution reactions (ORR and OER) are crucial for metal–air batteries, where more costly Pt- and Ir/Ru-based materials are the benchmark catalysts for ORR and OER, respectively. Herein, for the first time Ni is combined with MnO species, and a 3D porous graphene aerogel-supported Ni/MnO (Ni–MnO/rGO aerogel) bifunctional catalyst is prepared via a facile and scalable hydrogel route. The synthetic strategy depends on the formation of a graphene oxide (GO) crosslinked poly(vinyl alcohol) hydrogel that allows for the efficient capture of highly active Ni/MnO particles after pyrolysis. Remarkably, the resulting Ni–MnO/rGO aerogels exhibit superior bifunctional catalytic performance for both ORR and OER in an alkaline electrolyte, which can compete with the previously reported bifunctional electrocatalysts. The MnO mainly contributes to the high activity for the ORR, while metallic Ni is responsible for the excellent OER activity. Moreover, such bifunctional catalyst can endow the homemade Zn–air battery with better power density, specific capacity, and cycling stability than mixed Pt/C + RuO₂ catalysts, demonstrating its potential feasibility in practical application of rechargeable metal–air batteries.

A bifunctional 3D porous graphene aerogel-supported Ni/MnO (Ni–MnO/rGO aerogel) catalyst is reported that exhibits excellent electrocatalytic activity and stability for the oxygen-reduction and oxygen-evolution reactions in alkaline media. The Ni–MnO/rGO-driven Zn–air batteries can be stably charged and discharged over 100 cycles with high voltaic efficiency, outperforming the more costly Pt/C + RuO₂ catalyst-driven Zn–air batteries.

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High-Performance As-Cast Nonfullerene Polymer Solar Cells with Thicker Active Layer and Large Area Exceeding 11% Power Conversion Efficiency

Abstract

In this work, a nonfullerene polymer solar cell (PSC) based on a wide bandgap polymer donor PM6 containing fluorinated thienyl benzodithiophene (BDT-2F) unit and a narrow bandgap small molecule acceptor 2,2′-((2Z,2′Z)-((4,4,9,9-tetrahexyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene-2,7-diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (IDIC) is developed. In addition to matched energy levels and complementary absorption spectrum with IDIC, PM6 possesses high crystallinity and strong π–π stacking alignment, which are favorable to charge carrier transport and hence suppress recombination in devices. As a result, the PM6:IDIC-based PSCs without extra treatments show an outstanding power conversion efficiency (PCE) of 11.9%, which is the record value for the as-cast PSC devices reported in the literature to date. Moreover, the device performances are insensitive to the active layer thickness (≈95–255 nm) and device area (0.20–0.81 cm²) with PCEs of over 11%. Besides, the PM6:IDIC-based flexible PSCs with a large device area of 1.25 cm² exhibit a high PCE of 6.54%. These results indicate that the PM6:IDIC blend is a promising candidate for future roll-to-roll mass manufacturing and practical application of highly efficient PSCs.

An efficient polymer solar cell (PSC) based on a polymer donor PM6 containing BDT-2F unit and an n-type organic semiconductor acceptor 2,2′-((2Z,2′Z)-((4,4,9,9-tetrahexyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene-2,7-diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene))dimalononitrile (IDIC) is developed. The power conversion efficiencies of PSCs without extra treatments reach up to 11.9% and are insensitive to the active layer thickness (95–225 nm) and device area (0.20–0.81 cm²) with the values of over 11%.

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Increased resting-state brain entropy in Alzheimer’s disease

Entropy analysis of resting-state functional MRI (R-fMRI) is a novel approach to characterize brain temporal dynamics and facilitates the identification of abnormal brain activity caused by several disease conditions. However, Alzheimer's disease (AD)-related brain entropy mapping based on R-fMRI has not been assessed. Here, we measured the sample entropy and voxel-wise connectivity of the network degree centrality (DC) of the intrinsic brain activity acquired by R-fMRI in 26 patients with AD and 26 healthy controls. Compared with the controls, AD patients showed increased entropy in the middle temporal gyrus and the precentral gyrus and also showed decreased DC in the precuneus. Moreover, the magnitude of the negative correlation between local brain activity (entropy) and network connectivity (DC) was increased in AD patients in comparison with healthy controls. These findings provide new evidence on AD-related brain entropy alterations. Correspondence to Shao-Wei Xue, PhD, Center for Cognition and Brain Disorders, Hangzhou Normal University, Hangzhou, China, Room 301, Shuyuan Building No. 19, Yuhangtang Road No. 2318, Hangzhou 311121, Zhejiang Province, China Tel: +86 152 5715 2036; fax: +86 571 2886 7717; e-mail: xuedrm@126.com Received October 16, 2017 Accepted November 2, 2017 © 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Abnormalities of P300 before and after antidepressant treatment in depression: an ERP-sLORETA study

Despite a wide range of reports on depression-induced P300 changes, it is still debatable whether P300 can return to a pattern characteristic of healthy individuals following antidepressant treatment. Thus, the present study aims to compare P300 and its underlying neural activation in depressed patients before and after antidepressant treatment to explore the brain regions related to pathogenesis and to evaluate the prognosis after treatment. P300 was evoked by the oddball auditory paradigm and collected from 14 sex-matched, age-matched, and education level-matched patients and controls. P300 was also collected in the same patients after treatment. sLORETA was used to explore the source activation of P300 components. Depressed patients before and after antidepressant treatment tended to show lower P300 amplitudes compared with healthy controls, and their P300 amplitudes of F3 electrodes were correlated negatively to their scores on the 24-item Hamilton Depression Rating Scale, the Snaith-Hamilton Pleasure Scale, and the nine-item Patient Health Questionnaire. P300 amplitudes of P4 electrodes were correlated negatively with their scores on the Dysfunctional Attitude Scale. P300 source activation of depressed patients before antidepressant treatment was reduced in the left superior parietal lobule and the precuneus compared with healthy controls and depressed patients after treatment. No difference was found between healthy controls and depressed patients after treatment. The left superior parietal lobule and the precuneus might be therapeutic targets of depression. Correspondence to Gaohua Wang, MD, Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China Tel: +86 136 0716 7402; fax: +86 27 8807 2022; e-mail: wgh6402@163.com Received October 6, 2017 Accepted November 7, 2017 © 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins

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Management of actinic keratosis at specific body sites in patients at high risk of carcinoma lesions: expert consensus from the AKTeam™ of expert clinicians

Abstract

Background

Actinic keratoses (AK) arise on sun-exposed regions of the skin. If left untreated, AK may progress to invasive squamous cell carcinoma (SCC), although the rate of progression is low. A practical treatment algorithm for the treatment of AK in standard situations has been published by the AKTeam^™ expert panel. However, management of particular situations of AK with increasing/higher carcinoma risk or AK progressing into carcinomas with increased aggressiveness due to their anatomical location (risky areas), or in patients with an increased risk of SCC requires further discussion. These include AK on the dorsal hands, forearms, legs, periorbital region, eyelids, ears, or lips, and organ transplant recipients, patients undergoing treatment with carcinogenic agents, and patients with chronic lymphocytic leukemia.

Objective

The main objective was to propose therapeutic strategies for the treatment of AK located in risky areas, and in patients with more invasive/aggressive lesions and a higher risk of progression to SCC.

Methods

A systematic review of the literature was initially performed, and results were discussed by the experts to propose best management practices in specific situations. Finally, adapted management strategies for AK occurring in risky areas and in high-risk patients are presented, taking into account the experts' own clinical experience and current guidelines.

Results

In most of these 'at-risk' situations, patients can be treated according to the AKTeam^™ treatment algorithm. Difficult-to-treat lesions should be treated more aggressively due to their higher risk of transformation. For patients with skin that is highly susceptible to actinic damage, monitoring and sun-protection strategies are mandatory and patients should undergo more regular follow up. Further assessment of newer therapies in clinical trials is necessary to determine optimal treatment conditions.

Conclusion

This expert consensus provides guidance for the management of AK in risky body sites, and in patients with an increasing/higher risk for SCCs.

This article is protected by copyright. All rights reserved.

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Value of complex evoked auditory brainstem response in patients with post-stroke aphasia (prospective study)

Publication date: Available online 12 December 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): S. Mourad, M. Abd Al-Ghaffar, Mohamed Al-Amir Bassiony, G. Fawzi
ObjectiveTo evaluate the perception of complex ABR (C-ABR) in aphasic patients and to compare it before and 3 months after management of stroke.MethodologyA prospective study was conducted on 30 aphasic patients using C-ABR. The results were compared within 2 weeks post-stroke and 3 months after management. The results of aphasic patients were compared with normal subjects.ResultsThe seven C-ABR waves regarding the onset (wave V and A), offset (peak O), transition (peak C) and frequency following responses (peak D, E and F) were identified in all participants. There was a statistically significant difference in C-ABR latencies between control and study group in the waves D, E, F and O, this means that aphasic patients exhibited abnormal neural synchrony affecting the source elements (fundamental frequency) (waves D, E, F and O) however there was no effect on the filter elements (transients).ConclusionAphasic patients exhibited abnormal neural synchrony affecting the source elements (waves D, E, F and O) however there was no effect on the filter elements (transients).



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Acral melanoma foot lesions. Part 2: clinical presentation, diagnosis, and management

Summary

Acral melanoma (AM) is a rare subtype of cutaneous malignant melanoma found on acral skin, primarily on the soles of the feet. Although rare, it is the most common subtype of melanoma found in patients of African or Asian ethnicity and has a poor prognosis, often because of the more advanced stage of presentation at diagnosis. In the second of this two-part series, we review the clinical presentation, histopathology, diagnosis and management of AM. Clinically, AM presents as a variegated lesion with blue–black pigment and irregular borders on acral skin. A parallel-ridge pattern is a very specific dermoscopic finding for AM. The differential diagnoses of AM include acral naevus, pyoderma gangrenosum, pyogenic granuloma, verrucous carcinoma and peripheral neuropathy-induced foot ulcers. If there is a clinical suspicion of AM, an excisional biopsy should be taken. Once diagnosis is confirmed by histology, surgical excision is the standard treatment. Overall, dermoscopy and histopathology are key tools in the diagnosis of AM. A greater emphasis on melanoma screening and awareness is essential in minority populations to improve survival outcomes in AM.

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MPO-ANCA associated vasculitis with mononeuritis multiplex following influenza vaccination

Although influenza vaccines are generally safe and effective, a variety of autoimmune phenomena have been reported after vaccination over the past years, such as Guillain–Barre syndrome, rheumatoid arthritis, ...

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Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma

Abstract

The favorable features of high-risk human papillomavirus (HPV) in the head and neck are limited to those harboring transcriptionally-active HPV, which occur predominantly in the oropharynx (OP). Factors rendering the OP susceptible to HPV oncogenesis are largely unexplored. The role of cytokeratin 7 (CK7) in predisposition to HPV and cancer in the cervix has been evaluated. However, its significance in the H&N is unknown. CK7 immunohistochemistry was performed on a tissue microarray cohort of OP and non-oropharyngeal (NOP) squamous cell carcinomas (SCC) with known clinical follow-up and HPV E6/7 mRNA status. Expression was graded based on the distribution (1 ≤ 33%, 2 = 33–66%, 3 ≥ 66%) and intensity (1 = weak, 2 = strong) with combined score of ≥ 2 considered positive. Survival analysis was performed. Seventy-four NOPSCCs and 204 OPSCCs were studied. HPV was positive in 2.7% of NOPSCCs and 70.9% of OPSCCs. CK7 was positive in 23.0% of OPSCCs and 14.8% of NOPSCCs (p = 0.2), and in 24.1% of HPV positive versus 17.2% of negative patients (p = 0.2). There was no correlation with age, race, gender, HPV status, histologic type, tumor subsite, treatment, stage, or co-morbidities, and CK7 expression was not significantly associated with overall or disease specific survival. In our series, CK7 is positive in ~ 25% of H&N SCCs, although usually only focally. While CK7 has been suspected to be overexpressed selectively in HPV-related OPSCCs due to their origination from tonsillar crypt epithelium, we did not find any significant difference by anatomic H&N subsite, nor by HPV status, for its expression and found no association with patient survival.

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Lactose intolerance and gastrointestinal cow’s milk allergy in infants and children – common misconceptions revisited

Lactose is the main carbohydrate in human and mammalian milk. Lactose requires enzymatic hydrolysis by lactase into D-glucose and D-galactose before it can be absorbed. Term infants express sufficient lactase ...

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Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma

Abstract

The favorable features of high-risk human papillomavirus (HPV) in the head and neck are limited to those harboring transcriptionally-active HPV, which occur predominantly in the oropharynx (OP). Factors rendering the OP susceptible to HPV oncogenesis are largely unexplored. The role of cytokeratin 7 (CK7) in predisposition to HPV and cancer in the cervix has been evaluated. However, its significance in the H&N is unknown. CK7 immunohistochemistry was performed on a tissue microarray cohort of OP and non-oropharyngeal (NOP) squamous cell carcinomas (SCC) with known clinical follow-up and HPV E6/7 mRNA status. Expression was graded based on the distribution (1 ≤ 33%, 2 = 33–66%, 3 ≥ 66%) and intensity (1 = weak, 2 = strong) with combined score of ≥ 2 considered positive. Survival analysis was performed. Seventy-four NOPSCCs and 204 OPSCCs were studied. HPV was positive in 2.7% of NOPSCCs and 70.9% of OPSCCs. CK7 was positive in 23.0% of OPSCCs and 14.8% of NOPSCCs (p = 0.2), and in 24.1% of HPV positive versus 17.2% of negative patients (p = 0.2). There was no correlation with age, race, gender, HPV status, histologic type, tumor subsite, treatment, stage, or co-morbidities, and CK7 expression was not significantly associated with overall or disease specific survival. In our series, CK7 is positive in ~ 25% of H&N SCCs, although usually only focally. While CK7 has been suspected to be overexpressed selectively in HPV-related OPSCCs due to their origination from tonsillar crypt epithelium, we did not find any significant difference by anatomic H&N subsite, nor by HPV status, for its expression and found no association with patient survival.

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Statistical models to predict adverse perioperative outcomes: A case for longer follow up time frames

Large datasets have become available and widely adopted by perioperative medicine researchers in the last decade [1–3]. The use of electronic medical records has facilitated massive data collection not only by single institutions, but also by multicenter initiatives [4–6]. Large datasets enabled the evaluation of infrequent (but important) perioperative outcome with the expectation that interventions could have been implemented to improve the care of patients undergoing surgical procedures.

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Prognosticating hearing outcome in patients with idiopathic sudden sensorineural hearing loss by means of otoacoustic emissions and auditory brainstem response

Masoud Motasaddi Zarandy, MD; Mohammad Taghi Khorsandi Ashtiani, MD; Shahin Bastaninejad, MD; Sasan Dabiri Satri, MD; Sevil Nasirmohtaram, MD; Nourullah Agha Ebrahimi, BSC

Abstract

This is an analytic-descriptive study, parallel with a randomized, controlled trial performed at Amir'Alam Hospital, a tertiary referral center, with the aim of evaluating the correlation between otoacoustic emission (OAE) and auditory brainstem response (ABR) findings with hearing outcome after treatment of idiopathic sudden sensorineural hearing loss (SSNHL). Sixty patients with idiopathic SSNHL who presented to the emergency services and otology clinics between 2012 and 2014, and whose symptoms had begun <10 days previously, enrolled in this study. Before commencing treatment, distortion-product OAE (DP-OAE) and ABR were performed for all patients. They also underwent magnetic resonance imaging ± gadolinium. Therapeutic intervention was done in a parallel randomized, controlled trial, and responders to the medical therapy were selected for our final analysis. There was no significant correlation between the OAE record and responsiveness to treatment, but there was a correlation between ABR presence and the probability of responsiveness in patients with profound hearing loss who responded to medical therapy and had at least wave V ABR. However, in those who had no recorded wave, the response to treatment was variable. In conclusion, in patients with profound hearing loss, studying the waves of ABR could be a factor in predicting hearing loss resolution after treatment.

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Endoscopic endonasal management of recurrent maxillary mucoceles using biliary T-tube stenting

Noritsugu Ono, MD; Shin Ito, MD; Hirotomo Homma, MD; Hiroko Okada, MD; Junko Murata, MD; Katsuhisa Ikeda, MD, PhD

Abstract

Mucoceles of the paranasal sinus can be managed endoscopically with an extremely low recurrence rate. Frontal sinus mucoceles can sometimes be prevented from closing and reforming by stenting, which to the best of our knowledge has not yet been reported in the maxillary sinus. We describe the cases of 5 patients-3 men and 2 women, aged 47 to 75 years (mean: 59.6)-with a recurrent and intractable maxillary sinus mucocele that was managed with biliary T-tube stenting. The indications for stenting included recurrent episodes of mucocele with or without a lateral location with a relatively thick bony wall. A latex rubber pediatric biliary T-tube was endoscopically inserted through a window opening into the marsupialized mucocele. The stent was removed 6 to 14 months postoperatively in 4 cases; in the other case, the stent remained adequately positioned for 35 months. None of the patients experienced signs or symptoms of recurrence. We conclude that a T-tube stent can be used successfully to maintain long-term patency in patients with a recurrent and intractable maxillary mucocele, with patency being maintained even after removal of the stent.

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Head and neck surgical reconstruction in Operation Iraqi Freedom and Operation Enduring Freedom-Afghanistan: A systematic review

Samantha J. Mikals, MD; Joshua M. Jabaut, MD; Art A. Ambrosio, MD

Abstract

Historically, head and neck injuries constituted 16 to 20% of all nonfatal combat injuries. However, advances in body and vehicle armor in the context of the use of ambushes and improvised explosive devices by enemy combatants have resulted in fewer fatalities from head and neck wounds, and thus the incidence of nonfatal head and neck injuries has risen to as high as 52%. Despite this increase, data regarding specific injury distributions, surgical cases, and approaches to repair are lacking in the current literature. We conducted a study to systematically review the current literature regarding head and neck injuries and reconstructions during Operation Iraqi Freedom and Operation Enduring Freedom-Afghanistan. We found 44 articles that met our inclusion criteria. These articles covered 17,461 head and neck wounds sustained by 12,105 patients. Superficial soft-tissue facial injuries were most common wounds (31.7% of cases), followed by wounds to the neck (25.2%) and midface (17.9%). The 44 articles listed 5,122 discrete surgical reports covering 5,758 procedures. Of these procedures, simple facial laceration repairs (25.2%) and ophthalmologic surgeries (12.1%) were the most common soft-tissue repairs, and mandibular reconstructions (11.3%) were the most common type of bony reconstruction. Major flap reconstructions for coverage were required in only 0.4% of procedures. This information will be valuable for educating those involved in otolaryngology training programs, as well as civilian otolaryngologists regarding the types of injury patterns they should expect to see and treat in the returning veteran population.

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Clouds of different colors: A prospective look at head and neck surgical resident call experience

Jonathan Melzer, MD, LCDR, MC, USN

Abstract

Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs.

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Intracranial abscess formation following sphenoid sinus occlusion with nasoseptal flap skull base reconstruction: A cautionary tale

George S. Tarasidis, MD; Jeremiah A. Alt, MD, PhD; Richard R. Orlandi, MD

Abstract

The formation of an intracranial abscess secondary to sphenoid sinus occlusion after nasoseptal flap skull base reconstruction has not been previously described. We report such a case that occurred at our institution in a 23-year-old man who underwent flap reconstruction for a cerebrospinal fluid leak. We determined that occlusion of the sphenoid sinus outflow might have played a role in this complication. The patient was treated via a combined surgical and medical approach that entailed a bur-hole craniotomy and endoscopic debridement followed by administration of an intravenous antibiotic. The patient recovered without long-term deficit. When closing a defect of the posterior ethmoid and sphenoid skull base, especially with a pedicled graft, care must be taken to reduce the potential for retention of secretions and blood because this may lead to an intracranial complication.

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Preoperative evaluation and intraoperative protection of the facial nerve in congenital aural atresia

Jie Li, MD; Shouqin Zhao, PhD; Lin Yang, MD; Yi Li, PhD; Xiaobo Ma, PhD; Danni Wang, PhD; Ran Ren, MD; Ying Li, MD

Abstract

We conducted a prospective study to assess the value of high-resolution computed tomography (HRCT) in identifying facial nerve variations in patients with congenital aural atresia and to determine how they affect otologic reconstruction surgery. Our study population was made up of 65 patients (69 ears) aged 6 to 22 years (mean: 13.7) without regard to sex. They were classified into three groups according to their scores on the Jahrsdoerfer grading scale: 46 ears scored 8 or more, 18 had a score of 6 or 7, and 5 scored 5 or less. The course of each facial nerve as determined intraoperatively was compared with the preoperative HRCT findings. HRCT revealed that in most of the facial nerves, the tympanic segments overlapped the oval window partly or completely; this was confirmed by surgical findings in most cases. Three of the 69 facial nerves (4.3%) were bifurcated. It is interesting that in 1 ear in which the facial nerve completely covered the oval window, the angle of the second genu was acute, exhibiting a "sharp turn." We conclude that HRCT is undoubtedly of value in identifying the course of the facial nerve and is of critical importance in helping surgeons make correct decisions in otologic reconstruction surgery.

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Nasopharyngeal papillary adenocarcinoma

Lester D. Thompson, MD

Nasopharyngeal papillary adenocarcinoma may appear grossly as an exophytic, nodular, or polypoid mass, sometimes gritty if psammoma bodies are present.

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Multidisciplinary management of a giant cervico-mediastinal liposarcoma: A case report and literature review

Andrea Galli, MD; Leone Giordano, MD; Piergiorgio Muriana, MD; Alessandro Bandiera, MD; Giampiero Negri, MD; Piero Zannini, MD; Mario Bussi, MD

Abstract

Liposarcomas are rare mesenchymal tumors that usually develop in lower extremities or retroperitoneum; cervico-mediastinal presentation is quite uncommon. These neoplasms are commonly diagnosed at a late stage because they remain asymptomatic until nearby structures are compressed. This makes radical excision particularly challenging. To date, alternative chemoradiotherapy protocols have not yet been standardized. We report a case of a 55-year-old man with a right laterocervical mass and without substantial symptoms. Fine-needle aspiration cytology results were compatible with a well-differentiated liposarcoma. Contrast-enhanced magnetic resonance imaging revealed the magnitude of the mass, which was expanding into the mediastinum; displacing the trachea, esophagus, cervical neurovascular bundle, and thoracic aorta; and encasing the brachiocephalic artery. Compression of the left brachiocephalic vein resulted in a focal enhancement spot in the fourth liver segment, the expression of superior vena cava compression, which can promote the development of collateral venous pathways, such as the caval-mammary-phrenic-hepatic capsule-portal venous pathway. The mass was successfully excised by a team of surgical subspecialists (otorhinolaryngologists and thoracic, cardiac, and vascular surgeons). Adjuvant tomotherapy was administered to increase local disease control. The patient remained disease-free 38 months postoperatively. This case underlines the importance of accurate preoperative radiologic evaluation in patients presenting with neck masses but without substantial symptoms. Because of the involvement of many critical structures, the cooperation of many surgical subspecialties is mandatory to achieve a satisfying oncologic outcome.

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Skin necrosis in a magnet-based bone-conduction implant

Sara Gallant, MD; Judy Lee, MD; Daniel Jethanamest, MD

Patients with complicated wound sites or multiple surgeries should be counseled to carefully monitor their skin as they have reduced sensation.

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Proliferative pilomatricoma of the eyebrow in a 94-year-old patient

Christopher P. Nyte, DO

While pilomatricomas affect both the young and elderly, it is the elderly that tend to experience the advancing proliferative tumor type.

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Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma

Abstract

The favorable features of high-risk human papillomavirus (HPV) in the head and neck are limited to those harboring transcriptionally-active HPV, which occur predominantly in the oropharynx (OP). Factors rendering the OP susceptible to HPV oncogenesis are largely unexplored. The role of cytokeratin 7 (CK7) in predisposition to HPV and cancer in the cervix has been evaluated. However, its significance in the H&N is unknown. CK7 immunohistochemistry was performed on a tissue microarray cohort of OP and non-oropharyngeal (NOP) squamous cell carcinomas (SCC) with known clinical follow-up and HPV E6/7 mRNA status. Expression was graded based on the distribution (1 ≤ 33%, 2 = 33–66%, 3 ≥ 66%) and intensity (1 = weak, 2 = strong) with combined score of ≥ 2 considered positive. Survival analysis was performed. Seventy-four NOPSCCs and 204 OPSCCs were studied. HPV was positive in 2.7% of NOPSCCs and 70.9% of OPSCCs. CK7 was positive in 23.0% of OPSCCs and 14.8% of NOPSCCs (p = 0.2), and in 24.1% of HPV positive versus 17.2% of negative patients (p = 0.2). There was no correlation with age, race, gender, HPV status, histologic type, tumor subsite, treatment, stage, or co-morbidities, and CK7 expression was not significantly associated with overall or disease specific survival. In our series, CK7 is positive in ~ 25% of H&N SCCs, although usually only focally. While CK7 has been suspected to be overexpressed selectively in HPV-related OPSCCs due to their origination from tonsillar crypt epithelium, we did not find any significant difference by anatomic H&N subsite, nor by HPV status, for its expression and found no association with patient survival.

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Classification of cutaneous manifestations in patients with non-celiac gluten sensitivity (NCGS) and wheat allergy (WA)

http://ift.tt/2AQ9INE

Mohs micrographic surgery and dermatopathology concordance; An analysis of 1421 Mohs cases over 17 years

Mohs micrographic surgery depends on the surgeon's ability to correctly interpret intraoperative frozen sectionsWe reviewed 1421 Mohs cases and 6407 slides for possible disagreement between fellowship trained-Mohs surgeons and dermatopathologists; the concordance rate was 99.79%Fellowship-trained Mohs surgeons are proficient at interpreting histopathology slides in the setting of Mohs micrographic surgery

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Reply to: Comment on "Association of bullous pemphigoid with malignancy: A systematic review and meta-analysis”

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Association of Very Preterm Birth with Decreased Risk of Eczema: A Systematic Review and Meta-analysis

It is debated whether preterm infants are prone to developing eczema.This meta-analysis of 18 studies showed that very preterm birth is associated with a decreased risk of eczema.The underlying mechanisms of this association warrant further study.

http://ift.tt/2BVJpog

Metformin and skin cancer risk in Taiwanese patients with type 2 diabetes

Metformin, an antidiabetic drug, is associated with decreased cancer risk, but its effect on skin cancer is unknown.

http://ift.tt/2ANwjKt

Correction to Supporting Information for Alvarez et al., Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol [SI Correction]

GENETICS Correction to Supporting Information for "Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol," by Monica I. Alvarez, Luke C. Glover, Peter Luo, Liuyang Wang, Elizabeth Theusch, Stefan H. Oehlers, Eric M. Walton, Trinh Thi Bich Tram, Yu-Lin Kuang, Jerome I. Rotter, Colleen...

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Correction for Schulte et al., Prairie strips improve biodiversity and the delivery of multiple ecosystem services from corn-soybean croplands [Correction]

SUSTAINABILITY SCIENCE Correction for "Prairie strips improve biodiversity and the delivery of multiple ecosystem services from corn–soybean croplands," by Lisa A. Schulte, Jarad Niemi, Matthew J. Helmers, Matt Liebman, J. Gordon Arbuckle, David E. James, Randall K. Kolka, Matthew E. O'Neal, Mark D. Tomer, John C. Tyndall, Heidi Asbjornsen, Pauline...

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Correction for Alvarez et al., Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol [Correction]

GENETICS Correction for "Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol," by Monica I. Alvarez, Luke C. Glover, Peter Luo, Liuyang Wang, Elizabeth Theusch, Stefan H. Oehlers, Eric M. Walton, Trinh Thi Bich Tram, Yu-Lin Kuang, Jerome I. Rotter, Colleen M. McClean, Nguyen...

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Correction for Schroeder et al., Mutagenic cost of ribonucleotides in bacterial DNA [Correction]

GENETICS Correction for "Mutagenic cost of ribonucleotides in bacterial DNA," by Jeremy W. Schroeder, Justin R. Randall, William G. Hirst, Michael E. O'Donnell, and Lyle A. Simmons, which was first published October 16, 2017; 10.1073/pnas.1710995114 (Proc Natl Acad Sci USA 114:11733–11738). The authors note that, due to a printer's error,...

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Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in the Xenopus egg [Systems Biology]

Fertilization releases the meiotic arrest and initiates the events that prepare the egg for the ensuing developmental program. Protein degradation and phosphorylation are known to regulate protein activity during this process. However, the full extent of protein loss and phosphoregulation is still unknown. We examined absolute protein and phosphosite dynamics...

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Additive effects of climate and fisheries drive ongoing declines in multiple albatross species [Sustainability Science]

Environmental and anthropogenic factors often drive population declines in top predators, but how their influences may combine remains unclear. Albatrosses are particularly threatened. They breed in fast-changing environments, and their extensive foraging ranges expose them to incidental mortality (bycatch) in multiple fisheries. The albatross community at South Georgia includes globally...

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Vasopressin excites interneurons to suppress hippocampal network activity across a broad span of brain maturity at birth [Neuroscience]

During birth in mammals, a pronounced surge of fetal peripheral stress hormones takes place to promote survival in the transition to the extrauterine environment. However, it is not known whether the hormonal signaling involves central pathways with direct protective effects on the perinatal brain. Here, we show that arginine vasopressin...

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Phosphorylation of huntingtin at residue T3 is decreased in Huntington’s disease and modulates mutant huntingtin protein conformation [Neuroscience]

Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development....

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Expansion microscopy of zebrafish for neuroscience and developmental biology studies [Neuroscience]

Expansion microscopy (ExM) allows scalable imaging of preserved 3D biological specimens with nanoscale resolution on fast diffraction-limited microscopes. Here, we explore the utility of ExM in the larval and embryonic zebrafish, an important model organism for the study of neuroscience and development. Regarding neuroscience, we found that ExM enabled the...

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Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy [Medical Sciences]

Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin–sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of...

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Coupled European and Greenland last glacial dust activity driven by North Atlantic climate [Earth, Atmospheric, and Planetary Sciences]

Centennial-scale mineral dust peaks in last glacial Greenland ice cores match the timing of lowest Greenland temperatures, yet little is known of equivalent changes in dust-emitting regions, limiting our understanding of dust−climate interaction. Here, we present the most detailed and precise age model for European loess dust deposits to date,...

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FMRFamide-like peptides expand the behavioral repertoire of a densely connected nervous system [Developmental Biology]

Animals, including humans, can adapt to environmental stress through phenotypic plasticity. The free-living nematode Caenorhabditis elegans can adapt to harsh environments by undergoing a whole-animal change, involving exiting reproductive development and entering the stress-resistant dauer larval stage. The dauer is a dispersal stage with dauer-specific behaviors for finding and stowing...

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Storm, rogue wave, or tsunami origin for megaclast deposits in western Ireland and North Island, New Zealand? [Earth, Atmospheric, and Planetary Sciences]

The origins of boulderite deposits are investigated with reference to the present-day foreshore of Annagh Head, NW Ireland, and the Lower Miocene Matheson Formation, New Zealand, to resolve disputes on their origin and to contrast and compare the deposits of tsunamis and storms. Field data indicate that the Matheson Formation,...

http://ift.tt/2C7C2es

Bicaudal D2 facilitates the cytoplasmic trafficking and nuclear import of HIV-1 genomes during infection [Cell Biology]

Numerous viruses, including HIV-1, exploit the microtubule network to traffic toward the nucleus during infection. Although numerous studies have observed a role for the minus-end microtubule motor dynein in HIV-1 infection, the mechanism by which the viral core containing the viral genome associates with dynein and induces its perinuclear trafficking...

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Ideals, practices, and future prospects of stakeholder involvement in sustainability science [Sustainability Science]

This paper evaluates current stakeholder involvement (SI) practices in science through a web-based survey among scholars and researchers engaged in sustainability or transition research. It substantiates previous conceptual work with evidence from practice by building on four ideal types of SI in science. The results give an interesting overview of...

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Precision genome editing using synthesis-dependent repair of Cas9-induced DNA breaks [Genetics]

The RNA-guided DNA endonuclease Cas9 has emerged as a powerful tool for genome engineering. Cas9 creates targeted double-stranded breaks (DSBs) in the genome. Knockin of specific mutations (precision genome editing) requires homology-directed repair (HDR) of the DSB by synthetic donor DNAs containing the desired edits, but HDR has been reported...

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Prenatal stress accelerates offspring growth to compensate for reduced maternal investment across mammals [Anthropology]

Across mammals, prenatal maternal stress (PREMS) affects many aspects of offspring development, including offspring growth. However, how PREMS translates to offspring growth is inconsistent, even within species. To explain the full range of reported effects of prenatal adversity on offspring growth, we propose an integrative hypothesis: developmental constraints and a...

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Characterization of SPP inhibitors suppressing propagation of HCV and protozoa [Microbiology]

Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of...

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Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis [Biochemistry]

Kinetochores are superprotein complexes that orchestrate chromosome segregation via a dynamic interaction with spindle microtubules. A physical connection between CENP-C and the Mis12–Ndc80–Knl1 (KMN) protein network is an important pathway that is used to assemble kinetochores on CENP-A nucleosomes. Multiple outer kinetochore components are phosphorylated by Aurora B kinase to...

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Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis [Developmental Biology]

The receptor-like tyrosine kinase (Ryk), a Wnt receptor, is important for cell fate determination during corticogenesis. During neuronal differentiation, the Ryk intracellular domain (ICD) is cleaved. Cleavage of Ryk and nuclear translocation of Ryk-ICD are required for neuronal differentiation. However, the mechanism of translocation and how it regulates neuronal differentiation...

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Increased ratio of pollock roe-specific IgE to salmon roe-specific IgE levels is associated with a positive reaction to cooked pollock roe oral food challenge

Publication date: Available online 11 December 2017
Source:Allergology International
Author(s): Eishi Makita, Noriyuki Yanagida, Sakura Sato, Tomoyuki Asaumi, Motohiro Ebisawa
BackgroundAnaphylaxis and immediate-type fish roe allergies have been reported worldwide, and, in Japan, fish roe is the sixth most common food allergen. No oral food challenges (OFCs) have used pollock roe (PR), which is reported to have high cross-reactivity with salmon roe (SR). Therefore, we administered an OFC using cooked PR to evaluate PR- and SR-specific immunoglobulin E (IgE) levels and allergic reactions in patients with PR sensitivity.MethodsThis retrospective study evaluating patient characteristics and responses to OFCs was conducted with 10–20 g of cooked PR, between April 2006 and November 2016.ResultsWe assessed 51 patients (median age: 6.8 years). All had PR sensitization, 6 (12%) with a history of immediate reactions to PR, and 18 (35%) of immediate reactions to SR. Median PR-specific and SR-specific IgE values were 3.4 kUA/L and 9.9 kUA/L, respectively. Seven patients (14%) had a positive OFC. There was no anaphylaxis. Induced symptoms were mild and included localized urticaria, throat pruritus, intermittent cough, and mild abdominal pain. We treated one patient with mild abdominal pain with oral antihistamines. There were no significant differences in history of immediate reaction to PR and PR-specific IgE titers between OFC-positive and OFC-negative patients, although significant differences were found for PR-specific IgE titers adjusted for SR-specific IgE (p = 0.025) and PR-specific IgE/SR-specific IgE ratio (p = 0.009).ConclusionsIncreased PR-specific IgE/SR-specific IgE ratio or PR-specific IgE levels adjusted for SR-specific IgE levels were risk factors for OFC positivity.



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Predictors for incidence of increased time spent in hospital after ambulatory surgery in children: a retrospective cohort study

Abstract

Purpose

Recently, pediatric ambulatory surgery has become common. However, for some of these patients, unplanned admission or prolonged hospital stay is also necessary, which can increase the mental burden on these patients. The aim of this study was to identify the predictors of the incidence of increased time spent in hospitals associated with pediatric ambulatory surgery.

Methods

Data were obtained from the medical and anesthetic records of 1087 consecutive patients aged < 18 years who underwent ambulatory surgery under general anesthesia. We defined the incidence of increased time spent in a hospital as a composite outcome of unplanned admission and prolonged hospital stay. Multivariate logistic regression analysis was used to examine the associations between the incidence of increased time spent in a hospital and 14 parameters including patient characteristics, anesthesia, and operative factors.

Results

Multivariate analysis identified American Society of Anesthesiologist Physical Status (ASA-PS), type of regional block, intraoperative fluid volume, and type of surgery as predictors for the incidence of increased time spent in a hospital. Specifically, caudal block compared to no regional block [odds ratio (OR) (95% confidence interval (CI)) = 0.44 (0.22–0.90)]; increasing intraoperative fluid volume [OR (95% CI) = 0.71 (0.55–0.92) in every increment of 5 ml/kg/h); and ear, nose, and throat (ENT) and urology surgery compared to other types of surgery [OR (95% CI) = 0.13 (0.03–0.64), and 3.93 (1.99–7.77), respectively] were identified as strong predictors.

Conclusions

This study found that the incidence of increased time spent in a hospital in pediatric ambulatory surgery was affected by the type of regional block, intraoperative fluid volume, type of surgery. Potentially modifiable factors, such as intraoperative fluid volume or type of regional block, should be further investigated in future prospective studies.

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Mastocytosis Becomes a 'Disease You Don't Want to Miss'

A novel drug designed specifically to target a mutation found in 90% of cases shows marked activity, and has already sparked an increase in interest in this disease.
Medscape Medical News

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The Effect of Fecal Microbiota Transplantation on a Child with Tourette Syndrome

Tourette syndrome is a neuropsychiatric disorder with onset in childhood. New therapies are needed to effectively manage and treat this condition. Gut microbiota can affect central physiology and function via the microbiota-gut-brain axis. Here, we report a case in which fecal microbiota transplantation (FMT) is used to treat a child with Tourette syndrome, whose symptoms ameliorated dramatically in the following eight weeks.

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Immediate Reconstruction and Dental Rehabilitation of Maxillofacial Defects

Condition:   Maxillofacial Injuries
Interventions:   Device: NobelActive;   Device: KLS Martin Mandibular Reconstruction Implant
Sponsors:   University of Florida;   Osteo Science Foundation
Not yet recruiting

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Cetuximab & Nivolumab in Patients With Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma

Conditions:   Squamous Cell Carcinoma of the Oropharynx;   Squamous Cell Carcinoma of the Larynx;   Squamous Cell Carcinoma of the Oral Cavity;   Squamous Cell Carcinoma of the Hypopharynx;   Squamous Cell Carcinoma of the Paranasal Sinus;   Head and Neck Squamous Cell Carcinoma;   Squamous Cell Cancer;   Head and Neck Carcinoma
Interventions:   Drug: Nivolumab;   Drug: Cetuximab
Sponsors:   H. Lee Moffitt Cancer Center and Research Institute;   James and Esther King Biomedical Research Program;   Eli Lilly and Company
Recruiting

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Study of Chronic Rhinosinusitis Symptoms in Asthma Patients Undergoing Treatment With Reslizumab

Conditions:   Chronic Rhinosinusitis (Diagnosis);   Asthma;   Nasal Polyps
Intervention:   Drug: Reslizumab
Sponsor:   University of Rochester
Recruiting

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What is that Red Rash? Keeping Wrestlers Skin Healthy this Season

Winter sports season is upon us which means that sports like basketball and wrestling are getting into full swing this month.  Like other sports, wrestlers suffer injuries like sprains, strains, and fractures.  But unlike other sports, wrestlers suffer from a variety of skin infections that can lead to lost time from both practice and matches and can affect their ability to participate at their fullest potential.

 

Why do wrestlers have so many issues with their skin?  The uniform provides minimal coverage and it is a tactile sport requiring lots of skin to skin contact between participants.  They also have a lot of skin-to-skin contact with wrestling mats that may or may not be as clean as we would like.  This combination of exposure and equipment can lead to many different types of rashes that can be itchy, painful, and lead to disqualification if not treated.

 

The most common types of skin infections include:

1. Herpes Gladiatorum: This is a version of the herpes virus similar to what causes cold sores. Unlike cold sores, these can occur on the head, neck, ears, chest, and arms where the most contact with the opponent's skin occurs.  They look like a fluid-filled sac on a red spot of skin (but when burst they look crusty).  The first time a wrestler gets it, it will be quite painful and they may also have fevers and body aches like the flu.  If diagnosed, the doctor will prescribe medicine to help improve the symptoms.
2. Dermatophyte infections (Ring worm): Ringworm accounts for about 1/3 of all skin infections that occur in wrestlers. They look like scaly circular plaques with a clear center that can be itchy.  When occurring on the body, the wrestler will need a topical cream.  Ringworm on the head can be a bit trickier and requires a medicine by mouth.
3. Bacterial infections: Bacterial infections of the skin in wrestlers can be the most serious. If the go on for too long, they can lead to whole body infections, which could be life-threatening.  The infection starts as a small red area that can become widespread and get into the deeper skin.  One type of bacterial infection is MRSA (methicillin resistant Staph aureus) which was talked about in the news a few years ago.  These are sometimes hard to fix with antibiotics and require drainage if the infection gets deeper.

 

If you are concerned that your child may be developing one of these infections, check with your athletic trainer or doctor.  The earlier it's caught, the more quickly and more successfully it can be treated.

 

The most important thing to take away about wrestling skin infections is that it is preventable! Here are some things that your wrestler or child's wrestling team can do to prevent these from happening:

• Mats should be sanitized before and after each use
• Wrestlers should shower thoroughly after every practice or meet
  • No sharing things like towels or razors
• Wrestling rooms and locker rooms should have good ventilation—bacteria and viruses love hot moist environments!
• Skin checks before every practice and match—any signs of skin infection should be taken out until evaluated and treated by a doctor.

Click here for more information about skin infections or other skin conditions.

 

 

The post What is that Red Rash? Keeping Wrestlers Skin Healthy this Season appeared first on ChildrensMD.

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Thyrotoxic Atrial Fibrillation: Factors Associated with Persistence and Risk of Ischemic Stroke

Background. Atrial fibrillation (AF) is one of the commonest cardiovascular manifestations of thyrotoxicosis. A significant proportion of patients have persistent AF which may have long term consequences, for example, ischemic stroke. Methods. We performed a retrospective cohort study in a regional hospital from January 2004 to June 2016 to examine the clinical characteristics and outcomes of thyrotoxic patients who presented with atrial fibrillation and to investigate possible factors associated with persistent atrial fibrillation and ischemic stoke. Results. Among 1918 patients who had a diagnosis of thyrotoxicosis, 133 (6.9%) patients presented with AF. Spontaneous sinus conversion occurred in 89 (66.9%) patients in which 85 (94%) patients developed sinus conversion before or within 6 months after having achieved euthyroidism. The remaining 44 (33.1%) had persistent AF. The rate of ischemic stroke was numerically higher among patients who had persistent AF than those with spontaneous sinus conversion (15.9% versus 10.1%; log-rank 0.442, ). Patients who sustained an ischemic stroke were older (71 ± 11 years versus 62 ± 16 years, ) and had a trend towards higher -VASc score (2.9 ± 1.7 versus 2.3 ± 1.7, ). History of smoking (adjusted odds ratio 4.9, 95% CI ,), a larger left atrial diameter (adjusted odd ratio 2.6, 95% CI ,), and a relatively lower free thyroxine level at diagnosis (adjusted odd ratio 2.1, 95% CI ,) were associated with persistence of AF on multivariate analysis. Conclusion. Persistence of thyrotoxic AF occurred in one-third of patients and spontaneous sinus conversion was unlikely after six months of euthyroidism. High rate of ischemic stroke was observed among patients with persistent thyrotoxic AF and older age. Patients with factors associated with persistent AF, especially older people, should be closely monitored beyond 6 months so that anticoagulation can be initiated in a timely manner to reduce risk of ischemic stroke.

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The regulatory network behind MHC class I expression

Publication date: Available online 8 December 2017
Source:Molecular Immunology
Author(s): Marlieke L.M. Jongsma, Greta Guarda, Robbert M. Spaapen
The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or microbes. It is therefore important to identify the molecular mechanisms behind MHC class I expression, processing and antigen presentation. The identification of NLRC5 as regulator of MHC class I transcription was a huge step forward in understanding the transcriptional mechanism involved. Nevertheless, many questions concerning MHC class I transcription are yet unsolved. Here we illuminate current knowledge on MHC class I and NLRC5 transcription, we highlight some remaining questions and discuss the use of quickly developing high-content screening tools to reveal unknowns in MHC class I transcription in the near future.



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The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways

Publication date: February 2018
Source:Molecular Immunology, Volume 94
Author(s): Lu Meng, Longyun Li, Shan Lu, Kai Li, Zhenbo Su, Yunyun Wang, Xiaodi Fan, Xuyang Li, Guoqing Zhao
The aim of present study was to evaluate the protective effects of dexmedetomidine (DEX) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and investigate its possible mechanisms mediated by HMGB1. In vivo, pulmonary pathology observation and myeloperoxidase (MPO) activity were also examined to evaluate the protective effect of DEX in the lungs. Tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF), serum and lung tissues LPS-induced rats were detected. The oxidative indices including superoxide dismutase (SOD), Malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum were also determined. Additionally, nitric oxide (NO), TNF-α, IL-6 and IL-1β, MDA, SOD and GSH-Px in the supernatants of LPS-induced BEAS-2B cells were measured. Furthermore, we detected the protein expression of high mobility group box-1 protein (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), inhibitor of NF-κB (IκBα), p-IκBα, nuclear factor kappa-B (NF-κB), p-NF-κB, phosphatidylinositol 3′-kinase (PI3K), p-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR) and p-mTOR in LPS-induced ALI rats and LPS-induced BEAS-2B cells. Immunohistochemical and immunofluorescence analyses of HMGB1 in lung tissues or BEAS-2B cells were also conducted to evaluate the mechanisms of DEX. DEX effectively attenuated pulmonary pathology, and ameliorated the levels of MPO, SOD, MDA, GSH-Px, TNF-α, IL-6, IL-1β and NO in LPS-stimulated rats and BEAS-2B cells. Additionally, treatment with DEX inhibited the expression of HMGB1, TLR4, MyD88, p-IκB, p-NF-κB, p-PI3K, p-Akt and p-mTOR in vivo and in vitro. Immunohistochemical and immunofluorescence analyses also showed that DEX suppressed HMGB1 levels in lung sections and BEAS-2B cells. Treatment with glycyrrhizin, an inhibitor of HMGB1, confirmed that HMGB1 was involved in the mechanism of DEX on LPS-induced ALI. The transfection of HGMB1 siRNA also confirmed these findings in vitro. In conclusion, the present study showed that DEX exerted a protective effect on LPS-induced ALI rats likely through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways.



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Expression profiles of genes involved in TLRs and NLRs signaling pathways of water buffaloes infected with Fasciola gigantica

Publication date: February 2018
Source:Molecular Immunology, Volume 94
Author(s): Fu-Kai Zhang, Jun-Ling Hou, Ai-Jiang Guo, Ai-Ling Tian, Zhao-An Sheng, Wen-Bin Zheng, Wei-Yi Huang, Hany M. Elsheikha, Xing-Quan Zhu
Infection of ruminants and humans with Fasciola gigantica is attracting increasing attention due to its economic impact and public health significance. However, little is known of innate immune responses during F. gigantica infection. Here, we investigated the expression profiles of genes involved in Toll-like receptors (TLRs) and NOD-like receptors (NLRs) signaling pathways in buffaloes infected with 500F. gigantica metacercariae. Serum, liver and peripheral blood mononuclear cell (PBMC) samples were collected from infected and control buffaloes at 3, 10, 28, and 70days post infection (dpi). Then, the levels of 12 cytokines in serum samples were evaluated by ELISA. Also, the levels of expression of 42 genes, related to TLRs and NLRs signaling, in liver and PBMCs were determined using custom RT² Profiler PCR Arrays. At 3 dpi, modest activation of TLR4 and TLR8 and the adaptor protein (TICAM1) was detected. At 10 dpi, NF-κB1 and Interferon Regulatory Factor signaling pathways were upregulated along with activation of TLR1, TLR2, TLR6, TLR10, TRAF6, IRF3, TBK1, CASP1, CD80, and IFNA1 in the liver, and inflammatory response with activated TLR4, TLR9, TICAM1, NF-κB1, NLRP3, CD86, IL-1B, IL-6, and IL-8 in PBMCs. At 28 dpi, there was increase in the levels of cytokines along with induction of NLRP1 and NLRP3 inflammasomes-dependent immune responses in the liver and PBMCs. At 70 dpi, F. gigantica activated TLRs and NLRs, and their downstream interacting molecules. The activation of TLR7/9 signaling (perhaps due to increased B-cell maturation and activation) and upregulation of NLRP3 gene were also detected. These findings indicate that F. gigantica alters the expression of TLRs and NLRs genes to evade host immune defenses. Elucidation of the roles of the downstream effectors interacting with these genes may aid in the development of new interventions to control disease caused by F. gigantica infection.



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Identification and characterization of six peroxiredoxin transcripts from mud crab Scylla paramamosain: The first evidence of peroxiredoxin gene family in crustacean and their expression profiles under biotic and abiotic stresses

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Dan-Dan Tu, Yi-Lian Zhou, Wen-Bin Gu, Qi-Hui Zhu, Bin-Peng Xu, Zhong-Kai Zhou, Ze-Peng Liu, Cong Wang, Yu-Yin Chen, Miao-An Shu
The peroxiredoxins (Prxs) define a novel and evolutionarily conserved superfamily of peroxidases able to protect cells from oxidative damage by catalyzing the reduction of a wide range of cellular peroxides. Prxs have been identified in prokaryotes as well as in eukaryotes, however, the composition and number of Prxs family members vary in different species. In this study, six Prxs were firstly identified from the mud crab Scylla paramamosain by RT-PCR and RACE methods. Six SpPrxs can be subdivided into three classes: (a) three typical 2-Cys enzymes denominated as Prx1/2, 3, 4, (b) two atypical 2-Cys enzymes known as Prx5-1 and Prx5-2, and (c) a 1-Cys isoform named Prx6. The evolutionarily conserved signatures of peroxiredoxin catalytic center were identified in all six SpPrxs. Phylogenetic analysis revealed that SpPrx3, SpPrx4, SpPrx5s and SpPrx6 were clearly classified into Prx3-6 subclasses, respectively. Although SpPrx1/2 could not be grouped into any known Prx subclasses, SpPrx1/2 clustered together with other arthropods Prx1 or unclassified Prx and could be classified into the typical 2-Cys class. The comparative and evolutionary analysis of the Prx gene family in invertebrates and vertebrates were also conducted for the first time. Tissue-specific expression analysis revealed that these six SpPrxs were expressed in different transcription patterns while the highest expression levels were almost all in the hepatopancreas. Quantitative RT-PCR analysis exhibited that the gene expression profiles of six SpPrxs were distinct when crabs suffered biotic and abiotic stresses including the exposures of Vibrio alginolyticus, poly (I:C), cadmium and hypoosmotic salinity, suggesting that the SpPrxs might play different roles in response to various stresses. The recombinant proteins including the SpPrx1/2, SpPrx4, SpPrx5-1 and SpPrx6 were purified and the peroxidase activity assays indicated that all these proteins can reduce H2O2 in a typical DTT-dependent manner. To our knowledge, this is the first study about the comprehensive characterization of Prx gene family in Scylla paramamosain and even in crustaceans. These results would broaden the current knowledge of the whole Prx family as well as be helpful to understand and clarify the evolutionary pattern of Prx family in invertebrate and vertebrate taxa.



http://ift.tt/2jS5EVP

Activated human B cells stimulate COX-2 expression in follicular dendritic cell-like cells via TNF-α

Publication date: February 2018
Source:Molecular Immunology, Volume 94
Author(s): Jini Kim, Seungkoo Lee, Dooil Jeoung, Young-Myeong Kim, Jongseon Choe
In spite of the potential importance of cyclooxygenase (COX)-2 expression in the germinal center, its underlying cellular and molecular mechanisms are largely unknown. COX-2 is the key enzyme generating pleiotropic prostaglandins. Based on our previous findings, we hypothesized that lymphocytes would stimulate COX-2 expression in follicular dendritic cell (FDC) by liberating cytokines. In this study, we examined the effect of tonsillar lymphocytes on COX-2 expression in FDC-like cells by immunoblotting. B but not T cells induced COX-2 protein in a time- and dose-dependent manner. Sub-fractionation analysis of B cell subsets revealed that activated but not resting B cells were responsible for the COX-2 induction. Confocal microscopy of frozen tonsils demonstrated that FDCs indeed express COX-2 in situ, in line with the in vitro results. To identify the stimulating molecule, we added neutralizing antibodies to the coculture of FDC-like cells and B cells. COX-2 induction in FDC-like cells was markedly inhibited by TNF-α neutralizing antibody. Finally, the actual production of TNF-α by activated B cells was confirmed by an enzyme immunoassay. The current study implies an unrecognized cellular interaction between FDC and B cells leading to COX-2 expression during immune inflammatory responses.



http://ift.tt/2kq8lx6

Role of extracellular vesicles in rheumatoid arthritis

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Haitao Fu, Die Hu, Licheng Zhang, Peifu Tang
Cell-derived extracellular vesicles (EVs) are involved in the pathogenesis of rheumatoid arthritis (RA), playing important roles in antigen presentation, inflammation, angiogenesis, cell–cell signal communication, thrombosis, and articular cartilage extracellular matrix degradation. Understanding the pathogenic mechanism of RA is important for developing therapies. The pathogenic indicators of RA, such as submicron-sized EVs, represent promising biomarkers for evaluating RA activity. This review summarizes the recent advances in understanding the pathogenesis of RA, and sheds light on the pathogenic as well as anti-inflammatory or immunosuppressive roles of EVs. We suggest that EVs could be harnessed as tools for drug delivery or targets for RA therapies.



http://ift.tt/2jS5DRL

Crystal structures of murine and human Histamine-Releasing Factor (HRF/TCTP) and a model for HRF dimerisation in mast cell activation

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Katy A. Doré, Jun-ichi Kashiwakura, James M. McDonnell, Hannah J. Gould, Toshiaki Kawakami, Brian J. Sutton, Anna M. Davies
In allergic disease, mast cell activation is conventionally triggered by allergen-mediated cross-linking of receptor-bound IgE on the cell surface. In addition to its diverse range of intracellular roles in apoptosis, cell proliferation and cancer, Histamine-Releasing Factor (HRF) also activates mast cells and basophils. A subset of IgE antibodies bind HRF through their Fab regions, and two IgE binding sites on HRF have been mapped. HRF can form dimers, and a disulphide-linked dimer is critical for activity. The current model for the activity of HRF in mast cell activation involves cross-linking of receptor-bound IgE by dimeric HRF, mediated by HRF/Fab interactions. HRF crystal and solution structures have provided little insight into either the formation of disulphide-linked HRF dimers or the ability of HRF to activate mast cells. We report the first crystal structure of murine HRF (mHRF) to 4.0Å resolution, revealing a conserved fold. We also solved the structure of human HRF (hHRF) in two new crystal forms, one at the highest resolution (1.4Å) yet reported. The high resolution hHRF structure reveals a disulphide-linked dimer, in which the two molecules are closely associated, and provides a model for the role of both human and murine HRF in mast cell activation.



http://ift.tt/2jSRnIe

Characteristics of NK cells from leukemic microenvironment in MLL-AF9 induced acute myeloid leukemia

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Feifei Yang, Rong Wang, Wenli Feng, Chong Chen, Xiao Yang, Lina Wang, Yuting Hu, Qian Ren, Guoguang Zheng
NK cells are indispensable components of tissue microenvironment and play vital in both innate and adaptive immunity. The activation and function of NK cells are affected by tumor microenvironments. NK cells are also important players in leukemic microenvironment. However, their characteristics in leukemic microenvironment, including maturation status, phenotype, subpopulations and functional roles especially immunoregulatory potential, have not been well established. Here, we studied these characteristics of NK cells in MLL-AF9 induced mouse acute myeloid leukemia (AML) model. Increase of more mature NK cells were detected in the AML spleen. Splenic AML microenvironment promoted NK cell activation in early and middle stages of leukemia. Cytotoxicity molecules and cytokines were up-regulated in activated NK cells. Furthermore, NK cells from AML microenvironment regulated T cell function, not only by maintaining the activation of CD4⁺ and promoting the degranulation of cytotoxic CD8⁺ T cells but also by influencing the differentiation of CD4⁺ T cells. Moreover, two NK cell subpopulations marked by DNAM-1 (CD226) had distinct cytokine expression patterns but similar regulatory effects on T cells. Collectively, these findings highlight the significance of immunoregulatory role of NK cells, and suggest novel therapeutic potential for leukemia by manipulating NK cell immunoregulatory activity.

Graphical abstract

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Molecular mechanism of LPS-induced TNF-α biosynthesis in polarized human macrophages

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Erik Schilling, Ronald Weiss, Anja Grahnert, Michael Bitar, Ulrich Sack, Sunna Hauschildt
In response to environmental stimuli such as granulocyte-macrophage or macrophage colony stimulating factor (GM-CSF/M-CSF), macrophages (MΦ) can acquire distinct functional phenotypes that control inflammatory processes on the one hand and contribute to a broad spectrum of pathologies on the other. Potential intervention strategies will require an understanding of the signalling processes that are associated with macrophage polarization.In the present study, we show that M-MΦ produce more IFN-β and IL-10 and a lot less TNF-α than do GM-MΦ in response to LPS. To define the molecular mechanisms that underlie the biosynthesis of TNF-α we carried out a detailed investigation of the LPS-induced activation of the canonical and non-canonical myeloid differentiation primary response 88 (MyD88)-dependent signal transduction pathways as well as the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway. Our results show that all three pathways are activated in both cell types and that the activation is more pronounced in M-MΦ. While IL-10 was found to interfere with TNF-α production in M-MΦ, we exclude a decisive role for IFN-β in this respect. Furthermore, we demonstrate that TNF-α mRNA is markedly destabilized in M-MΦ and that expression of the mRNA destabilizing protein tristetraprolin is greatly enhanced in these cells.Collectively, our study suggests that differential effects of LPS on TNF-α mRNA turnover and on signal transduction pathways influence the amount of TNF-α finally produced by GM-MΦ and M-MΦ.



http://ift.tt/2kp00d6

Phospholipase A1-based cross-reactivity among venoms of clinically relevant Hymenoptera from Neotropical and temperate regions

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Amilcar Perez-Riverol, Luís Gustavo Romani Fernandes, Alexis Musacchio Lasa, José Roberto Aparecido dos Santos-Pinto, Débora Moitinho Abram, Gabriel Hideki Izuka Moraes, Frederic Jabs, Michaela Miehe, Henning Seismman, Mario Sergio Palma, Ricardo de Lima Zollner, Edzard Spillner, Márcia Regina Brochetto-Braga
Molecular cross-reactivity caused by allergen homology or cross-reactive carbohydrate determinants (CCDs) is a major challenge for diagnosis and immunotherapy of insect venom allergy. Venom phospholipases A1 (PLA1s) are classical, mostly non-glycosylated wasp and ant allergens that provide diagnostic benefit for differentiation of genuine sensitizations from cross-reactivity. As CCD-free molecules, venom PLA1s are not causative for CCD-based cross-reactivity. Little is known however about the protein-based cross-reactivity of PLA1 within vespid species. Here, we address PLA1-based cross-reactivity among ten clinically relevant Hymenoptera venoms from Neotropical and temperate regions including Polybia paulista (paulistinha) venom and Vespula vulgaris (yellow jacket) venom. In order to evaluate cross-reactivity, sera of mice sensitized with recombinant PLA1 (rPoly p 1) from P. paulista wasp venom were used. Pronounced IgE and IgG based cross-reactivity was detected for wasp venoms regardless the geographical region of origin. The cross-reactivity correlated well with the identity of the primary sequence and 3-D models of PLA1 proteins. In contrast, these mice sera showed no reaction with honeybee (HBV) and fire ant venom. Furthermore, sera from patients monosensitized to HBV and fire ants did not recognize the rPoly p 1 in immunoblotting. Our findings reveal the presence of conserved epitopes in the PLA1s from several clinically relevant wasps as major cause of PLA1-based in vitro cross-reactivity. These findings emphasize the limitations but also the potential of PLA1-based HVA diagnostics.

Graphical abstract

http://ift.tt/2jSCfKZ

Asparaginase inhibits the lectin pathway of complement activation

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): M.P. Keizer, C. Aarts, A.M. Kamp, H.N. Caron, M.D. van de Wetering, D. Wouters, T.W. Kuijpers
Oncological treatment has been associated with an increased risk of infection, most often related to therapy-induced pancytopenia. However, limited research has been conducted on the effect of oncological therapy on the complement system, being part of the non-cellular innate immune system. This became the rationale for an observational clinical study (C2012) in which we have investigated the prevalence of transient complement defects. Once we had observed such defects, a correlation of the complement defects to specific clinical parameters or to specific therapeutic regimens was investigated. A prominent defect observed in C2012 was the inhibition of the lectin pathway (LP) of complement activation during the treatment of acute lymphoblastic leukemia (ALL), which we could directly associate to the use of asparaginase (ASNase). Ex-vivo experiments confirmed a direct dose-dependent inhibitory effect of ASNase on the LP functionality.



http://ift.tt/2jRYPDz

DNA/RNA hybrid substrates modulate the catalytic activity of purified AID

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Hala S. Abdouni, Justin J. King, Atefeh Ghorbani, Heather Fifield, Lesley Berghuis, Mani Larijani
Activation–induced cytidine deaminase (AID) converts cytidine to uridine at Immunoglobulin (Ig) loci, initiating somatic hypermutation and class switching of antibodies. In vitro, AID acts on single stranded DNA (ssDNA), but neither double-stranded DNA (dsDNA) oligonucleotides nor RNA, and it is believed that transcription is the in vivo generator of ssDNA targeted by AID. It is also known that the Ig loci, particularly the switch (S) regions targeted by AID are rich in transcription-generated DNA/RNA hybrids. Here, we examined the binding and catalytic behavior of purified AID on DNA/RNA hybrid substrates bearing either random sequences or GC-rich sequences simulating Ig S regions. If substrates were made up of a random sequence, AID preferred substrates composed entirely of DNA over DNA/RNA hybrids. In contrast, if substrates were composed of S region sequences, AID preferred to mutate DNA/RNA hybrids over substrates composed entirely of DNA. Accordingly, AID exhibited a significantly higher affinity for binding DNA/RNA hybrid substrates composed specifically of S region sequences, than any other substrates composed of DNA. Thus, in the absence of any other cellular processes or factors, AID itself favors binding and mutating DNA/RNA hybrids composed of S region sequences. AID:DNA/RNA complex formation and supporting mutational analyses suggest that recognition of DNA/RNA hybrids is an inherent structural property of AID.



http://ift.tt/2koAKUi

Natural killer cells and anti-tumor immunity

Publication date: Available online 9 December 2017
Source:Molecular Immunology
Author(s): Sandra E. Nicholson, Narelle Keating, Gabrielle T. Belz
Immune checkpoint inhibitors harness the power of the immune system to fight cancer. The clinical success achieved with antibodies against the inhibitory T cell receptors PD-1 and CTLA4 has focused attention on the possibility of manipulating other immune cells, in particular those involved in innate immunity. Here we review the role of innate lymphoid cells (ILCs) and their contribution to tumor immunity. As the prototypical ILC, the natural killer (NK) cell has an intrinsic ability to detect and kill cancer cells. NK cells are dependent on the cytokine interleukin (IL)-15 for their development and effector activity. We discuss the role of the Suppressor of cytokine (SOCS) proteins in negatively regulating IL-15 and NK cell responses and the potential for targeting these small intracellular regulators as new immune checkpoints.



http://ift.tt/2jRYIb7

Silencing of H19 inhibits the adipogenesis and inflammation response in ox-LDL-treated Raw264.7 cells by up-regulating miR-130b

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Yong Han, Jie Ma, Junping Wang, Liping Wang
Atherosclerosis (AS) is the main cause of cardiovascular diseases (CADs). Lipid accumulation and inflammatory response in macrophages are two key factors in the pathogenesis of AS. In this study, we aimed to explore the regulating role of long non-coding RNA (LncRNA)-H19 in oxygenized low density lipoprotein (ox-LDL)-treated Raw264.7 cells. Compared with the healthy control, a relatively higher level of H19 was detected in the blood samples from AS patients. Obviously up-regulated expression of TG (triglycerides)/TC (total cholesterol)/LDL-C (low density lipoprotein-cholesterol) and down-regulated level of HDL-C (high density lipoprotein-cholesterol) were detected in ox-LDL-treated Raw264.7 cells. Besides that, increased expression of H19 was detected in ox-LDL-treated Raw264.7 cells. To examine the function of H19, gene knockdown was performed using short hairpin RNAs (shRNAs). The expression of TG, TC, LDL-C and HDL-C was detected by enzyme linked immunosorbent assay (Elisa) and the expression of lipolytic genes/lipogenic genes (PPARα, CPT-1/REBP-1c, ACS) was examined through western blot. In combination with the result of oil red O staining, we concluded that H19 shRNA effectively decreased lipid accumulation in ox-LDL-treated Raw264.7 cells. Besides that, H19 shRNA decreased the level of pro-inflammatory factors (TNF-α, IL-1β)/CD68+ cells and increased the level of anti-inflammatory factors (IL-4, IL-10)/CD163+ cells compared with the control group. Combined the bioinformatics analyses/luciferase assay with the promoting effect of H19 shRNA on the expression of miR-130b, we speculated that miR-130b was a target of H19 in ox-LDL-treated Raw264.7 cells. Moreover, the adding of LncRNA H19 abolished the facilitating effect of miR-130b inhibitor on adipogenesis and inflammation response by up-regulating the expression of miR-130b. Taken together, our research indicated a H19-miR130b pathway in regulating lipid metabolism and inflammation response in ox-LDL-treated Raw264.7 cells, providing new targets for AS treatment.



http://ift.tt/2koDDEP

The 20S immunoproteasome and constitutive proteasome bind with the same affinity to PA28αβ and equally degrade FAT10

Publication date: Available online 6 December 2017
Source:Molecular Immunology
Author(s): Gunter Schmidtke, Richard Schregle, Gerardo Alvarez, Eva M. Huber, Marcus Groettrup
The 20S immunoproteasome (IP) is an interferon(IFN)-γ − and tumor necrosis factor (TNF) −inducible variant of the 20S constitutive proteasome (CP) in which all its peptidolytically active subunits β1, β2, and β5 are replaced by their cytokine inducible homologues β1i (LMP2), β2i (MECL-1), and β5i (LMP7). These subunit replacements alter the cleavage specificity of the proteasome and the spectrum of proteasome-generated peptide ligands of MHC class I molecules. In addition to antigen processing, the IP has recently been shown to serve unique functions in the generation of pro-inflammatory T helper cell subtypes and cytokines as well as in the pathogenesis of autoimmune diseases, but the mechanistic involvement of the IP in these processes has remained elusive. In this study we investigated whether the IP differs from the CP in the interaction with two IFN-γ/TNF inducible factors: the 11S proteasome regulator PA28αβ and the ubiquitin-like modifier FAT10 (ubiquitin D). Using thermophoresis, we determined the affinity of PA28αβ for the CP and IP to be 12.2nM +/− 2.8nM and 15.3nM +/− 2.7nM, respectively, which is virtually identical. Also the activation of the peptidolytic activities of the IP and CP by PA28αβ did not differ. For FAT10 we determined the degradation kinetics in cycloheximide chase experiments in cells expressing almost exclusively IP or CP as well as in IFN-γ stimulated and unstimulated cells and found no differences between the degradation rates. Taken together, we conclude that neither differences in the binding strength to, nor activation by PA28αβ, nor a difference in the rate of FAT10-mediated degradation can account for distinct functional capabilities of the IP as compared to the CP.

Graphical abstract

http://ift.tt/2jQ49HA

Linking T cell epitopes to a common linear B cell epitope: A targeting and adjuvant strategy to improve T cell responses

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Sara M. Mangsbo, Erika A.K. Fletcher, Wendy W.C. van Maren, Anke Redeker, Robert A. Cordfunke, Inken Dillmann, Jasper Dinkelaar, Kahina Ouchaou, Jeroen D.C. Codee, Gijs A. van der Marel, Peter Hoogerhout, Cornelis J.M. Melief, Ferry Ossendorp, Jan W. Drijfhout
Immune complexes are potent mediators of cellular immunity and have been extensively studied for their disease mediating properties in humans and for their role in anti-cancer immunity. However, a viable approach to use antibody-complexed antigen as vehicle for specific immunotherapy has not yet reached clinical use. Since virtually all people have endogenous antibodies against tetanus toxoid (TTd), such commonly occurring antibodies are promising candidates to utilize for immune modulation. As an initial proof-of-concept we investigated if anti-tetanus IgG could induce potent cross-presentation of a conjugate with SIINFEKL, a MHC class I presented epitope of ovalbumin (OVA), to TTd. This protein conjugate enhanced OVA-specific CD8+ T cell responses when administrated to seropositive mice. Since TTd is poorly defined, we next investigated whether a synthetic peptide–peptide conjugate, with a chemically defined linear B cell epitope of tetanus toxin (TTx) origin, could improve cellular immune responses. Herein we identify one linear B cell epitope, here after named MTTE thru a screening of overlapping peptides from the alpha and beta region of TTx, and by assessment of the binding of pooled IgG, or individual human IgG from high-titer TTd vaccinated donors, to these peptides. Subsequently, we developed a chemical protocol to synthesize defined conjugates containing multiple copies of MTTE covalently attached to one or more T cell epitopes of choice. To demonstrate the potential of the above approach we showed that immune complexes of anti-MTTE antibodies with MTTE-containing conjugates are able to induce DC and T cell activation using model antigens.



http://ift.tt/2jRYAZb

Rational selection of immunodominant and preserved epitope Sm043300e from Schistosoma mansoni and design of a chimeric molecule for biotechnological purposes

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Cláudia de Souza, Marcelo Donizete Lopes, Flávio Martins De Oliveira, Maria Juliana Ferreira Passos, Laís Cunha Grossi Ferreira, Bruna Franciele Faria, José Augusto Ferreira Perez Villar, Moacyr Comar Junior, Alex Guterres Taranto, Luciana Lara dos Santos, Cristina Toscano Fonseca, Débora de Oliveira Lopes
Human schistosomiasis is a neglected tropical disease of great importance in public health. A large number of people are infected with schistosomiasis, making vaccine development and effective diagnosis important control strategies. A rational epitope prediction workflow using Schistosoma mansoni hypothetical proteins was previously presented by our group, and an improvement to that approach is presented here. Briefly, immunodominant epitopes from parasite membrane proteins were predicted by reverse vaccinology strategy with additional in silico analysis. Furthermore, epitope recognition was evaluated using sera of individuals infected with S. mansoni. The epitope that stood out in both in silico and in vitro assays was used to compose a rational chimeric molecule to improve immune response activation. Out of 2185 transmembrane proteins, four epitopes with high binding affinities for human and mouse MHCII molecules were selected through computational screening. These epitopes were synthesized to evaluate their ability to induce TCD4+ lymphocyte proliferation in mice. Sm204830e and Sm043300e induced significant TCD4+ proliferation. Both epitopes were submitted to enzyme-linked immunosorbent assay to evaluate their recognition by IgG antibodies from the sera of infected individuals, and epitope Sm043300 was significantly recognized in most sera samples. Epitope Sm043300 also showed good affinity for human MHCII molecules in molecular docking, and its sequence is curiously highly conserved in four S. mansoni proteins, all of which are described as G-protein-coupled receptors. In addition, we have demonstrated the feasibility of incorporating this epitope, which showed low similarity to human sequences, into a chimeric molecule. The stability of the molecule was evaluated by molecular modeling aimed at future molecule production for use in diagnosis and vaccination trials.



http://ift.tt/2kp9nJL

Recordings Reveal Deep Credibility Gap When Doctors And Parents Discuss Outcomes For Critically Ill Infants

An analysis of 16 audiotaped conversations between parents of infants in a neonatal intensive care unit (NICU) and clinicians found that medical staff routinely downplay quality of life issues and leave families more optimistic about their babies' prognoses than the clinicians intended.

http://ift.tt/2ANOu2Q

Reduced PTEN involved in primary immune thrombocytopenia via contributing to B cell hyper-responsiveness

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Shixuan Wang, Yue Guan, Yunlong Wang, Huiyuan Li, Donglei Zhang, Mankai Ju, Yating Hao, Xuewen Song, Boyang Sun, Xueqing Dou, Renchi Yang
Phosphatase and tensin homolog (PTEN) is thought to mediate B cell activation by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. This pathway is important for activation, growth, and proliferation. Although enhanced B cell receptor (BCR) signaling contributes to increased B cell activity in immune thrombocytopenia (ITP), the role of PTEN is unclear. In this study, we analyzed B cells of ITP patients using flow cytometry and found that all B cell subsets, excluding memory B cells, showed lower PTEN expression than cells from healthy controls (HCs). PTEN expression was also positively-correlated with blood platelet count, although levels were lower in patients who were platelet autoantibody-positive compared with those who were negative. We next evaluated the effects of IL-21, anti-IgM, and CD40L on PTEN expression, demonstrating that they were potent inducers of PTEN expression in normal B cells. Induction of PTEN expression was lower in B cells of ITP patients. We also found that IL-21 increased the proportion of plasma cells in peripheral blood mononuclear cells (PBMCs) of ITP patients, independent of BCR signaling. This effect was reproducible using PTEN inhibitors with cells from HCs. In summary, defective PTEN expression, regulation, and function all contribute to the B cell hyper-responsiveness that associates with ITP.



http://ift.tt/2jRYuRj

Discovery of microRNAs associated with the antiviral immune response of Atlantic cod macrophages

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Khalil Eslamloo, Sabrina M. Inkpen, Matthew L. Rise, Rune Andreassen
MicroRNAs (miRNAs) are known to play important immunoregulatory roles in teleosts, although miRNAs involved in the antiviral immune response of Atlantic cod (Gadus morhua) were previously uncharacterised. Using deep sequencing and qPCR, the present study was conducted to identify miRNAs responsive to the viral mimic, polyriboinosinic polyribocytidylic acid (pIC) in Atlantic cod macrophages. Macrophage samples isolated from Atlantic cod (n=3) and treated with pIC or phosphate buffered saline (PBS control) for 24 and 72h were used for miRNA profiling. Following deep sequencing, DESeq2 analyses identified four (miR-731-3p, miR-125b-3-3p, miR-150-3p and miR-462-3p) and two (miR-2188-3p and miR-462-3p) significantly differentially expressed miRNAs at 24 and 72h post-stimulation (HPS), respectively. Sequencing-identified miRNAs were subjected to qPCR validation using a larger number of biological replicates (n=6) exposed to pIC or PBS over time (i.e. 12, 24, 48 and 72 HPS). As in sequencing, miR-731-3p, miR-462-3p and miR-2188-3p showed significant up-regulation by pIC. The sequencing results were not qPCR-validated for miR-125b-3-3p and miR-150-3p as up- and down-regulated miRNAs at 24 HPS, respectively; however, qPCR results showed significant up-regulation in response to pIC stimulation at later time points (i.e. 48 and/or 72 HPS). We also used qPCR to assess the expression of other miRNAs that were previously shown as immune responsive in other vertebrates. qPCR results at 48 and/or 72 HPS revealed that miR-128-3-5p, miR-214-1-5p and miR-451-3p were induced by pIC, whereas miR-30b-3p and miR-199-1-3p expression were repressed in response to pIC. The present study identified ten pIC-stimulated miRNAs, suggesting them as important in antiviral immune responses of Atlantic cod macrophages. Some pIC-responsive miRNAs identified in this study were predicted to target putative immune-related genes of Atlantic cod (e.g. miR-30b-3p targeting herc4), although the regulatory functions of these miRNAs need to be validated by future studies.



http://ift.tt/2kp9ipr

IL-17 is a protection effector against the adherent-invasive Escherichia coli in murine colitis

Publication date: January 2018
Source:Molecular Immunology, Volume 93
Author(s): Hai-jia Zhang, Bin Xu, Hu Wang, Bing Xu, Guo-dong Wang, Ming-zuo Jiang, Chao Lei, Mei-ling Ding, Peng-fei Yu, Yong-zhan Nie, Kai-chun Wu, Su-mei Sha, Meng-bin Li
Inflammatory bowel disease (IBD) is caused by aberrant immune responses to the gut microbiota. Among the gut microbiota, adherent-invasive Escherichia Coli (AIEC) is thought to be the pathogen through invading the intestinal epithelial cells and causing inflammation. IL-17 secretion increase, induced by enhanced bacterial adhesion to the intestine epithelium, could on one hand protect the mucosa, but on the other hand, over amount of IL-17 initializes inflammation reactions that in turn damages the mucosa. The relationship between IL-17 and AIEC is still unclear. In this study, we tried to elucidate the function of IL-17 in AIEC-mediated colitis. Wild type (WT) and IL-17 knockout (IL-17 KO) mice were inoculated with AIEC strain E. coli LF82 and treated with dextran sodium sulphate (DSS). Histological examination of the colon was performed. Mucosa damage was assessed and scored. IL-22 and IL-17 in colon tissues were detected by ELISA, qPCR and immunohistochemistry methods. Transient AIEC colonization in IL-17 KO mice resulted in increased intestinal epithelial damage, systemic bacterial burden and mortality compared with WT controls. Moreover, IL-17 is required for the induction of IL-22 in the experimental animal models during AIEC strain E. coli LF82 colonization. These results indicate IL-17 plays a protective role in AIEC strain E. coli LF82 induced colitis by promoting IL-22 secretion.



http://ift.tt/2jRYqkx